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Herpesviruses are large DNA viruses and include important human and veterinary pathogens. Their genomes can be cloned as bacterial artificial chromosomes (BACs) and genetically engineered in Escherichia coliusing BAC recombineering methods. While the recombineering methods are efficient, the initial BAC-cloning step remains laborious. To overcome this limitation, we have developed a simple, rapid, and efficient BAC-cloning method based on single-step transformation-associated recombination (STAR) in Saccharomyces cerevisiae. The linear viral genome is directly integrated into a vector comprising a yeast centromeric plasmid and a BAC replicon. Following transfer into E. coli, the viral genome can be modified using standard BAC recombineering techniques. We demonstrate the speed, fidelity, and broad applicability of STAR by cloning two strains of both rat cytomegalovirus (a betaherpesvirus) and Kaposi’s sarcoma-associated herpesvirus (a gammaherpesvirus). STAR cloning facilitates the functional genetic analysis of herpesviruses and other large DNA viruses and their use as vaccines and therapeutic vectors.

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A major problem for the freshwater supply of coastal regions is the intrusion of saltwater into aquifers. Due to extensive extraction of freshwater to suffice increasing drinking water demands and/or in periods of reduced groundwater recharge, the equilibrium state may be disturbed. The result is an upconing or movement of the fresh–saline groundwater interface, which reduces the local drinking water resources at coastal regions or islands. The saltwater monitoring system (SAMOS) is a vertical electrode chain installed in a backfilled borehole. It provides a solution to observe the transition zone in detail, both temporally and spatially. We present monitoring data of the first year from three locations ‐ with different geological conditions that show disturbances in the resistivity distribution that result from the drilling processes. A clayey backfilling, for example, can lead to beam‐like artefacts, and a mixed fluid within the backfilling changes its bulk resistivity, both leading to misinterpretations. We performed data inversion under cylindrically symmetrical conditions in full‐space in order to separate these resistivity artefacts from the undisturbed background. Data inversion reveals that it is possible to separate drilling effects on the resistivity distribution from the undisturbed background. Thus, an interpretation of the natural transition zones can be made immediately after the installation.

There is an increasing demand for trustworthy engineering geological conceptual models in urban areas due to an increasing trend in the underground infrastructure construction. Good‐quality site investigations can reduce the risk of encountering unexpected geological conditions during construction. Geoelectrical measurements can be used as a tool for providing an overview of the site conditions and serve as a base for planning a geotechnical drilling program and for integration of the results. Geophysical surveys in urban environments may encounter problems due to strict logistical constraints and may be severely affected by electric and electromagnetic noise. Careful processing of the data is necessary to obtain a reliable estimation of the electrical properties of the ground, both electrical resistivity and chargeability. A large three‐dimensional dataset was acquired in the suburban area of Stockholm (Sweden), with the aim of investigating a weak zone in the crystalline bedrock, which had been pointed out by prior geological and geotechnical surveys. Full waveforms of potential dipoles were recorded and processed for removing harmonic noise and background drift. Moreover, a statistical algorithm for handling the quality of the full‐waveform shapes has been proposed. The goodness‐of‐fit test identifies full waveforms with noise that derives from direct current injections, caused by grounding spots of the adjacent metro line. The processed dataset is inverted for electrical resistivity and integral chargeability. The results image a large three‐dimensional volume of the underground. The inverted distribution of geophysical quantities marks out the presence of a wide zone of weak rock, which was not identified by geotechnical probing in the site investigation but documented during the construction phase. Such zones can potentially cause severe problems during the construction of underground infrastructure.

In the past few years, the focus on Alum shale hazards and the need for efficient mapping tools have increased in Norway. Alum shale is highly toxic and poses a substantial obstacle to infrastructure development such as tunnel projects. We present an evaluation of the ground‐based electrical resistivity tomography, induced polarisation, and airborne electromagnetic methods for mapping purposes using a recent case study. This evaluation is done in combination with resistivity and chargeability laboratory measurements applied to drill cores. The aim of the geophysical survey was to improve the knowledge of Alum shale occurrence to assist a tunnel project in Gran, southeast Norway. Resistivity and chargeability models derived from an electrical resistivity tomography/induced polarisation survey enabled us to map the presence of Alum shale during the tunnel investigation. The resistivity models point to geological layers that are in agreement with the rock types observed from early drillings together with subsequent geological logging during tunnelling. The time‐domain chargeability models are imperfect but nonetheless reveal the presence of polarisable minerals. These are likely due to the high levels of sulphides contained in black shale. An airborne electromagnetic survey was done close to the area of interest, which enabled us to fly some sparse lines across the tunnel alignment as a piggyback survey. Although the airborne electromagnetic resolution is lower than electrical resistivity tomography, the successful test flight lines illustrate the potential of airborne electromagnetic surveys for Alum shale mapping in Norway and affirm the promise of airborne electromagnetic in the early stages of project exploration.

