The endoscopist and malignant and non-malignant biliary obstruction

Patients with biliary strictures often represent a diagnostic and therapeutic challenge, due to the site and complexity of biliary obstruction and wide differential diagnosis. Multidisciplinary decision making is required to reach an accurate and timely diagnosis and to plan optimal care. Developments in endoscopic ultrasound and peroral cholangioscopy have advanced the diagnostic yield of biliary endoscopy, and novel optical imaging techniques are emerging. Endoscopic approaches to biliary drainage are preferred in most scenarios, and recent advances in therapeutic endoscopic ultrasound allow drainage where the previous alternatives were only percutaneous or surgical. Here we review recent advances in endoscopic practice for the diagnosis and management of biliary strictures. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.     

The response of previously irradiated skin to combinations of X radiation and ultrasound-induced hyperthermia

Areas of skin approximately 1.5 cm in diameter on the legs of mice were made hyperthermic (30 min at 42.7 degrees C) by exposure to an ultrasound beam (780 kHz), a single dose of X irradiation (2000 rad), or a combination of these treatments. After 35 days, when the acute reaction had reached a steady state, the same tissue was given a second treatment by either hyperthermia, irradiation, or a combination of hyperthermia and irradiation. When the first treatment was irradiation and the second treatment was either irradiation or a combination of hyperthermia and irradiation, the acute skin reactions were similar to those of skin not previously irradiated, indicating a large proportion of recovery from the first irradiation. When irradiation was the first treatment, a comparison of second treatments by hyperthermia plus irradiation with irradiation alone showed a thermal enhancement of 1.45. When the first treatment was hyperthermia plus irradiation, a comparison of second treatments by hyperthermia plus irradiation with irradiation also showed an enhancement factor of 1.45 for the combined treatment.     

The Carbocyclic Analogue of 5-(1-Propenyl)-2′-Deoxyuridine; Synthesis and Anti-Herpes Activity

Abstract

The title compound was synthesised and tested against HSV-1 in cell culture. Like related compounds, it was less active than the parent nucleoside.     

Neurobiological consequences of acute footshock stress: effects on tyrosine hydroxylase phosphorylation and activation in the rat brain and adrenal medulla

Stress activates selected neuronal systems in the brain and this leads to activation of a range of effector systems. Our aim was to investigate some of the relationships between these systems under basal conditions and over a 40‐min period in response to footshock stress. Specifically, we investigated catecholaminergic neurons in the locus coeruleus (LC), ventral tegmental area and medial prefrontal cortex (mPFC) in the brain, by measuring tyrosine hydroxylase (TH) protein, TH phosphorylation and TH activation. We also measured the effector responses by measuring plasma adrenocorticotrophic hormone, corticosterone, glucose and body temperature as well as activation of adrenal medulla protein kinases, TH protein, TH phosphorylation and TH activation. The LC, ventral tegmental area and adrenal medulla all had higher basal levels of Ser19 phosphorylation and lower basal levels of Ser31 phosphorylation than the mPFC, presumably because of their cell body versus nerve terminal location, while the adrenal medulla had the highest basal levels of Ser40 phosphorylation. Ser31 phosphorylation was increased in the LC at 20 and 40 min and in the mPFC at 40 min; TH activity was increased at 40 min in both tissues. There were significant increases in body temperature between 10 and 40 min, as well as increases in plasma adrenocorticotropic hormone at 20 min and corticosterone and glucose at 20 and 40 min. The adrenal medulla extracellular signal‐regulated kinase 2 was increased between 10 and 40 min and Ser31 phosphorylation was increased at 20 min and 40 min. Protein kinase A and Ser40 phosphorylation were increased only at 40 min. TH activity was increased between 20 and 40 min. TH protein and Ser19 phosphorylation levels were not altered in any of the brain regions or adrenal medulla over the first 40 min. These findings indicate that acute footshock stress leads to activation of TH in the LC, pre‐synaptic terminals in the mPFC and adrenal medullary chromaffin cells, as well as changes in activity of the hypothalamic‐pituitary‐adrenal axis.

