A user's guide to the encyclopedia of DNA elements (ENCODE).

The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome.

The Microbe browser for comparative genomics.

The Microbe browser is a web server providing comparative microbial genomics data. It offers comprehensive, integrated data from GenBank, RefSeq, UniProt, InterPro, Gene Ontology and the Orthologs Matrix Project (OMA) database, displayed along with gene predictions from five software packages. The Microbe browser is daily updated from the source databases and includes all completely sequenced bacterial and archaeal genomes. The data are displayed in an easy-to-use, interactive website based on Ensembl software. The Microbe browser is available at http://microbe.vital-it.ch/. Programmatic access is available through the OMA application programming interface (API) at http://microbe.vital-it.ch/api.

Phthalates in the NICU: Is it safe?

AIMS: As growing concerns exist regarding phthalate exposure, which could be teratogenic, carcinogenic or induce reproductive toxicity, we aimed to review the evidence of the risks due to the use of medical devices containing di(2-ethylhexyl)phthalate in hospitalized neonates. METHODS: We reviewed the literature, searching through medical literature databases (Pubmed, MEDLINE, EBM reviews, Cochrane database, Embase and Google Scholar) using the following keywords: phthalate, di(2-ethylhexyl)phthalate, newborn and neonate. RESULTS: We identified several associations with short and long term health dangers, mainly subfertility, broncho-pulmonary dysplasia, necrotising enterocolitis, parenteral nutrition associated cholestasis and neuro-developmental disorders. These data are based mainly on animal or observational human studies. CONCLUSION: Clinicians must be aware of the potential risks due to phthalate exposure in the NICU. Di(2-ethylhexyl)phthalate containing materials should be identified and alternative devices should be considered. There is a need to improve knowledge in this area.

Intravenous Lacosamide for Treatment of Status Epilepticus after Failing First-Line Therapy

Rationale: Treatment of status epilepticus (SE) usually requires intravenous anticonvulsant therapy. Although there are established drugs of first choice for its treatment, potentially hazardous side effects of these agents are not uncommon. Lacosamide (LCM) is a novel anticonvulsant drug that is available as infusion solution. LCM could be an alternative for treatment of SE when the standard drugs fail or should be avoided. Methods: We retrospectively identified patients from the hospital databases of two German and one Swiss neurological departments (University Hospital Marburg, Klinikum Osnabrueck, University Hospital Lausanne) between September 1st 2008 and May 22nd 2009 who were admitted because of SE and received at least one dose of intravenous LCM for treatment of SE. Results: Seventeen patients (11 female, 6 male) were identified. Median age was 71 years. 3 patients suffered from generalized convulsive SE, 8 patients had significant reduction of awareness with or without subtle motor symptoms, 6 patients had a simple focal status without relevant reduction of awareness. Etiology was acute symptomatic in 5 patients, remote symptomatic without pre-existing epilepsy in 6 patients, remote symptomatic and pre-existing epilepsy in 5 patients, and unknown in 1 patient. LCM was administered after failure of first line therapy in all cases. The first LCM bolus was 400mg in 13 patients and 200mg in 4 patients. LCM administration stopped SE in 7 patients. In 2 of them, LCM was administered immediately after benzodiazepine administration, in the others after failure of benzodiazepines and other first-line and/or second-line drugs. In 3 patients, SE was terminated by other anticonvulsants like Phenytoin, Phenobarbital or Oxcarbazepine. In 5 patients, SE could only be terminated by intubation and application of high-dose Midazolam, Propofol and/or Thiopental. In 2 patients, SE could not be terminated in spite of high doses of barbiturates. There was no serious adverse event documented that could possibly be attributed to LCM Conclusions: Intravenous LCM may be an alternative treatment for SE after failure of benzodiazepins and other established drugs, or when such agents are considered unsuitable.

Database construction and Peptide identification strategies for proteogenomic studies on sequenced genomes.

Since the advent of high-throughput DNA sequencing technologies, the ever-increasing rate at which genomes have been published has generated new challenges notably at the level of genome annotation. Even if gene predictors and annotation softwares are more and more efficient, the ultimate validation is still in the observation of predicted gene product( s). Mass-spectrometry based proteomics provides the necessary high throughput technology to show evidences of protein presence and, from the identified sequences, confirmation or invalidation of predicted annotations. We review here different strategies used to perform a MS-based proteogenomics experiment with a bottom-up approach. We start from the strengths and weaknesses of the different database construction strategies, based on different genomic information (whole genome, ORF, cDNA, EST or RNA-Seq data), which are then used for matching mass spectra to peptides and proteins. We also review the important points to be considered for a correct statistical assessment of the peptide identifications. Finally, we provide references for tools used to map and visualize the peptide identifications back to the original genomic information.