Zusammenfassung.Fragestellung:Der Verlauf von Lesestörungen wird durch häufig auftretende komorbide Verhaltensstörungen negativ beeinflusst. Querschnittstudien belegen diesen überzufälligen Zusammenhang zwischen Verhaltensproblemen und Teilleistungsstörungen. Bisher befassten sich wenige Studien mit der Veränderung des Verhaltens in Abhängigkeit mit der Leseentwicklung. Die vorliegende Longitudinalstudie geht der Frage nach, ob und in welcher Weise sich die Verhaltensbeurteilung von Kindern im Elternurteil (CBCL) vom Vorschulalter bis zum Ende der zweiten Klasse abhängig von den Leseleistungen der Kinder verändert. Methodik:Die Leseleistungen von 241 Kindern wurden vom Vorschulalter bis zur zweiten Klasse jährlich untersucht. Parallel beurteilten die Eltern mittels CBCL das Verhalten der Kinder. Ergebnisse:Varianzanalysen mit Messwiederholung zeigten, dass schwache Leser besonders in der ersten Klasse im Gesamtproblemwert der CBCL sowie im externalisierenden Verhalten auffälliger bewertet wurden als im Kindergarten. Im Vorschulalter unterschieden sich die später schwachen von guten Leser in externalisierenden und internalisierenden Symptomen noch nicht, jedoch wiesen sie mehr Aufmerksamkeitsprobleme auf. In der ersten und zweiten Klasse zeigten schwache Leser insgesamt mehr Verhaltensauffälligkeiten als gute Leser. Auch der Anteil der Kinder mit klinisch bedeutsamen Verhaltensauffälligkeiten nahm in der Gruppe der schwachen Leser in der Schulzeit zu. Schlussfolgerung:Diese Ergebnisse weisen darauf hin, dass die Konfrontation mit den Leistungsanforderungen in der Schule für die Kinder eine besondere Belastung darstellt.

Im Jahre 2015 wurden in Deutschland 890.000 Asylsuchende registriert. Die medizinische und psychosoziale Versorgung von Asylsuchenden ist mit zahlreichen Hürden und Schwierigkeiten versehen. Insbesondere während des Aufenthalts in den Erstaufnahmeeinrichtungen ist der Zugang zur Versorgung meist unzureichend. Die vorliegende Arbeit beschreibt die Entwicklung und Implementierung einer interdisziplinären medizinischen Ambulanz für Asylsuchende in der Registrierungsstelle des Landes Baden-Württemberg, die gleichermaßen von Ärzten des Universitätsklinikums Heidelberg als auch von der niedergelassenen Ärzteschaft in Heidelberg betrieben wird. Zur Planung und Umsetzung der medizinischen Ambulanz wurde ein Lenkungsausschuss eingerichtet. Neun Mitglieder des Lenkungsausschusses wurden anhand halbstandardisierter Interviews zu wahrgenommenen Barrieren der Implementierung und Herausforderungen im Rahmen der Entwicklung der Ambulanz befragt. Für das Gelingen des Implementierungsprozesses wurden das hohe persönliche Engagement der Ausschussmitglieder und die unparteiische Leitung durch das Gesundheitsamt gesehen. Wesentliche Barrieren zeigten sich in der Finanzierung von Personal, Einrichtungsgegenständen und Sprachmittlung sowie in haftungsrechtlichen und abrechnungsbezogenen Aspekten. Die Ergebnisse werden mit dem Fokus auf Fragen der Finanzierung, der administrativen und juristischen Rahmenbedingungen, Sprachmittlung, Dokumentation und weiteren Aspekten, die für eine Versorgung mit hoher Qualität notwendig sind, diskutiert.

ABSTRACTIntroduction: Epigenetic regulators including writers, erasers, and readers of chromatin marks have been implicated in numerous diseases and are therefore subject of intense academic and pharmaceutical research. While several small-molecule inhibitors targeting writers or erasers are either approved drugs or are currently being evaluated in clinical trials, the targeting of epigenetic readers has lagged behind. Proof-of-principle that epigenetic readers are also relevant drug targets was provided by landmark discoveries of selective inhibitors targeting the BET family of acetyl-lysine readers. More recently, high affinity chemical probes for non-BET acetyl- and methyl-lysine reader domains have also been developed.Areas covered: This article covers recent advances with the identification and validation of inhibitors and chemical probes targeting epigenetic reader domains. Issues related to epigenetic reader druggability, quality requirements for chemical probes, interpretation of cellular action, unexpected cross-talk, and future challenges are also discussed.Expert opinion: Chemical probes provide a powerful means to unravel biological functions of epigenetic readers and evaluate their potential as drug targets. To yield meaningful results, potency, selectivity, and cellular target engagement of chemical probes need to be stringently validated. Future chemical probes will probably need to fulfil additional criteria such as strict target specificity or the targeting of readers within protein complexes.

