Prevalence and diversity of type VI secretion systems in a model beneficial symbiosis

The type VI secretion system (T6SS) is widely distributed in diverse bacterial species and habitats where it is required for interbacterial competition and interactions with eukaryotic cells. Previous work described the role of a T6SS in the beneficial symbiont, Vibrio fischeri, during colonization of the light organ of Euprymna scolopes squid. However, the prevalence and diversity of T6SSs found within the distinct symbiotic structures of this model host have not yet been determined. Here, we analyzed 73 genomes of isolates from squid light organs and accessory nidamental glands (ANGs) and 178 reference genomes. We found that the majority of these bacterial symbionts encode diverse T6SSs from four distinct classes, and most share homology with T6SSs from more distantly related species, including pathogens of animals and humans. These findings indicate that T6SSs with shared evolutionary histories can be integrated into the cellular systems of host-associated bacteria with different effects on host health. Furthermore, we found that one T6SS in V. fischeri is located within a genomic island with high genomic plasticity. Five distinct genomic island genotypes were identified, suggesting this region encodes diverse functional potential that natural selection can act on. Finally, analysis of newly described T6SSs in roseobacter clade ANG isolates revealed a novel predicted protein that appears to be a fusion of the TssB-TssC sheath components. This work underscores the importance of studying T6SSs in diverse organisms and natural habitats to better understand how T6SSs promote the propagation of bacterial populations and impact host health

Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection.

Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed 'classic' features of apoptosis following exposure to pneumococci. Conversely, purified CD3(+) T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3(+) T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3(+) T-cells in PBMC cultures required 'classical' CD14(+) monocytes, which enhanced T-cell activation. CD3(+) T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3(+) T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease

Overview of systematic reviews of therapeutic ranges : methodologies and recommendations for practice

BACKGROUND: Many medicines are dosed to achieve a particular therapeutic range, and monitored using therapeutic drug monitoring (TDM). The evidence base for a therapeutic range can be evaluated using systematic reviews, to ensure it continues to reflect current indications, doses, routes and formulations, as well as updated adverse effect data. There is no consensus on the optimal methodology for systematic reviews of therapeutic ranges. METHODS: An overview of systematic reviews of therapeutic ranges was undertaken. The following databases were used: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts and Reviews of Effects (DARE) and MEDLINE. The published methodologies used when systematically reviewing the therapeutic range of a drug were analyzed. Step by step recommendations to optimize such systematic reviews are proposed. RESULTS: Ten systematic reviews that investigated the correlation between serum concentrations and clinical outcomes encompassing a variety of medicines and indications were assessed. There were significant variations in the methodologies used (including the search terms used, data extraction methods, assessment of bias, and statistical analyses undertaken). Therapeutic ranges should be population and indication specific and based on clinically relevant outcomes. Recommendations for future systematic reviews based on these findings have been developed. CONCLUSION: Evidence based therapeutic ranges have the potential to improve TDM practice. Current systematic reviews investigating therapeutic ranges have highly variable methodologies and there is no consensus of best practice when undertaking systematic reviews in this field. These recommendations meet a need not addressed by standard protocols

Surviving rectal cancer at the cost of a colostomy: global survey of long-term health-related quality of life in 10 countries

Background Colorectal cancer management may require an ostomy formation; however, a stoma may negatively impact health-related quality of life (HRQoL). This study aimed to compare generic and stoma-specific HRQoL in patients with a permanent colostomy after rectal cancer across different countries. Method A cross-sectional cohorts of patients with a colostomy after rectal cancer in Denmark, Sweden, Spain, the Netherlands, China, Portugal, Australia, Lithuania, Egypt, and Israel were invited to complete questionnaires regarding demographic and socioeconomic factors along with the Colostomy Impact (CI) score, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and five anchor questions assessing colostomy impact on HRQoL. The background characteristics of the cohorts from each country were compared and generic HRQoL was measured with the EORTC QLQ-C30 presented for the total cohort. Results were compared with normative data of reference European populations. The predictors of reduced HRQoL were investigated by multivariable logistic regression, including demographic and socioeconomic factors and stoma-related problems. Results A total of 2557 patients were included. Response rates varied between 51-93 per cent. Mean time from stoma creation was 2.5-6.2 (range 1.1-39.2) years. A total of 25.8 per cent of patients reported that their colostomy impairs their HRQoL 'some'/'a lot'. This group had significantly unfavourable scores across all EORTC subscales compared with patients reporting 'no'/'a little' impaired HRQoL. Generic HRQoL differed significantly between countries, but resembled the HRQoL of reference populations. Multivariable logistic regression showed that stoma dysfunction, including high CI score (OR 3.32), financial burden from the stoma (OR 1.98), unemployment (OR 2.74), being single/widowed (OR 1.35) and young age (OR 1.01 per year) predicted reduced stoma-related HRQoL. Conclusion Overall HRQoL is preserved in patients with a colostomy after rectal cancer, but a quarter of the patients interviewed reported impaired HRQoL. Differences among several countries were reported and socioeconomic factors correlated with reduced quality of life. In this global survey among 2557 individuals with a colostomy after rectal cancer, generic and stoma-specific HRQoL differed significantly between countries; however, it resembled that of country-specific population norms. The most important predictors of stoma-related reduced HRQoL were stoma dysfunction and being financially burdened by the colostomy

