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 Chronic Fatigue Syndrome Electronic Newsletter

 --------------------------------------------------------------------
 No. 44 February 28, 1995 Washington DC
 --------------------------------------------------------------------


 BIOMARKER REPORT FROM NEWCASTLE /
 UK TASK FORCE REPORT / WASHINGTON MEETINGS

 CONTENTS

 >>>1. Biomarker report from Dr. Hugh Dunstan, Univ. of Newcastle
 >>>2. British Task Force on CFS/ME/PVFS
 >>>3. Washington meetings on April 11 & 12: NIH workshop on
 designing CFS treatment trials, and ICC policy meeting


 -------------------------------------------------------------------

 >>>1. Biomarker report from Dr. Hugh Dunstan, Univ. of Newcastle

[The following article appeared in the December 1994 edition of
EMERGE, the Journal of the M.E. / Chronic Fatigue Syndrome Society of
Victoria Incorporated (Australia). References in the article which
refer to the editor and which appear in parentheses are referring to
the editor of the EMERGE journal, Mr. Jim Oakley.]

 New Approaches to Chronic Fatigue Syndrome Research

This is a summary of the talk given to our Society at the Annual
General Meeting on 19th November, 1994. The speaker was Dr Hugh
Dunstan, DPhil, senior lecturer in biochemistry and microbiology in
the Department of Biological Sciences at the University of Newcastle,
NSW.

**Introduction**

*Collaborative Pain Research Unit*

The Chronic Fatigue Syndrome (CFS) research that Dr Dunstan described
in his talk was undertaken by the Collaborative Pain Research Unit
(CPRU), which is a multi-disciplinary team of researchers from the
University of Newcastle and the University of Sydney. In addition to
Dr Dunstan, the team members include:

 + Dr Neil McGregor, MDSc, a periodontist who is completing a PhD on
 chronic pain and fatigue disorders
 + Dr Henry Butt, PhD, microbiologist
 + Associate Professor Tim Roberts, PhD, immunologist
 + Professor Iven Klineberg, PhD, FRACDS, neurophysiologist.

*General Comments*

At the outset, Dr Dunstan emphasised his belief that CFS is a
physiological disease. He said that to adequately study an illness
like CFS, skills are needed from a range of disciplines such as
biochemistry, toxicology, microbiology, immunology and medicine. Thus
a multi-disciplinary team approach is essential.

Dr Dunstan noted that chronic illnesses similar to CFS have been
around for a long time. The symptoms experienced by Florence
Nightingale after she became sick in 1854 in the Crimea resembled
those of CFS. The public image of Chronic Fatigue Syndrome as a
combination of fatigue and depression is not accurate, and does not
reflect the comprehensive array of serious symptoms that are
experienced by people with the illness.

Current hypotheses about the cause of CFS can be broken into at least
four categories:

 + CFS is a post-viral syndrome, perhaps involving Epstein-Barr virus
 or enterovirus
 + CFS is caused by an unknown infectious agent
 + CFS has multiple causations, and may result from an underlying
 infectious agent, or immune suppression, or from environmental
 effects
 + CFS is a neuroendocrine disturbance of unknown origin.

From Dr Dunstan's perspective as a biochemist, there are many factors
that can influence human health, such as the environment, drugs,
cleaners, pathogens, food etc. Humans have evolved to deal with most
environmental and psychological stressors, but it is important to
realise that individuals have differing thresholds of resistance to
these stressors. With this in mind, Dr Dunstan proceeded to describe
the three CFS studies of the CPRU.

**1992/3 Study**

The first CFS research program conducted by the CPRU was a
collaborative effort with a company called Environmental Health
Technology, which is headed by well-known Sydney clinical ecologist
Dr Mark Donohoe.

*Results*

Several immunological and biochemical tests were performed on
patients who met the Centers for Disease Control and Prevention
(CDC) criteria for CFS, and on age- and sex-matched healthy controls.
Compared with the healthy controls, it was found that:

 + CFS patients had significantly increased numbers of eosinophils
 (these are white blood cells associated with allergy)

 + CFS patients had a slight, but non-significant decrease in
 lymphocyte proliferation in response to mitogen stimulation (this
 is an immune system test)

 + CFS patients had no changes in absolute numbers of lymphocytes or
 lymphocyte subset ratios

 + CFS patients had alterations in the size and shape of their red
 blood cells

 + CFS patients had increased levels of organochlorine chemicals in
 their bodies. The chemicals included DDT, dieldrin and
 hexachlorobenzene.

