Abstracts-Chronic fatigue syndrome

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1-Chronic fatigue syndrome: the need for subtypes.

2-Evaluation of Autoantibodies to Common and Neuronal Cell Antigens in

Chronic Fatigue Syndrome.

3-Do vasoactive neuropeptides and heat shock proteins mediate

fatigue-related autoimmune disorders?

4-Are vasoactive neuropeptide autoimmune fatigue-related disorders mediated

via G protein-coupled receptors?

5-2',5'-Oligoadenylate size is critical to protect RNase L against

proteolytic cleavage in chronic fatigue syndrome.

6-Are attention deficit hyperactivity disorder and chronic fatigue syndrome

allergy related? what is fibromyalgia?

7-Exercise responsive genes measured in peripheral blood of women with

chronic fatigue syndrome and matched control subjects.

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Neuropsychol Rev. 2005 Mar;15(1):29-58.

Chronic fatigue syndrome: the need for subtypes.

LA, Corradi K, -Harding S, RR, King C.

De University, Chicago, Illinois 60614, USA. ljason@...

Chronic fatigue syndrome (CFS) is an important condition confronting

patients, clinicians, and researchers. This article provides information

concerning the need for appropriate diagnosis of CFS subtypes. We first

review findings suggesting that CFS is best conceptualized as a separate

diagnostic entity rather than as part of a unitary model of functional

somatic distress. Next, research involving the case definitions of CFS is

reviewed. Findings suggest that whether a broad or more conservative case

definition is employed, and whether clinic or community samples are

recruited, these decisions will have a major influence in the types of

patients selected.

Review of further findings suggests that subtyping individuals with CFS on

sociodemographic, functional disability, viral, immune, neuroendocrine,

neurology, autonomic, and genetic biomarkers can provide clarification for

researchers and clinicians who encounter CFS' characteristically confusing

heterogeneous symptom profiles. Treatment studies that incorporate subtypes

might be particularly helpful in better understanding the pathophysiology of

CFS.

This review suggests that there is a need for greater diagnostic clarity,

and this might be accomplished by subgroups that integrate multiple

variables including those in cognitive, emotional, and biological domains.

PMID: 15929497 [PubMed - in process]

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J Autoimmune Dis. 2005 May 25;2(1):5 [Epub ahead of print]

Evaluation of Autoantibodies to Common and Neuronal Cell Antigens in Chronic

Fatigue Syndrome.

Vernon SD, Reeves WC.

People with chronic fatigue syndrome (CFS) suffer from multiple symptoms

including fatigue, impaired memory and concentration, unrefreshing sleep and

musculoskeletal pain. The exact causes of CFS are not known, but the symptom

complex resembles that of several diseases that affect the immune system and

autoantibodies may provide clues to the various etiologies of CFS.

We used ELISA, immunoblot and commercially available assays to test serum

from subjects enrolled in a physician-based surveillance study conducted in

Atlanta, Georgia and a population-based study in Wichita, Kansas for a

number of common autoantibodies and antibodies to neuron specific antigens.

Subsets of those with CFS had higher rates of antibodies to

microtubule-associated protein 2 (MAP2) (p = 0.03) and ssDNA (p = 0.04).

There was no evidence of higher rates for several common nuclear and

cellular antigens in people with CFS.

Autoantibodies to specific host cell antigens may be a useful approach for

identifying subsets of people with CFS, identify biomarkers, and provide

clues to CFS etiologies.

PMID: 15916704 [PubMed - as supplied by publisher]

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Med Hypotheses. 2005;64(3):539-42.

Do vasoactive neuropeptides and heat shock proteins mediate fatigue-related

autoimmune disorders?

Staines DR.

Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Qld,

Australia. don_staines@...

Autoimmune dysfunction of certain vasoactive neuropeptides may be implicated

in a range of disorders associated with fatigue like states (chronic fatigue

syndrome, Gulf War syndrome) and even sudden infant death syndrome.

These substances have neurotrophic, neuroregulatory, and neurotransmission

functions, as well as that of immune modulators and hormones. They exert

significant control over carbohydrate and lipid metabolism. The hypothesis

is that because these substances have vital and indispensable roles in

cellular processes, loss or compromise of these roles would lead to

predictable and severe cellular and systemic effects.

The important roles of certain VNs make them a vulnerable target for

autoimmune dysfunction. They are known to be associated with heat shock

proteins for intracellular functioning with which they may form

immunostimulating complexes. While peptide-HSP complexes are a relatively

new area for research, this paper asserts that attention could be focused on

these substances and complexes in an effort to elucidate a number of

perplexing fatigue-associated disorders.

PMID: 15617862 [PubMed - in process]

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Med Hypotheses. 2005;65(1):29-31.

Are vasoactive neuropeptide autoimmune fatigue-related disorders mediated

via G protein-coupled receptors?

Staines D.

Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Qld.,

Australia.

Vasoactive neuropeptides such as pituitary adenylate cyclase activating

polypeptide (PACAP), calcitonin gene related peptide (CGRP) and vasoactive

intestinal peptide (VIP) have been implicated in a number of fatigue-related

conditions.

