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Posted to Co-Cure Mon, 6 Nov 2000 15:40:49 -0500 by Fred Springfield

The Biochemistry of Chronic Pain and Fatigue

ORIGINAL RESEARCH

Title: The Biochemistry of Chronic Pain and Fatigue
Journal: Journal of Chronic Fatigue Syndrome, Vol. 7(1) 2000 pp. 3-21
Authors: Neil R. McGregor, MDSc; Suzanne Niblett, BSc; Phillip Clifton Bligh, MB BS, BSc (Mcd); R. Hugh Dunstan, DPhil; Greg Fuicher, MB BS, MD; Leigh Hoskin, MPH; Henry L. Butt, PhD; Timothy K. Roberts, PhD; Katrina King, PhD; Iven Klineberg, PhD
Affiliations:
Neil R. McGregor, Suzanne Niblett, R. Hugh Dunstan, Henry L. Butt, Timothy K. Roberts and Katrina King are all affiliated with the Bioanalytical Research Group, Department of Biological Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
Neil R. McGregor is also with the Neurobiology Research Unit, Centre for Oral Health Research, University of Sydney, Westmead Hospital, Westmead, NSW 2084, Australia.
Phillip Clifton Bligh, Greg Fulcher, and Leigh Hoskin are affiliated with the Department of Endocrinology, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia.
Iven Klineberg is affiliated with the Neurobiology Research Unit, Centre for Oral Health Research, University of Sydney, Westmead Hospital, Westmead, NSW 2084, Australia.

ABSTRACT.
Background: Chronic pain and fatigue represent major reasons for seeking medical treatments, however, the mechanisms are poorly understood. Onset of these disorders has been associated with events (infections, trauma, stress) which initiate a host response requiring increased energy demands.

Objectives: To investigate the biochemical mechanisms of chronic pain and fatigue.

Methods: Data will be presented from 4 separate investigations of CFS and myofascial pain syndrome (MFPS) patients, and from age/sex-matched controls, using metabolite profiling techniques.

Results: Several types of chronic pain and fatigue disorders were discerned on the basis of their biochemistry. The metabolic events associated with chronic pain were distinct from those associated with chronic fatigue. The investigations have shown that chronic pain was associated with reductions in serum sodium, changes in urinary volume and output of amino and organic acids, increases in levels of markers of tissue damage (ALT, AST), and increases in the tyrosine: leucine ratio, which represents alterations in protein turnover. Fatigue was associated with alterations in urine excretion of amino and organic acids associated with tricarboxylic acid cycle (TCA) function. Levels of RNase-L were correlated with the expression of chronic fatigue related symptoms and were a good marker for CFS. Increased carriage of toxin-producing coagulase negative staphylococci was evident in MFPS and CFS patients, and this carriage was correlated with increased tyrosine: leucine ratios and pain severity. The toxin producing staphylococci appear to be a co-morbid pathogen that contributes to CFS patient morbidity.

Conclusion: These studies indicated that changes in nitrogen homeostasis were associated with pain and fatigue symptoms and carriage of certain pathogens may sustain or exaggerate the chronic disorder.

KEYWORDS. Nitrogen metabolism, RNase-L, staphylococci, tyrosine, chronic pain, fatigue

INTRODUCTION

Chronic pain and fatigue are major reasons for seeking medical treatment in general practice. The biochemical mechanisms leading to these symptoms are poorly understood. Three major diagnosed poiysymptomatic illnesses are myofascial pain syndrome (MFPS) (1), fibromyalgia (FM) (2) and chronic fatigue syndrome (CFS) (3-5). Importantly these separate clinical conditions may occur in one patient and provides a significant problem in diagnosis and research. Bombardier and Buchwald (6) showed that of 402 patients who attended a fatigue clinic, CFS and FM were diagnosed in 52% and 22%, respectively. Thirty-seven percent had CFS alone, 7% FM alone whilst 15% had to have both CFS and FM. The patients with both CFS and FM had a greater disability than patients with CFS, major depression or acute infectious mononucleosis (7). Both FM and CFS patients have increases in myofascial pain and other common pain conditions. Plesh et a!. (8) found that 18% of Temporomandibular Dysfunction (TMD) patients (1) had fibromyalgia whilst 75% of fibromyalgia patients had TMD symptoms. They concluded that TMD was a distinct disorder that occurred with increased prevalence in fibromyalgia patients. Our group has also reported that CFS patients have an increased prevalence of TMD and MFPS symptoms yet these conditions also occur in the normal general population. The findings of these studies (6,8) suggest that each of these clinically diagnosable conditions may be separate clinical conditions that simply occur with greater frequency in CFS patients and in turn increase morbidity and symptom heterogeneity.

