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Prevalence of dosing errors in elderly patients with impaired renal function: a survey in ambulatory patients (2010)

Ina Roehl Sebastian Harder

Meeting Abstract : Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie e.V. (GAA). 17. Jahrestagung der Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie. Osnabrück, 25.-26.11.2010. ntroduction: Several drugs require dose adjustment in patients with impaired renal function, which however, often goes undetected. Serum creatinine may be normal in patients while renal function is already reduced. The estimated GFR (eGFR) allows a more precise evaluation of the renal function. This study was carried out in a group practice for family medicine, in Frankfurt/ Main, Germany. The exploration aimed at investigating if patients with renal insufficiency were recognised and if their prescriptions were appropriate in terms of dose adjustment or contra-indications. Methods: In patients (>65yrs) with renal insufficiency (creatinine clearance <60 ml/min), their prescribed medication was retrospectively explored (Observation period 1.1.2008 to 1.4.2009). The Cockroft-Gault formula was used as estimate for the eGFR, using a creatinine value from the patient’s charts. In 90 patients, a second eGFR could be estimated from a second creatinine value obtained within 3-6 months. The recommended dose of each prescription in the SmPC (Fachinformation“) was compared to the dose that had been actually prescribed. Results: Out of 232 consecutively patients >65 yrs, 102 had an eGFR <60 ml/min, 16 of these had an eGFR <30 ml/min. The eGFR was closely correlated (r2=0.81) with an independent second eGFR. Out of these 102 patients, 48 had a serum creatinine level within the normal range. Renal adjustment was required in 263 of a total of 613 prescriptions. 72 prescriptions in a total of 45 patients were not appropriately adjusted (32) or prescribed despite a contraindication (40). For chronic prescriptions, metformin, ramipril, enalapril, HCTZ, and spironolactone accounted for 70% of inappropriate dosing; the magnitude of misdosing was 1.5 to 4 fold (median 2). 9 temporary prescriptions (of a total of 60 prescriptions) in 8 patients were not adjusted (cefuroxim, cefpodoxim, levofloxacin). We could not prove that patients with normal serum creatinine had a higher rate of inappropriate dosing than those with already elevated creatinine. Discussion and conclusion: In this GP practice, we have demonstrated a considerable prevalence of inappropriate dosing in patients with impaired renal function. It remains to be elucidated whether surveillance of appropriate dosing in renal impairment can be optimized e.g. with CPOE.

Genome-wide multi-parametric analysis of H2AX or γH2AX distributions during ionizing radiation-induced DNA damage response (2013)

Francesco Natale Alexander Rapp Wei Yu Marco Durante Gisela Taucher-Scholz Maria Cristina Cardoso

Background: After induction of DNA double strand breaks (DSBs), the DNA damage response (DDR) is activated. One of the earliest events in DDR is the phosphorylation of serine 139 on the histone variant H2AX (gH2AX) catalyzed by phosphatidylinositol 3-kinases-related kinases. Despite being extensively studied, H2AX distribution[1] across the genome and gH2AX spreading around DSBs sites[2] in the context of different chromatin compaction states or transcription are yet to be fully elucidated. Materials and methods: gH2AX was induced in human hepatocellular carcinoma cells (HepG2) by exposure to 10 Gy X-rays (250 kV, 16 mA). Samples were incubated 0.5, 3 or 24 hours post irradiation to investigate early, intermediate and late stages of DDR, respectively. Chromatin immunoprecipitation was performed to select H2AX, H3 and gH2AX-enriched chromatin fractions. Chromatin-associated DNA was then sequenced by Illumina ChIP-Seq platform. HepG2 gene expression and histone modification (H3K36me3, H3K9me3) ChIP-Seq profiles were retrieved from Gene Expression Omnibus (accession numbers GSE30240 and GSE26386, respectively). Results: First, we combined G/C usage, gene content, gene expression or histone modification profiles (H3K36me3, H3K9me3) to define genomic compartments characterized by different chromatin compaction states or transcriptional activity. Next, we investigated H3, H2AX and gH2AX distributions in such defined compartments before and after exposure to ionizing radiation (IR) to study DNA repair kinetics during DDR. Our sequencing results indicate that H2AX distribution followed H3 occupancy and, thus, the nucleosome pattern. The highest H2AX and H3 enrichment was observed in transcriptionally active compartments (euchromatin) while the lowest was found in low G/C and gene-poor compartments (heterochromatin). Under physiological conditions, the body of highly and moderately transcribed genes was devoid of gH2AX, despite presenting high H2AX levels. gH2AX accumulation was observed in 5’ or 3’ flanking regions, instead. The same genes showed a prompt gH2AX accumulation during the early stage of DDR which then decreased over time as DDR proceeded. Finally, during the late stage of DDR the residual gH2AX signal was entirely retained in heterochromatic compartments. At this stage, euchromatic compartments were completely devoid of gH2AX despite presenting high levels of non-phosphorylated H2AX. Conclusions: We show that gH2AX distribution ultimately depends on H2AX occupancy, the latter following H3 occupancy and, thus, nucleosome pattern. Both H2AX and H3 levels were higher in actively transcribed compartments. However, gH2AX levels were remarkably low over the body of actively transcribed genes suggesting that transcription levels antagonize gH2AX spreading. Moreover, repair processes did not take place uniformly across the genome; rather, DNA repair was affected by genomic location and transcriptional activity. We propose that higher H2AX density in euchromaticcompartments results in high relative gH2AXconcentration soon after the activation of DDR, thus favoring the recruitment of the DNA repair machinery to those compartments. When the damage is repaired and gH2AX is removed, its residual fraction is retained in the heterochromatic compartments which are then targeted and repaired at later times.

