Persistence of two genotypes of Neisseria gonorrhoeae during transmission.

Isolates of Neisseria gonorrhoeae were tested using a highly discriminatory typing method, opa typing, to examine the genetic diversity over a 2-year study period of isolates from all consecutive patients with gonorrhea attending the Genitourinary Medicine clinic in Sheffield, United Kingdom. Two opa genotypes were detected throughout the 2-year time period and comprised 41% of all strains tested. The persistence of two opa types was investigated further to determine the apparent genetic stability, by examining the ability of isolates to undergo intragenic and intergenic recombination and mutation in vitro. Intragenic recombination or mutation involving the opa genes of N. gonorrhoeae in the selected isolates was not detected, but intergenic recombination did occur. opa genes of N. gonorrhoeae in vivo appear to diversify primarily through intergenic recombination. Intergenic recombination in vivo would require the presence of a mixed gonococcal infection, in which an individual is concurrently colonized with more than one strain of N. gonorrhoeae. We propose that the level of diversity of opa genotypes in a population is linked to the degree of sexual mixing of individuals and the incidence of mixed infections of N. gonorrhoeae

Characterization of pathogenic germline mutations in human Protein Kinases

Background: Protein Kinases are a superfamily of proteins involved in crucial cellular processes such as cell cycle regulation and signal transduction. Accordingly, they play an important role in cancer biology. To contribute to the study of the relation between kinases and disease we compared pathogenic mutations to neutral mutations as an extension to our previous analysis of cancer somatic mutations. First, we analyzed native and mutant proteins in terms of amino acid composition. Secondly, mutations were characterized according to their potential structural effects and finally, we assessed the location of the different classes of polymorphisms with respect to kinase-relevant positions in terms of subfamily specificity, conservation, accessibility and functional sites.Results: Pathogenic Protein Kinase mutations perturb essential aspects of protein function, including disruption of substrate binding and/or effector recognition at family-specific positions. Interestingly these mutations in Protein Kinases display a tendency to avoid structurally relevant positions, what represents a significant difference with respect to the average distribution of pathogenic mutations in other protein families.Conclusions: Disease-associated mutations display sound differences with respect to neutral mutations: several amino acids are specific of each mutation type, different structural properties characterize each class and the distribution of pathogenic mutations within the consensus structure of the Protein Kinase domain is substantially different to that for non-pathogenic mutations. This preferential distribution confirms previous observations about the functional and structural distribution of the controversial cancer driver and passenger somatic mutations and their use as a proxy for the study of the involvement of somatic mutations in cancer development. © 2011 Izarzugaza et al; licensee BioMed Central Ltd

Pathophysiology, diagnosis and treatment of tachycardiomyopathy.

Tachycardiomyopathies (TCMP) are an important cause of left ventricular (LV) dysfunction that should be recognised by physicians as they are potentially reversible and have a significant impact on morbidity and prognosis. They are classically defined as the reversible impairment of ventricular function induced by persistent arrhythmia. However, it is becoming increasingly evident that they can be induced by atrial and ventricular ectopy promoting dyssynchrony and indeed the term ‘arrhythmia-induced cardiomyopathy’ is emerging to describe the phenomenon.1 2 A more current proposed definition highlights aetiology: ‘Atrial and/or ventricular dysfunction—secondary to rapid and/or asynchronous/irregular myocardial contraction, partially or completely reversed after treatment of the causative arrhythmia’ 3 (figure 1). Two categories of the condition exist: the arrhythmia is the only reason for ventricular dysfunction (arrhythmia-induced), and another where the arrhythmia exacerbates ventricular dysfunction and/or worsens heart failure (HF) in a patient with concomitant heart disease (arrhythmia-mediated).4 The exclusion of underlying structural heart disease can be challenging as current imaging techniques, for example, MRI cannot easily identify diffuse fibrosis which may itself be primary or secondary to the effects of arrhythmia promoting ventricular wall dyskinesis and stretch or valvular regurgitation

VIDA: a virus database system for the organization of animal virus genome open reading frames