Therefore, a major problem associated with diagnosis of CFS is the symptom and biochemical heterogeneity that may result from multiple confounding conditions such as MFPS and FM. Fukuda et al. (9) assessed Gulf war syndrome patients using factor analysis and found that three symptom groupings were present: (1) fatigue; (2) altered cognition and mood and; (3) musculoskeletal symptoms. Patients with CFS could be divided into those who suffered: (1) fatigue; (2) fatigue and pain; and (3) fatigue and mood change. The aim of this paper was to assess the differences in biochemistry between these different symptom sets.

© 2000 by The Haworth Press, Inc. All rights reserved

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Posted to Co-Cure Thu, 12 Oct 2000 04:47:01 -0400 by Fred Springfield

Immunology of Chronic Fatigue Syndrome

Journal: Journal of Chronic Fatigue Syndrome, Vol. 6, No. 3/4, 2000, pp. 69-107
Authors: Roberto Patarca-Montero, MD, PhD; Timothy Mark, MD; Mary Ann Fletcher, PhD; Nancy G. Klimas, MD
Affiliation: E. M. Papper Laboratory of Clinical Immunology, Department of Medicine (R-42), University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101.
Address correspondence to: Roberto Patarca-Montero (E-mail: rpatarca@pol.net ).

SUMMARY. A review of the literature on the immunology of CFS reveals that people who have Chronic Fatigue Syndrome (CFS) have two basic problems with immune function that have been documented by most research groups: 1. immune activation, as demonstrated by elevation of activated T lymphocytes, including cytotoxic T cells, as well as elevations of circulating cytokines; and 2. poor cellular function, with low natural killer cell cytotoxicity (NKCC), poor lymphocyte response to mitogens in culture, and frequent immunoglobulin deficiencies, most often IgG1 and IgG3. These findings have a waxing and waning temporal pattern which is consistent with episodic immune dysfunction (with predominance of so called T-helper type 2 and prointlammatory cytokines and low NKCC and lymphoproliferation) that can be associated as cause or effect of the physiological and psychological function derangement and/or activation of latent viruses or other pathogens. The interplay of these factors can account for the perpetuation of disease with remission/exacerbation cycles. Therapeutic intervention aimed at induction of a more favorable cytokine expression pattern and immune status is discussed.

KEYWORDS. T cells, immunoglobulins, cytokines, natural killer cells

INTRODUCTION
The nervous and immune systems respond to internal and external challenges and communicate and regulate each other by means of shared or system-unique hormones, growth factors, neurotransmitters and neuromodulators. Similar alterations in central catecholamine neurotransmitter levels are associated with immune activity and stressor exposure, alterations that are more pronounced in aged as opposed to younger animals (1). For example, a decreased norepinephrine turnover in the hypothalamus and brain stem of rats occurs at the peak of the immune response to sheep red blood cells (2,3), and increased serotonin metabolism is associated with depressed Arthus reaction and plaque-forming cell response in rats stressed either by overcrowding lasting two weeks or more or by repeated immunobilization for four days (4,5). The long-term effects of these acute changes are evidenced by chronic variable stress which facilitates tumor growth (6) and is associated with immune dysregulation in multiple sclerosis (7). The hypothalamic-pituitay-adrenal axis plays a pivotal role in stress-mediated changes, and stimulation of corticotropin-releasing factor in the central nervous system (8,9) has been shown to suppress rapidly a variety of immune responses, an effect which can be blocked by infusion into the brain of aipha-melanocyte-stimulating hormone, a tridecapeptide derived from pro-opiomelanocortin (10).

