Effects of steady state free precession parameters on cardiac mass, function, and volumes

G0400444/Medical Research Council/United Kingdom Wellcome Trust/United Kingdo

The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice.

The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model. The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression. Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo. These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice

Impact of metabolic comorbidity on the association between body mass index and heatlh-related quality of life: a Scotland-wide cross-sectional study of 5,608 participants

<p/>Background: The prevalence of obesity is rising in Scotland and globally. Overall, obesity is associated with increased morbidity, mortality and reduced health-related quality of life. Studies suggest that "healthy obesity" (obesity without metabolic comorbidity) may not be associated with morbidity or mortality. Its impact on health-related quality of life is unknown. <p/>Methods: We extracted data from the Scottish Health Survey on self-reported health-related quality of life, body mass index (BMI), demographic information and comorbidity. SF-12 responses were converted into an overall health utility score. Linear regression analyses were used to explore the association between BMI and health utility, stratified by the presence or absence of metabolic comorbidity (diabetes, hypertension, hypercholesterolemia or cardiovascular disease), and adjusted for potential confounders (age, sex and deprivation quintile). <p/>Results: Of the 5,608 individuals, 3,744 (66.8%) were either overweight or obese and 921 (16.4%) had metabolic comorbidity. There was an inverted U-shaped relationship whereby health utility was highest among overweight individuals and fell with increasing BMI. There was a significant interaction with metabolic comorbidity (p = 0.007). Individuals with metabolic comorbidty had lower utility scores and a steeper decline in utility with increasing BMI (morbidly obese, adjusted coefficient: -0.064, 95% CI -0.115, -0.012, p = 0.015 for metabolic comorbidity versus -0.042, 95% CI -0.067, -0.018, p = 0.001 for no metabolic comorbidity). <p/>Conclusions: The adverse impact of obesity on health-related quality of life is greater among individuals with metabolic comorbidity. However, increased BMI is associated with reduced health-related quality of life even in the absence of metabolic comorbidity, casting doubt on the notion of "healthy obesity"

Recovery from Posttraumatic Stress Symptoms: A Qualitative Study of Attributions in Survivors of War

This study was funded by a grant from the European Commission, contract number INCO-CT-2004-50917

The european primary care monitor: structure, process and outcome indicators

<p>Abstract</p> <p>Background</p> <p>Scientific research has provided evidence on benefits of well developed primary care systems. The relevance of some of this research for the European situation is limited.</p> <p>There is currently a lack of up to date comprehensive and comparable information on variation in development of primary care, and a lack of knowledge of structures and strategies conducive to strengthening primary care in Europe. The EC funded project Primary Health Care Activity Monitor for Europe (PHAMEU) aims to fill this gap by developing a Primary Care Monitoring System (PC Monitor) for application in 31 European countries. This article describes the development of the indicators of the PC Monitor, which will make it possible to create an alternative model for holistic analyses of primary care.</p> <p>Methods</p> <p>A systematic review of the primary care literature published between 2003 and July 2008 was carried out. This resulted in an overview of: (1) the dimensions of primary care and their relevance to outcomes at (primary) health system level; (2) essential features per dimension; (3) applied indicators to measure the features of primary care dimensions. The indicators were evaluated by the project team against criteria of relevance, precision, flexibility, and discriminating power. The resulting indicator set was evaluated on its suitability for Europe-wide comparison of primary care systems by a panel of primary care experts from various European countries (representing a variety of primary care systems).</p> <p>Results</p> <p>The developed PC Monitor approaches primary care in Europe as a multidimensional concept. It describes the key dimensions of primary care systems at three levels: structure, process, and outcome level. On structure level, it includes indicators for governance, economic conditions, and workforce development. On process level, indicators describe access, comprehensiveness, continuity, and coordination of primary care services. On outcome level, indicators reflect the quality, and efficiency of primary care.</p> <p>Conclusions</p> <p>A standardized instrument for describing and comparing primary care systems has been developed based on scientific evidence and consensus among an international panel of experts, which will be tested to all configurations of primary care in Europe, intended for producing comparable information. Widespread use of the instrument has the potential to improve the understanding of primary care delivery in different national contexts and thus to create opportunities for better decision making.</p

