T-profiler: scoring the activity of predefined groups of genes using gene expression data

One of the key challenges in the analysis of gene expression data is how to relate the expression level of individual genes to the underlying transcriptional programs and cellular state. Here we describe T-profiler, a tool that uses the t-test to score changes in the average activity of predefined groups of genes. The gene groups are defined based on Gene Ontology categorization, ChIP-chip experiments, upstream matches to a consensus transcription factor binding motif or location on the same chromosome. If desired, an iterative procedure can be used to select a single, optimal representative from sets of overlapping gene groups. T-profiler makes it possible to interpret microarray data in a way that is both intuitive and statistically rigorous, without the need to combine experiments or choose parameters. Currently, gene expression data from Saccharomyces cerevisiae and Candida albicans are supported. Users can upload their microarray data for analysis on the web at

Adult patients with pulmonary arterial hypertension due to congenital heart disease: a review on advanced medical treatment with bosentan

Pulmonary arterial hypertension (PAH) is a progressive disease with poor survival outcome. PAH is classified by the 2009 updated clinical classification of pulmonary hypertension and a major subgroup is PAH due to congenital heart disease (CHD) with systemic-to-pulmonary shunt. CHD-PAH is a result of systemic-to-pulmonary shunting and chronic increased flow that ultimately results in adaptations of pulmonary vasculature and endothelial dysfunction. The advanced stage is called Eisenmenger syndrome which forms a small percentage (1%) of all CHD patients. Therapies targeted on PAH symptoms are called primary therapy for PAH, but most CHD-PAH patients progress to advanced therapy which is directed at the PAH itself. In CHD-PAH, advanced therapies are extensively investigated for all three major pathways: endothelin-1 receptor antagonists such as bosentan, prostanoids such as epoprostenol and phosphodiesterase 5 inhibitors such as sildenafil. Endpoints in most trials were catheterization hemodynamics, World Health Organization functional class, six-minute walking distance and patient-focused outcomes, based on quality of life questionnaires and Borg dyspnea index. The BREATHE-5 and EARLY study were two important randomized controlled trials showing efficacy of bosentan at short follow-up. Moreover in patients with Eisenmenger syndrome, one recent survival retrospective study with majority of patients on bosentan showed strong survival benefit over conservative therapy. A diversity of prospective cohort and retrospective studies were performed but all with limited data, due to small numbers and heterogeneity of underlying CHD diagnoses. Further larger studies are needed to determine optimal treatment for adults with CHD-PAH. This review focuses on bosentan in CHD-PAH. In particular, we discuss outcome of various clinical trials and compare efficacy and safety of bosentan to other advanced therapies

On Perception and Consciousness in HPPD:A Systematic Review

Hallucinogen-persisting perception disorder (HPPD) features as a diagnostic category in the DSM-5, ICD-11, and other major classifications, but our knowledge of the phenomenology of the perceptual symptoms involved and the changes in consciousness during the characteristic “flashbacks” is limited. We systematically evaluated original case reports and case series on HPPD to define its phenomenology, associated (psycho)pathology, and course. Our search of PubMed and Embase yielded 66 relevant publications that described 97 people who, together, experienced 64 unique symptoms of HPPD. Of these, 76% concerned symptoms characteristic of Alice in Wonderland syndrome, over 50% non-visual symptoms, and 38% perceptual symptoms not clearly linked to prior intoxication states. This is in contrast with the DSM-5 diagnostic criteria for HPPD. Even though less than half of the patients showed a protracted disease course of over a year, a third achieved remission. However, in patients with co-occurring depression (with or without anxiety) HPPD symptoms persisted longer and treatment outcomes were more often negative. Thus, unlike the acute stages of psychedelic drug intoxication, which may be accompanied by altered states of consciousness, HPPD is rather characterized by changes in the content of consciousness and an attentional shift from exogenous to endogenous phenomena. Since HPPD is a more encompassing nosological entity than suggested in the DSM-5, we recommend expanding its diagnostic criteria. In addition, we make recommendations for clinical practice and future research