Besides external stimuli, intrinsic imbalances in neurotransmitter levels affect the immune system either directly by acting on immunocompetent cells or indirectly via induction of hormonal secretions. For instance, depression is associated with neurotransmitter imbalances and with decreased natural killer cell cytotoxic activity (11-14). Moreover, several studies have documented the existence of striking physiologic, neuroendocrine, metabolic, and pharmacologic differences between depressed and normal subjects and between depressed and severely ill subjects (15-20).

The examples mentioned above illustrate the fact that disorders, or persistent noxious stimulation, of the neuroimmunological circuitry can lead to, or result from, neurological, immunological, psychiatric or multiorgan pathology. The latter link has encouraged a search for neuroimmunological markers with functional or pathological correlates.

Although the cause of CFS remains to be elucidated, many studies summarized herein have provided evidence for abnormalities in immunological markers among individuals diagnosed with CFS. A clear picture has not been achieved because of the noticeable variability in the nature and magnitude of the findings reported by different groups (21,22). Moreover, little support has been garnered for an association between the latter abnormalities and the diverse physical and health status changes in the CFS population. For instance, Buchwald and coworkers (23) concluded that although a subset of CFS patients with immune system activation can be identified, serum markers of inflammation and immune activation are of limited diagnostic usefulness in the evaluation of patients with CFS and chronic fatigue because changes in their values may reflect an intercurrent, transient, common condition, such as an upper respiratory infection, or may be the result of an ongoing illness-associated process. On the other hand, Patarca and colleagues (24,25) have found that CFS patients can be categorized based on immunological findings. It is also worth noting that although the degree of overlap between distributions of soluble immune mediators in CFS and controls has fueled criticism on the validity or clinical significance of immune abnormalities in CFS, the latter degree of overlap is not unique to CFS and is also present, for instance, in sepsis syndrome and HIV-1-associated disease, clinical entities where studies of immune abnormalities are providing insight into pathophysiology (26).

The aim of this report is to comprehensively review the literature on the immunology of CFS, to formulate consensus by majority conclusions when possible, and to discuss how this knowledge may contribute to the understanding of the physiological and psychological function changes seen in CFS. Immunological status findings will be reviewed and discussed at three levels: immune cell phenotypic distributions, immune cell function, and cytokines and other soluble immune mediators.

[ Article copies available for a fee from The Haworth Document Delivery Service: 1-800-342-9678. E-mail address: getinfo@haworthpressinc.com .]

© 2000 by The Haworth Press, Inc. All rights reserved.

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Posted to Co-Cure Tue, 10 Oct 2000 19:29:19 -0400 by Fred Springfield

Neurological Dysfunction in Chronic Fatigue Syndrome

Journal: Journal of Chronic Fatigue Syndrome, Vol. 6, No. 3/4, 2000, pp. 51-68
Authors: Abhijit Chaudhuri, DM, MD, MRCP; Peter 0. Behan, DSc, MD, FACP, FRCP
Affiliation: Abhijit Chaudhuri is Clinical Lecturer in Neurology and Peter 0. Behan is Professor of Neurology (Retired), University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, United Kingdom.
Address correspondence to: Abhijit Chaudhuri (E-mail: ac54p@udcf.gla.ac.uk).

SUMMARY.
Chronic fatigue syndrome (CFS), popularly known in Europe as myalgic encephalomyelitis (ME), is a common but not a new illness. CFS/ME was classified as a neurological disease by the World Health Organisation in 1993. Neurological dysfunction is considered the principal mechanism of both physical and mental fatigue in this condition. This article reviews the neurological symptoms of the epidemic and sporadic forms of the illness. Paroxysmal changes in the severity of symptoms (fatigue and neuropsychiatric) are the hallmark features in the natural history of this disease. Ion channel abnormality leading to neuronal instability in selective anatomical pathways (basal ganglia circuitry) is proposed as the possible mechanism of fluctuating fatigue and related symptoms in CFS.

[ Article copies available for a fee from The Haworth Document Delivery Service: 1-800-342-9678. E-mail address: getinfo@haworthpressinc.com .]

