Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

FUNDING AND DISCLOSURE The research was funded by Wellcome Trust (WT098012) to LKH; and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The remaining authors declare no conflict of interest. ACKNOWLEDGMENTS We thank Dr Celine Cansell, Ms Raffaella Chianese and the staff of the Medical Research Facility for technical assistance. We thank Dr Vladimir Orduña for the scientific advice and technical assistance.Peer reviewedPublisher PD

The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis.

Background Clostridium difficile infection (CDI) is a major health problem. Epidemiological evidence suggests that there is an association between acid suppression therapy and development of CDI. Purpose We sought to systematically review the literature that examined the association between histamine 2 receptor antagonists (H2RAs) and CDI. Data source We searched Medline, Current Contents, Embase, ISI Web of Science and Elsevier Scopus from 1990 to 2012 for all analytical studies that examined the association between H2RAs and CDI. Study selection Two authors independently reviewed the studies for eligibility. Data extraction Data about studies characteristics, adjusted effect estimates and quality were extracted. Data synthesis Thirty-five observations from 33 eligible studies that included 201834 participants were analyzed. Studies were performed in 6 countries and nine of them were multicenter. Most studies did not specify the type or duration of H2RAs therapy. The pooled effect estimate was 1.44, 95% CI (1.22–1.7), I2 = 70.5%. This association was consistent across different subgroups (by study design and country) and there was no evidence of publication bias. The pooled effect estimate for high quality studies was 1.39 (1.15–1.68), I2 = 72.3%. Meta-regression analysis of 10 study-level variables did not identify sources of heterogeneity. In a speculative analysis, the number needed to harm (NNH) with H2RAs at 14 days after hospital admission in patients receiving antibiotics or not was 58, 95% CI (37, 115) and 425, 95% CI (267, 848), respectively. For the general population, the NNH at 1 year was 4549, 95% CI (2860, 9097). Conclusion In this rigorous systematic review and meta-analysis, we observed an association between H2RAs and CDI. The absolute risk of CDI associated with H2RAs is highest in hospitalized patients receiving antibiotics

Polymorphisms in the ADRB2 gene and Graves disease: a case-control study and a meta-analysis of available evidence

<p>Abstract</p> <p>Background</p> <p>The beta-2-Adrenergic receptor (<it>ADRB2</it>) gene on chromosome 5q33.1 is an important immunoregulatory factor. We and others have previously implicated chromosomal region 5q31-33 for contribution to the genetic susceptibility to Graves disease (GD) in East-Asian populations. Two recent studies showed associations between the single nucleotide polymorphism (SNP) rs1042714 in the <it>ADRB2 </it>gene and GD. In this study, we aimed to fully investigate whether the <it>ADRB2 </it>gene conferred susceptibility to GD in Chinese population, and to perform a meta-analysis of association between <it>ADRB2 </it>and GD.</p> <p>Methods</p> <p>Approximately 1 kb upstream the transcription start site and the entire coding regions of the <it>ADRB2 </it>gene were resequenced in 48 Han Chinese individuals to determine the linkage disequilibrium (LD) patterns. Tag SNPs were selected and genotyped in a case-control collection of 1,118 South Han Chinese subjects, which included 428 GD patients and 690 control subjects. A meta-analysis was performed with the data obtained in the present samples and those available from prior studies.</p> <p>Results</p> <p>Fifteen SNPs in the <it>ADRB2 </it>gene were identified by resequencing and one SNP was novel. Ten tag SNPs were investigated further to assess association of <it>ADRB2 </it>in the case-control collection. Neither individual tag SNP nor haplotypes showed association with GD in Han Chinese population (P > 0.05). Our meta-analysis of the <it>ADRB2 </it>SNP rs1042714 measured heterogeneity between the ethnic groups (I²= 53.1%) and no association to GD was observed in the overall three studies with a random effects model (OR = 1.13, 95% CI, 0.95 to 1.36; P = 0.18). However, significant association was found from the combined data of Caucasian population with a fixed effects model (OR = 1.18, 95% CI, 1.06 to 1.32; P = 0.002; I²= 5.9%).</p> <p>Conclusion</p> <p>Our study indicated that the <it>ADRB2 </it>gene did not exert a substantial influence on GD susceptibility in Han Chinese population, but contributed to a detectable GD risk in Caucasian population. This inconsistency resulted largely from between-ethnicity heterogeneity.</p

The 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) reduces palatable food consumption and BOLD fMRI responses to food images in healthy female volunteers