Communicating uncertainty - how Australian television reported H1N1 risk in 2009: a content analysis

<p>Abstract</p> <p>Background</p> <p>Health officials face particular challenges in communicating with the public about emerging infectious diseases of unknown severity such as the 2009 H1N1(swine 'flu) pandemic (pH1N1). Statements intended to create awareness and convey the seriousness of infectious disease threats can draw accusations of scare-mongering, while officials can be accused of complacency if such statements are not made. In these communication contexts, news journalists, often reliant on official sources to understand issues are pivotal in selecting and emphasising aspects of official discourse deemed sufficiently newsworthy to present to the public. This paper presents a case-study of news communication regarding the emergence of pH1N1.</p> <p>Methods</p> <p>We conducted a content analysis of all television news items about pH1N1. We examined news and current affairs items broadcast on 5 free-to-air Sydney television channels between April 25 2009 (the first report) and October 9 (prior to the vaccine release) for statements about <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> the seriousness of the disease <abbrgrp><abbr bid="B2">2</abbr></abbrgrp> how the public could minimise contagion <abbrgrp><abbr bid="B3">3</abbr></abbrgrp> government responses to emerging information.</p> <p>Results</p> <p>pH1N1 was the leading health story for eight of 24 weeks and was in the top 5 for 20 weeks. 353 news items were identified, yielding 3086 statements for analysis, with 63.4% related to the seriousness of the situation, 12.9% providing advice for viewers and 23.6% involving assurances from government. Coverage focused on infection/mortality rates, the spread of the virus, the need for public calm, the vulnerability of particular groups, direct and indirect advice for viewers, and government reassurances about effective management.</p> <p>Conclusions</p> <p>Overall, the reporting of 2009 pH1N1 in Sydney, Australia was generally non-alarmist, while conveying that pH1N1 was potentially serious. Daily infection rate tallies and commentary on changes in the pandemic alert level were seldom contextualised to assist viewers in understanding personal relevance. Suggestions are made about how future reporting of emerging infectious diseases could be enhanced.</p

A Research Agenda for Helminth Diseases of Humans: Towards Control and Elimination

Human helminthiases are of considerable public health importance in sub-Saharan Africa, Asia, and Latin America. The acknowledgement of the disease burden due to helminth infections, the availability of donated or affordable drugs that are mostly safe and moderately efficacious, and the implementation of viable mass drug administration (MDA) interventions have prompted the establishment of various large-scale control and elimination programmes. These programmes have benefited from improved epidemiological mapping of the infections, better understanding of the scope and limitations of currently available diagnostics and of the relationship between infection and morbidity, feasibility of community-directed or school-based interventions, and advances in the design of monitoring and evaluation (M&E) protocols. Considerable success has been achieved in reducing morbidity or suppressing transmission in a number of settings, whilst challenges remain in many others. Some of the obstacles include the lack of diagnostic tools appropriate to the changing requirements of ongoing interventions and elimination settings; the reliance on a handful of drugs about which not enough is known regarding modes of action, modes of resistance, and optimal dosage singly or in combination; the difficulties in sustaining adequate coverage and compliance in prolonged and/or integrated programmes; an incomplete understanding of the social, behavioural, and environmental determinants of infection; and last, but not least, very little investment in research and development (R&D). The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to undertake a comprehensive review of recent advances in helminthiases research, identify research gaps, and rank priorities for an R&D agenda for the control and elimination of these infections. This review presents the processes undertaken to identify and rank ten top research priorities; discusses the implications of realising these priorities in terms of their potential for improving global health and achieving the Millennium Development Goals (MDGs); outlines salient research funding needs; and introduces the series of reviews that follow in this PLoS Neglected Tropical Diseases collection, “A Research Agenda for Helminth Diseases of Humans.

Breast cancer prognostic classification in the molecular era: the role of histological grade

Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers. © 2010 BioMed Central Lt

A Research Agenda for Helminth Diseases of Humans: Social Ecology, Environmental Determinants, and Health Systems

In this paper, the Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), with the mandate to review helminthiases research and identify research priorities and gaps, focuses on the environmental, social, behavioural, and political determinants of human helminth infections and outlines a research and development agenda for the socioeconomic and health systems research required for the development of sustainable control programmes. Using Stockols' social-ecological approach, we describe the role of various social (poverty, policy, stigma, culture, and migration) and environmental determinants (the home environment, water resources development, and climate change) in the perpetuation of helminthic diseases, as well as their impact as contextual factors on health promotion interventions through both the regular and community-based health systems. We examine these interactions in regard to community participation, intersectoral collaboration, gender, and possibilities for upscaling helminthic disease control and elimination programmes within the context of integrated and interdisciplinary approaches. The research agenda summarises major gaps that need to be addressed

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms