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CFS and FMS Research
Background and Research Summary
The Bioanalytical Research Group (BRG) was established in 1990 at the University of Newcastle’s Department of Biological Sciences. The founding members saw the need to integrate diverse scientific expertise for developing new biotechnology applicable to the early detection of disease processes.
The most important feature of the group's research capacity is its multi-disciplinary approach. The members of the Biological Sciences Department contribute expertise in biochemistry, immunology, analytical biochemistry, physiology, microbiology, ecology and statistics. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
The Newcastle researchers collaborate with other university departments, as well as experts from private medical practice and industry to bring additional expertise in clinical medicine, clinical microbiology and psychology.
In 1992, members of the BRG began working with Dr. Neil McGregor, Professor Iven Klineberg (The University of Sydney) and Dr. Henry Butt (The John Hunter Hospital). In 1993 the BRG ran an intensive research program on chronic pain and fatigue. This collaborative effort was very fruitful, and a separate research unit: "The Collaborative Pain Research Unit" (CPRU) evolved to represent the collective findings of this research and to seek further research funding.
The basis of the collaborative research program revolves around the Cell and Molecular-Profiling (CMP) techniques that the CPRU have developed.The techniques involve making biochemical "snapshots" of the cell material or body fluids. The chemical balance is then assessed in relation to symptom incidence and severity. Changes in the chemical balance can then be associated with specific symptoms that should lead to:
1. Objective methods for diagnosis.
2. Screening procedures for identifying those individuals with a high susceptibility to pain and fatigue-related disorders.
3. Strategies for clinical management / treatment of pain and fatigue related conditions.
The Collaborative Pain Research Unit (CPRU) has been active in CFS research since the early 1990’s. The first study involved exploring the relationships between immunology, lipid metabolism, pesticides and oxidative damage in CFS patients. This was a very extensive investigation supported by Environmental Health Technologies Pty. Ltd., and produced an immense quantity of information. The collection of data was completed by early 1994. Processing and analysis of this information continues to be an ongoing task.
The researchers have published findings from the above study that relate to CFS, pesticides and red/white blood cell parameters. Further publications originating from this project include, or have included, studies on CFS-immunology and fatty acid metabolism.
A second major study started in 1993, and involved investigating:
1. the excretion of urinary metabolites
2. microbiology
3. symptom incidence and severity in CFS and control subjects.
The collection of samples for this study was completed by early 1994. Since then, a number of detailed papers have been published that describe:
1. Anomalies in urine excretion.
2. The association of urinary anomalies with physical and psychological symptom presentation.
3. Associations of symptom presentation and infectious events.
4. The association of coagulase negative staphylococci with chronic pain.
Further publications from both of these studies are either in press, or in preparation.
Current research
The CPRU has undertaken a large collaborative project with the Royal North Shore Hospital, Sydney. This was initiated in order to increase the researchers’ understanding of the underlying disturbances to metabolism.
This study has now completed its sample collection phase and has collated an enormous volume of data, including:
1. investigations of urine excretion in relation to blood profiles
2. blood biochemistry
3. microbiology
4. immunology
5. physical and psychological symptom reporting.
The urine test was the initial test designed by the research team. More recently, the faecal and the plasma lipid tests have been introduced. These provide important information to help evaluate the chronic fatigue/pain patient, and to design specific patient treatment protocols. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
The researchers continue to investigate specific components of microbiology and CFS in non-clinical laboratory investigations. They are pursuing some exciting microbiology work, but this work is progressing very slowly due to a lack of funds.
Fire: Unfortunately, the research laboratories had a fire in December 1996. Analytical equipment was destroyed, and valuable chemicals and resources were lost. The laboratory has been rebuilt and all testing and research activities are again fully active. Unfortunately, this event caused a substantial delay in the CPRU’s work.
Achievements
When the CPRU research started in 1992, the major question was whether or not CFS is a “real disease or was it all in the mind”. Newcastle research has therefore targeted the measurement of biochemical attributes to determine whether measurable anomalies occur in CFS patients compared to healthy people.
The CPRU’s first paper published in the Medical Journal of Australia indicated that organochlorine levels in a carefully selected group of CFS patients were significantly elevated compared to non-CFS controls.
The team’s second paper, published in Biochemical and Molecular Medicine, focused on comparing the urinary excretion of metabolites in CFS patients with that from non-CFS subjects. This publication showed that there were indeed anomalies in the patterns of excretion of urinary metabolites in CFS patients compared with controls. An unusual metabolite, coded CFSUM1, was found in elevated levels in the CFS patients and this compound was strongly associated with symptom severity and incidence. This paper provided strong evidence for a molecular basis to CFS. The significance of this is that CFS symptoms can now be associated with measurable biochemical anomalies. These anomalies are able to give significant physical evidence to show that CFS is a “real” physical illness.
The CPRU’s recent papers have:
1. Highlighted the metabolic changes in urine parameters seen in chronic pain.
2. Shown that the psychological tests applied to CFS patients are often interpreted incorrectly. Refer to the document: "A preliminary assessment of the association of SCL-90-R psychological inventory responses with changes in the urinary metabolites in patients with chronic fatigue syndrome. (J. Chronic Fatigue Syndrome, 1997, 3:17-37)
3. Found that staphylococci bacteria are intrinsically linked to the presentation of chronic pain. The research team’s biochemical investigations have concentrated on developing diagnostic tests and effective management and treatment protocols. Analyses of biochemical data by cluster analysis and multivariate techniques indicates that different types of CFS patients could be characterised on the basis of similarities in the metabolite profiles. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
The urine profiles can, therefore, be used to classify patients with similar excretion patterns to give relatively homogeneous sets of patients for investigation. Individual patients can also be aligned with the metabolic profiles to assign their altered homeostasis to a particular CFS type.
In a similar manner, plasma fatty acid profiles can be used to differentiate CFS patients from control subjects. Patients can be further characterised by statistical clustering techniques to align patients with similar fatty acid homeostasis.
The faecal analyses provide valuable insight on the integrity of the gut, by assessing the distribution of anaerobic and aerobic microflora as well as the lipid biochemistry. This test can also provide evidence of malabsorption and bacterial dysfunction.
The ability to group CFS patients into subgroups using objectively derived measurements represents a major advance in CFS research because it:
1. Provides the capacity to develop treatment regimes based on objectively measured parameters.
2. Minimises the confusing effects of heterogeneity in future research programs.
(Note: The fact that many patients appear to have a range of inconsistent and diverse symptoms has often confounded previous research efforts.)
A range of tests is now available to Australian and international chronic fatigue/pain patients. The testing of samples from overseas was organised very recently (in late 1998).
Newcastle researchers have recently held a number of CFS forums/workshops that were attended by doctors around Australia. The research team has presented some of their findings to a number of groups, heard case histories and promoted
discussion by the participants on patient diagnosis and management strategies.The team has learnt and benefited greatly from these forums. It is understood that the participants have also found them very useful and informative. The CPRU, through its newly formed company “Bioscreen”, would like to continue to promote these forums. Now known as “Bioscreen workshops”, these are designed to facilitate information transfer and to stimulate information networks.
In 1998 the research team organised the very successful Sydney ‘98 International CFS Conference.
The term “heterogeneity” refers to the observation that many CFS patients appear to have a diverse range of symptoms. As a result, chronic fatigue/pain patients have proved very difficult to study clinically and scientifically.
The main problem has been that patients who have met the CDC diagnostic criteria have been difficult to classify into coherent groups. There continues to be conflicting reports concerning various abnormalities observed in CFS patients. No single aetiological agent, consistent cellular or biochemical alteration has been found which could be used to differentiate the condition from similar fatigue related diseases.
(Note: Aetiology is the study of the causes of diseases.)
The primary symptomatic features of CFS, including fatigue and pain, can be initiated by many different mechanisms. It has been suggested that CFS results from a common host response to a heterogeneous group of aetiological agents.
There is strong evidence that CFS patients can now be differentiated into distinct subgroups via the use of objective biochemical measurements. Data from studies involving analyses of plasma lipids and urinary excretion of metabolites have been used to classify patients with similar metabolic profiles into subgroups.
These subgroups comprise relatively homogeneous sets of patients for investigation. Individual patients can also be aligned with the metabolic profiles from Newcastle’s research to assign their altered homeostasis patterns to a particular CFS type.
An obvious consequence from the issue of heterogeneity is that the practice of grouping all CFS patients into one heterogeneous category is an approach that can no longer be considered useful. Indeed, it is felt that this approach is incorrect. From Newcastle’s research, it is now clear that there is no evidence of a single aetiological agent for CFS.