Excavation and piling works related to seafront development in Oslo’s historic harbour area need to mitigate the risk of damaging buried archaeological objects. In the Bjørvika harbour in Oslo, Norway, electrical resistivity tomography was performed to detect structures with potential archaeological value. A 2.5 dataset consisting of four equally spaced parallel lines was collected, trimmed, and systematically processed with both 2D and 3D inversion routines. The results were in good agreement with known underground features, and for the present dataset, an iteratively reweighted least squares 2D inversion was clearly preferable over a 3D inversion. This conclusion is based on differences in model resolution, data processing costs, and the value of the final product for engineering decision‐making.

Self-assembled supramolecular coordination complexes (SCCs) hold promise for biomedical applications in cancer therapy, although their potential in the field of nuclear medicine is still substantially unexplored. Therefore, in this study an exo-functionalized cationic [Pd2L2]4+metallacycle (L = 3,5-bis(3-ethynylpyridine)phenyl), targeted to the somatostatin-2 receptor (sst2R) and featuring the DOTA chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) in order to bind the β–- and γ-emitter lutetium-177, was synthesized by self-assembly following ligand synthesis via standard solid-phase peptide synthesis (SPPS). This metallacycle was then characterized by reverse-phase high-performance liquid chromatography (RP-HPLC), electrospray ionization mass spectrometry (ESI-MS), and 1H and 1H-DOSY NMR (DOSY = diffusion-ordered spectroscopy). A procedure for the radiolabeling of the metallacycle with 177Lu was also optimized. The resulting [nat/177Lu]Lu-DOTA-metallacycle, termed [nat/177Lu]Lu-Cy, was evaluated concerning its stability and in vitroproperties. The compound was more lipophilic compared to the reference [177Lu]Lu-DOTA-TATE (logPOct/H2O= −0.85 ± 0.10 versus −3.67 ± 0.04, respectively). While [natLu]Lu-Cyrevealed low stability in a DMEM/F12 GlutaMax medium, it demonstrated good stability in other aqueous media as well as in DMSO. A high sst2R binding affinity (expressed as IC50) was determined in CHOsst2cells (Chinese hamster ovary cells that were stably transfected with human sst2R). Moreover, the metallacycle exhibited high human serum albumin binding, as assessed by high-performance affinity chromatography (HPAC), and moderate stability in human serum compared to [177Lu]Lu-DOTA-TATE (TATE = (Tyr3)-octreotate). In order to improve stability, a heteroleptic approach was used to develop a less sterically hindered cage-like SCC that is potentially endowed with host–guest chemistry capability, which has been preliminarily characterized by RP-HPLC and ESI-MS. Overall, our initial results encourage future studies on sst2R-directed SCCs and have led to new insights into the chemistry of ss2R-directed SCCs for radiopharmaceutical applications.

Management techniques, such as marketization and performance measurement of academic activities, can be evidenced in universities around the globe. They have given rise to extensive research in the higher education sector. This paper provides a systematic literature review of 236 papers on public sector accounting research in higher education from 83 analysed journals from the three areas of accounting, public management and administration, and higher education between 1980 and 2014. We analyse research location, theoretical approaches, research methods, and topics used in these fields and their change over time. We also compare our results with those of reviews on general public sector accounting research. Our results show a dominance of research from Anglo-American countries. The majority of papers informed by a radical/alternative theoretical approach use descriptive case and field research whereas studies with a functionalist approach apply mathematical analyses, surveys and archival research. In terms of topics, high importance is attached to accountability/governance, performance measurement, external reporting, and budgeting in which the adoption of accounting systems and their usefulness is often discussed. Furthermore, we cluster papers in 12 groups and find a highly fragmented body of research reflecting the different specifics of the higher education sector. From this we derive opportunities for future research.

Zusammenfassung.Eine Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) und eine Lese-Rechtschreibstörung (LRS) treten überdurchschnittlich häufig gemeinsam auf und können die Entwicklung betroffener Kinder negativ beeinflussen. Das Ziel der vorliegenden Studie war ein Vergleich der Aufmerksamkeits- und Leseleistungen von Kindern mit ADHS, LRS und ADHS plus LRS. Es wurden 99 Kinder der dritten und vierten Klasse (ADHS n= 26, LRS n= 22, ADHS plus LRS n= 24, Kontrollkinder n= 27) mittels verschiedener Lese-Rechtschreibtests und einer modellorientierten Aufmerksamkeitsdiagnostik untersucht. Zudem wurden mögliche Begleitstörungen erfasst. Die Kinder mit ADHS hatten Schwierigkeiten sowohl im Pseudowortlesen als auch im Wortverständnis, während die Kinder mit LRS zusätzliche Auffälligkeiten in der Aufmerksamkeitsleistung zeigten. Psychometrisch zeigten alle Kinder mit LRS Auffälligkeiten im internalisierenden und externalisierenden Bereich, wobei Kinder mit ADHS plus LRS in fast allen Skalen die höchsten Werte aufwiesen. Die Ergebnisse deuten darauf hin, dass die Probleme von Kindern mit ADHS beim Lesen z. T. ein Epiphänomen darstellen, das unter dem Zeitdruck des Testverfahrens entsteht. Die gefundenen Einschränkungen der Aufmerksamkeit bei Kindern mit LRS unterstreichen die Bedeutung einer ausführlichen Diagnostik im Hinblick auf eine möglicherweise vorliegende subklinische ADHS bei bestehendem LRS. Es bleibt zu klären, welchen Einfluss die frühzeitige Behandlung von Aufmerksamkeitsdefiziten auf den Leseerwerb und die Prognose betroffener Kinder hat.

