Phylogeography of Japanese encephalitis virus:genotype is associated with climate

The circulation of vector-borne zoonotic viruses is largely determined by the overlap in the geographical distributions of virus-competent vectors and reservoir hosts. What is less clear are the factors influencing the distribution of virus-specific lineages. Japanese encephalitis virus (JEV) is the most important etiologic agent of epidemic encephalitis worldwide, and is primarily maintained between vertebrate reservoir hosts (avian and swine) and culicine mosquitoes. There are five genotypes of JEV: GI-V. In recent years, GI has displaced GIII as the dominant JEV genotype and GV has re-emerged after almost 60 years of undetected virus circulation. JEV is found throughout most of Asia, extending from maritime Siberia in the north to Australia in the south, and as far as Pakistan to the west and Saipan to the east. Transmission of JEV in temperate zones is epidemic with the majority of cases occurring in summer months, while transmission in tropical zones is endemic and occurs year-round at lower rates. To test the hypothesis that viruses circulating in these two geographical zones are genetically distinct, we applied Bayesian phylogeographic, categorical data analysis and phylogeny-trait association test techniques to the largest JEV dataset compiled to date, representing the envelope (E) gene of 487 isolates collected from 12 countries over 75 years. We demonstrated that GIII and the recently emerged GI-b are temperate genotypes likely maintained year-round in northern latitudes, while GI-a and GII are tropical genotypes likely maintained primarily through mosquito-avian and mosquito-swine transmission cycles. This study represents a new paradigm directly linking viral molecular evolution and climate

Organizational factors and depression management in community-based primary care settings

Abstract Background Evidence-based quality improvement models for depression have not been fully implemented in routine primary care settings. To date, few studies have examined the organizational factors associated with depression management in real-world primary care practice. To successfully implement quality improvement models for depression, there must be a better understanding of the relevant organizational structure and processes of the primary care setting. The objective of this study is to describe these organizational features of routine primary care practice, and the organization of depression care, using survey questions derived from an evidence-based framework. Methods We used this framework to implement a survey of 27 practices comprised of 49 unique offices within a large primary care practice network in western Pennsylvania. Survey questions addressed practice structure (e.g., human resources, leadership, information technology (IT) infrastructure, and external incentives) and process features (e.g., staff performance, degree of integrated depression care, and IT performance). Results The results of our survey demonstrated substantial variation across the practice network of organizational factors pertinent to implementation of evidence-based depression management. Notably, quality improvement capability and IT infrastructure were widespread, but specific application to depression care differed between practices, as did coordination and communication tasks surrounding depression treatment. Conclusions The primary care practices in the network that we surveyed are at differing stages in their organization and implementation of evidence-based depression management. Practical surveys such as this may serve to better direct implementation of these quality improvement strategies for depression by improving understanding of the organizational barriers and facilitators that exist within both practices and practice networks. In addition, survey information can inform efforts of individual primary care practices in customizing intervention strategies to improve depression management.http://deepblue.lib.umich.edu/bitstream/2027.42/78269/1/1748-5908-4-84.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/2/1748-5908-4-84-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/3/1748-5908-4-84.pdfPeer Reviewe

Examination of the Cytotoxic and Embryotoxic Potential and Underlying Mechanisms of Next-Generation Synthetic Trioxolane and Tetraoxane Antimalarials

Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria

Perforated Meckel's diverticulum presenting with combined bowel and urinary obstruction and mimicking Crohn's disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>Meckel's diverticulum is a common congenital anomaly of the gastrointestinal tract, but is an uncommon cause of serious complications in adults. Although cases of patients with hemorrhage, bowel obstruction or perforation associated with Meckel's diverticulum have been reported, there have been no prior reports of patients with combined urinary and bowel obstruction due to abscess formation.</p> <p>Case presentation</p> <p>We describe the case of a 21-year-old man with a history of recurrent papillary thyroid cancer, but no prior abdominal surgeries, who presented with a one-month history of rectal pain and new-onset obstipation with urinary retention. He reported night sweats and weight loss, and had a second-degree relative with known Crohn's disease. A digital rectal examination was notable and revealed marked tenderness with proximal induration. A computed tomography scan of the patient's abdomen revealed a large, complex, circumferential perirectal abscess compressing the rectal lumen and base of the urinary bladder, associated with terminal ileal thickening and an ileocecal fistula. A flexible sigmoidoscopy with an endorectal ultrasound scan displayed a complex abscess with extensive mucosal and surrounding inflammation. An exploratory laparotomy revealed a Meckel's diverticulum with a large perforation at its base, positioned near the ileocecal fistula and immediately superior to the perirectal abscess. The section of small bowel containing the Meckel's diverticulum, the terminal ileum, and the cecum, were all resected, and the abscess was debrided.</p> <p>Conclusions</p> <p>Pre-operative diagnosis of Meckel's diverticulum can be difficult. If the nature of the complication makes ultimate surgical management likely, an early laparoscopic or open exploration should be performed to prevent the morbidity and mortality associated with late complications.</p

