Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver.

The liver and pancreas share a common origin and coexpress several transcription factors. To gain insight into the transcriptional networks regulating the function of these tissues, we globally identify binding sites for FOXA2 in adult mouse islets and liver, PDX1 in islets, and HNF4A in liver. Because most eukaryotic transcription factors bind thousands of loci, many of which are thought to be inactive, methods that can discriminate functionally active binding events are essential for the interpretation of genome-wide transcription factor binding data. To develop such a method, we also generated genome-wide H3K4me1 and H3K4me3 localization data in these tissues. By analyzing our binding and histone methylation data in combination with comprehensive gene expression data, we show that H3K4me1 enrichment profiles discriminate transcription factor occupied loci into three classes: those that are functionally active, those that are poised for activation, and those that reflect pioneer-like transcription factor activity. Furthermore, we demonstrate that the regulated presence of H3K4me1-marked nucleosomes at transcription factor occupied promoters and enhancers controls their activity, implicating both tissue-specific transcription factor binding and nucleosome remodeling complex recruitment in determining tissue-specific gene expression. Finally, we apply these approaches to generate novel insights into how FOXA2, PDX1, and HNF4A cooperate to drive islet- and liver-specific gene expression.

A literature review of interprofessional working and intermediate care in the UK.

AIMS AND OBJECTIVES: This systematic literature review aimed at addressing two questions: first, what evidence exists regarding intermediate care in the UK; and what interventions have been used to develop interprofessional working in intermediate care in the UK? A systematic review of the literature from 2000-2006 resulted in a total of 104 full-text articles describing research into intermediate care in the UK. BACKGROUND: The review was the first stage of a large, national project evaluating and developing interprofessional working among health and social care staff, particularly in relation to the intermediate care of older people. DESIGN: Systematic literature review. METHODS: All the literature was reviewed by one reviewer, and a second review was carried out by a team of reviewers to ensure each article was reviewed twice, independently. One article was reviewed by all the reviewers to ensure inter-rater reliability; finally, all the reviews were amalgamated, which resulted in one summary per article. RESULTS: The main findings drawn from this systematic literature review are that research carried out on intermediate care in the UK has a diverse set of aims, for example economic evaluations, delivery of intermediate care and exploring the views and perceptions of those involved in intermediate care. CONCLUSIONS: Although several articles include discussions about the importance of interprofessional working in intermediate care, no article specifically focused on the interprofessional focus of intermediate care, and there was no research about interventions used to develop interprofessional working. RELEVANCE TO CLINICAL PRACTICE: Intermediate care as a policy has been interpreted very differently across the four countries of the UK; there is no one preferred or consistent interpretation to its delivery.

Expression of Groucho/TLE proteins during pancreas development.

BACKGROUND: The full-length mammalian homologs of groucho, Tle1, 2, 3, and 4, act as transcriptional corepressors and are recruited by transcription factors containing an eh1 or WRPW/Y domain. Many transcription factors critical to pancreas development contain a Gro/TLE interaction domain and several have been shown to require Gro/TLE interactions for proper function during neuronal development. However, a detailed analysis of the expression patterns of the Gro/TLE proteins in pancreas development has not been performed. Moreover, little is known about the ability of Gro/TLE proteins to interact with transcription factors in the pancreas. RESULTS: We describe the expression of Gro/TLE family members, and of 34 different transcription factors that contain a Gro/TLE interaction motif, in the pancreas utilizing nine SAGE libraries created from the developing and adult pancreas, as well as the GenePaint database. Next, we show the dynamic expression of Tle1, 2, 3, 4, 5 and 6 during pancreas development by qRT-PCR. To further define the cell-type specificity of the expression of these proteins we use immunofluorescence to co-localize them with Pdx1 at embryonic day 12.5 (E12.5), Ngn3 at E14.5, Pdx1, Nkx2-2, Insulin, Glucagon, Pancreatic polypeptide and Somatostatin at E18.5, as well as Insulin and Glucagon in the adult. We then show that Tle2 can interact with Nkx2-2, Hes1, Arx, and Nkx6-1 which are all critical factors in pancreas development. Finally, we demonstrate that Tle2 modulates the repressive abilities of Arx in a beta-cell line. CONCLUSION: Although Tle1, 2, 3, and 4 show overlapping expression in pancreatic progenitors and in the adult islet, the expression of these factors is restricted to different cell types during endocrine cell maturation. Of note, Tle2 and Tle3 are co-expressed with Gro/TLE interaction domain containing transcription factors that are essential for endocrine pancreas development. We further demonstrate that Tle2 can interact with several of these factors and that Tle2 modulate Arx's repressive activity. Taken together our studies suggest that Gro/TLE proteins play a role in the repression of target genes during endocrine cell specification.