The human somatostatin receptor 3 (sst3) is expressed in about 50% of all neuroendocrine tumors and hence a promising target for multireceptor somatostatin analogs. The sst3receptor is unique among ssts in that it exhibits a very long intracellular C-terminal tail containing a huge number of potential phosphate acceptor sites. Consequently, our knowledge about the functional role of the C-terminal tail in sst3receptor regulation is very limited. Here, we have generated a series of phosphorylation-deficient mutants that enabled us to determine crucial sites for its agonist-induced β-arrestin mobilization, internalization, and down-regulation. Based on this information, we generated phosphosite-specific antibodies for C-terminal Ser337/Thr341, Thr348, and Ser361that enabled us to investigate the temporal patterns of sst3phosphorylation and dephosphorylation. We found that the endogenous ligand somatostatin induced a rapid and robust phosphorylation that was completely blocked by the sst3antagonist NVP-ACQ090. The stable somatostatin analogs pasireotide and octreotide promoted clearly less phosphorylation compared with somatostatin. We also show that sst3phosphorylation occurred within seconds to minutes, whereas dephosphorylation of the sst3receptor occurred at a considerable slower rate. In addition, we also identified G protein-coupled receptor kinases 2 and 3 and protein phosphatase 1α and 1β as key regulators of sst3phosphorylation and dephosphorylation, respectively. Thus, we here define the C-terminal phosphorylation motif of the human sst3receptor that regulates its agonist-promoted phosphorylation, β-arrestin recruitment, and internalization of this clinically relevant receptor.

Stable somatostatin analogues and dopamine receptor agonists are the mainstay for the pharmacological treatment of functional pituitary adenomas; however, only a few cellular assays have been developed to detect receptor activation of novel compounds without disrupting cells to obtain the second messenger content. Here, we adapted a novel fluorescence-based membrane potential assay to characterize receptor signaling in a time-dependent manner. This minimally invasive technique provides a robust and reliable read-out for ligand-induced receptor activation in permanent and primary pituitary cells. The mouse corticotropic cell line AtT-20 endogenously expresses both the somatostatin receptors 2 (sst2) and 5 (sst5). Exposure of wild-type AtT-20 cells to the sst2- and sst5-selective agonists BIM-23120 and BIM-23268, respectively, promoted a pertussis toxin- and tertiapin-Q-sensitive reduction in fluorescent signal intensity, which is indicative of activation of G protein-coupled inwardly rectifying potassium (GIRK) channels. After heterologous expression, sst1, sst3, and sst4 receptors also coupled to GIRK channels in AtT-20 cells. Similar activation of GIRK channels by dopamine required overexpression of dopamine D2 receptors (D2Rs). Interestingly, the presence of D2Rs in AtT-20 cells strongly facilitated GIRK channel activation elicited by the sst2-D2 chimeric ligand BIM-23A760, suggesting a synergistic action of sst2 and D2Rs. Furthermore, stable somatostatin analogues produced strong responses in primary pituitary cultures from wild-type mice; however, in cultures from sst2 receptor-deficient mice, only pasireotide and somatoprim, but not octreotide, induced a reduction in fluorescent signal intensity, suggesting that octreotide mediates its pharmacological action primarily via the sst2 receptor.

Complex regulation of viral transcription patterns and DNA replication levels is a feature of many DNA viruses. This is especially true for those viruses which establish latent or persistent infections (e.g., herpesviruses, papillomaviruses, polyomaviruses, or adenovirus), as long‐term persistence often requires adaptation of gene expression programs and/or replication levels to the cellular milieu. A key factor in the control of such processes is the establishment of a specific chromatin state on promoters or replication origins, which in turn will determine whether or not the underlying DNA is accessible for other factors that mediate downstream processes. Chromatin immunoprecipitation (ChIP) is a powerful technique to investigate viral chromatin, in particular to study binding patterns of modified histones, transcription factors or other DNA‐/chromatin‐binding proteins that regulate the viral lifecycle. Here, we provide protocols that are suitable for performing ChIP‐PCR and ChIP‐Seq studies on chromatin of large and small viral genomes.© 2016 by John Wiley & Sons, Inc.

