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Transcranial magnetic stimulation (TMS) is a non-invasive technique which can be used to study different intracortical excitatory and inhibitory neuronal circuits in the intact human being. In the primary motor cortex, there are essentially three different TMS measures of inhibitory neuronal circuits as determined by paired-pulse TMS: short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and interhemispheric inhibition (IHI). It was hypothesized that SICI is a GABAA receptor mediated inhibition (Ilic et al., 2002) whereas LICI and IHI are mediated by GABAB receptors (Daskalakis et al., 2002; McDonnell et al., 2006). Additionally, it was shown that these inhibitory circuits interact negatively, possible due to presynaptic GABAB receptor mediated inhibition (Sanger et al., 2001; Daskalakis et al., 2002). Which neuronal populations exactly underlie SICI, LICI and IHI, is not completely clear and by which mechanism these inhibitory circuits interact has never been tested pharmacologically so far. Thus, the effects of a single oral dose of Diazepam (DZP), a specific positive allosteric modulator at the GABAA receptor, and of Baclofen (BAC), a specific GABAB receptor agonist, on SICI, LICI and IHI as well as their interactions were tested here in a randomized, placebo controlled, double-blinded crossover study. SICI significantly increased after intake of DZP whereas BAC did not change SICI. Conversely, LICI significantly increased after intake of BAC but did not change after intake of DZP. IHI showed only a trend towards a decrease after intake of DZP but no change after intake of BAC. The interactions IHI-SICI, LICI-IHI and LICI-SICI were all negative at baseline. SICI and IHI were partially suppressed in the presence of IHI and LICI, respectively, and SICI in the presence of LICI was almost completely blocked. BAC did not change any of these interactions, whereas DZP significantly increased SICI in the presence of LICI. This study is the first to examine by means of pharmacological testing the complex interactions between different inhibitory circuits in the human motor cortex. The effects of DZP and BAC on SICI and LICI confirmed the notion that SICI is a GABAA receptor mediated intracortical inhibition whereas LICI depends on GABAB receptor mediated neurotransmission. The pharmacology of IHI at short interstimulus intervals of < 20 ms (12 ms in this study) remains still inconclusive and warrants further investigation. Findings further suggest that SICI, LICI and IHI represent three different inhibitory neuronal circuits which can be tested non-invasively by means of paired-pulse TMS. Furthermore, the data support the idea that the negative interactions IHI-SICI, LICI-IHI and LICI-SICI are most likely due to presynaptic GABAB receptor mediated autoinhibition.
Colorectal cancer is one of the most cause of cancer and death in Western societies. Recently, histone deacetylase inhibitors (HDIs), which regulate transcription through modification of chromatin structure, received considerable interest on the ground of they ability to stop the growth and induce cell death in colon cancer tumours, representing a promising transcriptional cancer therapy. This kind of cancer initiates with an activating mutation in the Wnt cascade, allowing the nuclear import of ß-catenin binding to LEF/TCF. This induces the overexpression of growthpromoting oncogenes affecting the cell cycle arrest, lineage-specific cell differentiation and apoptosis processes. In addition, ß-catenin also participates in cell-cell adhesion via interactions with E-cadherin, which can be repressed by families of transcription factors Snail and ZEB. This, and gain of vimentin has been closely correlated with local invasion and metastasis since they avoid the induction of apoptosis through the loss of cell anchorage, a phenomenon called anoikis. In this process the inactivation of the kinases Src an FAK provoking disruption of focal adhesion complexes through is involved. LAQ824 is a HDAC inhibitor derivative of hydroxamic acid, which present antitumor effect in colon and other cancer cells. The aim of this study is to analyse the effect of LAQ824 in cell proliferation, apoptosis, motility and tumour invasion in a colon carcinoma model based on the adenoma-carcinoma sequence descrying trough which pathways LAQ824 is able to cause these effects. Here I demonstrate for the first time that a HDAC inhibitor, LAQ824, induces detachmentinduced cell death of colon cancer cell lines HCT116 and HT-29, a phenomenon called anoikis, in a caspase-dependent and p53-independent manner. In this process the component of the Wnt signalling pathway ß-catenin is involved. Furthermore LAQ824 upregulates the adhesion molecule E-cadherin expression in these cell lines independently of its repressor Snail, but probably mediated by the repressor ZEB. In addition LAQ824-induced anoikis is caused by disruption of focal adhesion complexes through inhibition of the activity of the kinases FAK and Src inhibiting cell motility indicating a strong antimetastatic potential for LAQ824.
Die Nibelungenparodie, die, soweit uns bekannt ist, zuvor noch nicht publiziert wurde, ist in mehrfacher Hinsicht von besonderem Interesse: zum einen als ein literarisches Debüt einer weiblichen Autorin und angehenden jungen Wissenschaftlerin Ende der zwanziger Jahre des zwanzigsten Jahrhunderts, zum anderen als interessantes und aufschlussreiches Zeitzeugnis. So finden sich an mehreren Stellen Anzeichen einer Ironisierung des heroischen Männlichkeitsideals der Nibelungen und einer Entlarvung des germanischen Heldentums, parodistische Akzente, die zur aufkommenden Rassenideologie um 1930 markant quer liegen. Zugleich werden in augenzwinkernder Kontaktaufnahme mit dem Zuschauer bzw. Leser Elemente aus dem damaligen studentischen Leben wie der Besuch des Kleist-Seminars oder die beliebte Freizeitgestaltung mit Paddelbootausflügen auf der Lahn integriert, die einen Einblick in das damalige studentische Leben bieten. Im Text fungieren sie zudem als humoristische anachronistische Momente, die immer wieder zum Schmunzeln verführen. Darüber hinaus erweist sich die Nibelungenparodie als ein dichtes intertextuelles Gewebe mit zahlreichen Anspielungen, versteckten intertextuellen Referenzen und wörtlichen Zitaten aus den Opern Richard Wagners sowie Werken von Heinrich von Kleist, Adelbert von Chamisso und anderen Vertretern der klassisch-romantischen Tradition.