*Organochlorines*

The tests looking at organochlorine levels were performed on four
groups of people: 25 CFS patients with no history of toxic chemical
exposure; 20 non-CFS patients with a history of toxic chemical
exposure; 21 age- and sex-matched healthy controls (average age 43
years); and 25 age- and sex-matched healthy controls (average age 26
years). The highest average level of organochlorines was found in
the CFS group. There was a statistically significant difference in
levels between the CFS group and the healthy control groups, but no
significant difference between the CFS and toxic exposure groups.

One particular organochlorine chemical, hexachlorobenzene, was found
in 60% of people in the toxic exposure group, in 55% of people in the
CFS group, and in just 20% of the people in the healthy control
groups. The increase in incidence of this chemical in the toxic
exposure/CFS groups compared with healthy controls was statistically
significant.

Dr Dunstan stated that it is not known at this stage whether the
presence of organochlorine chemicals in CFS patients plays any role
in causing the illness or in producing symptoms.

**Urine Tests - The Next Step**

At present, there are no diagnostic laboratory tests available which
are specific for CFS. The researchers in the CPRU are attempting to
use science to understand how the disease occurs, so that they can
develop a test which is specific for CFS. To understand how the
illness occurs, Dr Dunstan and his colleagues have focussed on trying
to find out where things have gone wrong at the cellular level.

*Body Chemicals*

Dr Dunstan explained that all cells contain different organelles
which act like tiny factories. Some organelles make carbohydrates,
others make protein, and so on. It is essential that the organelles
within a cell maintain links between each other. If blockages occur
in the 'highways' between organelles, the normal route for energy
production will be disrupted, and energy production will come via an
indirect route. The CPRU team looked for blockages in the 'highways'
between organelles, which show up as disturbances in normal body
chemistry. Body chemicals which may give indications of malfunction
at the cellular level are present in urine. In fact, the urine can
serve as a detailed source of information on bodily malfunction, and
may contain compounds such as intermediary metabolites, unusual
metabolites, damage products, and chemicals produced by cells in
response to infectious and toxic agents.

*GC-MS*

To study the urine of CFS patients, the researchers used an expensive
instrument known as a gas chromatograph-mass spectrometer (GC-MS).
GC-MS machines are specialised instruments which are not available in
general pathology laboratories. The gas chromatograph separates
different chemicals, and determines the quantity of each present; the
mass spectrometer identifies the molecular weight of each chemical,
and provides a 'fingerprint' for identifying the chemical.

A GC-MS machine can separate and identify from 120 to 200 compounds
per analysis. It is an ideal instrument for probing samples for novel
products, and the researchers need only observe and quantify the
results. This analytical technique does not require any preconceived
expectation of what should be present in the sample under
investigation. The powerful analytical capabilities of this
instrument became evident in the CPRU's second study.

**1993/4 Study**

Twenty-two CFS patients and 44 healthy controls were enrolled in the
next phase of research. All CFS patients met CDC as well as British
criteria for CFS. Twenty of the 22 had been diagnosed by the CFS
research team at The Prince Henry Hospital in Sydney, thereby
satisfying Australian criteria for CFS. Urinary, microbiological,
psychological and symptom profiles were measured for all 66 study
participants.

*New Metabolites*

Through GC-MS analysis of urine samples, three chemicals were
identified that were present in CFS patients in significantly
different quantities than in controls. Two of the chemicals appeared
to be newly discovered compounds, and were labelled CFSUM1 and CFSUM2
(where CFSUM stands for Chronic Fatigue Syndrome Urinary Marker).
The third chemical was b-alanine. The researchers are now confident
that CFSUM1 is not of human origin, but are still trying to determine
the origin of CFSUM2. The structures of these compounds are being
investigated. It is believed that CFSUM1 is a toxic metabolite,
similar in structure to a neurotoxic compound used in psychological
research, and also similar to toxins derived from some
micro-organisms.

*Results*

 + CFSUM1 was present in higher concentrations in CFS patients than
 in controls (p<0.0002)

 + CFSUM1 occurred in 77.3% of CFS patients and in 48% of controls
 (p<0.05)

 + b-alanine was present in higher concentrations in CFS patients
 than in controls (p<0.006)

 + CFSUM2 was present in lower concentrations in CFS patients than in
 controls (p<0.0005).

(Ed: The p values quoted here arise from statistical analysis of the
data. P<0.0002 means that there is a probability of less than 2 in
10,000 that there is no difference in the average concentration of
the chemical in patients and controls, and that the differences
observed were due just to chance. Similarly, p<0.05 means that there
is a probability of less than 5 in 100 that no real differences
existed, and that the observed differences were simply due to chance.
The smaller the p value, the more statistically significant the
result. Values given above such as p<0.0002 are highly
statistically significant, and indicate very strongly that real
differences do exist).

*Symptoms*

All 66 subjects were classified into one of four groups, based on
numbers of CFS symptoms: 0 symptoms; 1-5 symptoms; 6-10 symptoms; and
more than 10 symptoms. It was found that the concentration of CFSUM1
in subjects increased substantially as the number of symptoms
increased. The urine concentration of CFSUM1 was highly correlated
with the following symptoms:

 _ fatigue, nausea, muscle weakness
 _ dizziness
 _ fever
 _ hyperaesthesia
 _ exertional breathlessness.

Using a statistical technique known as discriminant function
analysis, the team found that the presence of particular symptoms was
statistically correlated with altered levels of certain chemicals, as
outlined below.

 SYMPTOM is associated with altered level of CHEMICAL

 muscle pain b-alanine
 feverishness CFSUM1
 muscle weakness CFSUM1
 sore throat glutamate
 hyperaesthesia b-alanine
 nausea alanine
 diarrhoea aconitic acid
 dizziness CFSUM2
 fatigue CFSUM1

It was also found that the concentration of CFSUM1 correlated with
increases in:

 _ TCA cycle intermediates (p<0.002)
 _ tyrosine (p<0.001).

CFSUM1 concentration correlated with decreases in:

 _ glutamate
 _ alanine
 _ aspartate (urea cycle)
 _ ornithine (urea cycle).

The researchers concluded that CFSUM1 correlated with changes in:

 + TCA cycle and urea cycle
 + Inter-organ transport of nitrogen
 + Neurotransmitter amino-acid precursors.

Dr Dunstan noted that although 48% of control subjects had CFSUM1
present in their urine, these people also had some mild CFS symptoms.
The levels of CFSUM1 in these people were intermediate between those
of CFS patients, and controls with no symptoms. People with no CFS
symptoms had no detectable levels of CFSUM1 in their urine.

The concentration of three other chemicals was measured in all
subjects: alanine, succinate, and tyrosine. The levels of these
chemicals in the 48% of control subjects with the presence of CFSUM1
in their urine were always intermediate between those of the CFS
patients and the controls with zero levels of CFSUM1.

**So what is CFS?**

 + The data collected by the CPRU suggest that CFS is an illness
 which has:

 - altered mitochondrial energy production
 - altered inter-organ nitrogen transport
 - altered neurotransmitter precursor levels

 + CFSUM1 appears to interfere with amino-acid interconversion

 + CFS may be a syndrome with a more widespread distribution than
 presently defined.


**The Future**

Dr Dunstan and his colleagues will now pursue their research in a
logical fashion. The course of action will be to:

 + First establish the source of CFSUM1
 + Look for other causes of CFS/muscle pain
 + Try to eliminate the source if possible
 + If the source cannot be eliminated, establish symptomatic
 treatments based on knowledge of the disease process, not on
 speculation about the disease process
 + Develop diagnostic tests for routine use
 + Possibly develop vaccines.

**1995/6 Collaborative Study**

A major research program, coordinated through the Royal North Shore
Hospital and involving 600 people, began on 24th November 1994. The
study will seek to validate and extend the team's previous findings,
and will examine symptoms, psychology, urinary metabolites, hormones
and red blood cells in study participants. The 600 people will be
drawn from five groups:

 - adolescents with CFS
 - adults with CFS
 - people with illness due to Ross River virus
 - people with a diagnosis of depression
 - healthy people.

The research team for this study is outlined below:

 *University of Sydney*
 Dr Neil McGregor clinical and dental
 periodontist
 Professor Iven Klineberg neurophysiologist

 *University of Newcastle*
 Associate Professor Tim Roberts immunologist
 Dr Hugh Dunstan biochemist/analyst

 *Hunter Area Pathology Service*
 Dr Henry Butt microbiologist

 *Royal North Shore Hospital*
 Associate Professor Phillip Clifton-Bligh physician (endocrinology)
 Julie Dunsmore psychologist
 Leigh Hoskin trial coordinator

In addition, there will be at least two PhD students working on the
project.

**Funding**

In the CPRU studies to date, the researchers have donated their time,
and funding for other costs has been scrounged from a variety of
sources. This will not be possible for the large trial, and at least
half the analyses will not be performed until funding becomes
available. Dr Dunstan said that funding for new areas of research


 

(Continued from last message)
such as this is difficult to obtain from the National Health and
Medical Research Council, and even if money were made available from
this source, it could not now be obtained until the beginning of
1996. Thus money is desperately needed if progress is to be made in
the next year. Dr Dunstan urged all people with CFS to write to
Members of Parliament about the lack of money available for Chronic
Fatigue Syndrome research, and said that any financial contribution
that our Society could make would be greatly appreciated.