We here investigate the impact of antiviral treatments such as remdesivir on intra-host genomic diversity and emergence of SARS-CoV2 variants in patients with a prolonged course of infection. Sequencing and variant analysis performed in 112 longitudinal respiratory samples from 14 SARS-CoV2-infected patients with severe disease progression show that major frequency variants do not generally arise during prolonged infection. However, remdesivir treatment can increase intra-host genomic diversity and result in the emergence of novel major variant species harboring fixed mutations. This is particularly evident in a patient with B cell depletion who rapidly developed mutations in the RNA-dependent RNA polymerase gene following remdesivir treatment. Remdesivir treatment-associated emergence of novel variants is of great interest in light of current treatment guidelines for hospitalized patients suffering from severe SARS-CoV2 disease, as well as the potential use of remdesivir to preventively treat non-hospitalized patients at high risk for severe disease progression.

Zusammenfassung.Die Mehrzahl PC-gestützter Trainingsprogramme erhebt den Anspruch einer theoriegeleiteten Konzeption und weckt entsprechend hohe Erwartungen. Wissenschaftliche Wirksamkeitsnachweise existieren nur für wenige Verfahren. Der Arbeitskreis Aufmerksamkeit & Gedächtnis der GNP präsentiert hier die Struktur einer Programmrezension, die eine übersichtliche Zusammenfassung und transparente Bewertung von Trainingsprogrammen unter Bezug auf insgesamt 20 neuropsychologische, technische und pragmatische Kriterien erlaubt. Schließlich beschreiben wir den Aufbau eines Manuals, das für alle Kriterien die qualitäts-bestimmenden Programmeigenschaften spezifiziert und durch die Erstellung einer Rezension führt; das komplette Manual ist in diesem Heft abgedruckt. Die mit dieser Zeitschrift begonnene Veröffentlichung von Beispielrezensionen wird in loser Folge fortgesetzt.

ZusammenfassungFür Batteriemanagementsysteme (BMS) sind Umfang und Verlässlichkeit der Datenbasis von besonderer Bedeutung. Bisher kommt ein Großteil dieser Daten aus Prüfständen und wird dem BMS als Tabelle bereitgestellt. Um den Einfluss dieser Offline-Daten im BMS zu reduzieren und so die Leistungsfähigkeit eines Batteriesystems zu steigern, wurde eine Hardware entwickelt, welche eine Online-Messung des Impedanzspektrums von Batterien ermöglicht. Der Fokus liegt hierbei auf der Adaption der im Labor häufig eingesetzten Impedanzspektroskopie, um diese in mobilen Anwendungen mit Low-cost-Hardware verfügbar zu machen.

This paper summarizes the results on inkjet printing and characterization of functional structures on molded 2D and 3D devices. Different injection molded thermoplastics, a transfer molded thermoset and polyimide foil as substrate materials were used. Conductive structures were obtained by inkjet printing of a commercial available silver nanoparticle ink. The use of printable acrylic based ink enabled the fabrication of conductor crossovers or multilayers. Results on inkjet printed temperature sensitive structures and an inkjet printed intrusion sensor device as well as an inkjet printed electrical interconnect on a transfer molded package will be presented.

Objectives:Although clear advances have been achieved in the study of early-onset schizophrenia (EOS), little is known to date about premorbid and prodromal neuropsychological functioning in EOS. Method:Here, we report on a case of an adolescent male with EOS who underwent neuropsychological testing before and after illness onset. Results:Marked cognitive deficits in the domains of attention, set-shifting, and verbal memory were present both pre-onset and during the course of schizophrenia, though only deficits in verbal memory persisted after illness-onset and antipsychotic treatment. Conclusion:The findings of this case study suggest that impairments in the verbal memory domain are particularly prominent symptoms of cognitive impairment in prodromal EOS and persist in the course of the disorder, which further demonstrates the difficult clinical situation of adequate schooling opportunities for adolescent patients with EOS.

Development in instrumentation and data analysis of surface nuclear magnetic resonance has recently moved on from one‐dimensional (1D) soundings to two‐dimensional (2D) surveys, opening the method to a larger field of hydrological applications. Current analysis of 2D data sets, however, does not incorporate relaxation times and is therefore restricted to the water content distribution in the subsurface. We present a robust 2D inversion scheme, based on the qt approach, which jointly inverts for water content and relaxation time by taking the complete data set into account. The spatial distribution of relaxation time yields structural information of the subsurface and allows for additional petrophysical characterization. The presented scheme handles separated loop configurations for increased lateral resolution. Assuming a mono‐exponential relaxation in each model cell, using irregular meshes, and gate‐integrating the signal, the size of the inverse problem is significantly reduced and can be handled on a standard personal computer. A synthetic study shows that contrasts in both the quantities – water content and relaxation time – can be imaged. Inversion of a field data set outlines a buried glacial valley and allows the distinguishing of two aquifers with different grain sizes, which can be concisely interpreted together with a resistivity profile. The impact of the anisotropic weighting factor and subsurface resistivity on the inversion result are shown and discussed. A comparison of the results obtained by the previously used initial value and time‐step inversion approaches illustrates the improved stability and resolution capabilities of the 2D qt inversion scheme.

