A gene signature for post-infectious chronic fatigue syndrome

Abstract:

BACKGROUND: At present, there are no clinically reliable disease markers for chronic fatigue syndrome. DNA chip microarray technology provides a method for examining the differential expression of mRNA from a large number of genes. Our hypothesis was that a gene expression signature, generated by microarray assays, could help identify genes which are dysregulated in patients with post-infectious CFS and so help identify biomarkers for the condition.

METHODS: Human genome-wide Affymetrix GeneChip arrays (39,000 transcripts derived from 33,000 gene sequences) were used to compare the levels of gene expression in the peripheral blood mononuclear cells of male patients with post-infectious chronic fatigue (n = 8) and male healthy control subjects (n = 7).

RESULTS: Patients and healthy subjects differed significantly in the level of expression of 366 genes. Analysis of the differentially expressed genes indicated functional implications in immune modulation, oxidative stress and apoptosis. Prototype biomarkers were identified on the basis of differential levels of gene expression and possible biological significance.

CONCLUSION: Differential expression of key genes identified in this study offer an insight into the possible mechanism of chronic fatigue following infection. The representative biomarkers identified in this research appear promising as potential biomarkers for diagnosis and treatment.

 

Source: Gow JW, Hagan S, Herzyk P, Cannon C, Behan PO, Chaudhuri A. A gene signature for post-infectious chronic fatigue syndrome. BMC Med Genomics. 2009 Jun 25;2:38. doi: 10.1186/1755-8794-2-38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716361/ (Full article)

 

Sensitive, qualitative detection of human herpesvirus-6 and simultaneous differentiation of variants A and B

Abstract:

BACKGROUND: The current limitations of laboratory testing for the detection of human herpesvirus virus 6 (HHV-6) in clinical specimens with low HHV-6 viral loads make this area a priority for further research and development.

OBJECTIVES: To develop and validate a sensitive qualitative assay for simultaneous HHV-6 detection and variant differentiation.

METHODS: We developed a diagnostic procedure, which combines a magnetic bead-based nucleic acid extraction, PCR amplification, and colorimetric microtiter plate identification (MAG-PCR-EIA), for the sensitive detection of HHV-6 and the simultaneous differentiation of HHV-6A and HHV-6B.

RESULTS: Analytic sensitivities of the MAG-PCR-EIA assay were 10 copies per reaction for both HHV-6A and HHV-6B variants, which is equivalent to 20 copies/ml when 1ml of clinical specimen was processed. A proficiency panel containing 11 blinded specimens covering HHV-6A viral loads from 0 to 100,000 copies was tested, and the MAG-PCR-EIA was able to detect the lowest concentration at one copy in 200microl. A panel of 27 urine specimens, which were collected from patients with and without chronic fatigue syndrome, was tested by the MAG-PCR-EIA. HHV-6 was detected in two (HHV-6A) patients who have chromosomally integrated HHV-6A and in one (HHV-6B) patient who was a healthy control and diagnosed as cervical cancer later on. The HHV-6 results did not correlate with results previously determined by HHV-6 antigenemia in urine.

CONCLUSION: With large specimen volumes processed and an additional signal amplification incorporated, the MAG-PCR-EIA provides a sensitive and qualitative system for HHV-6 detection and simultaneous variant differentiation. Clinical relevance of the assay awaits further investigation.

 

Source: Li H, Meng S, Levine SM, Stratton CW, Tang YW. Sensitive, qualitative detection of human herpesvirus-6 and simultaneous differentiation of variants A and B. J Clin Virol. 2009 Sep;46(1):20-3. doi: 10.1016/j.jcv.2009.05.016. Epub 2009 Jun 21. https://www.ncbi.nlm.nih.gov/pubmed/19540801

 

An integrated approach to infer causal associations among gene expression, genotype variation, and disease

Abstract:

Gene expression data and genotype variation data are now capable of providing genome-wide patterns across many different clinical conditions. However, the separate analysis of these data has limitations in elucidating the complex network of gene interactions underlying complex traits, such as common human diseases. More information about the identity of key driver genes of common diseases comes from integrating these two heterogeneous types of data. We developed a two-step procedure to characterize complex diseases by integrating genotype variation data and gene expression data.

