Flexible Synthese enantiomerenreiner 1,2-Diamine und 2,3-Diaminocarbonsäuren aus 1,2,5-Thiadiazol-1,1-dioxiden

Chirale 1,2-Diamine und 2,3-Diaminocarbonsäuren haben als häufig auftretende Strukturmotive in Naturstoffen und biologisch aktiven Verbindungen das Interesse von organischen Chemikern geweckt. In dieser Arbeit wurde eine neuartige Synthesemethode entwickelt, die eine enantiomerenreine Darstellung dieser beiden Substanzklassen aus ein und den selben Vorläufermolekülen, den 1,2,5-Thiadiazol-1,1-dioxiden, ermöglicht. Dazu wurde eine bestehende Methode zur Synthese chiraler 1,2-Diamine aus 3,4- disubstituierten 1,2,5-Thiadiazol-1,1-dioxiden entscheidend verbessert. Dies beinhaltete einerseits eine Steigerung der Enantiomerenüberschüsse der isolierten 1,2-Diamine. Andererseits konnte die Methode dahingehend erweitert werden, dass die beiden Aminofunktionen schrittweise geschützt werden können. Somit ist es möglich,diese in nachfolgenden Reaktionen nun chemisch unterschiedlich zu adressieren. Im Rahmen dieser Untersuchungen zeigte sich weiterhin, dass aus den 1,2,5-Thiadiazol-1,1-dioxiden ebenfalls die Synthese enantiomerenreiner a-tertiärer 2,3-Diamine und somit der Aufbau quartärer Stereozentren möglich ist. Die Synthese von enantiomerenreinen 2,3-Diaminocarbonsäuren aus 1,2,5- Thiadiazol-1,1-dioxiden gelang durch das Verwenden von 3-Aryl-substituierten 1,2,5-Thiadiazol-1,1-dioxiden als Startmaterialien. Der Aryl-Rest wurde dazu nach erfolgter Synthese der entsprechenden enantiomerenreinen 1,2-Diamine durch oxidativen Abbau in eine Carboxylgruppe überführt

Pharmacodynamic response modelling of arterial blood pressure in adult volunteers during propofol anaesthesia

International audienceBackground: Concentration effect relationships are commonly described with a direct response model as for example the sigmoid Emax model with one effect compartment as site of action. In this study we investigated whether models with more than one effect site, or indirect response, or counter-regulatory response models may be more appropriate for modelling the propofol effect on arterial blood pressure.Methods: Nine young healthy volunteers received propofol as target controlled infusion with predefined increasing and decreasing plasma target concentrations. Propofol concentrations were determined from arterial blood samples. Arterial blood pressure was measured invasively at radial artery site. Pharmacokinetic/-pharmacodynamic modelling was performed by population analysis with MONOLIX, testing different direct, indirect and counter-regulatory response models.Results: Propofol plasma concentrations were well described by a three-compartment model. The propofol effect on arterial blood pressure was best described by a direct sigmoid Emax model with two effect site compartments.Conclusions: Two effect sites were needed to describe the propofol effect on arterial blood pressure. This may reflect different pathways of arterial blood pressure response to propofol

Reproducibility of different screening classifications in ultrasonography of the newborn hip

<p>Abstract</p> <p>Background</p> <p>Ultrasonography of the hip has gained wide acceptance as a primary method for diagnosis, screening and treatment monitoring of developmental hip dysplasia in infants. The aim of the study was to examine the degree of concordance of two objective classifications of hip morphology and subjective parameters by three investigators with different levels of experience.</p> <p>Methods</p> <p>In 207 consecutive newborns (101 boys; 106 girls) the following parameters were assessed: bony roof angle (α-angle) and cartilage roof angle (β-angle) according to Graf's basic standard method, "femoral head coverage" (FHC) as described by Terjesen, shape of the bony roof and position of the cartilaginous roof. Both hips were measured twice by each investigator with a 7.5 MHz linear transducer (SONOLINE G60S^®ultrasound system, SIEMENS, Erlangen, Germany).</p> <p>Results</p> <p>Mean kappa-coefficients for the subjective parameters shape of the bony roof (0.97) and position of the cartilaginous roof (1.0) demonstrated high intra-observer reproducibility. Best results were achieved for α-angle, followed by β-angle and finally FHC. With respect to limits of agreement, inter-observer reproducibility was calculated less precisely.</p> <p>Conclusions</p> <p>Higher measurement differences were evaluated more in objective scorings. Those variations were observed by every investigator irrespective of level of experience.</p

The Core Protein of Classical Swine Fever Virus Is Dispensable for Virus Propagation In Vitro

Core protein of Flaviviridae is regarded as essential factor for nucleocapsid formation. Yet, core protein is not encoded by all isolates (GBV- A and GBV- C). Pestiviruses are a genus within the family Flaviviridae that affect cloven-hoofed animals, causing economically important diseases like classical swine fever (CSF) and bovine viral diarrhea (BVD). Recent findings describe the ability of NS3 of classical swine fever virus (CSFV) to compensate for disabling size increase of core protein (Riedel et al., 2010). NS3 is a nonstructural protein possessing protease, helicase and NTPase activity and a key player in virus replication. A role of NS3 in particle morphogenesis has also been described for other members of the Flaviviridae (Patkar et al., 2008; Ma et al., 2008). These findings raise questions about the necessity and function of core protein and the role of NS3 in particle assembly. A reverse genetic system for CSFV was employed to generate poorly growing CSFVs by modification of the core gene. After passaging, rescued viruses had acquired single amino acid substitutions (SAAS) within NS3 helicase subdomain 3. Upon introduction of these SAAS in a nonviable CSFV with deletion of almost the entire core gene (Vp447Δc), virus could be rescued. Further characterization of this virus with regard to its physical properties, morphology and behavior in cell culture did not reveal major differences between wildtype (Vp447) and Vp447Δc. Upon infection of the natural host, Vp447Δc was attenuated. Hence we conclude that core protein is not essential for particle assembly of a core-encoding member of the Flaviviridae, but important for its virulence. This raises questions about capsid structure and necessity, the role of NS3 in particle assembly and the function of core protein in general

microRNA-122 stimulates translation of hepatitis C virus RNA

Hepatitis C virus (HCV) is a positive strand RNA virus that propagates primarily in the liver. We show here that the liver-specific microRNA-122 (miR-122), a member of a class of small cellular RNAs that mediate post-transcriptional gene regulation usually by repressing the translation of mRNAs through interaction with their 3′-untranslated regions (UTRs), stimulates the translation of HCV. Sequestration of miR-122 in liver cell lines strongly reduces HCV translation, whereas addition of miR-122 stimulates HCV translation in liver cell lines as well as in the non-liver HeLa cells and in rabbit reticulocyte lysate. The stimulation is conferred by direct interaction of miR-122 with two target sites in the 5′-UTR of the HCV genome. With a replication-defective NS5B polymerase mutant genome, we show that the translation stimulation is independent of viral RNA synthesis. miR-122 stimulates HCV translation by enhancing the association of ribosomes with the viral RNA at an early initiation stage. In conclusion, the liver-specific miR-122 may contribute to HCV liver tropism at the level of translation

Flexible Synthese enantiomerenreiner 1,2-Diamine und 2,3-Diaminocarbonsäuren aus 1,2,5-Thiadiazol-1,1-dioxiden

Chirale 1,2-Diamine und 2,3-Diaminocarbonsäuren haben als häufig auftretende Strukturmotive in Naturstoffen und biologisch aktiven Verbindungen das Interesse von organischen Chemikern geweckt. In dieser Arbeit wurde eine neuartige Synthesemethode entwickelt, die eine enantiomerenreine Darstellung dieser beiden Substanzklassen aus ein und den selben Vorläufermolekülen, den 1,2,5-Thiadiazol-1,1-dioxiden, ermöglicht. Dazu wurde eine bestehende Methode zur Synthese chiraler 1,2-Diamine aus 3,4- disubstituierten 1,2,5-Thiadiazol-1,1-dioxiden entscheidend verbessert. Dies beinhaltete einerseits eine Steigerung der Enantiomerenüberschüsse der isolierten 1,2-Diamine. Andererseits konnte die Methode dahingehend erweitert werden, dass die beiden Aminofunktionen schrittweise geschützt werden können. Somit ist es möglich,diese in nachfolgenden Reaktionen nun chemisch unterschiedlich zu adressieren. Im Rahmen dieser Untersuchungen zeigte sich weiterhin, dass aus den 1,2,5-Thiadiazol-1,1-dioxiden ebenfalls die Synthese enantiomerenreiner a-tertiärer 2,3-Diamine und somit der Aufbau quartärer Stereozentren möglich ist. Die Synthese von enantiomerenreinen 2,3-Diaminocarbonsäuren aus 1,2,5- Thiadiazol-1,1-dioxiden gelang durch das Verwenden von 3-Aryl-substituierten 1,2,5-Thiadiazol-1,1-dioxiden als Startmaterialien. Der Aryl-Rest wurde dazu nach erfolgter Synthese der entsprechenden enantiomerenreinen 1,2-Diamine durch oxidativen Abbau in eine Carboxylgruppe überführt

Synthesis of Molecular Nanostructures by Multicomponent Condensation Reactions in a Ball Mill

The condensation of multiple building blocks in a ball mill allows molecular cages with a size up to 3.1 nm to be built

Post-resuscitation haemodynamics in a novel acute myocardial infarction cardiac arrest model in the pig

Background and objectives Although a considerable amount of promising experimental research has been performed on cardiopulmonary resuscitation, clinical data indicate an ongoing limited outcome in human beings. One reason for this discrepancy could be that experimental studies use healthy animals whereas most human beings undergoing cardiopulmonary resuscitation suffer from acute or chronic myocardial dysfunction. To overcome this problem, we sought to develop a new model of myocardial infarction, that is easy to perform in all kind of laboratories and compromises on the myocardial function significantly. Methods Following approval by the local authorities, 14 domestic pigs were instrumented for measurement of arterial, central venous, left atrial and left ventricular pressures. Myocardial infarction was induced in eight pigs by clipping the circumflex artery close to its origin from the left coronary artery (infarction group; n = 8). Six animals (no infarction group, n = 6) served as no-infarct controls. Following a 4-min period of cardiac arrest, internal cardiac massage was performed in these two groups, and haemodynamics were recorded during the first 30 min of reperfusion. Results All animals were resuscitated successfully. Compared to the no-infarction group, the infarction group showed significantly decreased myocardial contractility, coronary perfusion pressure and cardiac index (30 min after restoration of spontaneous circulation: infarction group: 57 ± 7 and 89 ± 19 mL min−1 kg−1 in the no-infarction group; mean ± SD; P < 0.05) during reperfusion. Two animals from the infarction group (25%), but none of the animals in the no-infarction group, died during the reperfusion period. Conclusion These data demonstrate that clipping of the circumflex artery leads to a reduced myocardial performance after successful resuscitation, whereas the rate of restoration of spontaneous circulation is not reduced. Therefore, this set-up provides a reproducible model for future studies of post-resuscitation haemodynamics and treatment