The purpose of this cross-sectional study was to compare performance on visual and auditory attention tasks along with the developmental trajectories of these systems. Participants between 7 and 77 years of age were examined: 490 subjects (229 males and 261 females) completed the visual and auditory part of a focused-attention task, and 688 subjects (320 males and 368 females) were tested with an alertness task in the two different modalities. Shorter reaction times were observed in the visual condition compared to the auditory condition. This difference was particularly large for children and for the more complex, focused-attention task. However, the gap between the two modalities decreased with age, resulting in significant interaction effects between age and modality for both attention tasks. Attentional performance increased with age, and maximum performance was achieved in early adulthood. For nearly all performance variables, no decrease could be detected with increasing age. In addition, the results of a principal components analysis suggest that, independent of modality, all alertness variables load on one component, whereas the performance variables of the visual and the auditory focused-attention task load on two separate components. Thus, our data suggest that visual and auditory attention rely on distinct attentional systems within the selectivity domain of attention and have distinct developmental trajectories.

The t(12;21) chromosomal translocation, targeting the gene encoding the RUNX1 transcription factor, is observed in 25% of pediatric acute lymphoblastic leukemia (ALL) and is an initiating event in the disease. To elucidate the mechanism by which RUNX1disruption initiates leukemogenesis, we investigated its normal role in murine B-cell development. This study revealed 2 critical functions of Runx1: (1) to promote survival and development of progenitors specified to the B-cell lineage, a function that can be substituted by ectopic Bcl2 expression, and (2) to enable the developmental transition through the pre-B stage triggered by the pre-B-cell antigen receptor (pre-BCR). Gene expression analysis and genomewide Runx1 occupancy studies support the hypothesis that Runx1 reinforces the transcription factor network governing early B-cell survival and development and specifically regulates genes encoding members of the Lyn kinase subfamily (key integrators of interleukin-7 and pre-BCR signaling) and the stage-specific transcription factors SpiB and Aiolos (critical downstream effectors of pre-BCR signaling). Interrogation of expression databases of 257 ALL samples demonstrated the specific down-regulation of the SPIBand IKZF3genes (the latter encoding AIOLOS) in t(12;21) ALL, providing novel insight into the mechanism by which the translocation blocks B-cell development and promotes leukemia.

Am Beispiel zweier mittelständischer Unternehmen der metallverarbeitenden Industrie werden exemplarisch Unterschiede in der Realisierung arbeitsmedizinischer und sicherheitstechnischer Betreuung aufgezeigt und deren betriebswirtschaftliche Wirkungen analysiert. Die Analyse erfolgt auf Basis eines Indikatorensystems, in das Daten zur Qualität des präventiven Arbeits- und Gesundheitsschutzes und Daten des Unternehmenscontrollings einfließen. Im Beitrag wird der Nutzen einer solchen ganzheitlichen Analyse aufgezeigt. Illustré par des exemples de deux entreprises moyennes de l’industrie métallurgique, la recherche présente les différences dans la réalisation de la prise en charge médicale du travail et techniques de sécurité et examine leurs conséquences économiques. L’analyse s’effectue sur la base d’un système des indicateurs en tenant compte les données de la sécurité au travail et de la protection sanitaire ainsi que les données de contrôle de gestion. L’avantage d’une telle analyse intégrante est montré dans cet article. Preventive occupational health and safety is an important component of successful corporate management. It aims at an intangible improvement of efficiency initially, which leads to an improvement of a firm’s competitive position in the medium to long term by means of cost savings or increase of turnover (Zangenmeister & Nolting 1997). Effects of occupational health and safety (OHS) measures to workers’ health are hard to assess which means that investments in occupational health and safety are difficult to approach for an economical analysis. Available instruments for measurement, assessment and improvement of occupational health and safety as well as their costs and benefits for companies are rarely open to the public so far. An essential result of the project PAGSmonitor (http://www.pags-monitor.de) is an internet based tool for self assessment of occupational health and safety, which was funded by the Federal Ministry of Education and Research. This tool allows companies to get an assessment of their occupational health and safety and to compare their achievements with other participating companies. The final assessment is integrating different points of view like occupational medicine, safety, and business administration. The tool’s general approach, its reporting and the interpretation of used indicators are introduced exemplarily by means of two medium-sized metal-working companies.

The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase inhibitor (HDAC-I) vorinostat restored physiological levels of histone H3 acetylation, decreased NF-E2 expression, and normalized platelet numbers. Similarly, MPN patients treated with an HDAC-I exhibited a decrease in NF-E2 expression. These data establish a role for NF-E2 in the pathophysiology of MPNs and provide a molecular rationale for investigating epigenetic alterations as novel targets for rationally designed MPN therapies.

