Adverse drug events associated with vitamin K antagonists: factors of therapeutic imbalance

Nancy El-Helou, Amal Al-Hajje, Rola Ajrouche, Sanaa Awada, Samar Rachidi, Salam Zein, Pascale SalamehClinical and Epidemiological Research Laboratory, Faculty of Pharmacy, Lebanese University, Beirut, LebanonBackground: Adverse drug events (ADE) occur frequently during treatment with vitamin K antagonists (AVK) and contribute to increase hemorrhagic risks.Methods: A retrospective study was conducted over a period of 2 years. Patients treated with AVK and admitted to the emergency room of a tertiary care hospital in Beirut were included. The aim of the study was to identify ADE characterized by a high international normalized ratio (INR) and to determine the predictive factors responsible for these events. Statistical analysis was performed with the SPSS statistical package.Results: We included 148 patients. Sixty-seven patients (47.3%) with an INR above the therapeutic range were identified as cases. The control group consisted of 81 patients (54.7%) with an INR within the therapeutic range. Hemorrhagic complications were observed in 53.7% of cases versus 6.2% of controls (P < 0.0001). No significant difference was noticed between cases and controls regarding the indication and the dose of AVK. Patients aged over 75 years were more likely to present an INR above the therapeutic range (58.2%, P = 0.049). Recent infection was present in 40.3% of cases versus 6.2% of controls (P < 0.0001) and hypoalbuminemia in 37.3% of cases versus 6.1% of controls (P < 0.0001). Treatment with antibiotics, amiodarone, and anti-inflammatory drugs were also factors of imbalance (P < 0.0001).Conclusion: Many factors may be associated with ADE related to AVK. Monitoring of INR and its stabilization in the therapeutic range are important for preventing these events.Keywords: adverse drug events, vitamin K antagonists, bleeding risks, therapeutic imbalanc

Polarimetric radar characteristics of lightning initiation and propagating channels

In this paper we present an analysis of a large dataset of lightning and polarimetric weather radar data collected in the course of a lightning measurement campaign that took place in the summer of 2017 in the area surrounding Säntis, in the northeastern part of Switzerland. For this campaign and for the first time in the Alps, a lightning mapping array (LMA) was deployed. The main objective of the campaign was to study the atmospheric conditions leading to lightning production with a particular focus on the lightning discharges generated due to the presence of the 124¿m tall Säntis telecommunications tower. In this paper we relate LMA very high frequency (VHF) sources data with co-located radar data in order to characterise the main features (location, timing, polarimetric signatures, etc.) of both the flash origin and its propagation path. We provide this type of analysis first for all of the data and then we separate the datasets into intra-cloud and cloud-to-ground flashes (and within this category positive and negative flashes) and also upward lightning. We show that polarimetric weather radar data can be helpful in determining regions where lightning is more likely to occur but that lightning climatology and/or knowledge of the orography and man-made structures is also relevant.Peer ReviewedPostprint (author's final draft

Biohydrogen production from fermentation of organic waste, storage and applications

open access articleBiohydrogen is a carbon-free alternative energy source, that can be obtained from fermentation of organic waste, biomass-derived sugars, and wastewater. This article reviews the current processes for fermentative biohydrogen production from biomass including its appropriate storage and transport challenges. The review showed that a comparison of fermentation pretreatment methods across the literature is complicated and that fermentability tests are necessary to determine the best combination of pretreatment/feedstock. Operational parameters, such as temperature, pH, macro/micronutrients addition are widely dependent on the type of fermentation and microorganisms used and hence their content need to be tailored to the process. For immobilized cells, the range of hydrogen production rate values reported for granulation processes using mixed microbial cultures, were higher (13–297 mmol H2/L h) than those reported for entrapment (1–115 mmol H2/L h) and adsorption (3–83 mmol H2/L h), suggesting an achievable and sustainable route for full-scale applications. A purification phase is mandatory before the final use of biohydrogens. Sorption techniques and the use of membranes are the most widely used approaches. Pressure swing adsorption has the highest recovery rate (it reaches 96%). In addition, storage of biohydrogen can have several forms with varying storage capacities (depending on the form and/or storage materials used). The transport of biohydrogen often faces technical and economic challenges requiring optimization to contribute to the development of a biohydrogen economy

Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes

<p>Abstract</p> <p>Background</p> <p>Down syndrome (DS; trisomy 21) is the most common genetic cause of mental retardation in the human population and key molecular networks dysregulated in DS are still unknown. Many different experimental techniques have been applied to analyse the effects of dosage imbalance at the molecular and phenotypical level, however, currently no integrative approach exists that attempts to extract the common information.</p> <p>Results</p> <p>We have performed a statistical meta-analysis from 45 heterogeneous publicly available DS data sets in order to identify consistent dosage effects from these studies. We identified 324 genes with significant genome-wide dosage effects, including well investigated genes like <it>SOD1</it>, <it>APP</it>, <it>RUNX1 </it>and <it>DYRK1A </it>as well as a large proportion of novel genes (N = 62). Furthermore, we characterized these genes using gene ontology, molecular interactions and promoter sequence analysis. In order to judge relevance of the 324 genes for more general cerebral pathologies we used independent publicly available microarry data from brain studies not related with DS and identified a subset of 79 genes with potential impact for neurocognitive processes. All results have been made available through a web server under <url>http://ds-geneminer.molgen.mpg.de/</url>.</p> <p>Conclusions</p> <p>Our study represents a comprehensive integrative analysis of heterogeneous data including genome-wide transcript levels in the domain of trisomy 21. The detected dosage effects build a resource for further studies of DS pathology and the development of new therapies.</p

Phenotypic and genotypic diversity of wine yeasts used for acidic musts

The aim of this study was to examine the physiological and genetic stability of the industrial wine yeasts Saccharomyces cerevisiae and Saccharomyces bayanus var. uvarum under acidic stress during fermentation. The yeasts were sub-cultured in aerobic or fermentative conditions in media with or without l-malic acid. Changes in the biochemical profiles, karyotypes, and mitochondrial DNA profiles were assessed after minimum 50 generations. All yeast segregates showed a tendency to increase the range of compounds used as sole carbon sources. The wild strains and their segregates were aneuploidal or diploidal. One of the four strains of S. cerevisiae did not reveal any changes in the electrophoretic profiles of chromosomal and mitochondrial DNA, irrespective of culture conditions. The extent of genomic changes in the other yeasts was strain-dependent. In the karyotypes of the segregates, the loss of up to 2 and the appearance up to 3 bands was noted. The changes in their mtDNA patterns were much broader, reaching 5 missing and 10 additional bands. The only exception was S. bayanus var. uvarum Y.00779, characterized by significantly greater genome plasticity only under fermentative stress. Changes in karyotypes and mtDNA profiles prove that fermentative stress is the main driving force of the adaptive evolution of the yeasts. l-malic acid does not influence the extent of genomic changes and the resistance of wine yeasts exhibiting increased demalication activity to acidic stress is rather related to their ability to decompose this acid. The phenotypic changes in segregates, which were found even in yeasts that did not reveal deviations in their DNA profiles, show that phenotypic characterization may be misleading in wine yeast identification. Because of yeast gross genomic diversity, karyotyping even though it does not seem to be a good discriminative tool, can be useful in determining the stability of wine yeasts. Restriction analysis of mitochondrial DNA appears to be a more sensitive method allowing for an early detection of genotypic changes in yeasts. Thus, if both of these methods are applied, it is possible to conduct the quick routine assessment of wine yeast stability in pure culture collections depositing industrial strains