Para além da influência geral de Rousseau na constituição do ideário estético do Romantismo, as relações mais diretas que o ligam ao grande romântico alemão E. T. A. Hoffmann são merecedoras de um estudo detalhado. Um tal estudo deveria confrontar não só as obras, mas as próprias vidas, já que são notáveis os paralelos biográficos entre os dois autores. Neste trabalho limito-me a examinar um único texto de Hoffmann, o conto de fadas "Das fremde Kind", buscando mostrar que os ecos rousseaunianos nessa obra são bem mais profundos do que uma mera re-elaboração do desgastado e superficial clichê do "bom selvagem".
In dieser Diplomarbeit wird ein Echtzeit-Verfahren vorgestellt, um einen wassergefüllten Ballon zu simulieren. Grundlage des Verfahrens ist ein Feder-Masse-Dämpfer–System, das zusammen mit Methoden zur Erhaltung des Innenvolumens sowie einer topologieerhaltenden Datenstruktur kombiniert wurde. Die Masse des Wassers wird dabei auf Massepartikel an der Oberfläche des Gummiballons aufgeteilt, an denen die Wirkung der physikalischen Kräfte Gravitation, Innendruck und elastische Zugkraft der Oberfläche ausgewertet wird. Dies erfolgt durch iterative Anwendung eines Simulationsschrittes, bei dem die auf die Massepartikel wirkenden Beschleunigungen ermittelt und in eine Bewegung übertragen wird. Bei der Umsetzung in C++ wurde das Verfahren mit Hilfe des Echtzeit-3D-Szenengraphen OGRE (Object-oriented Graphics Rendering Engine) implementiert.
Mögliche Einsatzgebiete sind interaktive Simulationsumgebungen oder andere Echtzeit-Anwendungen in den Bereichen Multimedia und Unterhaltung sowie Nicht-Echtzeit-Verfahren zur Bildgenerierung und physikalischen Simulation.
Hintergrund: Die studentische Ausbildung sollte sowohl inhaltlich als auch organisatorisch auf qualitativ hohem Niveau durchgeführt werden. Während die Evidenzbasierte Medizin (EbM) auf inhaltlicher Ebene die medizinische Ausbildung optimieren kann, vermag dies auf organisatorischer Ebene das Qualitätsmanagement (QM). Aus diesem Grund führte die Arbeitsgruppe EBM Frankfurt des Instituts für Allgemeinmedizin am Universitätsklinikum Frankfurt am Main ein umfassendes Qualitätsmanagementsystem (QMS) ein.
Methoden: Auf Eigeninitiative einiger Arbeitsgruppenmitglieder wurde mit Unterstützung der Stabsstelle Qualitätsmanagement des Uniklinikums Frankfurt ab Oktober 2002 ein alle Teilbereiche der Arbeitsgruppe umfassendes QMS eingeführt. Unter Führung des QM-Lenkungsteams der Arbeitsgruppe wurden für alle relevanten Prozesse des Lehrbetriebs Ablaufdiagramme, Checklisten, Prozessbeschreibungen und Mindeststandards definiert und eingeführt. Hierbei wurden alle Mitglieder aktiv und kontinuierlich in den Erstellungsprozeß eingebunden.
Ergebnisse: Durch die kontinuierliche Beteiligung aller Mitarbeiter konnte ein allgemein akzeptiertes, lebendiges, effektives und zertifizierbares Qualitätsmanagementsystem eingeführt und aufrechterhalten werden. Wichtiger als eine Zertifizierung erscheint jedoch die kontinuierliche Verbesserung des Lehrbetriebs, die sich in zunehmend besseren Benotungen des curricularen EbM-Seminars (WiSe 2003/04: 2,37 vs. SoSe 2006: 1,54) und effektiver Kursgestaltung bei geringer Personalkapazität wiederspiegelt.
Schlussfolgerung/Implikation: Die Implementierung eines QMS auf freiwilliger Basis ist in Bereichen akademischer Lehre unter Beachtung wichtiger Erfolgsfaktoren mit moderatem Personal- und Sachkostenaufwand möglich und ein effektives Instrument zur Verbesserung der von den Studierenden wahrgenommenen Dienstleistungsqualität.
This paper reports on the developmental and psychometric properties of an early writing task. The study was carried out over four years in Toronto, Canada with L1 English-speaking children. Two cohorts of children who began in Nursery School were followed to the end of their Grade 1 year. Children were administered the same writing task at four time points along with standardized measures of early reading. The early writing task required children to write words and number and word combinations; we examined how children move from understanding print as "objects" to understanding print as representation of sounds. We also examined how writing in Nursery School and Kindergarten related to later literacy skills. The methodology allowed us to examine the extent to which early writing in Nursery School (3 years old) and Junior Kindergarten (4 years old) predicted later literacy skills when children were in Grade 1 (6 years old) and were receiving formal reading instruction. Results show characteristic features of children's early writing of number and word combinations at each of the four grade levels and show that performance on the writing task in Kindergarten predicted reading skills at the end of Grade 1.
This paper documents the experiences of assurance evaluation during the early stage of a large software development project. This project researches, contracts and integrates privacy-respecting software to business environments. While assurance evaluation with ISO 15408 Common Criteria (CC) within the certification schemes is done after a system has been completed, our approach executes evaluation during the early phases of the software life cycle. The promise is to increase quality and to reduce testing and fault removal costs for later phases of the development process. First results from the still-ongoing project suggests that the Common Criteria can define a framework for assurance evaluation in ongoing development projects.