Characterization of a new clinical yeast species, Candida tunisiensis sp. nov., isolated from a strain collection from Tunisian hospitals.

From a collection of yeast isolates isolated from patients in Tunisian hospitals between September 2006 and July 2010, the yeast strain JEY63 (CBS 12513), isolated from a 50-year-old male that suffered from oral thrush, could not be identified to the species level using conventional methods used in clinical laboratories. These methods include matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), germ tube formation, and the use of CHROMagar Candida and metabolic galleries. Sequence analysis of the nuclear rRNA (18S rRNA, 5.8S rRNA, and 26S rRNA) and internal transcribed spacer regions (ITS1 and ITS2) indicated that the ribosomal DNA sequences of this species were not yet reported. Multiple gene phylogenic analyses suggested that this isolate clustered at the base of the Dipodascaceae (Saccharomycetales, Saccharomycetes, and Ascomycota). JEY63 was named Candida tunisiensis sp. nov. according to several phenotypic criteria and its geographical origin. C. tunisiensis was able to grow at 42°C and does not form chlamydospores and hyphae but could grow as yeast and pseudohyphal forms. C. tunisiensis exhibited most probably a haploid genome with an estimated size of 10 Mb on at least three chromosomes. Using European Committee for Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) Candida albicans susceptibility breakpoints as a reference, C. tunisiensis was resistant to fluconazole (MIC = 8 μg/ml), voriconazole (MIC = 0.5 μg/ml), itraconazole (MIC = 16 μg/ml), and amphotericin B (MIC = 4 μg/ml) but still susceptible to posaconazole (MIC = 0.008 μg/ml) and caspofungin (MIC = 0.5 μg/ml). In conclusion, MALDI-TOF MS permitted the early selection of an unusual isolate, which was still unreported in molecular databases but could not be unambiguously classified based on phylogenetic approaches.

ViralZone: a knowledge resource to understand virus diversity.

The molecular diversity of viruses complicates the interpretation of viral genomic and proteomic data. To make sense of viral gene functions, investigators must be familiar with the virus host range, replication cycle and virion structure. Our aim is to provide a comprehensive resource bridging together textbook knowledge with genomic and proteomic sequences. ViralZone web resource (www.expasy.org/viralzone/) provides fact sheets on all known virus families/genera with easy access to sequence data. A selection of reference strains (RefStrain) provides annotated standards to circumvent the exponential increase of virus sequences. Moreover ViralZone offers a complete set of detailed and accurate virion pictures.

Comparison of human chromosome 21 conserved nongenic sequences (CNGs) with the mouse and dog genomes shows that their selective constraint is independent of their genic environment.

The analysis of conservation between the human and mouse genomes resulted in the identification of a large number of conserved nongenic sequences (CNGs). The functional significance of this nongenic conservation remains unknown, however. The availability of the sequence of a third mammalian genome, the dog, allows for a large-scale analysis of evolutionary attributes of CNGs in mammals. We have aligned 1638 previously identified CNGs and 976 conserved exons (CODs) from human chromosome 21 (Hsa21) with their orthologous sequences in mouse and dog. Attributes of selective constraint, such as sequence conservation, clustering, and direction of substitutions were compared between CNGs and CODs, showing a clear distinction between the two classes. We subsequently performed a chromosome-wide analysis of CNGs by correlating selective constraint metrics with their position on the chromosome and relative to their distance from genes. We found that CNGs appear to be randomly arranged in intergenic regions, with no bias to be closer or farther from genes. Moreover, conservation and clustering of substitutions of CNGs appear to be completely independent of their distance from genes. These results suggest that the majority of CNGs are not typical of previously described regulatory elements in terms of their location. We propose models for a global role of CNGs in genome function and regulation, through long-distance cis or trans chromosomal interactions.

How quickly should we titrate antihypertensive medication? Systematic review modelling blood pressure response from trial data.

