Up-Regulation of Annexin-A1 and Lipoxin A4 in Individuals with Ulcerative Colitis May Promote Mucosal Homeostasis

PubMed ID: 22723974This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Dengue contingency planning: from research to policy and practice

Background Dengue is an increasingly incident disease across many parts of the world. In response, an evidence-based handbook to translate research into policy and practice was developed. This handbook facilitates contingency planning as well as the development and use of early warning and response systems for dengue fever epidemics, by identifying decision-making processes that contribute to the success or failure of dengue surveillance, as well as triggers that initiate effective responses to incipient outbreaks. Methodology/Principal findings Available evidence was evaluated using a step-wise process that included systematic literature reviews, policymaker and stakeholder interviews, a study to assess dengue contingency planning and outbreak management in 10 countries, and a retrospective logistic regression analysis to identify alarm signals for an outbreak warning system using datasets from five dengue endemic countries. Best practices for managing a dengue outbreak are provided for key elements of a dengue contingency plan including timely contingency planning, the importance of a detailed, context-specific dengue contingency plan that clearly distinguishes between routine and outbreak interventions, surveillance systems for outbreak preparedness, outbreak definitions, alert algorithms, managerial capacity, vector control capacity, and clinical management of large caseloads. Additionally, a computer-assisted early warning system, which enables countries to identify and respond to context-specific variables that predict forthcoming dengue outbreaks, has been developed. Conclusions/Significance Most countries do not have comprehensive, detailed contingency plans for dengue outbreaks. Countries tend to rely on intensified vector control as their outbreak response, with minimal focus on integrated management of clinical care, epidemiological, laboratory and vector surveillance, and risk communication. The Technical Handbook for Surveillance, Dengue Outbreak Prediction/ Detection and Outbreak Response seeks to provide countries with evidence-based best practices to justify the declaration of an outbreak and the mobilization of the resources required to implement an effective dengue contingency plan

Gendered health systems: evidence from low- and middle-income countries

Background Gender is often neglected in health systems, yet health systems are not gender neutral. Within health systems research, gender analysis seeks to understand how gender power relations create inequities in access to resources, the distribution of labour and roles, social norms and values, and decision-making. This paper synthesises findings from nine studies focusing on four health systems domains, namely human resources, service delivery, governance and financing. It provides examples of how a gendered and/or intersectional gender approach can be applied by researchers in a range of low- and middle-income settings (Cambodia, Zimbabwe, Uganda, India, China, Nigeria and Tanzania) to issues across the health system and demonstrates that these types of analysis can uncover new and novel ways of viewing seemingly intractable problems. Methods The research used a combination of mixed, quantitative, qualitative and participatory methods, demonstrating the applicability of diverse research methods for gender and intersectional analysis. Within each study, the researchers adapted and applied a variety of gender and intersectional tools to assist with data collection and analysis, including different gender frameworks. Some researchers used participatory tools, such as photovoice and life histories, to prompt deeper and more personal reflections on gender norms from respondents, whereas others used conventional qualitative methods (in-depth interviews, focus group discussion). Findings from across the studies were reviewed and key themes were extracted and summarised. Results Five core themes that cut across the different projects were identified and are reported in this paper as follows: the intersection of gender with other social stratifiers; the importance of male involvement; the influence of gendered social norms on health system structures and processes; reliance on (often female) unpaid carers within the health system; and the role of gender within policy and practice. These themes indicate the relevance of and need for gender analysis within health systems research. Conclusion The implications of the diverse examples of gender and health systems research highlighted indicate that policy-makers, health practitioners and others interested in enhancing health system research and delivery have solid grounds to advance their enquiry and that one-size-fits-all heath interventions that ignore gender and intersectionality dimensions require caution. It is essential that we build upon these insights in our efforts and commitment to move towards greater equity both locally and globally

RelB-deficient autoinflammatory pathology presents as interferonopathy, but in mice is interferon-independent.