Novel Exon of Mammalian ADAR2 Extends Open Reading Frame

Background: The post-transcriptional processing of pre-mRNAs by RNA editing contributes significantly to the complexity of the mammalian transcriptome. RNA editing by site-selective A-to-I modification also regulates protein function through recoding of genomically specified sequences. The adenosine deaminase ADAR2 is the main enzyme responsible for recoding editing and loss of ADAR2 function in mice leads to a phenotype of epilepsy and premature death. Although A-to-I RNA editing is known to be subject to developmental and cell-type specific regulation, there is little knowledge regarding the mechanisms that regulate RNA editing in vivo. Therefore, the characterization of ADAR expression and identification of alternative ADAR variants is an important prerequisite for understanding the mechanisms for regulation of RNA editing and the causes for deregulation in disease. Methodology/Principal Findings: Here we present evidence for a new ADAR2 splice variant that extends the open reading frame of ADAR2 by 49 amino acids through the utilization of an exon located 18 kilobases upstream of the previously annotated first coding exon and driven by a candidate alternative promoter. Interestingly, the 49 amino acid extension harbors a sequence motif that is closely related to the R-domain of ADAR3 where it has been shown to function as a basic, single-stranded RNA binding domain. Quantitative expression analysis shows that expression of the novel ADAR2 splice variant is tissue specific being highest in the cerebellum

Inferring signalling networks from longitudinal data using sampling based approaches in the R-package 'ddepn'

<p>Abstract</p> <p>Background</p> <p>Network inference from high-throughput data has become an important means of current analysis of biological systems. For instance, in cancer research, the functional relationships of cancer related proteins, summarised into signalling networks are of central interest for the identification of pathways that influence tumour development. Cancer cell lines can be used as model systems to study the cellular response to drug treatments in a time-resolved way. Based on these kind of data, modelling approaches for the signalling relationships are needed, that allow to generate hypotheses on potential interference points in the networks.</p> <p>Results</p> <p>We present the R-package 'ddepn' that implements our recent approach on network reconstruction from longitudinal data generated after external perturbation of network components. We extend our approach by two novel methods: a Markov Chain Monte Carlo method for sampling network structures with two edge types (activation and inhibition) and an extension of a prior model that penalises deviances from a given reference network while incorporating these two types of edges. Further, as alternative prior we include a model that learns signalling networks with the scale-free property.</p> <p>Conclusions</p> <p>The package 'ddepn' is freely available on R-Forge and CRAN <url>http://ddepn.r-forge.r-project.org</url>, <url>http://cran.r-project.org</url>. It allows to conveniently perform network inference from longitudinal high-throughput data using two different sampling based network structure search algorithms.</p

SICTIN: Rapid footprinting of massively parallel sequencing data

BACKGROUND: Massively parallel sequencing allows for genome-wide hypothesis-free investigation of for instance transcription factor binding sites or histone modifications. Although nucleotide resolution detailed information can easily be generated, biological insight often requires a more general view of patterns (footprints) over distinct genomic features such as transcription start sites, exons or repetitive regions. The construction of these footprints is however a time consuming task. METHODS: The presented software generates a binary representation of the signals enabling fast and scalable lookup. This representation allows for footprint generation in mere minutes on a desktop computer. Several different input formats are accepted, e.g. the SAM format, bed-files and the UCSC wiggle track. CONCLUSIONS: Hypothesis-free investigation of genome wide interactions allows for biological data mining at a scale never before seen. Until recently, the main focus of analysis of sequencing data has been targeted on signal patterns around transcriptional start sites which are in manageable numbers. Today, focus is shifting to a wider perspective and numerous genomic features are being studied. To this end, we provide a system allowing for fast querying in the order of hundreds of thousands of features

Major combined electrolyte deficiency during therapy with low-dose Cisplatin, 5-Fluorouracil and Interferon alpha: report on several cases and review of the literature [ISRCTN62866759]

BACKGROUND: Low-dose Cisplatin and Interferon alpha treatment of solid tumors rarely has been associated with severe hypocalcaemia. To the authors knowledge the phenomenon has not been reported previously in patients with pancreatic carcinoma. CASE PRESENTATION: A patient with resected adenocarcinoma of the pancreas was treated with adjuvant radio-chemo-immunotherapy using a combination of low-dose Cisplatin, 5-Fluorouracil and Interferon alpha together with external beam radiation. Severe hypocalcaemia without signs of acute renal failure or electrolyte disturbance occurred within 2 days at the 4th week of treatment and required intensive care treatment. CONCLUSION: Combination of biological and cytotoxic therapies may increase the incidence of severe hypocalcaemia in pancreatic cancer. Oncologists should remain attentive of this problem as more highly active regimes become available