The first step elucidates the causal relationship among genetic variation, gene expression level, and disease. Based on the causal relationship determined at the first step, the second step identifies significant gene expression traits whose effects on disease status or whose responses to disease status are modified by the specific genotype variation. For the selected significant genes, a pathway enrichment analysis can be performed to identify the genetic mechanism of a complex disease. The proposed two-step procedure was shown to be an effective method for integrating three different levels of data, i.e., genotype variation, gene expression and disease status.

By applying the proposed procedure to a chronic fatigue syndrome (CFS) dataset, we identified a list of potential causal genes for CFS, and found an evidence for difference in genetic mechanisms of the etiology between CFS without ‘a major depressive disorder with melancholic features’ (CFS) and CFS with ‘a major depressive disorder with melancholic features’ (CFS-MDD/m). Especially, the SNPs within NR3C1 gene were shown to differently influence the susceptibility of developing CFS and CFS-MDD/m through integrative action with gene expression levels.

 

Source: Lee E, Cho S, Kim K, Park T. An integrated approach to infer causal associations among gene expression, genotype variation, and disease. Genomics. 2009 Oct;94(4):269-77. doi: 10.1016/j.ygeno.2009.06.002. Epub 2009 Jun 18. http://www.sciencedirect.com/science/article/pii/S0888754309001347 (Full article)

 

Chronic fatigue syndrome: comments on deconditioning, blood volume and resulting cardiac function

Abstract:

Cardiovascular and autonomic dysfunction have been suggested to underlie the symptoms accompanying CFS (chronic fatigue syndrome). In the present issue of Clinical Science, Hurwitz and co-workers have investigated whether deficits were present in cardiac output and blood volume in a cohort of patients with CFS and if these were linked to illness severity and sedentary lifestyle. The results clearly demonstrate reduced cardiac stroke volume and cardiac output in more severely afflicted patients with CFS, which is primarily attributable to a measurable reduction in blood volume. Similar findings are observed in microgravity and bed rest deconditioning, in forms of orthostatic intolerance and, to a lesser extent, in sedentary people. The circulatory consequences of reduced cardiac output may help to account for many of the findings of the syndrome.

You can read the rest of this comment here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236909/

 

Source: Stewart JM. Chronic fatigue syndrome: comments on deconditioning, blood volume and resulting cardiac function. Clin Sci (Lond). 2009 Oct 19;118(2):121-3. doi: 10.1042/CS20090327. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236909/ (Full article)

 

Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome?

Abstract:

This article posits that infection of the peripheral ganglia causes at least some cases of Chronic Fatigue Syndrome (CFS), with a neurotropic herpesvirus, particularly varicella-zoster virus (VZV), as the most likely cause of the infection. Virtually all CFS symptoms could be produced by an infection of the peripheral ganglia, with infection of the autonomic ganglia causing fatigue, postural hypotension, and sleep disturbances, and infection of the sensory ganglia causing sensory symptoms such as chronic pain. Furthermore, infections of the peripheral ganglia are known to cause long-term nerve dysfunction, which would help explain the chronic course of CFS.

Herpesviruses have long been suspected as the cause of CFS; this theory has recently been supported by studies showing that administering antiherpes agents causes substantial improvement in some CFS patients. VZV is known to frequently reactivate in the peripheral ganglia of previously healthy adults and cause sudden, debilitating illness, making it a likely candidate as a cause of CFS. Moreover, many of the symptoms of CFS overlap with those of herpes zoster (shingles), with the exception that painful rash is not one of the symptoms of CFS.

A model is therefore proposed in which CFS is one of the many manifestations of zoster sine herpete; that is, herpes zoster without rash. Furthermore, re-exposure to VZV in the form of chickenpox has become less common in the past few decades; without such re-exposure, immunity to VZV drops, which could explain the increased incidence of CFS. Co-infection with multiple herpesviruses is a possibility, as some CFS patients show signs of infection with other herpesviruses including Epstein-Barr, Cytomegalovirus, and HHV6. These three herpesviruses can attack immune cells, and may therefore promote neurotropic herpesvirus reactivation in the ganglia.