Transdisciplinary research on biodiversity : steps towards integrated biodiversity research (2012)

Marion Mehring Estelle V. Balian Angelique Berhault Engelbert Schramm

The workshop “Transdisciplinary Research on Biodiversity, Steps towards Integrated Biodiversity Research” was organized on 14-15 November 2011 in Brussels by the German-based Institute for Social-Ecological Research (ISOE) in cooperation with the European Platform for Biodiversity Research Strategy (EPBRS) and the Belgian Biodiversity Platform. The workshop was a follow up of the EPBRS summit “Positive Visions for Biodiversity” organized in November 2010, and its aim was to explore ways to further increase the capacities of transdisciplinary biodiversity research in Europe. It brought together researchers and experts, representatives and decision-makers from European institutions and research funding agencies, as well as members from civil society and the private sector. Participants discussed and identified in working groups key research topics and the added value of transdisciplinary approaches for three main themes of the “Positive Visions for Biodiversity” summit: 1/ The integration of biodiversity into every part of life 2/ Values and behaviours to a more harmonious way of life 3/ Governance that is more transparent and effective and that balances global and local responsibilities. During the final plenary panel discussion, participants highlighted recommendations for promoting transdisciplinary biodiversity research: ➢ Scientists have a role to play in raising awareness on the importance of biodiversity as a transdisciplinary issue. ➢ Environmental policy representatives at national and European level have to open up to and interact with other sectors to better advocate for global biodiversity agreements and mobilize more funding for transdisciplinary research on biodiversity. ➢ There is a need for scientists who are interested in comunicating and advocating. The biodiversity community needs people who are able to bridge between worlds, both science and advocacy, to get transdisciplinary biodiversity topics on European research agendas. ➢ Scientific academic training should provide means and opportunities to train these new professionals to become the “in-between” links. Current educational and insitutional frameworks need to be adapted to provide such training and career opportunities. ➢ Innovation should be understood in a broader sense than technology and products with market value. Research is needed on innovative ways to increase sustainable use, recycling of natural resources and learning from natural processes. ➢ The biodiversity community needs to reinforce its identity and build up larger influential groups to be able to advocate more efficiently at national and European levels. Among the main barriers to developing and implementing an efficient transdisciplinary research on biodiversity issues, the current trends in European research agendas to focus on technological and product oriented research is particularly detrimental. Improving advocacy on biodiversity and the implementation of transdisciplinary biodiversity research will be critical for the next decade to ensure the necessary knowledge for informing political decisions.