RATIONALE: Brain 5-HT2C receptors form part of a neural network that controls eating behaviour. 5-HT2C receptor agonists decrease food intake by activating proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, but recent research in rodents has suggested that 5-HT2C receptor agonists may also act via dopaminergic circuitry to reduce the rewarding value of food and other reinforcers. No mechanistic studies on the effects of 5-HT2C agonists on food intake in humans have been conducted to date. OBJECTIVES: The present study examined the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) on food consumption, eating microstructure and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) responses to food pictures in healthy female volunteers. METHODS: In a double-blind, placebo-controlled, crossover design, participants were randomized immediately after screening to receive oral mCPP (30mg) in a single morning dose, or placebo, in a counterbalanced order. Test foods were served from a Universal Eating Monitor (UEM) that measured eating rate and fMRI BOLD signals to the sight of food and non-food images were recorded. RESULTS: mCPP decreased rated appetite and intake of a palatable snack eaten in the absence of hunger but had no significant effect on the consumption of a pasta lunch (although pasta eating rate was reduced). mCPP also decreased BOLD fMRI responses to the sight of food pictures in areas of reward-associated circuitry. A post hoc analysis identified individual variability in the response to mCPP (exploratory responder-non-responder analysis). Some participants did not reduce their cookie intake after treatment with mCPP and this lack of response was associated with enhanced ratings of cookie pleasantness and enhanced baseline BOLD responses to food images in key reward and appetite circuitry. CONCLUSIONS: These results suggest that 5-HT2C receptor activation in humans inhibits food reward-related responding and that further investigation of stratification of responding to mCPP and other 5-HT2C receptor agonists is warranted

Adjuvant chemotherapy for resected early-stage non-small cell lung cancer

BACKGROUND: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. OBJECTIVES: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. SEARCH METHODS: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations. SELECTION CRITERIA: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. MAIN RESULTS: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. AUTHORS' CONCLUSIONS: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out

Complete Mitochondrial Genome Sequence of Three Tetrahymena Species Reveals Mutation Hot Spots and Accelerated Nonsynonymous Substitutions in Ymf Genes

The ciliate Tetrahymena, a model organism, contains divergent mitochondrial (Mt) genome with unusual properties, where half of its 44 genes still remain without a definitive function. These genes could be categorized into two major groups of KPC (known protein coding) and Ymf (genes without an identified function). To gain insights into the mechanisms underlying gene divergence and molecular evolution of Tetrahymena (T.) Mt genomes, we sequenced three Mt genomes of T.paravorax, T.pigmentosa, and T.malaccensis. These genomes were aligned and the analyses were carried out using several programs that calculate distance, nucleotide substitution (dn/ds), and their rate ratios (ω) on individual codon sites and via a sliding window approach. Comparative genomic analysis indicated a conserved putative transcription control sequence, a GC box, in a region where presumably transcription and replication initiate. We also found distinct features in Mt genome of T.paravorax despite similar genome organization among these ∼47 kb long linear genomes. Another significant finding was the presence of at least one or more highly variable regions in Ymf genes where majority of substitutions were concentrated. These regions were mutation hotspots where elevated distances and the dn/ds ratios were primarily due to an increase in the number of nonsynonymous substitutions, suggesting relaxed selective constraint. However, in a few Ymf genes, accelerated rates of nonsynonymous substitutions may be due to positive selection. Similarly, on protein level the majority of amino acid replacements occurred in these regions. Ymf genes comprise half of the genes in Tetrahymena Mt genomes, so understanding why they have not been assigned definitive functions is an important aspect of molecular evolution. Importantly, nucleotide substitution types and rates suggest possible reasons for not being able to find homologues for Ymf genes. Additionally, comparative genomic analysis of complete Mt genomes is essential in identifying biologically significant motifs such as control regions

XplorSeq: A software environment for integrated management and phylogenetic analysis of metagenomic sequence data