Neben anderen Voraussetzungen sind beim Lese- und Rechtschreiberwerb Aufmerksamkeitsprozesse essentiell. In der vorliegenden Studie wurde modellorientiert erfasst, in welchen Teilkomponenten der Aufmerksamkeit Kinder mit einer Lese- Rechtschreibstörung (LRS) auffällig sind. Dazu wurden 32 Kinder mit einer LRS aus dem dritten und vierten Schuljahr mit 31 Kontrollkindern verglichen. Alle Kinder führten computergestützte Aufmerksamkeitsaufgaben durch, mit denen Intensitätsaspekte, Selektivitätsaspekte, Kontrollfunktionen und räumliche Ausrichtung der Aufmerksamkeit überprüft wurden. Es zeigte sich, dass Defizite im Lesen und Schreiben mit Leistungen im Bereich der Aufmerksamkeit korrelieren. Im Vergleich zur Kontrollgruppe konnten Defizite für Intensitätsaspekte der Aufmerksamkeit, räumliche Aufmerksamkeitsaspekte und kontrollierende Aufmerksamkeitsfunktionen festgestellt werden. Schlussfolgernd sprechen die Ergebnisse dafür, dass eine LRS mit Defiziten in der Aufmerksamkeit assoziiert ist.

The current paper stresses the high priority of accurate taxi time calculation and suitable pre-departure management strategies in the context of Airport Collaborative Decision Making (Airport CDM) and contributes to an improved overall understanding of the associated requirements. Based on data analysis performed at Frankfurt Airport this paper compares results of static and advanced taxi time calculation. Contrarily to static calculations, where look-up tables for stand-runway-relations are used, advanced taxi time calculation takes into account the current traffic situation and calculates taxi times dynamically. The paper shows that the taxi time uncertainties when using static data lead to only 42% of flights within the accuracy of ± 2 minutes according to the requirements of the Airport CDM Implementation Manual for short term predictions (maximum 30 minutes before off-block). The application of advanced taxi time calculation leads to significant improvements with 66% of flights within the accuracy of ± 2 minutes at the moment when the aircraft leaves the stand. Hence, app. 50% more predictions are compliant with the Airport CDM requirements compared to static data. Based on these results, the paper assesses the effects of improved taxi time predictability onto airport operation efficiency with particular focus set to taxi time reductions due to minimized queuing at the departure runway. It is shown that advanced taxi time calculation contributes to a reduction of delays, fuel burn, CO2emissions and costs for airspace users compared to the use of static look-up tables. However, it is also emphasized that the shifting of delays from the runway holding positions to the stand does not necessarily contribute to efficiency improvements. It is recommended that the pre-departure sequencing strategy must be chosen cautiously in dependence on the fuel and time costs for airlines as well the amount of departure delay that has to be absorbed.

Obwohl Psychostimulanzien zu den Behandlungsmethoden der ersten Wahl bei Kindern mit einer Aufmerksamkeitsdefizit/-Hyperaktivitätsstörung (ADHS) im Kindes- und Jugendalter gehören, sind mögliche Langzeitfolgen einer Stimulanzientherapie noch nicht ausreichend erforscht. Während eine kurzzeitige positive Wirkung von Stimulanzien auf Aufmerksamkeitsleistungen als gesichert gilt, sind die langfristigen Auswirkungen insbesondere einer Medikation in der frühen Kindheit sowie einer Dauermedikation noch weitestgehend unbekannt. Verschiedene Studien ergaben Hinweise auf einen Einfluss einer Dauermedikation mit Stimulanzien sowohl auf die strukturelle als auch auf funktionelle Hirnentwicklung. Des Weiteren sollten mögliche unerwünschte kognitive und motivationale Nebenwirkungen einer Medikation mit Methylphenidat genauer in Betracht gezogen werden. Insgesamt zeigt sich die Datenlage heterogen und es mangelt an Studien mit ausreichend großen Fallzahlen.

The technique of magnetic resonance sounding (MRS) has shown several improvements in data processing, inversion and interpretation during the last years. Along with these improvements, detailed innovations on instrumentation have been demanded to support their use. Latest developments in surface nuclear magnetic resonance (NMR) instrumentation promise to fulfil these hardware requirements such as decreased dead time, improved digital signal detection, multi‐channel capabilities and improved reference techniques with the second generation surface NMR instruments. In this paper, we compare data from two generations of instruments and assess the impact of the improvements on practical issues, i.e., the increased accuracy of data due to shorter dead times and new noise reduction approaches and the feasibility for efficient 2D measuring schemes. Well‐known and documented test sites and synthetic considerations are used to evaluate these developments. First, the relaxation signals of different devices using the same loop match each other. The inversion results coincide within the range of data errors. Decay time estimation appears to be more stable for the new generation instrument. Second, the potential of shorter effective dead times (considering a relaxation of the protons during the pulse) is investigated using statistical analysis of synthetic data sets with different decay times and noise levels. The additionally measured data at early times significantly improve the scope and accuracy of the determined parameters initial amplitude and T2*time and thus extend the range of formations to be characterized. A field example comparing an effective dead time of 18 ms and 45 ms is presented. Two different reference techniques were successfully applied for noise cancellation at the very noisy test site Nauen. We observed an equivalent signal improvement using the software‐based and hardware‐based technique. However, software noise cancellation approaches are easily adaptable and extendable. Finally, considerations are given how to efficiently carry out 2D surveys using multi‐channel instruments. A 2D field data set using the GMR demonstrates that 2D surveys can already be realized in moderate measuring times. The new generation of instruments provides comparable results and improved capabilities that will enable surface NMR measurements to be applied in a wider range of applications.