The possibility of VZV as the causal agent in CFS has previously received almost no attention; the possibility that CFS involves infection of the peripheral ganglia has likewise been largely overlooked. This suggests that the search for a viral cause of CFS has been far from exhaustive. Several antiherpes drugs are available, as is a vaccine for VZV; more research into such agents as possible treatments for CFS is urgently needed.

 

Source: Shapiro JS. Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome? Med Hypotheses. 2009 Nov;73(5):728-34. doi: 10.1016/j.mehy.2009.04.043. Epub 2009 Jun 10. https://www.ncbi.nlm.nih.gov/pubmed/19520522

 

Pharmacological treatment of chronic fatigue syndrome: focusing on the role of antidepressants

Abstract:

Chronic fatigue syndrome (CFS) is characterized by chronic, medically unexplained fatigue associated with effort- and stress-intolerance, widespread pain, and impairment in sleep and concentration. Although this constellation of symptoms is highly prevalent in clinical practice, the pathophysiological mechanisms underlying CFS are poorly understood. Current evidence indicates similarities in symptomatology, and possibly etiology and pathogenesis, between CFS and depression. Additionally, there is significant overlap between CFS and the syndrome of fibromyalgia for which antidepressants have shown consistent efficacy.

Data regarding antidepressant treatment of CFS is less copious and less uniformly positive, such that antidepressant use in CFS remains controversial. The current review aims to summarize available data related to antidepressants and other psychotropic agents in CFS to provide a platform for clinicians to make decisions in their treatment of this challenging syndrome.

We identified relevant studies through a PubMed literature search with a combination of the following search terms: ‘fatigue,’ ‘depression,’ ‘antidepressant,’ ‘etiology’ (e.g., ‘neurobiology,’ ‘neurotransmitter,’ ‘genetic’), ‘diagnosis,’ and ‘treatment’ (e.g., ‘antidepressant’ plus the specific name). In addition, studies were also identified via the reference sections of retrieved articles. The authors thoroughly reviewed major findings from the scanned literatures and eventually synthesized them, providing summary, interpretation, and future directions.

 

Source: Pae CU, Marks DM, Patkar AA, Masand PS, Luyten P, Serretti A. Pharmacological treatment of chronic fatigue syndrome: focusing on the role of antidepressants. Expert Opin Pharmacother. 2009 Jul;10(10):1561-70. Doi: 10.1517/14656560902988510. https://www.ncbi.nlm.nih.gov/pubmed/19514866

 

Effects of the intelligent-turtle massage on the physical symptoms and immune functions in patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: To evaluate the effects of the intelligent-turtle massage on the physical symptoms and immune functions in patients with chronic fatigue syndrome (CFS).

METHODS: 182 cases of CFS were randomly divided into an experimental group of 91 cases treated by the intelligent-turtle massage, and a control group of 91 cases treated with the conventional massage method. After 2 courses of treatment, the therapeutic effects were statistically analyzed with the accumulated score for the improved clinical symptoms; and the changes of IgA, IgM and IgG were compared in 96 cases.

RESULTS: There was a significant difference between the two groups in the accumulated scores for improvement of the symptoms (P<0.05). A remarkable difference was found in the therapeutic effect. And there was a significant difference in the IgA, IgM and IgG levels between the two groups (P<0.05).

CONCLUSION: The intelligent-turtle massage is an effective therapy for relieving the physical symptoms of CFS, and it may show certain effects on the immune functions.

 

Source: Wang JH, Chai TQ, Lin GH, Luo L. Effects of the intelligent-turtle massage on the physical symptoms and immune functions in patients with chronic fatigue syndrome. J Tradit Chin Med. 2009 Mar;29(1):24-8. http://www.journaltcm.com/modules/Journal/contents/stories/091/7.pdf (Full article)

 

Severe versus Moderate criteria for the new pediatric case definition for ME/CFS

Abstract:

The new diagnostic criteria for pediatric ME/CFS are structurally based on the Canadian Clinical Adult case definition, and have more required specific symptoms than the (Fukuda et al. Ann Intern Med 121:953-959, 1994) adult case definition.

