The value of selected in vitro and in silico methods to predict acute oral toxicity in a regulatory context: results from the European Project ACuteTox.

ACuteTox is a project within the 6th European Framework Programme which had as one of its goals to develop, optimise and prevalidate a non-animal testing strategy for predicting human acute oral toxicity. In its last 6 months, a challenging exercise was conducted to assess the predictive capacity of the developed testing strategies and final identification of the most promising ones. Thirty-two chemicals were tested blind in the battery of in vitro and in silico methods selected during the first phase of the project. This paper describes the classification approaches studied: single step procedures and two step tiered testing strategies. In summary, four in vitro testing strategies were proposed as best performing in terms of predictive capacity with respect to the European acute oral toxicity classification. In addition, a heuristic testing strategy is suggested that combines the prediction results gained from the neutral red uptake assay performed in 3T3 cells, with information on neurotoxicity alerts identified by the primary rat brain aggregates test method. Octanol-water partition coefficients and in silico prediction of intestinal absorption and blood-brain barrier passage are also considered. This approach allows to reduce the number of chemicals wrongly predicted as not classified (LD50>2000 mg/kg b.w.).

The size and burden of mental disorders and other disorders of the brain in Europe 2010.

Aims: To provide 12-month prevalence and disability burden estimates of a broad range of mental and neurological disorders in the European Union (EU) and to compare these findings to previous estimates. Referring to our previous 2005 review, improved up-to-date data for the enlarged EU on a broader range of disorders than previously covered are needed for basic, clinical and public health research and policy decisions and to inform about the estimated number of persons affected in the EU. Method: Stepwise multi-method approach, consisting of systematic literature reviews, reanalyses of existing data sets, national surveys and expert consultations. Studies and data from all member states of the European Union (EU-27) plus Switzerland, Iceland and Norway were included. Supplementary information about neurological disorders is provided, although methodological constraints prohibited the derivation of overall prevalence estimates for mental and neurological disorders. Disease burden was measured by disability adjusted life years (DALY). Results: Prevalence: It is estimated that each year 38.2% of the EU population suffers from a mental disorder. Adjusted for age and comorbidity, this corresponds to 164.8 million persons affected. Compared to 2005 (27.4%) this higher estimate is entirely due to the inclusion of 14 new disorders also covering childhood/adolescence as well as the elderly. The estimated higher number of persons affected (2011: 165 m vs. 2005: 82 m) is due to coverage of childhood and old age populations, new disorders and of new EU membership states. The most frequent disorders are anxiety disorders (14.0%), insomnia (7.0%), major depression (6.9%), somatoform (6.3%), alcohol and drug dependence (>4%), ADHD (5%) in the young, and dementia (1-30%, depending on age). Except for substance use disorders and mental retardation, there were no substantial cultural or country variations. Although many sources, including national health insurance programs, reveal increases in sick leave, early retirement and treatment rates due to mental disorders, rates in the community have not increased with a few exceptions (i.e. dementia). There were also no consistent indications of improvements with regard to low treatment rates, delayed treatment provision and grossly inadequate treatment. Disability: Disorders of the brain and mental disorders in particular, contribute 26.6% of the total all cause burden, thus a greater proportion as compared to other regions of the world. The rank order of the most disabling diseases differs markedly by gender and age group; overall, the four most disabling single conditions were: depression, dementias, alcohol use disorders and stroke. Conclusion: In every year over a third of the total EU population suffers from mental disorders. The true size of "disorders of the brain" including neurological disorders is even considerably larger. Disorders of the brain are the largest contributor to the all cause morbidity burden as measured by DALY in the EU. No indications for increasing overall rates of mental disorders were found nor of improved care and treatment since 2005; less than one third of all cases receive any treatment, suggesting a considerable level of unmet needs. We conclude that the true size and burden of disorders of the brain in the EU was significantly underestimated in the past.Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research in order to identify better strategies for improved prevention and treatment for isorders of the brain as the core health challenge of the 21st century. (C) 2011 Published by Elsevier B.V.

Von Wien her, auf Wien hin : Ilse Aichingers "Geographie der eigenen Existenz"

Zusammenfassung In Wien hat Ilse Aichinger (*1921) das Glück der Kindheit erlebt und die Verfolgung durch die Nazis, die ihre jüdischen Verwandten ermordeten. Aichingers Texte zu Wien, die zwischen 1945 und 2005 entstanden sind, suchen in der Topographie der Stadt nach den vergangenen Zeiten und abwesenden Menschen. Sie bilden ein singuläres Erinnerungsprojekt, das einer »Vergangenheitsbewältigung« aus gesicherter Position ein Gedenken entgegengesetzt, das mitsamt seinen Gegenständen im Fluss bliebt. Das Schreiben über Wien bildet einen gewichtigen Strang in einem Werk, das durch Brüche und Lücken gekennzeichnet ist, einen kleinen, immer neu erzählten Stoff und eine immense Spanne an Textformen. In seiner Entwicklung vom Frühwerk, das auf ein emphatisch sich selbst setzendes, existentialistisches Subjekt zentriert ist, zu dem feuilletonistischen Projekt einer »Autobiographie ohne Ich« spiegeln sich 50 Jahre deutscher Literatur- und Kulturgeschichte. Die Einleitung widmet sich der topographischen Poetologie, mit der Ilse Aichinger, Paul Celan, Günter Eich und Ingeborg Bachmann im Diskurs der Standort- und Richtungsbestimmung der Nachkriegsjahre einen eigenen Akzent setzen. Kapitel 1 rekonstruiert am Beispiel der Erzählung Das Plakat (1948) das Raum-, Zeichenund Lektüremodell, das Aichingers hochgradig selbstreferentiellen Texte sowohl abbilden als auch in ihrer Struktur realisieren. Kapitel 2 gewinnt über die Lokalisierung der Schauplätze des Romans Die größere Hoffnung (1948/60) in der Wiener Topographie Aufschluss über die Form des Romans. Der Weg des Romans durch die Stadt integriert die räumlich und zeitlich diskontinuierlichen Kapitel zu einem übergreifenden Ganzen. Kapitel 3 widmet sich den szenischen Dialogen Zu keiner Stunde (1957), die durch ihre Titel in Wien lokalisiert sind. Zeichnet Die größere Hoffnung eine Topographie des Terrors, gehen die Dialoge von Orten der Kunst und des Gedenkens aus und thematisieren die Bedingungen eines Erinnerns, das lebendig bleibt. Kapitel 4 zeichnet nach, wie in den Prosagedichten im Band Kurzschlüsse (1954/2001) und in der autobiographischen Prosa in Kleist, Moos, Fasane (1987) die Gegenwartsebene eines erinnernden Ichs entsteht, die sich zunehmend dynamisiert und mit dem Schreibvorgang verbindet. Kapitel 5 beschäftigt sich mit dem feuilletonistischen Spätwerk, in dem mit dem Kino und dem Café auch die Orte des Erinnerns und Schreibens Teil der Wiener Topographie werden. Film und Verhängnis. Blitzlichter auf ein Leben (2001) ist eine Autobiographie, die auf das Verschwinden der eigenen Person zielt.

Antirotavirus immunoglobulin A neutralizes virus in vitro after transcytosis through epithelial cells and protects infant mice from diarrhea.

Rotaviruses are the major cause of severe diarrhea in infants and young children worldwide. Due to their restricted site of replication, i.e., mature enterocytes, local intestinal antibodies have been proposed to play a major role in protective immunity. Whether secretory immunoglobulin A (IgA) antibodies alone can provide protection against rotavirus diarrhea has not been fully established. To address this question, a library of IgA monoclonal antibodies (MAbs) previously developed against different proteins of rhesus rotavirus was used. A murine hybridoma "backpack tumor" model was established to examine if a single MAb secreted onto mucosal surfaces via the normal epithelial transport pathway was capable of protecting mice against diarrhea upon oral challenge with rotavirus. Of several IgA and IgG MAbs directed against VP8 and VP6 of rotavirus, only IgA VP8 MAbs (four of four) were found to protect newborn mice from diarrhea. An IgG MAb recognizing the same epitope as one of the IgA MAbs tested failed to protect mice from diarrhea. We also investigated if antibodies could be transcytosed in a biologically active form from the basolateral domain to the apical domain through filter-grown Madin-Darby canine kidney (MDCK) cells expressing the polymeric immunoglobulin receptor. Only IgA antibodies with VP8 specificity (four of four) neutralized apically administered virus. The results support the hypothesis that secretory IgA antibodies play a major role in preventing rotavirus diarrhea. Furthermore, the results show that the in vivo and in vitro methods described are useful tools for exploring the mechanisms of viral mucosal immunity.