Associations of these vasoactive neuropeptides with heat shock proteins

(hsps) and cytosine-guanosine dinucleotide (CpG) DNA fragments in autoimmune

phenomena have been postulated to interfere with receptor signal activation

for adenylate cyclase and other vital cellular processes. However, a

specific mechanism for receptor dysfunction has not been explored to date. G

protein-coupled receptors (GPCRs) constitute a high proportion of biological

receptor mechanisms and serve a wide range of substances including

nucleosides, nucleotides, catecholamines, calcium, histamine, serotonin and

prostaglandins.

They are complex transmembrane hepta-helical serpentine structures with

specific binding capabilities resulting in conformational changes that

activate cognate cyclic GMP (G proteins). GPCRs adapt to certain stimuli

through desensitisation and changes in phosphorylation and are subject to

distortions of signalling processes. Hence, these vital signalling

structures are susceptible to impairment of function through a range of

mechanisms. One of their vital functions is signalling through adenylate

cyclase, a vital step in cyclic AMP metabolism. This step involves ATP

metabolism and therefore is a crucial mediator of cellular energy pathways.

Some GPCRs act to inhibit adenylate cyclase (Gi proteins).

Also vasoactive neuropeptides, such as PACAP display a number of receptor

isotypes including null variants. Overexpression of Gi proteins and null

variant receptors may account for major disruptions of signal transduction

and ATP/cAMP metabolism.

This paper examines the possible role of GPCR dysfunction in contributing to

fatigue-related vasoactive neuropeptide autoimmune disorders which may

include chronic fatigue syndrome (CFS), Gulf War syndrome (GWS) and even

sudden infant death syndrome (SIDS).

PMID: 15893112 [PubMed - in process]

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Exp Mol Pathol. 2005 Jun;78(3):239-46. Epub 2005 Mar 2.

2',5'-Oligoadenylate size is critical to protect RNase L against proteolytic

cleavage in chronic fatigue syndrome.

Fremont M, El Bakkouri K, Vaeyens F, Herst CV, De Meirleir K, Englebienne P.

RED Laboratories, Pontbeek 61, B-1731 Zellik, Belgium.

A dysregulation in the 2',5'-oligoadenylate (2-5A)-dependent RNase L

antiviral pathway has been detected in peripheral blood mononuclear cells

(PBMC) of chronic fatigue syndrome (CFS) patients, which is characterized by

upregulated 2-5A synthetase and RNase L activities, as well as by the

presence of a low molecular weight (LMW) 2-5A-binding protein of 37-kDa

related to RNase L.

This truncated protein has been shown to originate from proteolytic cleavage

of the native 83-kDa RNase L by m-calpain and human leukocyte elastase

(HLE). We investigated the possible role of 2-5A oligomers in the

proteolytic action toward the endonuclease and show that incubation of CFS

PBMC extracts with 2-5A trimer and tetramer, but not with the dimer, results

in a significant protection of the native 83-kDa RNase L against cleavage by

endogenous and purified proteases.

Similar results are obtained with a purified recombinant RNase L. An

analysis of the size of 2-5A oligomers produced by the catalytic activity of

the 2-5A synthetase present in PBMC extracts further shows that samples

containing the 37-kDa RNase L preferentially produce 2-5A dimers instead of

higher oligomers.

Taken together, our results indicate that homodimerization of RNase L by

2-5A oligomers higher than the dimer prevents its cleavage by proteolytic

enzymes. The presence of the truncated 37-kDa RNase L in PBMC extracts is

therefore likely to result, not only from the abnormal activation of

inflammatory proteases, but also from a dysregulation in 2-5A synthetase

induction or activation towards the preferential production of 2-5A dimers.

PMID: 15924878 [PubMed - in process]

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Allergy Asthma Proc. 2005 Jan-Feb;26(1):19-28.

Are attention deficit hyperactivity disorder and chronic fatigue syndrome

allergy related? what is fibromyalgia?

Bellanti JA, Sabra A, Castro HJ, Chavez JR, Malka-Rais J, de Inocencio JM.

Departments of Pediatrics , town University Medical Center,

Washington, D.C. 20057, USA.

Despite the progress made in the field of allergy-immunology in recent

years, there are a group of diseases that the allergist-immunologist may be

called on to manage in which their precise etiologies have not been

identified but that appear to be initiated or exacerbated by allergic

mechanisms.

Attention deficit hyperactivity disorder (ADHD), chronic fatigue syndrome

(CFS), and fibromyalgia (FM) fall into this category of disorders. Although

the precise etiology of ADHD still remains unknown, the most prevalent

theory is that it represents a neurobiologically based developmental

disability leading to inadequate production of the neurotransmitter

dopamine. In patients with CFS, there appears to be a fundamental

dysfunction of the neuroendocrine-immunological system with deficiencies of

immunological and neurological function, which, together with chronic viral

infection, may lead to a sequence of events responsible for the symptoms of

this disorder.

FM appears to be a variant of CFS with a predominance of hypothalamic

pituitary axis dysfunction. The disorder is characterized by chronic

widespread pain and the finding of 11/18 tender points on examination.