KEYWORDS. Ion channels, myalgic encephalomyelitis, basal ganglia

INTRODUCTION.
Chronic fatigue syndrome (CFS) is a common disorder, occurring worldwide. It is however, not a new illness and had probably existed in the papyrus Ebers (circa 1400 BC) (1). Early cases of this syndrome were only recorded during epidemic outbreaks. The first epidemic of CFS to strike the Western civilisation dates back to the time of Henry VIII in England when one of his wives, Anne Boleyn, fell ill during an attack of what was called the “English Sweats” (2). In the nineteenth century, neurasthenia was the popular name for this illness, introduced by a New York neurologist, George Beard (3). In the middle of the twentieth century, neuromyasthenia replaced neurasthenia as the preferred term to take into account the muscle fatigue (myasthenia) that was an important symptom of this syndrome. Sporadic, pre-epidemic and epidemic forms of neurasthenia were already recognised in the late nineteenth century though it was the epidemic form that was most common (4). The geographic location where an epidemic had occurred provided names (e.g., Akureyri disease or Royal Free Hospital Disease); in addition, the names often reflected the suspected pathology of the illness (e.g., atypical poliomyelitis or poliomyelitis-like disease, myalgic encephalomyelitis). It is the sporadic form of the disease that is commonly encountered in present clinical practice.

Neurological symptoms and subtle neurological signs are well recognised in both the epidemic and sporadic forms of CFS (5). Neurological signs in some of the well studied epidemic outbreaks were, however, more dramatic. Another characteristic distinguishing feature of the epidemic outbreaks was the rapid evolution of neurological symptoms within the first week of the illness, often simulating poliomyelitis (6-8). We shall therefore discuss the neurological dysfunction in the epidemic and sporadic forms of CFS separately.

© 2000 by The Haworth Press, Inc. All rights reserved.

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Posted to Co-Cure Wed, Mon, 9 Oct 2000 14:00:50 -0400 by Fred Springfield

Human Herpes Virus 6 (HHV-6) Infection in Patients with CFS...

Full Title: Human Herpes Virus 6 (HHV-6) Infection in Patients with Chronic Fatigue Syndrome and Its Relationship to Activation-Induced Cell Death
Journal: Journal of Chronic Fatigue Syndrome, Vol. 6, No. 3/4, 2000, pp. 41-50
Authors: Alan M. Cocchetto, MS; Mary E. McNamara, MBA; Edward F. Jordan, MD
Affiliations: Alan M. Cocchetto is Associate Professor of Electrical Engineering Technology, Alfred State College, SUNY at Alfred, Alfred, NY 14802 and is Medical Advisor for the National CFIDS Foundation, Inc., Needham, MA 02492.
Mary E. McNamara is Vice President and Director of Research of the New Jersey Chronic Fatigue Syndrome Association, Inc., Chatham, NJ 07928.
Edward F. Jordan is Internist and Oncologist who maintains a private practice in Olean, NY 14760.
Address correspondence to: Profesor Alan M. Cocchetto, 1113 Sharps Hill Road, Arkport, NY 14807 (E-mail: cocc1113@linkny.com ).

SUMMARY. Using evidence-based medical research techniques, current knowledge about the presence of active HHV-6 infections, in a sub-population of patients with chronic fatigue syndrome (CFS), has been reviewed and implications to activation-induced cell death are presented. Therapeutic intervention methods are also disclosed with a call for clinical studies to test the hypothesis presented.

[ Article copies available for a fee from The Haworth Document Delivery Service: 1-800-342-9678. E-mail address: getinfo@haworthpressinc.com .]

KEYWORDS. Human herpes virus 6 (HHV-6), activation-induced cell death, chronic fatigue syndrome

© 2000 by The Haworth Press, Inc. All rights reserved.

