In addition to their well characterized role in allergic inflammation, recent data confirm that mast cells play a more extensive role in a variety of immune responses. However, their contribution to autoimmune and neurologic disease processes has not been investigated. Experimental allergic encephalomyelitis (EAE) and its human disease counterpart, multiple sclerosis, are considered to be CD4+ T cell-mediated autoimmune diseases affecting the central nervous system. Several lines of indirect evidence suggest that mast cells could also play a role in the pathogenesis of both the human and murine disease. Using a myelin oligodendrocyte glycoprotein (MOG)-induced model of acute EAE, we show that mast cell-deficient W/W(v) mice exhibit significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores when compared with their wild-type congenic littermates. No differences were observed in MOG-specific T and B cell responses between the two groups, indicating that a global T or B cell defect is not present in W/W(v) animals. Reconstitution of the mast cell population in W/W(v) mice restores induction of early and severe disease to wild-type levels, suggesting that mast cells are critical for the full manifestation of disease. These data provide a new mechanism for immune destruction in EAE and indicate that mast cells play a broader role in neurologic inflammation.
Background: In sub-Saharan Africa, women's disclosure of HIVpositive status to others may affect their use of services for prevention of mother-to-child transmission of HIV (PMTCT) of HIV and maternal and child health-including antenatal care, antiretroviral drugs (ARVs) for PMTCT, and skilled birth attendance.Methods: Using data from the Migori and AIDS Stigma Study conducted in rural Nyanza Province, Kenya, we compared the use of PMTCT and maternal health services for all women by HIV status and disclosure category (n = 390). Among HIV-infected women (n = 145), associations between disclosure of HIV-positive status and the use of services were further examined with bivariate and multivariate logistic regression analyses.Results: Women living with HIV who had not disclosed to anyone had the lowest levels of maternity and PMTCT service utilization. For example, only 21% of these women gave birth in a health facility, compared with 35% of HIV-negative women and 49% of HIV-positive women who had disclosed (P < 0.001). Among HIVpositive women, the effect of disclosure to anyone on ARV drug use [odds ratio (OR) = 5.8; 95% confidence interval (CI): 1.9 to 17.8] and facility birth (OR = 2.9; 95% CI: 1.4 to 5.7) remained large and significant after adjusting for confounders. Disclosure to a male partner had a particularly strong effect on the use of ARVs for PMTCT (OR = 7.9; 95% CI: 3.7 to 17.1).Conclusions: HIV-positive status disclosure seems to be a complex yet critical factor for the use of PMTCT and maternal health services in this setting. The design of interventions to promote such disclosure must recognize the impact of HIV-related stigma on disclosure decisions and protect women's rights, autonomy, and safety.
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Lori N. Eidson;
George T. Kannarkat;
Christopher J. Barnum;
Jianjun Chang;
Jaegwon Chung;
Chelsea Caspell-Garcia;
Peggy Taylor;
Brit Mollenhauer;
Michael G. Schlossmacher;
Larry Ereshefsky;
Mark Yen;
Catherine Kopil;
Mark Frasier;
Kenneth Marek;
Vicki Hertzberg;
MariadeLourdes Tansey
Background: Efforts to identify fluid biomarkers of Parkinson's disease (PD) have intensified in the last decade. As the role of inflammation in PD pathophysiology becomes increasingly recognized, investigators aim to define inflammatory signatures to help elucidate underlying mechanisms of disease pathogenesis and aid in identification of patients with inflammatory endophenotypes that could benefit from immunomodulatory interventions. However, discordant results in the literature and a lack of information regarding the stability of inflammatory factors over a 24-h period have hampered progress. Methods: Here, we measured inflammatory proteins in serum and CSF of a small cohort of PD (n=12) and age-matched healthy control (HC) subjects (n=6) at 11 time points across 24h to (1) identify potential diurnal variation, (2) reveal differences in PD vs HC, and (3) to correlate with CSF levels of amyloid β (Aβ) and α-synuclein in an effort to generate data-driven hypotheses regarding candidate biomarkers of PD. Results: Despite significant variability in other factors, a repeated measures two-way analysis of variance by time and disease state for each analyte revealed that serum IFNγ, TNF, and neutrophil gelatinase-associated lipocalin (NGAL) were stable across 24h and different between HC and PD. Regression analysis revealed that C-reactive protein (CRP) was the only factor with a strong linear relationship between CSF and serum. PD and HC subjects showed significantly different relationships between CSF Aβ proteins and α-synuclein and specific inflammatory factors, and CSF IFNγ and serum IL-8 positively correlated with clinical measures of PD. Finally, linear discriminant analysis revealed that serum TNF and CSF α-synuclein discriminated between PD and HC with a minimum of 82% sensitivity and 83% specificity. Conclusions: Our findings identify a panel of inflammatory factors in serum and CSF that can be reliably measured, distinguish between PD and HC, and monitor inflammation as disease progresses or in response to interventional therapies. This panel may aid in generating hypotheses and feasible experimental designs towards identifying biomarkers of neurodegenerative disease by focusing on analytes that remain stable regardless of time of sample collection.