Physicians specializing in pediatric ME/CFS referred thirty-three pediatric patients with ME/CFS and 21 youth without the illness. Those who met ME/CFS criteria were separated into Severe and Moderate categories. Significant differences were found for symptoms within each of the six major categories: fatigue, post-exertional malaise, sleep, pain, neurocognitive difficulties, and autonomic/neuroendocrine/immune manifestations.

In general, the results showed participants who met the Severe ME/CFS criteria reported the highest scores, the Moderate ME/CFS group show scores that were a little lower, and the control group evidenced the lowest scores. Findings indicate that the Pediatric Case Definition for ME/CFS can distinguish between those with this illness and controls, and between those with Severe versus Moderate manifestations of the illness.

 

Source: Jason L, Porter N, Shelleby E, Till L, Bell DS, Lapp CW, Rowe K, De Meirleir K. Severe versus Moderate criteria for the new pediatric case definition for ME/CFS. Child Psychiatry Hum Dev. 2009 Dec;40(4):609-20. doi: 10.1007/s10578-009-0147-8. Epub 2009 Jun 10.https://www.ncbi.nlm.nih.gov/pubmed/19513826

 

Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study

Abstract:

Chronic fatigue syndrome (CFS) is a disabling condition characterized by unexplained chronic fatigue that impairs normal activities. Although immunological and psychological aspects are present, symptoms related to skeletal muscles, such as muscle soreness, fatigability and increased lactate accumulation, are prominent in CFS patients.

In this case-control study, the phenotype of the same biopsy samples was analyzed by determining i) fibre-type proportion using myosin isoforms as fibre type molecular marker and gel electrophoresis as a tool to separate and quantify myosin isoforms, and ii) contractile properties of manually dissected, chemically made permeable and calcium-activated single muscle fibres.

The results showed that fibre-type proportion was significantly altered in CSF samples, which showed a shift from the slow- to the fast-twitch phenotype. Cross sectional area, force, maximum shortening velocity and calcium sensitivity were not significantly changed in single muscle fibres from CSF samples. Thus, the contractile properties of muscle fibres were preserved but their proportion was changed, with an increase in the more fatigue-prone, energetically expensive fast fibre type.

Taken together, these results support the view that muscle tissue is directly involved in the pathogenesis of CSF and it might contribute to the early onset of fatigue typical of the skeletal muscles of CFS patients.

 

Source: Pietrangelo T, Toniolo L, Paoli A, Fulle S, Puglielli C, Fanò G, Reggiani C. Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study. Int J Immunopathol Pharmacol. 2009 Apr-Jun;22(2):427-36. https://www.ncbi.nlm.nih.gov/pubmed/19505395

 

Gene expression in peripheral blood leukocytes in monozygotic twins discordant for chronic fatigue: no evidence of a biomarker

Abstract:

BACKGROUND: Chronic fatiguing illness remains a poorly understood syndrome of unknown pathogenesis. We attempted to identify biomarkers for chronic fatiguing illness using microarrays to query the transcriptome in peripheral blood leukocytes.

METHODS: Cases were 44 individuals who were clinically evaluated and found to meet standard international criteria for chronic fatigue syndrome or idiopathic chronic fatigue, and controls were their monozygotic co-twins who were clinically evaluated and never had even one month of impairing fatigue. Biological sampling conditions were standardized and RNA stabilizing media were used. These methodological features provide rigorous control for bias resulting from case-control mismatched ancestry and experimental error. Individual gene expression profiles were assessed using Affymetrix Human Genome U133 Plus 2.0 arrays.

FINDINGS: There were no significant differences in gene expression for any transcript.

CONCLUSIONS: Contrary to our expectations, we were unable to identify a biomarker for chronic fatiguing illness in the transcriptome of peripheral blood leukocytes suggesting that positive findings in prior studies may have resulted from experimental bias.

 

Source: Byrnes A, Jacks A, Dahlman-Wright K, Evengard B, Wright FA, Pedersen NL, Sullivan PF. Gene expression in peripheral blood leukocytes in monozygotic twins discordant for chronic fatigue: no evidence of a biomarker. PLoS One. 2009 Jun 5;4(6):e5805. doi: 10.1371/journal.pone.0005805. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688030/ (Full article)