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Posted to Co-Cure Wed, 4 Oct 2000 20:55:30 -0400 by Fred Springfield

Role of Mycoplasmal Infections in Fatigue Illnesses: CFS, FMS, GWI and RA

Full Title: Role of Mycoplasmal Infections in Fatigue Illnesses: Chronic Fatigue and Fibromyalgia Syndromes, Gulf War Illness and Rheumatoid Arthritis
Journal: Journal of Chronic Fatigue Syndrome, Vol. 6, No. 3/4, 2000, pp. 23-39
Authors: G. L. Nicolson, PhD; M. Y. Nasralla, PhD; A. R. Franco, MD; K. De Meirleir, MD, PhD; N. L. Nicolson, PhD; R. Ngwenya, MD; J. Haier, MD, PhD
SUMMARY.
Bacterial and viral infections are purported to be associated with several fatigue illnesses, including Chronic Fatigue Syndrome (CFS), Fibromyalgia Syndrome (FMS), Gulf War Illnesses (GWI) and Rheumatoid Arthritis (RA), as causative agents, cofactors or opportunistic infections. We and others have looked for the presence of invasive pathogenic mycoplasmal infections in patients with CFS, FMS, GWI and RA and have found significantly more mycoplasmal infections in CFS, FMS, GWI and RA patients than in healthy controls. Most patients had multiple mycoplasmal infections (more than one species). Patients with chronic fatigue as a major sign often have different clinical diagnoses but display overlapping signs/symptoms similar to many of those found in CFS/FMS. When a chronic fatigue illness, such as GWI, spreads to immediate family members, they present with similar signs/symptoms and mycoplasmal infections. CFS/FMS/GWI patients with mycoplasmal infections generally respond to particular antibiotics (doxycycline, minocycline, ciprofloxacin, azithromycin and clarithromycin), and their long-term administration plus nutritional support, immune enhancement and other supplements appear to be necessary for recovery. Examination of the efficacy of antibiotics in recovery of chronic illness patients reveals that the majority of mycoplasma-positive patients respond and many eventually recover. Other chronic infections, such as viral infections, may also be involved in various chronic fatigue illnesses with or without mycoplasmal and other bacterial infections, and these multiple infections could be important in causing patient morbidity and difficulties in treating these illnesses.

[ Article copies available for a fee from The Haworth Document Delivery Service: 1-800-342-9678. E-mail address: getinfo@haworthpressinc.com .]

KEYWORDS. Mycoplasma, Gulf War syndrome, fibromyalgia, rheumatoid arthritis, antibiotics

© 2000 by The Haworth Press, Inc. All rights reserved.

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Posted to Co-Cure Wed, Thu, 5 Oct 2000 22:41:04 -0400by Fred Springfield

Editors' Introduction, J of CFS, Vol. 6, No. 3/4, 2000

Introduction

Journal of Chronic Fatigue Syndrome, Vol. 6, No. 3/4, 2000, p. 1
Kenny De Meirleir, MD, PhD, Guest Editor
Roberto Patarca-Montero, MD, PhD, Editor

The reviews in this publication provide the specialized views of different schools of thought, research and clinical intervention for chronic fatigue syndrome and myalgic encephalomyelitis (CFS/ME). This apparently divergent specialization trend is providing very important information on particular subpopulations of patients. For instance, some patients present with a clear picture of immune activation while in others autonomic dysfunction is the predominant disorder. As we deepen our vertical knowledge of particular clinical presentations that recruit the talents and experience of diverse specialists, we may start to find unifying principles with more solid holding, a process that may allow the pinpointing of a common etiology to become a reality. The evolution of the study of CFS/ME has witnessed several inductive-deductive cycles, each one increasing our knowledge base and creating more effective therapeutic approaches for particular symptomatologies. We may find that, even if we decipher the common etiopathological denominator, the pharmacological and therapeutic armamentarium available may not be effective for the treatment of CFS/ ME as is the case for the treatment of many infectious, neurological or autoimmune diseases. We are pleased to continue to provide a scholarly forum for these challenging ailments and to bring sound research, hypotheses, reviews, and preliminary clinical reports to expanding professional and lay audiences. Dr. Rosamund Vallings wrote a report for this issue on the highlights of the Second World Congress on Chronic Fatigue Syndrome and Related Disorders.

© 2000 by The Haworth Press, Inc. All rights reserved.

(Note: Dr. Vallings report was originally published by Roger Burns in his CFS-NEWS Electronic Newsletter, in two parts, on October 28 and 29, 1999. It can be read at http://www.co-cure.org/infocon1.htm .)

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Note: All abstract summaries, unless otherwise noted, were prepared by Margaret Bailey.


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