Ultrasound-guided musculocutaneous nerve block: a description of a novel technique.

BACKGROUND AND OBJECTIVE: Localizing the musculocutaneous nerve for neural blockade is crucial to providing surgical anesthesia for the distal forearm. We present a novel approach for localizing and anesthetizing the musculocutaneous nerve. CASE REPORTS: Ten patients underwent successful ultrasound-guided musculocutaneous nerve blocks. In this technique, either a 10-MHz or a 12-MHz linear probe was placed at the junction of the pectoralis major muscle and the biceps muscle such that the axillary artery was visualized in cross section. The probe was moved towards the biceps muscle until the musculocutaneous nerve was visualized lying between the coracobrachialis and biceps muscles. A 22-gauge, 50-mm b-bevel needle was inserted under direct vision until the needle was adjacent to the nerve. Local anesthetic was then injected, which generated surgical anesthetic conditions in all patients. CONCLUSION: Ultrasound can facilitate the localization and local anesthetic block of the musculocutaneous nerve.

Modifying exposure to smoking depicted in movies: a novel approach to preventing adolescent smoking.

BACKGROUND: Most behavioral approaches to adolescent smoking address the behavior directly. We explore an indirect approach: modifying exposure to portrayals of smoking in movies. OBJECTIVES: To describe adolescents' exposure to smoking in movies and to examine factors that could modify such exposure. DESIGN: Occurrences of smoking were counted in each of 601 popular movies. Four thousand nine hundred ten northern New England junior high school students were asked to report which movies they had seen from a randomly generated subsample of 50 films, and responses were used to estimate exposure to the entire sample. Analysis The outcome variable was exposure to movie smoking, defined as the number of smoking occurrences seen. Risk factors for exposure included access to movies (movie channels, videotape use, and movie theater); parenting (R [restricted]-rated movie restrictions, television restrictions, parenting style); and characteristics of the child (age, sex, school performance, sensation-seeking propensity, rebelliousness, and self-esteem). We used multiple regression to assess the association between risk factors and exposure to movie smoking. RESULTS: Subjects had seen an average of 30% of the movie sample (interquartile range, 20%-44%), from which they were exposed to 1160 (interquartile range, 640-1970) occurrences of smoking. In a multivariate model, exposure to movie smoking increased (all P values <.001) by about 10% for each additional movie channel and for every 2 videos watched per week. Exposure increased by 30% for those going to the movie theater more than once per month compared with those who did not go at all. Parent restriction on viewing R-rated movies resulted in a 50% reduction in exposure to movie smoking. There was no association between parenting style and exposure to movie smoking. Much of the protective effect of parent R-rated movie restriction on adolescent smoking was mediated through lower exposure to movie smoking. CONCLUSIONS: Adolescents see thousands of smoking depictions in movies, and this influences their attitudes and behavior. Exposure to movie smoking is reduced when parents limit movie access. Teaching parents to monitor and enforce movie access guidelines could reduce adolescent smoking in an indirect, yet powerful, manner.

Identification of transcripts with enriched expression in the developing and adult pancreas.

BACKGROUND: Despite recent advances, the transcriptional hierarchy driving pancreas organogenesis remains largely unknown, in part due to the paucity of comprehensive analyses. To address this deficit we generated ten SAGE libraries from the developing murine pancreas spanning Theiler stages 17-26, making use of available Pdx1 enhanced green fluorescent protein (EGFP) and Neurog3 EGFP reporter strains, as well as tissue from adult islets and ducts. RESULTS: We used a specificity metric to identify 2,536 tags with pancreas-enriched expression compared to 195 other mouse SAGE libraries. We subsequently grouped co-expressed transcripts with differential expression during pancreas development using K-means clustering. We validated the clusters first using quantitative real time PCR and then by analyzing the Theiler stage 22 pancreas in situ hybridization staining patterns of over 600 of the identified genes using the GenePaint database. These were then categorized into one of the five expression domains within the developing pancreas. Based on these results we identified a cascade of transcriptional regulators expressed in the endocrine pancreas lineage and, from this, we developed a predictive regulatory network describing beta-cell development. CONCLUSION: Taken together, this work provides evidence that the SAGE libraries generated here are a valuable resource for continuing to elucidate the molecular mechanisms regulating pancreas development. Furthermore, our studies provide a comprehensive analysis of pancreas development, and insights into the regulatory networks driving this process are revealed.