VIDA is a new virus database that organizes open reading frames (ORFs) from partial and complete genomic sequences from animal viruses. Currently VIDA includes all sequences from GenBank for Herpesviridae, Coronaviridae and Arteriviridae. The ORFs are organized into homologous protein families, which are identified on the basis of sequence similarity relationships, Conserved sequence regions of potential functional importance are identified and can be retrieved as sequence alignments. We use a controlled taxonomical and functional classification for all the proteins and protein families in the database. When available, protein structures that are related to the families have also been included. The database is available for online search and sequence information retrieval at http://www.biochem.ucl.ac.uk/bsm/virus-database/ VIDA.html

An integrated approach to the interpretation of Single Amino Acid Polymorphisms within the framework of CATH and Gene3D

Background: The phenotypic effects of sequence variations in protein-coding regions come about primarily via their effects on the resulting structures, for example by disrupting active sites or affecting structural stability. In order better to understand the mechanisms behind known mutant phenotypes, and predict the effects of novel variations, biologists need tools to gauge the impacts of DNA mutations in terms of their structural manifestation. Although many mutations occur within domains whose structure has been solved, many more occur within genes whose protein products have not been structurally characterized.Results: Here we present 3DSim (3D Structural Implication of Mutations), a database and web application facilitating the localization and visualization of single amino acid polymorphisms (SAAPs) mapped to protein structures even where the structure of the protein of interest is unknown. The server displays information on 6514 point mutations, 4865 of them known to be associated with disease. These polymorphisms are drawn from SAAPdb, which aggregates data from various sources including dbSNP and several pathogenic mutation databases. While the SAAPdb interface displays mutations on known structures, 3DSim projects mutations onto known sequence domains in Gene3D. This resource contains sequences annotated with domains predicted to belong to structural families in the CATH database. Mappings between domain sequences in Gene3D and known structures in CATH are obtained using a MUSCLE alignment. 1210 three-dimensional structures corresponding to CATH structural domains are currently included in 3DSim; these domains are distributed across 396 CATH superfamilies, and provide a comprehensive overview of the distribution of mutations in structural space.Conclusion: The server is publicly available at http://3DSim.bioinfo.cnio.es/. In addition, the database containing the mapping between SAAPdb, Gene3D and CATH is available on request and most of the functionality is available through programmatic web service access

Syncope in a young man: Role of Purkinje fibres in idiopathic ventricular fibrillation

A young man suffered cardiac arrests with polymorphic ventricular tachycardia (PVT) and ventricular fibrillation (VF) triggered by ventricular premature contractions (PVCs). The arrhythmia was resistant to anti-arrhythmics, so after ICD implantation he underwent successful ablation of the triggering VE beat, which was pace-mapped to the left posterior hemi-fascicle. We review the evidence for the role of the Purkinje network in the initiation and maintenance of PVT and VF, postulating a channelopathy as a possible underlying cause, and provide recommendations for PVC ablation

Health information needs, source preferences and engagement behaviours of women with metastatic breast cancer across the care continuum: protocol for a scoping review

INTRODUCTION: The health information needs, information source preferences and engagement behaviours of women with metastatic breast cancer (mBC) depend on personal characteristics such as education level, prior knowledge, clinical complications, comorbidities and where they are in the cancer journey. A thorough understanding of the information behaviours of women living with mBC is essential to the provision of optimal care. A preliminary literature review suggests that there is little research on this topic, but that there may be lessons from a slightly broader literature. This review will identify what is known and what is not known about the health information needs, acquisition and influences of women with mBC across the care continuum. Findings will help to identify research needs and specific areas where in-depth systematic reviews may be feasible, as well as inform evidence-based interventions to address the health information needs of female patients with mBC with different demographics and characteristics and across the mBC journey. METHODS AND ANALYSIS: A scoping review will be performed using the guidelines of Arksey and O'Malley as updated by subsequent authors to systematically search scientific and grey literature for articles in English that discuss the health information needs, source preferences, engagement styles, and associated personal and medical attributes of women ≥18 years living with mBC at different stages of the disease course. A variety of databases (including Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Excerpta Medica Database (EMBASE), Academic Search Premier, Cochrane Database of Systematic Reviews, PsycINFO, Health Source: Nursing/Academic Edition, and PQDT Open), oncology, patient advocacy and governmental websites will be searched from inception to present day. Research and non-research literature will be included; no study designs will be excluded. The six-stage Arksey and O'Malley scoping review methodological framework involves: (1) identifying the research question; (2) searching for relevant studies; (3) selecting studies; (4) charting the data; (5) collating, summarising and reporting the results; and (6) consulting with stakeholders to inform or validate study findings (optional). Data will be extracted and analysed using a thematic chart and descriptive content analysis. ETHICS AND DISSEMINATION: Being a secondary analysis, this research will not require ethics approval. Results will be disseminated through patient support organisations and websites and publications targeting healthcare professionals, advocates and patients

