Case-Based Decision Support for Disaster Management

Disasters are characterized by severe disruptions of the society’s functionality and adverse impacts on humans, the environment, and economy that cannot be coped with by society using its own resources. This work presents a decision support method that identifies appropriate measures for protecting the public in the course of a nuclear accident. The method particularly considers the issue of uncertainty in decision-making as well as the structured integration of experience and expert knowledge

Nanobody selection from a highly variable gene library using mRNA/cDNA display

Besides their function in vertebrate immune systems, antibodies are useful tools in immunohistochemistry, structural biology, diagnostics, and as therapeutics. With a molecular weight of 15 kDa, single-domain antibodies or Nanobodies are the smallest functional antibody units. Nanobodies are derived from heavy chain antibodies, which can be found in camelid species like dromedaries, camels, llamas, or alpacas. Compared to canonical antibodies, Nanobodies provide several advantages like cheap and fast production in bacterial hosts, enhanced stability, low-immunogenicity, and high tissue penetration and are promising molecules for research and as therapeutics. Generation of new Nanobodies is traditionally performed by immunization of camelids with the target antigen. In the past, several Nanobody selection methods have been established that avoid animal immunization entirely. Additionally, these animal-free selection methods, called phage display, yeast display, or mRNA/cDNA display, provide benefits like the ability to generate Nanobodies against nonimmunogenic or toxic targets. Starting point of every animal-free selection is a Nanobody gene library. The design of these Nanobody gene libraries greatly influences the success of a selection. Larger, more variable gene libraries increase the chance of selecting high-affinity binders, while smaller, more conservative library designs usually deliver more well-behaved proteins. For this study, we designed a highly variable Nanobody gene library that uses only few invariant positions, based on multiple sequence alignments of published Nanobody sequences. This Nanobody gene library provides a huge sequence space, which enables selection of Nanobodies for a variety of target antigens. The mRNA/cDNA display selection method is performed entirely ex vivo and allows the use of very large gene libraries. Therefore, this selection method is the right fit for our highly variable Nanobody gene library and was chosen for this project. The proteins retinal guanylate cyclase 1 (retGC1) and its main regulator guanylate cyclase activating protein 1 (GCAP1) are localized in the outer segments of photoreceptor cells and play important roles in the visual phototransduction cycle. At low intracellular Ca2+ concentrations, GCAP1 strongly activates retGC1, which then synthesizes cGMP. This is essential to restore the photoreceptor dark state. Multiple mutations in the retGC1 and GCAP1 genes are associated with rare retinopathies like Leber’s congenital amaurosis or autosomal dominant cone-rod dystrophy. RetGC1- and GCAP1-binding Nanobodies could provide useful tools to gain a better understanding of the function of these two proteins and the mechanisms that influence retinopathies. To date, no retGC1 purification protocol has been published. In this study, we provide a solubilization and purification protocol for retGC1 after expression in a stable TREx293 cell line

Operative Therapie von akral lokalisierten Melanomen

Zusammenfassung: Akrolentiginöse Melanome (ALM) umfassen 4-10% der kutanen Melanome bei Hellhäutigen. Patienten mit ALM wird oft eine schlechtere Prognose zugeschrieben, meist aufgrund zu später Diagnosestellung. Unter Einsatz der 3D-Histologie können akral lokalisierte Melanome mit kontinuierlichem Ausbreitungsmuster lokal chirurgisch mit kleineren Sicherheitsabständen und einem guten funktionellen und kosmetischen Ergebnis behandelt werden. In einer Studie wurden bei 244Patienten mit ALM die konventionelle Histologie vs. 3D-Histologie neben anderen prognostischen Parametern verglichen. Klinische und chirurgische Risikofaktoren beeinflussen die Prognose des ALM. Tumordicke und Ulzeration sind die wichtigsten Risikofaktoren. Die 3D-Histologie in Paraffintechnik ermöglicht es, Sicherheitsabstände zu reduzieren und Lokalrezidive zu vermeiden. Subunguale Melanome machen nur etwa 2-3% der kutanen Melanome beim kaukasischen und etwa 20% der Melanome beim afrikanischen oder asiatischen Hauttyp aus und werden klinisch häufig fehldiagnostiziert. Sie sind oft an Daumen und Großzehe lokalisiert. Die Entfernung von subungualen Melanomen mit 3D-Histologie und tumorfreien Schnitträndern unter Einschluss der Nagelmatrix kann als sichere Strategie angesehen werden, welche die Prognose nicht beeinträchtigt. Funktion und Kosmetik eines Fingers oder Zehs bleiben erhalten. Amputationen bei subungualen Melanomen sollten fortgeschrittenen Verläufen mit Knochen- oder Gelenkbefall vorbehalten bleibe

Indomethacin decreases viscosity of gallbladder bile in patients with cholesterol gallstone disease

There is experimental evidence that inhibition of cyclooxygenase with nonsteroidal anti-inflammatory drugs may decrease cholesterol gall-stone formation and mitigate biliary pain in gall-stone patients. The mechanisms by which NSAIDs exert these effect are unclear. In a prospective, controlled clinical trial we examined the effects of oral indomethacin on the composition of human gall-bladder bile. The study included 28 patients with symptomatic cholesterol or mixed gallstones. Of these, 8 were treated with 3 × 25 mg indomethacin daily for 7 days prior to elective cholecystectomy while 20 received no treatment and served as controls. Bile and tissue samples from the gallbladder were obtained during cholecystectomy. Indomethacin tissue levels in the gallbladder mucosa, as assessed by HPLC, were 1.05±0.4 ng/mg wet weight, a concentration known to inhibit effectively cyclooxygenase activity. Nevertheless, no differences between the treated and untreated groups were found in the concentrations of biliary mucus glycoprotein (0.94±0.27 versus 0.93±0.32 mg/ml) or total protein (5.8±0.9 versus 6.4±1.3 mg/ml), cholesterol saturation (1.3±0.2 versus 1.5±0.2), or nucleation time (2.0±3.0 versus 1.5±2.0 days). However, biliary viscosity, measured using a low-shear rotation viscosimeter, was significantly lower in patients receiving indomethacin treatment (2.9±0.6 versus 5.6±1.2 mPa.s; P < 0.02). In conclusion, in man oral indomethacin decreases bile viscosity without alteration of bile lithogenicity or biliary mucus glycoprotein content. Since mucus glycoproteins are major determinants of bile viscosity, an alteration in mucin macromolecular composition may conceivably cause the indomethacin-induced decrease in biliary viscosity and explain the beneficial effects of nonsteroidal anti-inflammatory drugs in gallstone disease

National Socialist Language as Exemplified by the SS Propaganda Unit Kommando Adria: Combat Propaganda Platoon of the SS-Standarte Kurt Eggers

Based on the premise that language is political and thus accomplishes political action, this article analyzes Nazi occupation propaganda in occupied northeastern Italy for the period from November 1943 to January 19451. Using the example of written language of the SS propaganda unit “Kommando Adria,” which has hardly been considered in research, and which was deployed in the Adriatic Litoral, a differentiation is made between internal communication and propaganda directed outward 2. Central questions of the analysis are: What linguistic means did the Adria Kommando use to accompany the German occupation regime? How did internal communiqués differ linguistically from the propaganda produced for the widest possible public? And finally, to what extent did language specifics exist for the multi-ethnic area inhabited equally by Italians, Slovenes and Croat

GABAB Receptor Agonist R-Baclofen Reverses Altered Auditory Reactivity and Filtering in the Cntnap2 Knock-Out Rat

Altered sensory information processing, and auditory processing, in particular, is a common impairment in individuals with autism spectrum disorder (ASD). One prominent hypothesis for the etiology of ASD is an imbalance between neuronal excitation and inhibition. The selective GABAB receptor agonist R-Baclofen has been shown previously to improve social deficits and repetitive behaviors in several mouse models for neurodevelopmental disorders including ASD, and its formulation Arbaclofen has been shown to ameliorate social avoidance symptoms in some individuals with ASD. The present study investigated whether R-Baclofen can remediate ASD-related altered sensory processing reliant on excitation/inhibition imbalance in the auditory brainstem. To assess a possible excitation/inhibition imbalance in the startle-mediating brainstem underlying ASD-like auditory-evoked behaviors, we detected and quantified brain amino acid levels in the nucleus reticularis pontis caudalis (PnC) of rats with a homozygous loss-of-function mutation in the ASD-linked gene Contactin-associated protein-like 2 (Cntnap2) and their wildtype (WT) littermates using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry (MALDI MS). Abnormal behavioral read-outs of brainstem auditory signaling in Cntnap2 KO rats were accompanied by increased levels of GABA, glutamate, and glutamine in the PnC. We then compared the effect of R-Baclofen on behavioral read-outs of brainstem auditory signaling in Cntnap2 KO and WT rats. Auditory reactivity, sensory filtering, and sensorimotor gating were tested in form of acoustic startle response input-output functions, short-term habituation, and prepulse inhibition before and after acute administration of R-Baclofen (0.75, 1.5, and 3 mg/kg). Systemic R-Baclofen treatment improved disruptions in sensory filtering in Cntnap2 KO rats and suppressed exaggerated auditory startle responses, in particular to moderately loud sounds. Lower ASR thresholds in Cntnap2 KO rats were increased in a dose-dependent fashion, with the two higher doses bringing thresholds close to controls, whereas shorter ASR peak latencies at the threshold were further exacerbated. Impaired prepulse inhibition increased across various acoustic prepulse conditions after administration of R-Baclofen in Cntnap2 KO rats, whereas R-Baclofen did not affect prepulse inhibition in WT rats. Our findings suggest that GABAB receptor agonists may be useful for pharmacologically targeting multiple aspects of sensory processing disruptions involving neuronal excitation/inhibition imbalances in ASD

PCR-correction strategies for malaria drug trials: Updates and Clarifications

Malaria drug trials conducted in endemic areas face a major challenge in their analysis because it is difficult to establish whether parasitaemia in blood samples collected after treatment indicate drug failure or a new infection acquired after treatment. It is therefore vital to reliably distinguish drug failures from new infections in order to obtain accurate estimates of drug failure rates. This distinction can be achieved for Plasmodium falciparum by comparing parasite genotypes obtained at the time of treatment (the baseline) and on the day of recurring parasitaemia. Such PCR correction is required to obtain accurate failure rates, even for new effective drugs. Despite the routine use of PCR correction in surveillance of drug resistance and in clinical drug trials, limitations inherent to the molecular genotyping methods have led some researchers to question the validity of current PCR correction strategies. Here we describe and discuss recent developments in these genotyping approaches, with a particular focus on method validation and limitations of the genotyping strategies. Our aim is to update scientists from public and private bodies who are working on the development, deployment, and surveillance of new malaria drugs. We aim to promote discussion around these issues and argue for the adoption of improved standardised PCR correction methodologies

Die Geschäftsordnung des Nationalrates im Vergleich mit der Geschäftsordnung des Deutschen Bundestages unter besonderer Berücksichtigung der Minderheitenrechte und der Rechte des einzelnen Abgeordneten

Die vorliegende Arbeit untersucht anhand eines funktionalen Rechtsvergleichs die Unterschiede und Gemeinsamkeiten der Geschäftsordnungen des Österreichischen Nationalrates und des Deutschen Bundestages. Die Geschäftsordnungen, zentrale Instrumente im verfassungsrechtlich und politisch vorgegebenen Rahmen der parlamentarischen Demokratie, werden im Kontext ihrer praktischen Bedeutung für den Parlamentsalltag und für das verfassungsrechtliche Gefüge beleuchtet. Das Hauptaugenmerk der Untersuchung liegt dabei auf den parlamentarischen Minderheitenrechten sowie auf den Rechten des einzelnen Abgeordneten. Die Arbeit legt zunächst die Entwicklung der parlamentarischen Rechtsgrundlagen in Österreich und Deutschland dar, die trotz desselben historischen Ursprungs maßgebliche Unterschiede im modernen Parlamentarismus der beiden Länder hervorgebracht haben. Nach der Einordnung in das jeweilige Rechtsquellensystem werden ferner die Rechtsfolgen verglichen, die auf den unterschiedlichen Charakter der Geschäftsordnungen zurückgehen. Vor dem Hintergrund der europäischen Integration bildet die Arbeit überdies ab, welche Mitwirkungsrechte der Nationalrat und der Deutsche Bundestag am Rechtsetzungsverfahren der Europäischen Union besitzen. Konkret werden die Auswirkungen des Vertrags von Lissabon auf die Praxis und den Wesensgehalt des österreichischen und deutschen Parlamentarismus‘ analysiert. Die Kontraste in der Organisation der Parlamente und der Ausgestaltung des Abgeordnetenstatus‘ bilden einen Kern der Arbeit. Beim Vergleich der Rechte und Pflichten eines Nationalratsabgeordneten mit denen eines Bundestagsabgeordneten wird die verfassungsrechtliche Stellung des Mandatars einbezogen, aber auch Rechtsfragen in Hinblick auf die Immunität der Abgeordneten. Von besonderer Relevanz ist, wie unterschiedlich die jeweiligen Minderheitenrechte gemäß Verfassung und Geschäftsordnung ausgeprägt sind. Die Arbeit integriert hier Vorschläge zu möglichen Reformen der Geschäftsordnungen. Schließlich werden auch die jeweiligen Rechtsschutzinstrumente dargestellt, die einen parlamentsrechtlichen Bezug aufweisen. Der Verfasser kommt zu dem Schluss, dass der österreichische und deutsche Parlamentarismus sich die Geschäftsordnung der jeweils anderen Volksvertretung zumindest teilweise zum Vorbild nehmen können. So empfiehlt er beispielsweise, das parlamentarische Untersuchungsrecht des Nationalrates als Minderheitenrecht auszugestalten. Dem Bundestag schlägt er etwa vor, Elemente aus dem lebendigen und direkten parlamentarischen Fragerecht des Nationalrates zu übernehmen