Molecular dynamics simulations and docking of non-nucleoside reverse transcriptase inhibitors (NNRTIs): a possible approach to personalized HIV treatment (2012)

Florian D. Roessler Oliver Korb Andreas Bender Werner Mäntele Peter J. Bond

The human immunodeficiency virus (HIV) is currently ranked sixth in the worldwide causes of death [1]. One treatment approach is to inhibit reverse transcriptase (RT), an enzyme essential for reverse transcription of viral RNA into DNA before integration into the host genome [2]. By using non-nucleoside RT inhibitors (NNRTIs) [3], which target an allosteric binding site, major side effects can be evaded. Unfortunately, high genetic variability of HIV in combination with selection pressure introduced by drug treatment enables the virus to develop resistance against this drug class by developing point mutations. This situation necessitates treatment with alternative NNRTIs that target the particular RT mutants encountered in a patient. Previously, proteochemometric approaches have demonstrated some success in predicting binding of particular NNRTIs to individual mutants; however a structurebased approach may help to further improve the predictive success of such models. Hence, our aim is to rationalize the experimental activity of known NNRTIs against a variety of RT mutants by combining molecular modeling, long-timescale atomistic molecular dynamics (MD) simulation sampling and ensemble docking. Initial control experiments on known inhibitor-RT mutant complexes using this protocol were successful, and the predictivity for further complexes is currently being evaluated. In addition to predictive power, MD simulations of multiple RT mutants are providing fundamental insight into the dynamics of the allosteric NNRTI binding site which is useful for the design of future inhibitors. Overall, work of this type is hoped to contribute to the development of predictive efficacy models for individual patients, and hence towards personalized HIV treatment options.

GCC2011 – 25 years of computational chemistry meetings (2012)

Frank Oellien Uli Fechner Thomas Engel

Design of dual ligands using excessive pharmacophore query alignment (2012)

Daniel Moser Joanna Wisniewska Steffen Hahn Estel la Buscató Franca-Maria Klingler Janosch Achenbach Bettina Hofmann Dieter Steinhilber Ewgenij Proschak

Oral presentation Dual- or multi-target ligands have gained increased attention in the past years due to several advantages, including more simple pharmacokinetic and phamarcodynamic properties compared to a combined application of several drugs. Furthermore multi-target ligands often possess improved efficacy [1]. We present a new approach for the discovery of dual-target ligands using aligned pharmacophore models combined with a shape-based scoring. Starting with two sets of known active compounds for each target, a number of different pharmacophore models is generated and subjected to pairwise graph-based alignment using the Kabsch-Algorithm [2,3]. Since a compound may be able to bind to different targets in different conformations, the algorithm aligns pairs of pharmacophore models sharing the same features which are not necessarily at the exactly same spatial distance. Using the aligned models, a pharmacophore search on a multi-conformation-database is performed to find compounds matching both models. The potentially “dual” ligands are scored by a shape-based comparison with the known active molecules using ShaEP [4]. Using this approach, we performed a prospective fragment-based virtual screening for dual 5-LO/sEH inhibitors. Both enzymes play an important role in the arachidonic acid cascade and are involved in inflammatory processes, pain, cardiovascular diseases and allergic reactions [5,6]. Beside several new selective inhibitors we were able to find a compound inhibiting both enzymes in low micromolar concentrations. The results indicate that the idea of aligned pharmacophore models can be successfully employed for the discovery of dual-target ligands.

Open Access 7th German Conference on Chemoinformatics: 25 CIC-Workshop : Goslar, Germany. 6-8 November 2011 ; meeting abstracts (2012)

Water Resources in the Future Climate Change Scenario: Development of an Integrated Management Concept for Water Supply in the Federal District of Brasília – DF (Central Brazil) (2009)

Arne P. Willner Hans-Joachim Massonne Axel Gerdes Francisco Hervé Masafumi Sudo Stuart N. Thomson

U-Pb LA-ICP-MS age determinations of growth impulses in zircons from Carboniferous post-orogenic granites, Sierra de Velasco (NW-Argentina) (2009)

Frank Söllner Pablo Grosse Axel Gerdes Alejandro J. Toselli Juana Norma Rossi

Provenance of Ordovician and Devonian sandstones from southern Peru and northern Bolivia - U-Pb and Lu-Hf isotope evidence of detrital zircons and its implications for the geodynamic evolution of the Western Gondwana margin (14°-17°S) (2009)

Cornelia R. Reimann Heinrich Bahlburg Ellen Kooijman Jasper Berndt Axel Gerdes Victor Carlotto

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