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Was hat dieses Buch über einen wenig bekannten Herzog von Bourbon, von dem selbst die französische Geschichtsschreibung bislang eher den Eindruck einer "personnalité parfois effacée" (S. 218) vermittelte, einem deutschen Publikum – und das gilt selbst für die kleine Zunft der Mittelalterhistoriker – schon groß zu sagen? Allenfalls Johanns II. (1456–1488) im Obertitel angesprochene Konfrontation mit Ludwig XI. lässt vielleicht etwas aufmerken, doch gerade dieser König inszenierte so viele Prozesse gegen adelige Gegner (vgl. S. 234 Anm. 2; dem Verfahren gegen Ludwig V. Luxemburg, Graf von St-Pol, galten in den letzten Jahren gleich mehrere Arbeiten: S. 2 Anm. 5), dass man geneigt ist, die Studie nicht zur Kenntnis zu nehmen, denn: "Noch ein Prozess mehr oder weniger, was soll’s?" Doch dieser Prozeß macht, wie noch darzulegen, schon einen erheblichen Unterschied aus; zudem rührt er bei aller spezifisch französischen Grundierung an grundsätzlichen Fragen der Souveränität der Krongewalt und deren Verhältnis zu den Fürstentümern; Fragen, die, was die Machtgewichtung anbelangt, zwar unter eher umgekehrten Vorzeichen, so doch prinzipiell in ähnlicher Weise das deutsche Spätmittelalter durchziehen – Kenntnisnahme ist mithin durchaus angesagt. Zudem liefert Mattéoni einmal mehr den Nachweis, wie ertragreich eine (eigentlich nicht mehr so) neue politische Geschichtsschreibung sein kann, die etwa die Sakralisierung von Herrschaft integral einzubeziehen weiß. Und dieses Thema wird obendrein genau an der rechten Stelle einer überlegten Gesamtkonzeption platziert. ...
Lange ist es noch nicht her, da klagte Werner Paravicini in seiner Besprechung der Biographie Ludwigs XI. von Jean Favier, dass dieser Herrscher seit einigen Jahrzehnten in recht dichter Folge mit beleg- und anmerkungslosen Arbeiten im Stil der "haute vulgarisation" bedacht werde (Kendall, Gaussin, Bordenove, Heers, Gobry und eben Favier), ein wissenschaftlichen Ansprüchen genügendes Werk seit dem 1928 von Pierre Champion vorgelegten dagegen fehle (Francia 30/1 [2003], S. 376f.). Und nunmehr erneut ein Buch, das sich nahtlos in diese Reihe fügt und obendrein den Blickwinkel sogar noch bewusst verengt: Der Verfasser konzentriert sich ausschließlich auf die Person Ludwigs und will darüber hinaus keine Zeit und Welt erschließen; er beschränkt sich auf die Darstellung dessen, was den Herrscher nach seinem Dafürhalten – bis auf Jagd, Tiere und Musik – allein interessierte: "Louis se passionnait pour le pouvoir, la guerre et la politique, il en sera donc question presque à chaque page" (S. 10). ...
Background: Radiofrequency ablation is a minimal invasive therapy in the treatment of bone metastases. In this study we present a new ablation system enabling an ablation in multiple directions and with an adaptable size and shape.
Material and methods: VX-2 tumor was used for the induction of experimental bone metastases in the femur of six New Zealand white rabbits. X-ray imaging as well as CT and MRI scans before and after treatment was carried out. After detecting bone tumor, radiofrequency ablation was performed. The ablation instrument contained a 10 g bipolar, articulated extendable electrode and a proprietary generator with an impedance controlled algorithm. All bones and the soft tissue were examined histologically.
Results: All animals developed local bone tumor. Mean duration until first osteolytic lesions on CT-scans was 48±14 days. The mean lesion area was 26 mm(2). No systemic tumor spread was seen. 6 radiofrequency procedures were carried out with a mean application time of 6 min±2:30 and an average temperature in the region of effect of 55 °C±4. MRI imaging demonstrated an ablation zone of 23±6 mm around the electrode. Histopathology showed an extensive heat necrosis with no remaining tumor cells in the ablation area.
Conclusion: Radiofrequency ablation is a quickly developing treatment option on the field of minimal invasive bone tumor therapy. The electrode enables an ablation adapted to size and shape of the metastases. Further clinical studies are necessary to test and enhance this radiofrequency system.
Meyer, Hartwig ; Stöver, Timo ; Fouchet, Florian ; Bastiat, Guillaume ; Saulnier, Patrick ; Bäumer, Wolfgang ; Lenarz, Thomas ; Scheper, Verena
Objective: Sensorineural hearing loss leads to the progressive degeneration of spiral ganglion cells (SGC). Next to postoperative fibrous tissue growth, which should be suppressed to assure a close nerve–electrode interaction, the density of healthy SGC is one factor that influences the efficiency of cochlear implants (CI), the choice of treatment for affected patients. Rolipram, a phosphodiesterase-4 inhibitor, has proven neuroprotective and anti-inflammatory effects and might also reduce SGC degeneration and fibrosis, but it has to pass the cellular membrane to be biologically active.
Methods: Lipidic nanocapsules (LNC) can be used as biodegradable drug carriers to increase the efficacy of conventional application methods. We examined the biological effects of rolipram and LNC's core encapsulated rolipram on SGC and dendritic cell (DC) tumor necrosis factor-α (TNF-α) production in vitro and on SGC survival in systemically-deafened guinea pigs in vivo.
Results: Our results prove that rolipram does not have a beneficial effect on cultured SGC. Incorporation of rolipram in LNC increased the survival of SGC significantly. In the DC study, rolipram significantly inhibited TNF-α in a dose-dependent manner. The rolipram-loaded LNC provided a significant cytokine inhibition as well. In vivo data do not confirm the in vitro results.
Conclusion: By transporting rolipram into the SGC cytoplasm, LNC enabled the neuroprotective effect of rolipram in vitro, but not in vivo. This might be due to dilution of test substances by perilymph or an inadequate release of rolipram based on differing in vivo and in vitro conditions. Nevertheless, based on in vitro results, proving a significantly increased neuronal survival when using LNC-rolipram compared to pure rolipram and pure LNC application, we believe that the combination of rolipram and LNC can potentially reduce neuronal degeneration and fibrosis after CI implantation. We conclude that rolipram is a promising drug that can be used in inner ear therapy and that LNC have potential as an inner ear drug-delivery system. Further experiments with modified conditions might reveal in vivo biological effects.
Lange, Christian ; Bibert, Stephanie ; Kutalik, Zoltán ; Burgisser, Philippe ; Cerny, Andreas ; Dufour, Jean-Francois ; Geier, Andreas ; Gerlach, Tilman J. ; Heim, Markus H. ; Malinverni, Raffaele ; Negro, Francesco ; Regenass, Stephan ; Badenhoop, Klaus ; Bojunga, Jörg ; Sarrazin, Christoph ; Zeuzem, Stefan ; Müller, Tobias ; Berg, Thomas ; Bochud, Pierre-Yves ; Moradpour, Darius
Background: To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C.
Methodology/Principal Findings: Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome.
Conclusions/Significance: Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome.
Romero-Brey, Inés ; Merz, Andreas ; Chiramel, Abhilash ; Lee, Ji-Young ; Chlanda, Petr ; Haselman, Uta ; Santarella-Mellwig, Rachel ; Habermann, Anja ; Hoppe, Simone ; Kallis, Stephanie ; Walther, Paul ; Antony, Claude ; Krijnse-Locker, Jacomine ; Bartenschlager, Ralf
All positive strand RNA viruses are known to replicate their genomes in close association with intracellular membranes. In case of the hepatitis C virus (HCV), a member of the family Flaviviridae, infected cells contain accumulations of vesicles forming a membranous web (MW) that is thought to be the site of viral RNA replication. However, little is known about the biogenesis and three-dimensional structure of the MW. In this study we used a combination of immunofluorescence- and electron microscopy (EM)-based methods to analyze the membranous structures induced by HCV in infected cells. We found that the MW is derived primarily from the endoplasmic reticulum (ER) and contains markers of rough ER as well as markers of early and late endosomes, COP vesicles, mitochondria and lipid droplets (LDs). The main constituents of the MW are single and double membrane vesicles (DMVs). The latter predominate and the kinetic of their appearance correlates with kinetics of viral RNA replication. DMVs are induced primarily by NS5A whereas NS4B induces single membrane vesicles arguing that MW formation requires the concerted action of several HCV replicase proteins. Three-dimensional reconstructions identify DMVs as protrusions from the ER membrane into the cytosol, frequently connected to the ER membrane via a neck-like structure. In addition, late in infection multi-membrane vesicles become evident, presumably as a result of a stress-induced reaction. Thus, the morphology of the membranous rearrangements induced in HCV-infected cells resemble those of the unrelated picorna-, corona- and arteriviruses, but are clearly distinct from those of the closely related flaviviruses. These results reveal unexpected similarities between HCV and distantly related positive-strand RNA viruses presumably reflecting similarities in cellular pathways exploited by these viruses to establish their membranous replication factories.
Die Stiftung Weimarer Klassik (SWK) wurde als Nachfolgerin der Nationalen Forschungs- und Gedenkstätten der klassischen deutschen Literatur in Weimar (NFG) in zwei Schritten errichtet: 1991 durch Erlass des Thüringer Ministeriums für Wissenschaft und Kultur als "unselbständige", 1994 durch Gesetz als "rechtsfähige Stiftung des öffentlichen Rechts". Schon im ersten Dokument sind die "Bewahrung und Erhaltung", "Erschließung und Erforschung" sowie "Vermittlung und Verbreitung" der überlieferten Traditionsbestände als Aufgaben dieser Institution festgeschrieben. Und im 'Thüringer Gesetz über die Errichtung der Stiftung Weimarer Klassik' vom 8. Juli 1994 ist als Stiftungszweck formuliert, "die Stätten und Sammlungen der klassischen deutschen Literatur in Thüringen in ihrer Einheit zu erhalten, zu bewahren und zu ergänzen, sie in geeigneter Weise der Öffentlichkeit zugänglich zu machen und die Erschließung, Erforschung sowie die Präsentation, Vermittlung und Verbreitung dieses kulturellen Erbes zu fördern." Demnach sind "Bewahrung und Erhaltung", "Erschließung und Erforschung" und "Vermittlung und Verbreitung" als untrennbare Einheit zu begreifen. Doch dürfte genauso klar sein, dass die bewahrenden und erschließenden Funktionen prioritär zu verwirklichen sind, denn ohne die vollständige Erfüllung dieser vorrangigen Aspekte des Stiftungszweckes könnte sich die Institution den weiteren wissenschaftlichen und kulturellen Pflichten überhaupt nicht erfolgreich zuwenden. Daher hat sich das vordringliche Interesse der SWK darauf zu richten, die überlieferten Bestände einerseits in ihrer materiellen Substanz (Bauwerke, Bücher, Handschriften, Kunstsammlungen etc.) zu bewahren und zu sichern und andererseits zu erschließen. Nur bei unbedingter Beachtung dieser Voraussetzung ist es möglich, die kulturellen Traditionen durch Ausstellungen, Tagungen und künstlerische Inszenierungen in ihrer gegenwärtigen geistigen und ästhetischen Bedeutsamkeit zu vermitteln, mit welcher Konzeption und in welchen Proportionen dies auch immer sein mag. Es ist also zu klären, inwieweit die einzelnen Elemente des Stiftungszweckes in den ersten Jahren nach Errichtung der SWK zur Geltung kamen, welche kurzfristigen, vor allem aber langfristigen Schwerpunkte sie setzte und durchsetzte.
Fusco, Francesco Maria ; Schilling, Stefan ; De Iaco, Giuseppina ; Brodt, Hans-Reinhard ; Brouqui, Philippe ; Maltezou, Helena C. ; Bannister, Barbara ; Gottschalk, René ; Thomson, Gail ; Puro, Vincenzo ; Ippolito, Giuseppe
Background: In Emergency and Medical Admission Departments (EDs and MADs), prompt recognition and appropriate infection control management of patients with Highly Infectious Diseases (HIDs, e.g. Viral Hemorrhagic Fevers and SARS) are fundamental for avoiding nosocomial outbreaks.
Methods: The EuroNHID (European Network for Highly Infectious Diseases) project collected data from 41 EDs and MADs in 14 European countries, located in the same facility as a national/regional referral centre for HIDs, using specifically developed checklists, during on-site visits from February to November 2009.
Results: Isolation rooms were available in 34 facilities (82,9%): these rooms had anteroom in 19, dedicated entrance in 15, negative pressure in 17, and HEPA filtration of exhausting air in 12. Only 6 centres (14,6%) had isolation rooms with all characteristics. Personnel trained for the recognition of HIDs was available in 24 facilities; management protocols for HIDs were available in 35.
Conclusions: Preparedness level for the safe and appropriate management of HIDs is partially adequate in the surveyed EDs and MADs.
Bleicher, Marcus ; Burigo, Lucas ; Durante, Marco ; Herrlitz, Maren ; Krämer, Michael ; Mishustin, Igor N. ; Müller, Iris ; Natale, Francesco ; Pshenichnov, Igor A. ; Schramm, Stefan ; Taucher-Scholz, Gisela ; Wälzlein, Cathrin
The biological effects of energetic heavy ions are attracting increasing interest for their applications in cancer therapy and protection against space radiation. The cascade of events leading to cell death or late effects starts from stochastic energy deposition on the nanometer scale and the corresponding lesions in biological molecules, primarily DNA. We have developed experimental techniques to visualize DNA nanolesions induced by heavy ions. Nanolesions appear in cells as “streaks” which can be visualized by using different DNA repair markers. We have studied the kinetics of repair of these “streaks” also with respect to the chromatin conformation. Initial steps in the modeling of the energy deposition patterns at the micrometer and nanometer scale were made with MCHIT and TRAX models, respectively.
Michaelis, Martin ; Rothweiler, Florian ; Agha, B. ; Barth, Susanne ; Voges, Yvonne ; Löschmann, Nadine ; Deimling, Andreas von ; Breitling, Rainer ; Doerr, Hans Wilhelm ; Rödel, Franz ; Speidel, Daniel ; Cinatl, Jindrich
Adaptation of wild-type p53 expressing UKF-NB-3 cancer cells to the murine double minute 2 inhibitor nutlin-3 causes de novo p53 mutations at high frequency (13/20) and multi-drug resistance. Here, we show that the same cells respond very differently when adapted to RITA, a drug that, like nutlin-3, also disrupts the p53/Mdm2 interaction. All of the 11 UKF-NB-3 sub-lines adapted to RITA that we established retained functional wild-type p53 although RITA induced a substantial p53 response. Moreover, all RITA-adapted cell lines remained sensitive to nutlin-3, whereas only five out of 10 nutlin-3-adapted cell lines retained their sensitivity to RITA. In addition, repeated adaptation of the RITA-adapted sub-line UKF-NB-3rRITA10 μM to nutlin-3 resulted in p53 mutations. The RITA-adapted UKF-NB-3 sub-lines displayed no or less pronounced resistance to vincristine, cisplatin, and irradiation than nutlin-3-adapted UKF-NB-3 sub-lines. Furthermore, adaptation to RITA was associated with fewer changes at the expression level of antiapoptotic factors than observed with adaptation to nutlin-3. Transcriptomic analyses indicated the RITA-adapted sub-lines to be more similar at the gene expression level to the parental UKF-NB-3 cells than nutlin-3-adapted UKF-NB-3 sub-lines, which correlates with the observed chemotherapy and irradiation sensitivity phenotypes. In conclusion, RITA-adapted cells retain functional p53, remain sensitive to nutlin-3, and display a less pronounced resistance phenotype than nutlin-3-adapted cells.