A Predictive Model of the Oxygen and Heme Regulatory Network in Yeast

Deciphering gene regulatory mechanisms through the analysis of high-throughput expression data is a challenging computational problem. Previous computational studies have used large expression datasets in order to resolve fine patterns of coexpression, producing clusters or modules of potentially coregulated genes. These methods typically examine promoter sequence information, such as DNA motifs or transcription factor occupancy data, in a separate step after clustering. We needed an alternative and more integrative approach to study the oxygen regulatory network in Saccharomyces cerevisiae using a small dataset of perturbation experiments. Mechanisms of oxygen sensing and regulation underlie many physiological and pathological processes, and only a handful of oxygen regulators have been identified in previous studies. We used a new machine learning algorithm called MEDUSA to uncover detailed information about the oxygen regulatory network using genome-wide expression changes in response to perturbations in the levels of oxygen, heme, Hap1, and Co2+. MEDUSA integrates mRNA expression, promoter sequence, and ChIP-chip occupancy data to learn a model that accurately predicts the differential expression of target genes in held-out data. We used a novel margin-based score to extract significant condition-specific regulators and assemble a global map of the oxygen sensing and regulatory network. This network includes both known oxygen and heme regulators, such as Hap1, Mga2, Hap4, and Upc2, as well as many new candidate regulators. MEDUSA also identified many DNA motifs that are consistent with previous experimentally identified transcription factor binding sites. Because MEDUSA's regulatory program associates regulators to target genes through their promoter sequences, we directly tested the predicted regulators for OLE1, a gene specifically induced under hypoxia, by experimental analysis of the activity of its promoter. In each case, deletion of the candidate regulator resulted in the predicted effect on promoter activity, confirming that several novel regulators identified by MEDUSA are indeed involved in oxygen regulation. MEDUSA can reveal important information from a small dataset and generate testable hypotheses for further experimental analysis. Supplemental data are included

LTR Retrotransposons in Fungi

Transposable elements with long terminal direct repeats (LTR TEs) are one of the best studied groups of mobile elements. They are ubiquitous elements present in almost all eukaryotic genomes. Their number and state of conservation can be a highlight of genome dynamics. We searched all published fungal genomes for LTR-containing retrotransposons, including both complete, functional elements and remnant copies. We identified a total of over 66,000 elements, all of which belong to the Ty1/Copia or Ty3/Gypsy superfamilies. Most of the detected Gypsy elements represent Chromoviridae, i.e. they carry a chromodomain in the pol ORF. We analyzed our data from a genome-ecology perspective, looking at the abundance of various types of LTR TEs in individual genomes and at the highest-copy element from each genome. The TE content is very variable among the analyzed genomes. Some genomes are very scarce in LTR TEs (<50 elements), others demonstrate huge expansions (>8000 elements). The data shows that transposon expansions in fungi usually involve an increase both in the copy number of individual elements and in the number of element types. The majority of the highest-copy TEs from all genomes are Ty3/Gypsy transposons. Phylogenetic analysis of these elements suggests that TE expansions have appeared independently of each other, in distant genomes and at different taxonomical levels. We also analyzed the evolutionary relationships between protein domains encoded by the transposon pol ORF and we found that the protease is the fastest evolving domain whereas reverse transcriptase and RNase H evolve much slower and in correlation with each other

Systematic Identification of Balanced Transposition Polymorphisms in Saccharomyces cerevisiae

High-throughput techniques for detecting DNA polymorphisms generally do not identify changes in which the genomic position of a sequence, but not its copy number, varies among individuals. To explore such balanced structural polymorphisms, we used array-based Comparative Genomic Hybridization (aCGH) to conduct a genome-wide screen for single-copy genomic segments that occupy different genomic positions in the standard laboratory strain of Saccharomyces cerevisiae (S90) and a polymorphic wild isolate (Y101) through analysis of six tetrads from a cross of these two strains. Paired-end high-throughput sequencing of Y101 validated four of the predicted rearrangements. The transposed segments contained one to four annotated genes each, yet crosses between S90 and Y101 yielded mostly viable tetrads. The longest segment comprised 13.5 kb near the telomere of chromosome XV in the S288C reference strain and Southern blotting confirmed its predicted location on chromosome IX in Y101. Interestingly, inter-locus crossover events between copies of this segment occurred at a detectable rate. The presence of low-copy repetitive sequences at the junctions of this segment suggests that it may have arisen through ectopic recombination. Our methodology and findings provide a starting point for exploring the origins, phenotypic consequences, and evolutionary fate of this largely unexplored form of genomic polymorphism

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively