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Based on Foucault’s analysis of German Neoliberalism and his thesis of ambiguity, the following paper draws a two-level distinction between individual and regulatory ethics. The individual ethics level – which has received surprisingly little attention – contains the Christian foundation of values and the liberal-Kantian heritage of so called Ordoliberalism – as one variety of neoliberalism. The regulatory or formal-institutional ethics level on the contrary refers to the ordoliberal framework of a socio-economic order. By differentiating these two levels of ethics incorporated in German Neoliberalism, it is feasible to distinguish dissimilar varieties of neoliberalism and to link Ordoliberalism to modern economic ethics. Furthermore, it allows a revision of the dominant reception of Ordoliberalism which focuses solely on the formal-institutional level while mainly neglecting the individual ethics level.
Background: Microvolt T-wave alternans (MTWA) testing in many studies has proven to be a highly accurate predictor of ventricular tachyarrhythmic events (VTEs) in patients with risk factors for sudden cardiac death (SCD) but without a prior history of sustained VTEs (primary prevention patients). In some recent studies involving primary prevention patients with prophylactically implanted cardioverter-defibrillators (ICDs), MTWA has not performed as well.
Objective: This study examined the hypothesis that MTWA is an accurate predictor of VTEs in primary prevention patients without implanted ICDs, but not of appropriate ICD therapy in such patients with implanted ICDs.
Methods: This study identified prospective clinical trials evaluating MTWA measured using the spectral analytic method in primary prevention populations and analyzed studies in which: (1) few patients had implanted ICDs and as a result none or a small fraction (≤15%) of the reported end point VTEs were appropriate ICD therapies (low ICD group), or (2) many of the patients had implanted ICDs and the majority of the reported end point VTEs were appropriate ICD therapies (high ICD group).
Results: In the low ICD group comprising 3,682 patients, the hazard ratio associated with a nonnegative versus negative MTWA test was 13.6 (95% confidence interval [CI] 8.5 to 30.4) and the annual event rate among the MTWA-negative patients was 0.3% (95% CI: 0.1% to 0.5%). In contrast, in the high ICD group comprising 2,234 patients, the hazard ratio was only 1.6 (95% CI: 1.2 to 2.1) and the annual event rate among the MTWA-negative patients was elevated to 5.4% (95% CI: 4.1% to 6.7%). In support of these findings, we analyzed published data from the Multicenter Automatic Defibrillator Trial II (MADIT II) and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) trials and determined that in those trials only 32% of patients who received appropriate ICD therapy averted an SCD.
Conclusion: This study found that MTWA testing using the spectral analytic method provides an accurate means of predicting VTEs in primary prevention patients without implanted ICDs; in particular, the event rate is very low among such patients with a negative MTWA test. In prospective trials of ICD therapy, the number of patients receiving appropriate ICD therapy greatly exceeds the number of patients who avert SCD as a result of ICD therapy. In trials involving patients with implanted ICDs, these excess appropriate ICD therapies seem to distribute randomly between MTWA-negative and MTWA-nonnegative patients, obscuring the predictive accuracy of MTWA for SCD. Appropriate ICD therapy is an unreliable surrogate end point for SCD.
Background: Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats.
Methods: Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed.
Results: The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling.
Conclusion: The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.
Background: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB) prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods. Methodology: The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA) or human serum albumin (PLGA/HSA) as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA) were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3×2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density. Conclusion: The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations.
PAX2 regulates ADAM10 expression and mediates anchorage-independent cell growth of melanoma cells
(2011)
PAX transcription factors play an important role during development and carcinogenesis. In this study, we investigated PAX2 protein levels in melanocytes and melanoma cells by Western Blot and immunofluorescence analysis and characterized the role of PAX2 in the pathogenesis of melanoma. In vitro we found weak PAX2 protein expression in keratinocytes and melanocytes. Compared to melanocytes increased PAX2 protein levels were detectable in melanoma cell lines. Interestingly, in tissue sections of melanoma patients nuclear PAX2 expression strongly correlated with nuclear atypia and the degree of prominent nucleoli, indicating an association of PAX2 with a more atypical cellular phenotype. In addition, with chromatin immunoprecipitation assay, PAX2 overexpression and PAX2 siRNA we present compelling evidence that PAX2 can regulate ADAM10 expression, a metalloproteinase known to play important roles in melanoma metastasis. In human tissue samples we found co-expression of PAX2 and ADAM10 in melanocytes of benign nevi and in melanoma cells of patients with malignant melanoma. Importantly, the downregulation of PAX2 by specific siRNA inhibited the anchorage independent cell growth and decreased the migratory and invasive capacity of melanoma cells. Furthermore, the downregulation of PAX2 abrogated the chemoresistance of melanoma cells against cisplatin, indicating that PAX2 expression mediates cell survival and plays important roles during melanoma progression.