To investigate the causes of these chronic fatigue disorders, it is absolutely essential to develop standardised and objective protocols for characterising CFS patients into homogeneous subgroups. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
The possibility of finding consistent aetiology’s for the sub-types of chronic fatigue disorders may then become a reality, and might include combinations of many underlying conditions. These conditions would require the investigation of the following areas:
1. genetic make-up
2. dietary considerations
3. immunological parameters
4. environmental and/or pathogen altered responses.
CFS research:
CFS is primarily diagnosed on a basis of exclusion of other possible causes of prolonged fatigue and pain conditions. The primary symptoms are not specific and can arise from many possible causes. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
Future research in chronic fatigue disorders therefore demands very comprehensive investigations of biochemical and pathological anomalies in relation to symptom expression. This requires the interaction of research personnel with specialised training in biochemistry, analytical chemistry, microbiology, immunology, pathology and the philosophy of science, as well as clinical medicine.
Personal comment:
From personal experience, I have found that essential fatty acid anomalies and chronic bacterial infections play very significant roles in the CFS disease process. The Bioscreen blood lipid test and the newly developed staphylococci toxin test are able to give detailed results in these areas.
The researchers are determined to publish all of their research data to date. The CPRU is involved in continuously processing data and in the preparation of manuscripts for publication. The process is very time-consuming, and takes from 4-8 months per publication.
The research team wants to foster new directions in CFS research, with Australia leading the way. The CPRU's major goals are to:
1. Develop the laboratory tests that differentiate the types of chronic fatigue/pain disorders that “fall under the umbrella of CFS”.
2. Continue to refine treatment strategies that emanate from the biochemical research data. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
3. Delineate the potential pathogenic components involved in the aetiology of the various CFS subgroups.
4. Enhance and refine the understanding of the disease processes involved. The full realisation of these goals is dependent on finding suitable financial support to transfer the current technology to automated systems and to test kits.
The team’s laboratory studies are focused on developing a better understanding of the molecular basis to the disease and in trying to pinpoint where the metabolic problems exist. The ultimate goal here is to actually produce a "model" of CFS that accounts for the diversity of symptoms reported and the different types of onset events associated with the syndrome. This approach is hoped to provide a better insight to produce effective patient management programs based on urine, blood,faecal and other test data.
International co-operation
It has recently been announced that the CPRU is exploring the possibility of co-operating with international research efforts.
During his recent visit to Australia, Professor Garth Nicolson of California held discussions with the team to explore future collaborative efforts. Professor Nicolson is a leading expert on mycoplasma infections and the Gulf War Syndrome.
The research team continues to be chronically short of money for staff and equipment. At the moment, research funding comes mainly from private donations, the Alison Hunter Memorial Foundation, and CFS support groups.
Funding requirements
Unfortunately, a good deal of time continues to be spent by the researchers in trying to obtain funding. Some specific funding requirements are:
1. The first project, started in 1992, had sufficient funding to collect and analyse samples over the 2 year period. Since no more funds were available, the data processing and interpretation activities have proceeded very slowly.
Completion of this project will result in more published research, increasing the CPRU’s reputation and credibility. It is hoped that this will increase the chances of obtaining government and industry funding.
2. The second project was entirely privately funded by Dr Neil McGregor and the CPRU. Again, resources were available to complete the sample collection and analyses, but completion of the data processing and interpretation has been slow due to the time required to raise money. Five papers have been published from this work, and it is planned that an additional 7 papers are required to complete this project.
3. The Royal North Shore Hospital project has been supported mainly by 2 private donations. The staffing resources were largely met by the researchers involved donating their time and expertise.
Samples collected from this project have been stored (eg. organochlorine pesticides samples) until the CPRU has adequate resources for their analysis. Many publications have been planned from this project, but time and limiting resources comprise the major constraining factors. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
4. The equipment utilised is high technology and has a very high usage with sample processing. It is subject to periodic breakdowns, and some replacement components can cost up to $1,500 each. We need therefore to always have reserve funds to cover such breakdowns. The microbiology studies comprise a very promising avenue for CFS research.
The CPRU knows of 2 other laboratories in the USA which are working on similar approaches but are under industrial patent protection. They have talked to these people and are very encouraged by what is being done.
(Note: It is hoped that the recently established company “Bioscreen” will eventually become another source of revenue.)
© CPRU and F Bartosy 1999
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