Zusammenfassung:Die Aufgaben der Neuropsychologie im Rahmen der Diagnostik von psychischen Störungen im Kindes- und Jugendalter hat sich in den letzten Jahren sehr verändert. Während es früher häufig um die Frage ging, ob bei dem jungen Patienten eine Hirnschädigung vorliegt oder nicht, ist diese Aufgabe heute aufgrund der besseren Möglichkeiten der bildgebenden Verfahren eher in den Hintergrund gerückt. Anhand von vier Einzelfällen wird verdeutlicht, dass frühe Hirnschädigungen nicht nur unmittelbar, sondern auch mittelbar zu Beeinträchtigungen führen. Insbesondere die mittelbaren Folgen, wie z.B. Verhaltensauffälligkeiten und persistierende neuropsychologische Defizite im Entwicklungsverlauf, sind häufig der Grund für eine klinische Vorstellung. Die Besonderheiten von kinder- und jugendpsychiatrischen Patienten mit organisch bedingten psychischen Störungen hinsichtlich Diagnostik und Therapieverlauf werden anhand der ausgewählten Kasuistiken ausführlich diskutiert.

This study aims to examine the influence of risperidone on various attentional functions, including intensity and selectivity aspects of attention plus inhibitory control in children with attention deficit/hyperactivity disorder (ADHD) with co-morbid Disruptive Behavior Disorders (DBD) and normal IQ. Children with ADHD and DBD, aged 8–15 years, were treated with risperidone (mean daily dose: 1.5 mg; n = 23) and examined with three attentional paradigms before and after a 4-week treatment period. Age- and IQ-matched normal controls (n = 23) were also tested without medication on the same two occasions. No influence of the medication could be detected for any neuropsychological variable, neither as a positive enhancement nor as adverse side effects. However, clinical symptoms of ADHD and DBD assessed on the IOWA Conners Scale significantly improved after the 4-week treatment period. Divergent behavioral and cognitive effects of risperidone on ADHD symptoms were observed, with a significant reduction in behavioral symptoms, whereas no positive treatment effects were found on laboratory tasks of impulsivity. Thus, the cognitive effects of risperidone seem to differ from the cognitive effects of stimulant treatments in children with ADHD + DBD. However, no negative impact of risperidone was observed on attentional functions either, i.e., there was no slowing of cognitive speed.

This study investigated the cognitive side effects of a 6-week course of sertraline treatment on verbal memory and attention in children and adolescents. Children with various anxiety disorders (social phobia, generalized and separation anxiety disorder; n = 28), between 8 and 17 years of age, received a standardized, computerized neuropsychological assessment before treatment and another 6 weeks after treatment onset with sertraline (daily dose range between 25 and 100 mg). The patient group was compared to healthy controls (n = 28), who were matched for age and IQ and were also tested twice over a 6-week period. Sertraline did not have any negative effects on attentional performance (p > 0.05) but did increase response speed in a divided attention paradigm (p = 0.02). By contrast, performance of the interference part of a verbal memory task decreased (p = 0.05). The described results also remained stable over a 12-week period after treatment onset. Thus, the cognitive side effects of sertraline seemed to differ slightly between pediatric patients and those described in adult patient groups, should, therefore, be carefully assessed.

The aim of this study was to determine drug-dependent effects on attention and motor activity in children with attention-deficit/hyperactivity disorder (ADHD) in a double-blind methylphenidate (MPH) trial using both subjective behavior ratings and objective measures of function. In particular, we were interested in the relationship between changes of those subjective and objective measures. A total of 44 ADHD children with the combined subtype completed a randomized, double-blind, placebo-controlled, crossover trial with 2 doses of MPH (0.25; 0.5 mg/kg body weight) and placebo. In each condition, computerized attention tasks were performed, teacher-behavior ratings were obtained, and actigraph data were collected in both clinical and naturalistic settings. Trend tests revealed linear effects of MPH dose on actigraph data in the test session (p = 0.02) and at school (p = 0.001), as well as on sustained attention (p < 0.001), while inhibitory control showed a quadratic dose-response curve (p < 0.001). Multivariate regression analyses revealed that changes of both, hyperactive-impulsive symptoms (28%) and inattentive symptoms (23%) could be explained by objective changes of motor activity. Thus, for clinical practice, it should be taken into account that behavior ratings of ADHD symptoms seemed to be predominantly influenced by changes of motor activity.