Functional Substitution by TAT-Utrophin in Dystrophin-Deficient Mice

James Ervasti and colleagues show that injection of a truncated form of utrophin transduced all tissues examined, integrated with members of the dystrophin complex, and reduced serum levels of creatine kinase in a mouse model of muscular dystrophy

Identification of epitopes recognised by mucosal CD4+ T-cell populations from cattle experimentally colonised with Escherichia coli O157:H7

Additional file 5. Sequence alignment of Intimin epitopes against Intimin sequences from non-O157 EHEC serotypes. Alignment of Intimin CD4+ T-cell epitope sequences with representative Intimin sequences from EHEC serotypes O145, O127, O26, O103, O121, O45 and O111. Percentage values indicate % similarity to the EHEC O157:H7 reference sequence

Development of the Bi-Partite Gal4-UAS System in the African Malaria Mosquito, Anopheles gambiae

Functional genetic analysis in Anopheles gambiae would be greatly improved by the development of a binary expression system, which would allow the more rapid and flexible characterisation of genes influencing disease transmission, including those involved in insecticide resistance, parasite interaction, host and mate seeking behaviour. The Gal4-UAS system, widely used in Drosophila melanogaster functional genetics, has been significantly modified to achieve robust application in several different species. Towards this end, previous work generated a series of modified Gal4 constructs that were up to 20 fold more active than the native gene in An. gambiae cells. To examine the Gal4-UAS system in vivo, transgenic An. gambiae driver lines carrying a modified Gal4 gene under the control of the carboxypeptidase promoter, and responder lines carrying UAS regulated luciferase and eYFP reporter genes have been created. Crossing of the Gal4 and UAS lines resulted in progeny that expressed both reporters in the expected midgut specific pattern. Although there was minor variation in reporter gene activity between the different crosses examined, the tissue specific expression pattern was consistent regardless of the genomic location of the transgene cassettes. The results show that the modified Gal4-UAS system can be used to successfully activate expression of transgenes in a robust and tissue specific manner in Anopheles gambiae. The midgut driver and dual reporter responder constructs are the first to be developed and tested successfully in transgenic An. gambiae and provide the basis for further advancement of the system in this and other insect species

Asthma-susceptibility variants identified using probands in case-control and family-based analyses

<p>Abstract</p> <p>Background</p> <p>Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs.</p> <p>Methods</p> <p>We used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study designs: (1) probands were combined with publicly available population controls in a case-control design, and (2) probands and their parents were used in a family-based design. We followed a two-stage replication process utilizing three independent populations to validate our primary findings.</p> <p>Results</p> <p>We found that single nucleotide polymorphisms with similar case-control and family-based association results were more likely to replicate in the independent populations, than those with the smallest p-values in either the case-control or family-based design alone. The single nucleotide polymorphism that showed the strongest evidence for association to asthma was rs17572584, which replicated in 2/3 independent populations with an overall p-value among replication populations of 3.5E-05. This variant is near a gene that encodes an enzyme that has been implicated to act coordinately with modulators of Th2 cell differentiation and is expressed in human lung.</p> <p>Conclusions</p> <p>Our results suggest that using probands from family-based studies in case-control designs, and combining results of both family-based and case-control approaches, may be a way to augment our ability to find SNPs associated with asthma and other complex diseases.</p

A comprehensive resequence analysis of the KLK15–KLK3–KLK2 locus on chromosome 19q13.33

Single nucleotide polymorphisms (SNPs) in the KLK3 gene on chromosome 19q13.33 are associated with serum prostate-specific antigen (PSA) levels. Recent genome wide association studies of prostate cancer have yielded conflicting results for association of the same SNPs with prostate cancer risk. Since the KLK3 gene encodes the PSA protein that forms the basis for a widely used screening test for prostate cancer, it is critical to fully characterize genetic variation in this region and assess its relationship with the risk of prostate cancer. We have conducted a next-generation sequence analysis in 78 individuals of European ancestry to characterize common (minor allele frequency, MAF >1%) genetic variation in a 56 kb region on chromosome 19q13.33 centered on the KLK3 gene (chr19:56,019,829–56,076,043 bps). We identified 555 polymorphic loci in the process including 116 novel SNPs and 182 novel insertion/deletion polymorphisms (indels). Based on tagging analysis, 144 loci are necessary to tag the region at an r2 threshold of 0.8 and MAF of 1% or higher, while 86 loci are required to tag the region at an r2 threshold of 0.8 and MAF >5%. Our sequence data augments coverage by 35 and 78% as compared to variants in dbSNP and HapMap, respectively. We observed six non-synonymous amino acid or frame shift changes in the KLK3 gene and three changes in each of the neighboring genes, KLK15 and KLK2. Our study has generated a detailed map of common genetic variation in the genomic region surrounding the KLK3 gene, which should be useful for fine-mapping the association signal as well as determining the contribution of this locus to prostate cancer risk and/or regulation of PSA expression