Charlotte, NC, United States
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Broderick G.,University of Alberta | Katz B.Z.,Anne And Robert H Lurie Childrens Hospital Of Chicago | Fernandes H.,University of Alberta | Fletcher M.A.,University of Miami | And 4 more authors.
Journal of Translational Medicine | Year: 2012

Background: As Chronic Fatigue Syndrome (CFS) has been known to follow Epstein-Bar virus (EBV) and other systemic infections; our objective was to describe differences in immune activation in post-infective CFS (PI-CFS) patients and recovered controls. We studied 301 adolescents prospectively over 24 months following the diagnosis of monospot-positive infectious mononucleosis (IM). We found an incidence of CFS at 6, 12 and 24 months of 13%, 7% and 4% respectively.Methods: Using chemiluminescent imaging we measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70), 13, 15, 17 and 23, IFN-γ, TNF-α and TNF-β in duplicate plasma samples available in bio-bank from 9 PI-CFS subjects and 12 recovered controls at 24 months post-infection.Results: Standard comparative analysis indicated significant differences in IL-8 and 23 across subject groups. In constructing a linear classification model IL-6, 8 and 23 were selected by two different statistical approaches as discriminating features, with IL-1a, IL-2 and IFN-γ also selected in one model or the other. This supported an assignment accuracy of better than 80% at a confidence level of 0.95 into PI-CFS versus recovered controls.Conclusion: These results suggest that co-expression patterns in as few as 5 cytokines associated with Th17 function may hold promise as a tool for the diagnosis of post-infectious CFS. © 2012 Broderick et al.; licensee BioMed Central Ltd.


Edwards K.A.,University of Washington | Terry S.F.,Genetic Alliance Inc. | Gold D.,University of Washington | Horn E.J.,LHC BioSolutions | And 3 more authors.
Biopreservation and Biobanking | Year: 2016

Biobanks are increasingly powerful tools used in translational research, and disease advocacy organizations (DAOs) are making their presence known as research drivers and partners. We examined DAO approaches to biobanking to inform how the enterprise of biobanking can grow and become even more impactful in human health. In this commentary, we outline overarching approaches from successful DAO biobanks. These lessons learned suggest principles that can create a more participant-centric approach and illustrate the key roles DAOs can play as partners in research initiatives. DAO approaches to biobanking for translational research include the following: be outcome driven; forge alliances that are unexpected - build bridges to enhance translation; come ready for success; be nimble, flexible, and adaptable; and remember that people matter. Each of these principles led to particular practices that have increased the translational impact of biobank collections. The research practices discussed can inform partnerships in all sectors going forward. © Copyright 2016, Mary Ann Liebert, Inc. 2016.


Broderick G.,University of Alberta | Fletcher M.A.,University of Miami | Fletcher M.A.,Miami Veterans Affairs Medical Center | Gallagher M.,University of Calgary | And 4 more authors.
Methods in Molecular Biology | Year: 2012

Complex disorders like Gulf War Illness (GWI) often defy diagnosis on the basis of a single biomarker and may only be distinguishable by considering the coexpression of multiple markers measured in response to a challenge. We demonstrate the practical application of such an approach using an example where blood was collected from 26 GWI, 13 healthy control subjects, and 9 unhealthy controls with Chronic Fatigue at three points during a graded exercise challenge. A 3-way multivariate projection model based on 12 markers of endocrine and immune function was constructed using a training set of n = 10 GWI and n = 11 healthy controls. These groups were separated almost completely on the basis of two coexpression patterns. In a separate test set these same features allowed for discrimination of new GWI subjects (n = 16) from unhealthy (n = 9) and healthy control subjects with a sensitivity of 70% and a specificity of 90%. © 2012 Springer Science+Business Media, LLC.