Now, there is emerging evidence to suggest that adverse reactions to foods

or food components also may be associated with behavioral disturbances that

may play a role in each of these disorders.

An understanding of the interactive responses involved in the

neuroendocrine-immunological network is essential for a comprehension of the

pathophysiology of ADHD, CFS, and FM and the role of allergies appears to be

an important triggering event in each of the disorders.

PMID: 15813284 [PubMed - in process]

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BMC Physiol. 2005 Mar 24;5(1):5.

Exercise responsive genes measured in peripheral blood of women with chronic

fatigue syndrome and matched control subjects.

Whistler T, JF, Unger ER, Vernon SD.

Viral Exanthems and Herpesvirus Branch, Centers for Disease Control and

Prevention, Atlanta, GA 30333, USA. taw6@...

BACKGROUND: Chronic fatigue syndrome (CFS) is defined by debilitating

fatigue that is exacerbated by physical or mental exertion. To search for

markers of CFS-associated post-exertional fatigue, we measured peripheral

blood gene expression profiles of women with CFS and matched controls before

and after exercise challenge.

RESULTS: Women with CFS and healthy, age-matched, sedentary controls were

exercised on a stationary bicycle at 70% of their predicted maximum

workload. Blood was obtained before and after the challenge, total RNA was

extracted from mononuclear cells, and signal intensity of the labeled cDNA

hybridized to a 3800-gene oligonucleotide microarray was measured.

We identified differences in gene expression among and between subject

groups before and after exercise challenge and evaluated differences in

terms of Gene Ontology categories. Exercise-responsive genes differed

between CFS patients and controls.

These were in genes classified in chromatin and nucleosome assembly,

cytoplasmic vesicles, membrane transport, and G protein-coupled receptor

ontologies. Differences in ion transport and ion channel activity were

evident at baseline and were exaggerated after exercise, as evidenced by

greater numbers of differentially expressed genes in these molecular

functions.

CONCLUSION: These results highlight the potential use of an exercise

challenge combined with microarray gene expression analysis in identifying

gene ontologies associated with CFS.

PMID: 15790422 [PubMed - in process]

http://www.biomedcentral.com/1472-6793/5/5

Background

In a state of health, physical exercise has a quantifiable effect on

neuroendocrine, autonomic, and immune systems influencing metabolic and

immune responses. However, in the initial phase of acute illness, there is

an avoidance of physical stressors so energy can be dedicated to healing and

a return to homeostasis. While physiologic disturbance in acute illness is

transient, chronic illnesses, such as chronic fatigue syndrome (CFS), have

prolonged disturbances that have a debilitating effect both physiologically

and psychologically. Consequently, activities that are physiologic

stressors, such as physical exercise, exacerbate the symptoms that define

CFS.

CFS is a complex, multifactorial illness whose etiology and pathophysiology

remain unclear [1]. CFS is defined by a characteristic symptom complex in

the absence of other medical or psychiatric conditions with similar clinical

characteristics [2,3]. Subtle differences in hypothalamic-pituitary-adrenal

axis function [4], immune system function [5], and psychological profiles

[6] between CFS patients and controls have been reported; however, no

consistent distinguishing difference or frank abnormality has been confirmed

[7,8], and it remains unclear whether CFS represents a unique disease or a

common illness response to a variety of insults.

Perhaps the greatest methodological problem with studying CFS is that many

individuals identified in population studies have been sick for at least 5

years [9]. During this time, the illness waxes and wanes, making it

difficult to identify biomarkers or define pathogenesis. Physical, mental,

and emotional stress exacerbate CFS and result in case-defining

post-exertional fatigue [2] with measurable physiologic differences [10].

Therefore, exercise challenge of people with CFS is an effective method for

calibrating CFS subjects and thus increasing the likelihood of uniformly

identifying biomarkers and/or physiologic abnormalities.

We used gene expression profiling of peripheral blood to evaluate

differences between CFS subjects and sedentary healthy controls both before

and following an exercise challenge. Overall, we found the gene expression

profiles to be quite similar, and of importance, most differences were

present prior to exercise challenge. These differences were in G

protein-coupled receptor and ion transport and ion channel activity

ontologies. The latter was exaggerated after exercise as evidenced by

differential expression of a greater number of genes involved in these

molecular functions. Differences were also evident in exercise response,

including chromatin and nucleosome assembly, cytoplasmic vesicles, membrane

transport and G-protein coupled receptor ontologies. These differences may

help explain the symptoms of CFS.

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One interesting correlate of this study was the finding that the complement

pathway showed significant differences between CFS and control subjects

after exercise. This has been reported previously in the analysis of these

same exercise challenge-derived specimens. Sorensen et al. [22] measured

levels of complement split products in the sera of these subjects and found

differences between CFS and control subjects in C4a after exercise

challenge. Complement activation was identified as an ontology that was

significantly different between CFS and control subjects after exercise. The

correlates on the data are interesting as their study measured protein

levels (i.e., gene product levels) and this study measured the transcript

levels.