Context There are no evidence syntheses available to guide clinicians on when to titrate antihypertensive medication after initiation. Objective To model the blood pressure (BP) response after initiating antihypertensive medication. Data sources electronic databases including Medline, Embase, Cochrane Register and reference lists up to December 2009. Study selection Trials that initiated antihypertensive medication as single therapy in hypertensive patients who were either drug naive or had a placebo washout from previous drugs. Data extraction Office BP measurements at a minimum of two weekly intervals for a minimum of 4 weeks. An asymptotic approach model of BP response was assumed and non-linear mixed effects modelling used to calculate model parameters. Results and conclusions Eighteen trials that recruited 4168 patients met inclusion criteria. The time to reach 50% of the maximum estimated BP lowering effect was 1 week (systolic 0.91 weeks, 95% CI 0.74 to 1.10; diastolic 0.95, 0.75 to 1.15). Models incorporating drug class as a source of variability did not improve fit of the data. Incorporating the presence of a titration schedule improved model fit for both systolic and diastolic pressure. Titration increased both the predicted maximum effect and the time taken to reach 50% of the maximum (systolic 1.2 vs 0.7 weeks; diastolic 1.4 vs 0.7 weeks). Conclusions Estimates of the maximum efficacy of antihypertensive agents can be made early after starting therapy. This knowledge will guide clinicians in deciding when a newly started antihypertensive agent is likely to be effective or not at controlling BP.

Registries in rheumatological and musculoskeletal conditions. Paediatric Behçet's disease: an international cohort study of 110 patients. One-year follow-up data.

OBJECTIVE: To set-up an international cohort of patients suspected with Behçet's disease (BD). The cohort is aimed at defining an algorithm for definition of the disease in children. METHODS: International experts have defined the inclusion criteria as follows: recurrent oral aphthosis (ROA) plus one of following-genital ulceration, erythema nodosum, folliculitis, pustulous/acneiform lesions, positive pathergy test, uveitis, venous/arterial thrombosis and family history of BD. Onset of disease is <16 years, disease duration is ≤3 years, future follow-up duration is ≥4 years and informed consent is obtained. The expert committee has classified the included patients into: definite paediatric BD (PED-BD), probable PED-BD and no PED-BD. Statistical analysis is performed to compare the three groups of patients. Centres document their patients into a single database. RESULTS: At January 2010, 110 patients (56 males/54 females) have been included. Mean age at first symptom: 8.1 years (median 8.2 years). At inclusion, 38% had only one symptom associated with ROA, 31% had two and 31% had three or more symptoms. A total of 106 first evaluations have been done. Seventeen patients underwent the first-year evaluation, and 36 had no new symptoms, 12 had one and 9 had two. Experts have examined 48 files and classified 30 as definite and 18 as probable. Twenty-six patients classified as definite fulfilled the International Study Group criteria. Seventeen patients classified as probable did not meet the international criteria. CONCLUSION: The expert committee has classified the majority of patients in the BD group although they presented with few symptoms independently of BD classification criteria.

Nontraumatic spinal epidural hematoma during pregnancy: diagnosis and management concerns.

OBJECTIVE: Nontraumatic spinal epidural hematoma (SEH) during pregnancy is rare. Therefore, appropriate management of this occurrence is not well defined. The aim of this study was to extensively review the literature on this subject, to propose some novel treatment guidelines. METHODS: Electronic databases, manual reviews and conference proceedings up to December 2011 were systematically reviewed. Articles were deemed eligible for inclusion in this study if they dealt with nontraumatic SEH during pregnancy. Search protocols and data were independently assessed by two authors. RESULTS: In all, 23 case reports were found to be appropriate for review. The mean patient age was 28 years and gestational age was 33.2 weeks. Thirteen cases presented with acute interscapular pain. The clinical picture consisted of paraplegia, which occurred approximately 63 h after pain onset. Spinal cord decompression was performed within an average time of 20 h after neurological deficit onset. Fifteen patients had cesarean deliveries, even when the gestational age was less than 36 weeks. CONCLUSION: This review failed to identify articles, other than case reports, which could assist in the formation of new guidelines to treat SEH in pregnancy. However, we believe that SEH may be managed neurosurgically, without requiring prior, premature, cesarean section.

Paper 4: EUROCAT statistical monitoring: identification and investigation of ten year trends of congenital anomalies in Europe.