De Vega W.C.,University of Toronto | Vernon S.D.,CFIDS Association of America | McGowan P.O.,University of Toronto
PLoS ONE | Year: 2014

Chronic Fatigue Syndrome (CFS), also known as myalgic encephalomyelitis, is a complex multifactorial disease that is characterized by the persistent presence of fatigue and other particular symptoms for a minimum of 6 months. Symptoms fail to dissipate after sufficient rest and have major effects on the daily functioning of CFS sufferers. CFS is a multi-system disease with a heterogeneous patient population showing a wide variety of functional disabilities and its biological basis remains poorly understood. Stable alterations in gene function in the immune system have been reported in several studies of CFS. Epigenetic modifications have been implicated in long-term effects on gene function, however, to our knowledge, genome-wide epigenetic modifications associated with CFS have not been explored. We examined the DNA methylome in peripheral blood mononuclear cells isolated from CFS patients and healthy controls using the Illumina HumanMethylation450 BeadChip array, controlling for invariant probes and probes overlapping polymorphic sequences. Gene ontology (GO) and network analysis of differentially methylated genes was performed to determine potential biological pathways showing changes in DNA methylation in CFS. We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity. Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS. These data are consistent with evidence of multisystem dysregulation in CFS and implicate the involvement of DNA modifications in CFS pathology. © 2014 de Vega et al.


Irlbeck D.M.,Glaxosmithkline | Vernon S.D.,CFIDS Association of America | McCleary K.K.,CFIDS Association of America | Bateman L.,Fatigue Consultation Clinic | And 7 more authors.
BMC Research Notes | Year: 2014

Background: In 2009, a retrospective study reported the detection of xenotropic murine leukemia virus-related virus (XMRV) in clinical isolates derived from individuals with chronic fatigue syndrome or myalgic encephalomyelitis (CFS). While many efforts to confirm this observation failed, one report detected polytropic murine leukemia virus (pMLV), instead of XMRV. In both studies, Polymerase Chain Reaction (PCR)-based methods were employed which could provide the basis for the development of a practical diagnostic tool. To confirm these studies, we hypothesized that the ability to detect these viruses will not only depend upon the technical details of the methods employed but also on the criteria used to diagnose CFS and the availability of well characterized clinical isolates.Methods. A repository of clinical isolates from geographically distinct sites was generated by the collection of fresh blood samples from well characterized CFS and healthy subjects. Molecular techniques were used to generate assay positive controls and to determine the lower limit of detection (LLOD) for murine retroviral and Intracisternal A particle (Cell 12(4):963-72, 1977) detection methods.Results: We report the establishment of a repository of well-defined, clinical isolates from five, geographically distinct regions of the US, the comparative determination of the LLODs and validation efforts for the previously reported detection methods and the results of an effort to confirm the association of these retroviral signatures in isolates from individuals with CFS in a blinded, multi-site, prospective study. We detected various, murine retroviral DNA signatures but were unable to resolve a difference in the incidence of their detection between isolates from CFS (5/72; 6.7%) and healthy (2/37; 5.4%) subjects (Fisher's Exact Test, p-value = 1). The observed sequences appeared to reflect the detection of endogenous murine retroviral DNA, which was not identical to either XMRV or pMLV.Conclusions: We were unable to confirm a previously reported association between the detection of XMRV or pMLV sequences and CFS in a prospective, multi-site study. Murine retroviral sequences were detected at a low frequency that did not differ between CFS and control subjects. The nature of these sequences appeared to reflect the detection of pre-existing, endogenous, murine retroviral DNA in the PCR reagents employed. © 2014 Irlbeck et al.; licensee BioMed Central Ltd.


PubMed | University of Toronto and CFIDS Association of America
Type: Journal Article | Journal: PloS one | Year: 2014

Chronic Fatigue Syndrome (CFS), also known as myalgic encephalomyelitis, is a complex multifactorial disease that is characterized by the persistent presence of fatigue and other particular symptoms for a minimum of 6 months. Symptoms fail to dissipate after sufficient rest and have major effects on the daily functioning of CFS sufferers. CFS is a multi-system disease with a heterogeneous patient population showing a wide variety of functional disabilities and its biological basis remains poorly understood. Stable alterations in gene function in the immune system have been reported in several studies of CFS. Epigenetic modifications have been implicated in long-term effects on gene function, however, to our knowledge, genome-wide epigenetic modifications associated with CFS have not been explored. We examined the DNA methylome in peripheral blood mononuclear cells isolated from CFS patients and healthy controls using the Illumina HumanMethylation450 BeadChip array, controlling for invariant probes and probes overlapping polymorphic sequences. Gene ontology (GO) and network analysis of differentially methylated genes was performed to determine potential biological pathways showing changes in DNA methylation in CFS. We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity. Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS. These data are consistent with evidence of multisystem dysregulation in CFS and implicate the involvement of DNA modifications in CFS pathology.

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