<p>Abstract</p> <p>Background</p> <p>Advances in automated DNA sequencing technology have accelerated the generation of metagenomic DNA sequences, especially environmental ribosomal RNA gene (rDNA) sequences. As the scale of rDNA-based studies of microbial ecology has expanded, need has arisen for software that is capable of managing, annotating, and analyzing the plethora of diverse data accumulated in these projects.</p> <p>Results</p> <p>XplorSeq is a software package that facilitates the compilation, management and phylogenetic analysis of DNA sequences. XplorSeq was developed for, but is not limited to, high-throughput analysis of environmental rRNA gene sequences. XplorSeq integrates and extends several commonly used UNIX-based analysis tools by use of a Macintosh OS-X-based graphical user interface (GUI). Through this GUI, users may perform basic sequence import and assembly steps (base-calling, vector/primer trimming, contig assembly), perform BLAST (Basic Local Alignment and Search Tool; <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr></abbrgrp>) searches of NCBI and local databases, create multiple sequence alignments, build phylogenetic trees, assemble Operational Taxonomic Units, estimate biodiversity indices, and summarize data in a variety of formats. Furthermore, sequences may be annotated with user-specified meta-data, which then can be used to sort data and organize analyses and reports. A document-based architecture permits parallel analysis of sequence data from multiple clones or amplicons, with sequences and other data stored in a single file.</p> <p>Conclusion</p> <p>XplorSeq should benefit researchers who are engaged in analyses of environmental sequence data, especially those with little experience using bioinformatics software. Although XplorSeq was developed for management of rDNA sequence data, it can be applied to most any sequencing project. The application is available free of charge for non-commercial use at <url>http://vent.colorado.edu/phyloware</url>.</p

A multiple timepoint pre-post evaluation of a ‘sexual respect’ dvd to improve competence in discussing sex with patients with disability

Sexual problems are common after chronic illnesses and disability, yet research indicates that this is a neglected area in healthcare services. Evaluation studies provide evidence of the effectiveness of education in enhancing professionals’ knowledge, skills, and comfort in addressing patients’ sexual concerns. However, there are limited evaluations aimed at improving ability to discuss sexuality when working with people with disabilities. The overall aim of this study was to evaluate a ‘Sexual Respect’ DVD as an intervention to improve competence in addressing ‘sexuality and disability’. A mixed methods design was used with both quantitative and qualitative components. Nursing students’ self-report ratings of knowledge, confidence, comfort and willingness (to discuss sexuality) levels were collected across four time points: baseline, pre-intervention, post-intervention, and follow-up. Data were analysed using one-way repeated measures ANOVAs with post hoc comparisons. Open-ended qualitative comments relating to the barriers and facilitators to discussing sexuality were analysed using content analysis and subsequent frequency analysis. Reported barriers included lack of knowledge about sex¬uality and disability issues, the patient’s level of disability, and waiting for the patient to raise sexuality issues first. Facilitators included education/training, written information, and if the patient raised it first. Overall, the DVD intervention had a significant and positive impact on nursing students’ self-reported knowledge, confidence, comfort and willingness levels. The findings are discussed in relation to the PLISSIT model, which emphasises the importance of a proactive approach to addressing sexuality issues

Application of biomedical informatics to chronic pediatric diseases: a systematic review

<p>Abstract</p> <p>Background</p> <p>Chronic diseases affect millions of children worldwide leading to substantial disease burden to the children and their families as well as escalating health care costs. The increasing trend in the prevalence of complex pediatric chronic diseases requires innovative and optimal delivery of care. Biomedical informatics applications play an important role in improving health outcomes while being cost-effective. However, their utility in pediatric chronic diseases has not been studied in a comprehensive and systematic way. The objective of this study was to conduct a systematic review of the effects of biomedical informatics applications in pediatric chronic diseases.</p> <p>Methods</p> <p>A comprehensive literature search was conducted using MEDLINE, the Cochrane Library and EMBASE databases from inception of each database to September 2008. We included studies of any methodological type and any language that applied biomedical informatics to chronic conditions in children and adolescents 18 years of age or younger. Two independent reviewers carried out study selection and data extraction. Quality assessment was performed using a study design evaluation instrument to appraise the strength of the studies and their methodological adequacy. Because of heterogeneity in the conditions and outcomes we studied, a formal meta-analysis was not performed.</p> <p>Results</p> <p>Based on our search strategy, 655 titles and abstracts were reviewed. From this set we identified 27 relevant articles that met our inclusion criteria. The results from these studies indicated that biomedical informatics applications have favourable clinical and patient outcomes including, but not limited to, reduced number of emergency room visits, improved knowledge on disease management, and enhanced satisfaction. Seventy percent of reviewed papers were published after year 2000, 89% of users were patients and 11% were either providers or caregivers. The majority (96%) of the selected studies reported improved outcomes.</p> <p>Conclusion</p> <p>Published studies suggested positive impacts of informatics predominantly in pediatric asthma. As electronic tools become more widely adopted, there will be opportunities to improve patient care in a wide range of chronic illnesses through informatics solutions.</p