The indications for allogeneic stem cell transplantation (SCT) in Acute Myeloid Leukemia (AML) represent a real challenge due to the clinical and genetic heterogeneity of the disorder. Therefore, an optimized indication for SCT in AML first requires the determination of the individual relapse risk based on diverse chromosomal and molecular prognosis-defining aberrations. A broad panel of diagnostic methods is needed to allow such subclassification and prognostic stratification: cytomorphology, cytogenetics, molecular genetics, and immunophenotyping by multiparameter flow cytometry. These methods should not be seen as isolated techniques but as parts of an integral network with hierarchies and interactions. Examples for a poor risk constellation as a clear indication for allogeneic SCT are provided by anomalies of chromosome 7, complex aberrations, or FLT3-length mutations. In contrast, the favorable reciprocal translocations such as the t(15;17)/PML-RARA or t(8;21)/AML1-ETO are not indications for SCT in first remission due to the rather good prognosis after standard therapy. Further, the indication for SCT should include the results of minimal residual disease (MRD) diagnostics by polymerase chain reaction (PCR) or flow cytometry. New aspects for a safe and fast risk stratification as basis for an optimized indication for SCT in AML might be provided by novel technologies such as microarray-based gene expression profiling. Keywords: Acute Myeloid Leukemia (AML), Allogeneic Stem Cell Transplantation (SCT), Indication, Cytogenetics, Polymerase Chain Reaction (PCR)
In dyadic communication, both interlocutors adapt to each other linguistically, that is, they align interpersonally. In this article, we develop a framework for modeling interpersonal alignment in terms of the structural similarity of the interlocutors’ dialog lexica. This is done by means of so-called two-layer time-aligned network series, that is, a time-adjusted graph model. The graph model is partitioned into two layers, so that the interlocutors’ lexica are captured as subgraphs of an encompassing dialog graph. Each constituent network of the series is updated utterance-wise. Thus, both the inherent bipartition of dyadic conversations and their gradual development are modeled. The notion of alignment is then operationalized within a quantitative model of structure formation based on the mutual information of the subgraphs that represent the interlocutor’s dialog lexica. By adapting and further developing several models of complex network theory, we show that dialog lexica evolve as a novel class of graphs that have not been considered before in the area of complex (linguistic) networks. Additionally, we show that our framework allows for classifying dialogs according to their alignment status. To the best of our knowledge, this is the first approach to measuring alignment in communication that explores the similarities of graph-like cognitive representations. Keywords: alignment in communication; structural coupling; linguistic networks; graph distance measures; mutual information of graphs; quantitative network analysis
The Dagstuhl Perspectives Workshop "Online Privacy: Towards Informational Self-Determination on the Internet" (11061) has been held in February 6-11, 2011 at Schloss Dagstuhl. 30 participants from academia, public sector, and industry have identified the current status-of-the-art of and challenges for online privacy as well as derived recommendations for improving online privacy. Whereas the Dagstuhl Manifesto of this workshop concludes the results of the working groups and panel discussions, this article presents the talks of this workshop by their abstracts.
The article discusses current transformations in the education systems worldwide. Focusing on the European Union (EU) and the Organisation for Economic Cooperation and Development (OECD) as policy actors, it argues that these transformations imply a triple economization of education policy which can be observed at all levels of the education sector. The increasing importance of these organizations in educational issues marks a transition to a "postnational constellation" also in the education field insofar as the national educational sovereignty is being at least readjusted. The economization of education policy is however not restricted to bringing education closer to the needs of the economy and to turning its services into tradable goods. Rather, it also impinges on the operative level of education. A logics of production is being implemented in the self-description of the institutions of the education system, which are no longer bureaucratically administered establishments, but are rather conceived of as managerially conducted production business in which entrepreneurial action is needed. This new governance raises the problem of democratic legitimation of political decisions which ideally combines three elements: democratic, expertocratic, and ethico-professional. The article discusses the consequences of a shift in the balance of the three components with reference to Germany.
In this work we present a study of the influence of nucleus initializations on the event-by-event elliptic flow coefficient, v2. In most Monte-Carlo models, the initial positions of the nucleons in a nucleus are completely uncorrelated, which can lead to very high density regions. In a simple, yet more realistic model where overlapping of the nucleons is avoided, fluctuations in the initial conditions are reduced. However, v2 distributions are not very sensitive to the initialization choice.