BACKGROUND: As part of EUROCAT's surveillance of congenital anomalies in Europe, a statistical monitoring system has been developed to detect recent clusters or long-term (10 year) time trends. The purpose of this article is to describe the system for the identification and investigation of 10-year time trends, conceived as a "screening" tool ultimately leading to the identification of trends which may be due to changing teratogenic factors.METHODS: The EUROCAT database consists of all cases of congenital anomalies including livebirths, fetal deaths from 20 weeks gestational age, and terminations of pregnancy for fetal anomaly. Monitoring of 10-year trends is performed for each registry for each of 96 non-independent EUROCAT congenital anomaly subgroups, while Pan-Europe analysis combines data from all registries. The monitoring results are reviewed, prioritized according to a prioritization strategy, and communicated to registries for investigation. Twenty-one registries covering over 4 million births, from 1999 to 2008, were included in monitoring in 2010.CONCLUSIONS: Significant increasing trends were detected for abdominal wall anomalies, gastroschisis, hypospadias, Trisomy 18 and renal dysplasia in the Pan-Europe analysis while 68 increasing trends were identified in individual registries. A decreasing trend was detected in over one-third of anomaly subgroups in the Pan-Europe analysis, and 16.9% of individual registry tests. Registry preliminary investigations indicated that many trends are due to changes in data quality, ascertainment, screening, or diagnostic methods. Some trends are inevitably chance phenomena related to multiple testing, while others seem to represent real and continuing change needing further investigation and response by regional/national public health authorities.

Geoheritage popularisation and cartographic visualisation in the Tsanfleuron-Sanetsch area (Valais, Switzerland)

This paper presents the underlying concepts developed by the Institute of Geography of the University of Lausanne (Switzerland) for a popularisation project of the geoheritage in the Tsanfleuron-Sanetsch area (Valais, Switzerland). Due to its wide scientific interest, the local geoheritage is of great value (Reynard, 2008). The article details the complementary links existing between the different parts of a geotourist project - databases, educational panels, educational material and geotourist map - developed for popularising the geoheritage value of the area. Each element of the project is briefly presented. Special focus is set on mapping questions: how cartographic design and information structure can be set in order to facilitate map's use and comprehension. In this way, the Tsanfleuron-Sanetsch map is presented as an applied example of the guiding principles proposed by Coratza and Regolini-Bissig (2009).

The Gene Ontology: enhancements for 2011.

The Gene Ontology (GO) (http://www.geneontology.org) is a community bioinformatics resource that represents gene product function through the use of structured, controlled vocabularies. The number of GO annotations of gene products has increased due to curation efforts among GO Consortium (GOC) groups, including focused literature-based annotation and ortholog-based functional inference. The GO ontologies continue to expand and improve as a result of targeted ontology development, including the introduction of computable logical definitions and development of new tools for the streamlined addition of terms to the ontology. The GOC continues to support its user community through the use of e-mail lists, social media and web-based resources.

Soft tissue sarcomas of the trunk wall (STS-TW): a study of 343 patients from the French Sarcoma Group (FSG) database.

BACKGROUND: Soft tissue sarcomas of the trunk wall (STS-TW) are usually studied together with soft tissue sarcomas of other locations. We report a study on STS-TW forming part of the French Sarcoma Group database. PATIENTS AND METHODS: Three hundred and forty-three adults were included. We carried out univariate and multivariate analysis for overall survival (OS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS). RESULTS: Tumor locations were as follows: thoracic wall, 82.5%; abdominal wall, 12.3% and pelvic wall, 5.2%. Median tumor size was 6.0 cm. The most frequent tumor types were unclassified sarcoma (27.7%) and myogenic sarcoma (19.2%). A total of 44.6% of cases were grade 3. In all, 21.9% of patients had a previous medical history of radiotherapy (PHR). Median follow-up was 7.6 years. The 5-year OS, MFS and LRFS rates were 60.4%, 68.9% and 58.4%, respectively. Multivariate analysis retained PHR and grade for predicting LRFS and PHR, size and grade as prognostic factors of MFS. Factors influencing OS were age, size, PHR, depth, grade and surgical margins. The predictive factors of incomplete response were PHR, size and T3. CONCLUSIONS: Our results suggest similar classical prognostic factors as compared with sarcomas of other locations. However, a separate analysis of STS-TW revealed a significant poor prognosis subgroup of patients with PHR.