BACKGROUND: Autoimmune diseases are leading causes of ill health and morbidity and have diverse etiology. Two signaling pathways are key drivers of autoimmune pathology, interferon and nuclear factor-κB (NF-κB)/RelA, defining the 2 broad labels of interferonopathies and relopathies. Prior work has established that genetic loss of function of the NF-κB subunit RelB leads to autoimmune and inflammatory pathology in mice and humans. OBJECTIVE: We sought to characterize RelB-deficient autoimmunity by unbiased profiling of the responses of immune sentinel cells to stimulus and to determine the functional role of dysregulated gene programs in the RelB-deficient pathology. METHODS: Transcriptomic profiling was performed on fibroblasts and dendritic cells derived from patients with RelB deficiency and knockout mice, and transcriptomic responses and pathology were assessed in mice deficient in both RelB and the type I interferon receptor. RESULTS: We found that loss of RelB in patient-derived fibroblasts and mouse myeloid cells results in elevated induction of hundreds of interferon-stimulated genes. Removing hyperexpression of the interferon-stimulated gene program did not ameliorate the autoimmune pathology of RelB knockout mice. Instead, we found that RelB suppresses a different set of inflammatory response genes in a manner that is independent of interferon signaling but associated with NF-κB binding motifs. CONCLUSION: Although transcriptomic profiling would describe RelB-deficient autoimmune disease as an interferonopathy, the genetic evidence indicates that the pathology in mice is interferon-independent

Matrix metalloproteinase 9 contributes to gut microbe homeostasis in a model of infectious colitis

Abstract Background Inflammatory bowel diseases are associated with increased expression of zinc-dependent Matrix Metalloproteinase 9 (MMP-9). A stark dysregulation of intestinal mucosal homeostasis has been observed in patients with chronic inflammatory bowel diseases. We therefore sought to determine the contribution of MMP-9 to the pathogenesis of Citrobacter rodentium-induced colitis and its effects on gut microbiome homeostasis. Results Wild-type and MMP-9−/− mice aged 5–6 weeks were challenged with C. rodentium by orogastric gavage and sacrificed either 10 or 30 days post-infection. Disease severity was assessed by histological analysis of colonic epithelial hyperplasia and by using an in vivo intestinal permeability assay. Changes in the inflammatory responses were measured by using qPCR, and the composition of the fecal microbiome evaluated with both qPCR and terminal restriction fragment length polymorphism. Activation and localization of MMP-9 to the apical surface of the colonic epithelium in response to C. rodentium infection was demonstrated by both zymography and immunocytochemistry. The pro-inflammatory response to infection, including colonic epithelial cell hyperplasia and barrier dysfunction, was similar, irrespective of genotype. Nonmetric multidimensional scaling of terminal restriction fragments revealed a different fecal microbiome composition and C. rodentium colonization pattern between genotypes, with MMP-9−/− having elevated levels of protective segmented filamentous bacteria and interleukin-17, and lower levels of C. rodentium. MMP-9−/− but not wild-type mice were also protected from reductions in fecal microbial diversity in response to the bacterial enteric infection. Conclusions These results demonstrate that MMP-9 expression in the colon causes alterations in the fecal microbiome and has an impact on the pathogenesis of bacterial-induced colitis in mice

Matrix metalloproteinase 9 contributes to gut microbe homeostasis in a model of infectious colitis

Abstract Background Inflammatory bowel diseases are associated with increased expression of zinc-dependent Matrix Metalloproteinase 9 (MMP-9). A stark dysregulation of intestinal mucosal homeostasis has been observed in patients with chronic inflammatory bowel diseases. We therefore sought to determine the contribution of MMP-9 to the pathogenesis of Citrobacter rodentium-induced colitis and its effects on gut microbiome homeostasis. Results Wild-type and MMP-9−/− mice aged 5–6 weeks were challenged with C. rodentium by orogastric gavage and sacrificed either 10 or 30 days post-infection. Disease severity was assessed by histological analysis of colonic epithelial hyperplasia and by using an in vivo intestinal permeability assay. Changes in the inflammatory responses were measured by using qPCR, and the composition of the fecal microbiome evaluated with both qPCR and terminal restriction fragment length polymorphism. Activation and localization of MMP-9 to the apical surface of the colonic epithelium in response to C. rodentium infection was demonstrated by both zymography and immunocytochemistry. The pro-inflammatory response to infection, including colonic epithelial cell hyperplasia and barrier dysfunction, was similar, irrespective of genotype. Nonmetric multidimensional scaling of terminal restriction fragments revealed a different fecal microbiome composition and C. rodentium colonization pattern between genotypes, with MMP-9−/− having elevated levels of protective segmented filamentous bacteria and interleukin-17, and lower levels of C. rodentium. MMP-9−/− but not wild-type mice were also protected from reductions in fecal microbial diversity in response to the bacterial enteric infection. Conclusions These results demonstrate that MMP-9 expression in the colon causes alterations in the fecal microbiome and has an impact on the pathogenesis of bacterial-induced colitis in mice