Jim Oakley

Ed: Thanks to Dr Dunstan for reviewing this summary before
publication.

 ----------------------------------------------------------------

[The following is a portion of a notice requesting donations which
also appeared in this same edition of EMERGE. The phrase "tax
deductible" as used below means tax deductible in Australia. --
CFS-NEWS.]

Help Us Support the University of Newcastle / University of Sydney
Research Team

We are commencing fundraising efforts to support the University of
Newcastle/University of Sydney CFS research program. Details of this
innovative and exciting research can be found in the 'Medical Pages'
in this Emerge. The research team has commenced a large trial
involving 600 people at the Royal North Shore Hospital in Sydney, and
if the findings of this trial support those of the initial studies,
there will be enormous advances in the diagnosis, and ultimately the
treatment, of CFS.

The Royal North Shore Hospital trial is not receiving significant
funding from any source. As a result, a substantial proportion of the
laboratory analyses will not be completed until more funds are made
available. If progress is to be made soon, we must help to raise the
money needed to complete the trial.

This is our Society's first major research fundraising campaign since
1989, when we raised money for gamma-globulin trials. We are now
inviting all members to make a donation to help fund the trial at the
Royal North Shore Hospital. We are also asking you for fundraising
ideas, and we are hoping that our support groups will be able to
contribute to fundraising activities.

Tax deductible donations can be made directly to the research
team. Cheques should be made payable to The University of
Newcastle, and should be sent to the following address: Associate
Professor Tim Roberts, Collaborative Pain Research Unit, Department
of Biological Sciences, The University of Newcastle, Callaghan, NSW
2308, AUSTRALIA.

All donations are deposited into the team's research account, and
will be utilised 100% for research into CFS.

[Thanks to EMERGE editor Jim Oakley for getting an electronic version
of this article to CFS-NEWS.]


 -=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-

 >>>2. British Task Force on CFS/ME/PVFS

[The following article is copied from the Autumn 1994 edition of
InterAction, the journal of the Action for M.E. organization in
Britain. Note: the term "chronic fatigue syndromes" in the article
below is used in the usual British sense to mean all chronically
fatiguing conditions and not just CFS as a specific illness. The
British refer to the specific illness of CFS as M.E. -- myalgic
encephalomyelitis -- and sometimes also as PVFS -- post-viral fatigue
syndrome. The abbreviation NHS refers to the British National Health
Service.

Copyright: Permission is granted to copy or quote articles from
Interaction for non-commercial purposes provided the intended meaning
is preserved and appropriate credit is given to the author and
InterAction, including its postal address and telephone number:
InterAction, Action for M.E., P.O. Box 1302, WELLS, BA5 2WE. Tel:
0749 670799.

 The National Task Force Report CFS/PVFS/ME
 Report by Dr Anne Macintyre

Background to the Task Force

In 1992 the M.E. organisations (M.E. Association, M.E. Action and
Westcare) asked the Department of Health to send out guidelines to
healthcare professionals (mainly GP's) on the diagnosis and
management of M.E. In response the Department suggested that a Task
Force should be set up. Its remit was to review current knowledge
and research and produce a detailed report. The Task Force resulted
largely from the initiative of Westcare, and was funded by a grant
from the Department of Health plus assistance from the Wellcome
Trust.

Following a feasibility study then a steering group, the Task Force
proper was formally established on 1 September 1993. The Task Force
includes Dr David Tyrell, Chairman, plus eleven doctors who come
from a wide range of specialities that include general practice,
psychiatry, virology, neurology, psychology and paediatrics. In the
early stages there were widely differing views, but after many
meetings and much studying of literature, some important consensus
opinions about chronic fatigue syndromes were reached. The final
report owes much to presentations and critiques by the M.E.
organisations.

Summary of the main conclusions in the Task Force Report:

 - Chronic fatigue syndromes do exist and pose a significant health
 problem

 - There is currently widespread ignorance and mismanagement of
 chronic fatigue syndromes. Patients often encounter lack of
 support from doctors, healthcare professionals, educational
 authorities and society.

 - Chronic fatigue syndromes cover a spectrum of disease, and can
 cause severe and persistent debility. At the one end of the
 spectrum is severe fatigue of unknown origin. At the other end
 are those suffering from profound fatiguability, with somatic
 symptoms and objective central nervous system defects. The names
 M.E. and PVFS are frequently applied to this subgroup.