Detecting Regulatory Mechanisms in Endocrine Time Series Measurements

The regulatory mechanisms underlying pulsatile secretion are complex, especially as it is partly controlled by other hormones and the combined action of multiple agents. Regulatory relations between hormones are not directly observable but may be deduced from time series measurements of plasma hormone concentrations. Variation in plasma hormone levels are the resultant of secretion and clearance from the circulation. A strategy is proposed to extract inhibition, activation, thresholds and circadian synchronicity from concentration data, using particular association methods. Time delayed associations between hormone concentrations and/or extracted secretion pulse profiles reveal the information on regulatory mechanisms. The above mentioned regulatory mechanisms are illustrated with simulated data. Additionally, data from a lean cohort of healthy control subjects is used to illustrate activation (ACTH and cortisol) and circadian synchronicity (ACTH and TSH) in real data. The simulation and the real data both consist of 145 equidistant samples per individual, matching a 24-hr time span with 10 minute intervals. The results of the simulation and the real data are in concordance

Expression of oncoproteins and the amount of eosinophilic and lymphocytic infiltrates can be used as prognostic factors in gastric cancer. Dutch Gastric Cancer Group (DGCG).

Preoperative staging of gastric cancer is difficult. Several molecular markers associated with initiation and progression of cancer seem promising for obtaining preoperative prognostic information. To investigate whether these markers are indicative especially for the presence of lymph node metastases in patients with gastric cancer, we have examined primary tumour specimens from 105 patients with primary adenocarcinoma of the stomach entered in a surgical trial. In this trial, lymph node status was determined by strictly quality-controlled lymph node dissection and examination. The selected markers were growth regulators (p53, Rb and myc), metastasis-suppressor gene product (nm23), adhesion molecules (Ep-CAM, E-cadherin, CD44v5 and CD44v6) and urokinase-type plasminogen activator (u-PA). Also, the amount of eosinophilic and lymphocytic infiltrates available post-operatively was analysed with respect to its prognostic value for lymph node status. Moreover, the association of these parameters with survival and disease-free period (DFP) was evaluated. Of all molecular markers investigated, only Rb expression had a significant association with the presence of lymph node metastasis in both univariate and multivariate analysis. For curative resectability, a significant association was found with Rb and E-cadherin expression, while in multivariate analysis Rb and myc were selected as the combination with additional independent prognostic value, and E-cadherin had no additional independent value. For overall survival in univariate analysis, the amount of both eosinophilic and lymphocytic infiltrates and Rb and myc expression were of significant prognostic value. Only the amount of lymphocytic infiltrate had a prognostic significance for DFP. In stepwise multivariate analysis, TNM stage (I + II) and marked lymphocytic infiltrate were associated with better overall survival and longer DFP. We conclude that, if these results are confirmed in a larger series of patients, molecular markers can provide useful prognostic information

The effectiveness of non-native fish removal techniques in freshwater ecosystems: a systematic review

In aquatic systems, biological invasions can result in adverse ecological effects. Man-agement techniques available for non-native fish removal programs (including eradica-tion and population size control) vary widely, but include chemicals, harvest regimes, physical removal, or biological control. For management agencies, deciding on what non-native fish removal program to use has been challenging because there is little reliable information about the relative effectiveness of these measures in controlling or eradicat-ing non-native fish. We conducted a systematic review, including a critical appraisal of study validity, to assess the effectiveness of different non-native fish removal methods, and to identify the factors that influence the overall success rate of each type of method. We found 95 relevant studies, generating 158 data sets. The evidence base was dominated by poorly documented studies with inadequate experimental designs (76% of removal projects). When the management goal was non-native fish eradication, chemical treat-ments were relatively successful (antimycin 89%; rotenone 75%) compared to other in-terventions. Electrofishing and passive removal measure studies indicated successful eradication was possible (58% each respectively) but required intensive effort and multi-ple treatments over a number of years. Of these studies with sufficient information, elec-trofishing had the highest success for population size control (56% of data sets). Overall, inadequate data quality and completeness severely limited our ability to make strong con-clusions about the relationships between non-native fish abundance and different methods of eradication and population control, and the factors influencing the overall success rate of each method. Our review highlights that there is considerable scope for improving our evaluations of non-native fish removal methods. It is recommended that programs should have explicitly stated objectives, better data reporting, and study designs that (when pos-sible and appropriate) incorporate replicated and controlled investigations with rigorous, long-term quantitative monitoring. Future research on the effectiveness of non-native fish removal methods should focus on: (1) the efficacy of existing or potentially new removal measures in larger, more complex environments; (2) a broader range of removal measures in general, and (3) phenotypic characteristics of individual fish within a population that fail to be eradicated or controlled