     

Multiple factors interact to produce responses resembling spectrum of human disease in Campylobacter jejuni infected C57BL/6 IL-10-/- mice

Background  

Campylobacter jejuni infection produces a spectrum of clinical presentations in humans - including asymptomatic carriage, watery diarrhea, and bloody diarrhea - and has been epidemiologically associated with subsequent autoimmune neuropathies. This microorganism is genetically variable and possesses genetic mechanisms that may contribute to variability in nature. However, relationships between genetic variation in the pathogen and variation in disease manifestation in the host are not understood. We took a comparative experimental approach to explore differences among different C. jejuni strains and studied the effect of diet on disease manifestation in an interleukin-10 deficient mouse model.     

Interfering ribonucleic acids that suppress expression of multiple unrelated genes

Background  

Short interfering RNAs (siRNAs) have become the research tool of choice for gene suppression, with human clinical trials ongoing. The emphasis so far in siRNA therapeutics has been the design of one siRNA with complete complementarity to the intended target. However, there is a need for multi-targeting interfering RNA in diseases in which multiple gene products are of importance. We have investigated the possibility of using a single short synthetic duplex RNA to suppress the expression of VEGF-A and ICAM-1; genes implicated in the progression of ocular neovascular diseases such as diabetic retinopathy.     

Combining spatial-temporal and phylogenetic analysis approaches for improved understanding on global H5N1 transmission

Background

Since late 2003, the highly pathogenic influenza A H5N1 had initiated several outbreak waves that swept across the Eurasia and Africa continents. Getting prepared for reassortment or mutation of H5N1 viruses has become a global priority. Although the spreading mechanism of H5N1 has been studied from different perspectives, its main transmission agents and spread route problems remain unsolved.

Methodology/Principal Findings

Based on a compilation of the time and location of global H5N1 outbreaks from November 2003 to December 2006, we report an interdisciplinary effort that combines the geospatial informatics approach with a bioinformatics approach to form an improved understanding on the transmission mechanisms of H5N1 virus. Through a spherical coordinate based analysis, which is not conventionally done in geographical analyses, we reveal obvious spatial and temporal clusters of global H5N1 cases on different scales, which we consider to be associated with two different transmission modes of H5N1 viruses. Then through an interdisciplinary study of both geographic and phylogenetic analysis, we obtain a H5N1 spreading route map. Our results provide insight on competing hypotheses as to which avian hosts are responsible for the spread of H5N1.

Conclusions/Significance

We found that although South China and Southeast Asia may be the virus pool of avian flu, East Siberia may be the source of the H5N1 epidemic. The concentration of migratory birds from different places increases the possibility of gene mutation. Special attention should be paid to East Siberia, Middle Siberia and South China for improved surveillance of H5N1 viruses and monitoring of migratory birds.     

Proteomic and computational analysis of secreted proteins with type I signal peptides from the Antarctic archaeon Methanococcoides burtonii

LC-MS/MS was used to identify secreted proteins in the Antarctic archaeon Methanococcoides burtonii. Seven proteins possessing a classical class 1 signal peptide were identified in the supernatant from cultures grown at 4 and 23 degrees C. The proteins included a putative S-layer cell surface protein, cell surface protein involved with cell adhesion, and trypsin-like serine protease. Protease activity was detected in the secreted fraction, and the signal peptide cleavage site of the protease was confirmed using Edman sequencing. The expression profile of putative cell surface proteins suggests a requirement for cell interactions during growth at low temperature. Sequences of the secreted proteins were used to compile a dataset containing a further 32 predicted secreted proteins from the Methanosarcinaceae. Many of these proteins were also S-layer cell surface proteins with a variety of predicted roles, particularly in cell-cell interaction. Computational analysis of signal peptides revealed a preference for lysine in the n-region, leucine in the h-region, and a eucaryal-type cleavage site, highlighting the mosaic nature of signal peptides in Archaea. This is the first study to experimentally characterize secreted proteins from a cold-adapted archaeon and provides new insight and a functional dataset for studying secretion in Archaea.