 - Chronic fatigue is a common complaint in the population.
 However the incidence of chronic fatigue syndromes is around
 1 per cent, and the subgroup CFS(M.E.) is lower still, around
 1-2/1000.

 - The causes of chronic fatigue syndromes are complex, and cases
 are not all the same.

 - The right balance between rest, physical and mental activity
 (pacing) is the key to recovery in most patients. Appropriate
 psychological treatments also have a place: however there is no
 generally effective drug treatment.

 - Progress in understanding is hampered by using heterogeneous study
 groups: study groups selected using different definitions of
 chronic fatigue; lack of adequate comparison groups; and
 contradictory research findings stemming from the above. There is
 need for high quality research into chronic fatigue syndromes.

The recommendations of the Task Force were summed up as:

 - Clarify the differences between various chronic fatigue syndromes.

 - Educate professionals and public to accept their existence .

 - Train relevant professionals to identify and manage them.

 - Improve services to patients. Actively encourage research.

At the press launch, brief presentations were given by the chairman
Dr David Tyrell; Professor Ted Dinan on research; Dr Charles Shepherd
on management of the illness; Professor Ariel Lant on NHS services;
and Dr Clare Fleming (ex GP who has M.E.) on a patient's perspective.

Then followed questions by representatives from the media. The
British Medical Association and the Department of Health were also
represented, but sadly there was no-one from the BBC nor any
national newspapers; however there was good coverage by ITN and Sky
News, as well as nationally various local papers and radio stations.

The report of the Task Force is the first comprehensive report in the
UK about chronic fatigue syndromes. It is not the final word on
CFS/M.E., rather a springboard for positive action to improve the
care of people with these illnesses. Everyone whose life has been
devastated by M.E. should welcome the result of the Task Force's two
year study, as it is a major step towards getting the illness widely
recognised and understood.

Copies of this report are available from Westcare, 155, Whiteladies
Road, Clifton, Bristol BS8 2RF. Tel: 0272 239341. Price 6.95 pounds
including p+p.

[Thanks to David Ward for assistance in publishing this report in
CFS-NEWS.]


 -=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-

 >>>3. Washington meetings on April 11 & 12: NIH workshop on
 designing CFS treatment trials, and ICC policy meeting

[The first report below is copied from the Winter 1995 edition of the
CFIDS Chronicle, journal of the CFIDS Association of America.
Copyright '95. The CFIDS Association of America, Inc., P.O. Box
220398, Charlotte, NC 28222-0398, USA. Tel: 1-800-442-3437 or
1-704-362-2343. Permission is granted to copy or quote articles for
non-commercial purposes provided the intended meaning is preserved
and appropriate credit is given to the author and the CFIDS Chronicle
(including the postal address and toll-free telephone number of The
CFIDS Association of America, Inc.).]

 Clinical Outcome Workshop Scheduled

How do researchers know when CFIDS treatment is really effective? As
more clinical trials for CFIDS are being developed and patients are
constantly bombarded with information about the "latest thing",
definitive answers to these questions are becoming increasingly
important. In an attempt to address this issue, the National
Institutes of Health (NIH) will sponsor a workshop on "Outcome
Endpoint Measures for Studies of CFS" on April 11 at its campus in
Bethesda, Md. Geared to "researchers who are interested in treatment
of CF(ID)S or whose studies of pathogenesis will reveal intervention
strategies and targets," the workshop will be highly technical in
nature and interested parties should bear in mind that no specific
treatments will be discussed. For more information, please call
Eveline Tierney at 301/402-7453 or fax your name and address to
301/402-0659 to be placed on the mailing list.

 ----------------------------------------------------

[This next report is exclusive to CFS-NEWS.]

 U.S. Policy Meeting on CFS to Be Held on April 12

The U.S. Inter-agency Coordinating Committee (ICC) for CFS will hold
a public meeting on April 12 in Washington, D.C. to review all U.S.
government efforts on CFS research and policy, including those by the
National Institutes of Health (NIH), the Centers for Disease Control
and Prevention (CDC), the Food and Drug Administration (FDA), and the
Social Security Administration (SSA). The ICC was created at the
request of the U.S. Congress and is chaired by the Assistant
Secretary for Health Dr. Philip Lee, who is also the Director of the
U.S. Public Health Service. Further news about this event will
appear in future editions of CFS-NEWS.

[Thanks to the CFIDS Association of America for news about this
event.]


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