Genetic disorders of the surfactant system: Focus on adult disease

Genes involved in the production of pulmonary surfactant are crucial for the development and maintenance of healthy lungs. Germline mutations in surfactant-related genes cause a spectrum of severe monogenic pulmonary diseases in patients of all ages. The majority of affected patients present at a very young age, however, a considerable portion of patients have adult-onset disease. Mutations in surfactant-related genes are present in up to 8% of adult patients with familial interstitial lung disease (ILD) and associate with the development of pulmonary fibrosis and lung cancer. High disease penetrance and variable expressivity underscore the potential value of genetic analysis for diagnostic purposes. However, scarce genotype–phenotype correlations and insufficient knowledge of mutation-specific pathogenic processes hamper the development of mutation-specific treatment options. This article describes the genetic origin of surfactant-related lung disease and presents spectra for gene, age, sex and pulmonary phenotype of adult carriers of germline mutations in surfactant-related genes

The unusual ISM in blue and dusty gas-rich galaxies (BADGRS)

The Herschel-ATLAS unbiased survey of cold dust in the local Universe is dominated by a surprising population of very blue (FUV-K 0.5 fHI=MHI/(M∗+M+HI)>0.5 ). Dubbed ‘Blue and Dusty Gas-Rich Sources’ (BADGRS) they have cold diffuse dust temperatures, and the highest dust-to-stellar mass ratios of any galaxies in the local Universe. Here, we explore the molecular interstellar medium in a representative sample of BADGRS, using very deep CO(J up =1,2,3) CO(Jup=1,2,3) observations across the central and outer disc regions. We find very low CO brightnesses (Tp = 5–30 mK), despite the bright far-infrared emission and metallicities in the range 0.5 < Z/Z⊙ < 1.0. The CO line ratios indicate a range of conditions with R 21 =T 21 b /T 10 b =0.6−2.1 R21=Tb21/Tb10=0.6−2.1 and R 31 =T 32 b /T 10 b =0.2−1.2 R31=Tb32/Tb10=0.2−1.2 . Using a metallicity-dependent conversion from CO luminosity to molecular gas mass, we find M H 2 /M d ∼7−27 MH2/Md∼7−27 and Σ H 2 =0.5−6M ⊙ pc −2 ΣH2=0.5−6M⊙pc−2 , around an order of magnitude lower than expected. The BADGRS have lower molecular gas depletion time-scales (τd ∼ 0.5 Gyr) than other local spirals, lying offset from the Kennicutt–Schmidt relation by a similar factor to Blue Compact Dwarf galaxies. The cold diffuse dust temperature in BADGRS (13–16 K) requires an interstellar radiation field 10–20 times lower than that inferred from their observed surface brightness. We speculate that the dust in these sources has either a very clumpy geometry or a very different opacity in order to explain the cold temperatures and lack of CO emission. BADGRS also have low UV attenuation for their UV colour suggestive of an SMC-type dust attenuation curve, different star formation histories or different dust/star geometry. They lie in a similar part of the IRX-β space as z z ∼ 5 galaxies and may be useful as local analogues for high gas fraction galaxies in the early Universe