Global oceanic emission of ammonia: constraints from seawater and atmospheric observations

Current global inventories of ammonia emissions identify the ocean as the largest natural source. This source depends on seawater pH, temperature, and the concentration of total seawater ammonia (NHx(sw)), which reflects a balance between remineralization of organic matter, uptake by plankton, and nitrification. Here we compare [NHx(sw)] from two global ocean biogeochemical models (BEC and COBALT) against extensive ocean observations. Simulated [NHx(sw)] are generally biased high. Improved simulation can be achieved in COBALT by increasing the plankton affinity for NHx within observed ranges. The resulting global ocean emissions is 2.5 TgN a−1, much lower than current literature values (7–23 TgN a−1), including the widely used Global Emissions InitiAtive (GEIA) inventory (8 TgN a−1). Such a weak ocean source implies that continental sources contribute more than half of atmospheric NHx over most of the ocean in the Northern Hemisphere. Ammonia emitted from oceanic sources is insufficient to neutralize sulfate aerosol acidity, consistent with observations. There is evidence over the Equatorial Pacific for a missing source of atmospheric ammonia that could be due to photolysis of marine organic nitrogen at the ocean surface or in the atmosphere. Accommodating this possible missing source yields a global ocean emission of ammonia in the range 2–5 TgN a−1, comparable in magnitude to other natural sources from open fires and soils

In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine.

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3-fold and >2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo

Application of knowledge-driven spatial modelling approaches and uncertainty management to a study of Rift Valley fever in Africa

BACKGROUND: There are few studies that have investigated uncertainties surrounding the scientific community's knowledge of the geographical distribution of major animal diseases. This is particularly relevant to Rift Valley fever (RVF), a zoonotic disease causing destructive outbreaks in livestock and man, as the geographical range of the disease is widening to involve previously unaffected regions. In the current study we investigate the application of methods developed in the decision sciences: multiple criteria decision making using weighted linear combination and ordered weighted averages, and Dempster-Shafer theory, implemented within the geographical information system IDRISI, to obtain a greater understanding of uncertainty related to the geographical distribution of RVF. The focus is on presenting alternate methods where extensive field data are not available and traditional, model-based approaches to disease mapping are impossible to conduct. RESULTS: Using a compensatory multiple criteria decision making model based on weighted linear combination, most of sub-Saharan Africa was suitable for endemic circulation of RVF. In contrast, areas where rivers and lakes traversed semi-arid regions, such as those bordering the Sahara, were highly suitable for RVF epidemics and wet, tropical areas of central Africa had low suitability. Using a moderately non-compensatory model based on ordered weighted averages, the areas considered suitable for endemic and epidemic RVF were more restricted. Varying the relative weights of the different factors in the models did not affect suitability estimates to a large degree, but variations in model structure had a large impact on our suitability estimates. Our Dempster-Shafer analysis supported the belief that a range of semi-arid areas were suitable for RVF epidemics and the plausibility that many other areas of the continent were suitable. Areas where high levels of uncertainty were highlighted included the Ethiopian Highlands, southwest Kenya and parts of West Africa. CONCLUSION: We have demonstrated the potential of methods developed in the decision sciences to improve our understanding of uncertainties surrounding the geographical distribution of animal diseases, particularly where information is sparse, and encourage wider application of the decision science methodology in the field of animal health