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Julie A. Womack;
Terrence E. Murphy;
Harini Bathulapalli;
Kathleen M. Akgun;
Cynthia Gibert;
Ken M. Kunisaki;
David Rimland;
Maria Rodriguez-Barradas;
H. Klar Yaggi;
Amy C. Justice;
Nancy S. Redeker
Fatigue is one of the most common and distressing symptoms, leading to markedly decreased quality of life among a large subset of patients with a variety of disorders. Susceptibility to fatigue may be influenced by genetic factors including single nucleotide polymorphisms (SNPs), especially in the regulatory regions, of relevant genes. To further investigate the association of SNPs with fatigue in various patient populations, a systematic search was conducted on Pubmed, CINAHL, PsycINFO, and Sociological Abstracts Database for fatigue related-terms in combination with polymorphisms or genetic variation-related terms. Fifty papers in total met the inclusion and exclusion criteria for this analysis. These 50 papers were further classified into three subgroups for evaluation: chronic fatigue syndrome (CFS), cancer-related fatigue (CRF) and other disease-related fatigue. SNPs in regulatory pathways of immune and neurotransmitter systems were found to play important roles in the etiologies of CFS, CRF and other disease-related fatigue. Evidence for associations between elevated fatigue and specific polymorphisms in TNFα, IL1b, IL4 and IL6 genes was revealed for all three subgroups of fatigue. We also found CFS shared a series of polymorphisms in HLA, IFN-γ, 5-HT and NR3C1 genes with other disease-related fatigue, however these SNPs (excluding IFN-γ) were not found to be adequately investigated in CRF. Gaps in knowledge related to fatigue etiology and recommendations for future research are further discussed.
Parkinson disease (PD) is a progressive neurodegenerative disease that affects peripheral organs as well as the central nervous system and involves a fundamental role of neuroinflammation in its pathophysiology. Neurohistological and neuroimaging studies support the presence of ongoing and end-stage neuroinflammatory processes in PD. Moreover, numerous studies of peripheral blood and cerebrospinal fluid from patients with PD suggest alterations in markers of inflammation and immune cell populations that could initiate or exacerbate neuroinflammation and perpetuate the neurodegenerative process. A number of disease genes and risk factors have been identified as modulators of immune function in PD and evidence is mounting for a role of viral or bacterial exposure, pesticides and alterations in gut microbiota in disease pathogenesis. This has led to the hypothesis that complex gene-by-environment interactions combine with an ageing immune system to create the ‘perfect storm’ that enables the development and progression of PD. We discuss the evidence for this hypothesis and opportunities to harness the emerging immunological knowledge from patients with PD to create better preclinical models with the long-term goal of enabling earlier identification of at-risk individuals to prevent, delay and more effectively treat the disease.
There is a high burden of human papillomavirus (HPV) associated cancers in low- and middle-income countries (LMICs). Reducing the recommended dosing schedule from two doses to one makes the vaccine schedule logistically simpler and lowers the cost. This could make the distribution of the current vaccine supply more equitable and lead to the protection of more people. However, the clinical trials studying the efficacy of a single-dose schedule have not yet delivered final results. Against this background, the question is whether a single-dose HPV vaccine recommendation is appropriate now, and if so, what are the ethical considerations of such a recommendation? We developed three ethical recommendations: (1) adopt a holistic view of evidence to justify policy decisions; (2) prioritize the reduction in global disparities in decision-making at all levels; and (3) be transparent in the reporting of how key stakeholder interests have shaped the collection and interpretation of the evidence, and ultimate decisions. The complex discussion regarding the HPV single-dose vaccine schedule highlights the need for in-depth engagement globally to improve our understanding of country-specific contexts, and how those contexts influence decisions regarding the HPV vaccine single-dose recommendation.