Mutagenesis and computer modeling studies of a GPCR conserved residue W5.43(194) in ligand recognition and signal transduction for CB2 receptor

W5.43(194), a conserved tryptophan residue among G-protein coupled receptors (GPCRs) and cannabinoid receptors (CB), was examined in the present report for its significance in CB2 receptor ligand binding and adenylyl cyclase (AC) activity. Computer modeling postulates that this site in CB2 may be involved in the affinity of WIN55212-2 and SR144528 through aromatic contacts. In the present study, we reported that a CB2 receptor mutant, W5.43(194)Y, which had a tyrosine (Y) substitution for tryptophan (W), retained the binding affinity for CB agonist CP55940, but reduced binding affinity for CB2 agonist WIN55212-2 and inverse agonist SR144528 by 8-fold and 5-fold, respectively; the CB2 W5.43(194)F and W5.43(194)A mutations significantly affect the binding activities of CP55940, WIN55212-2 and SR144528. Furthermore, we found that agonist-mediated inhibition of the forskolin-induced cAMP production was dramatically diminished in the CB2 mutant W5.43(194)Y, whereas W5.43(194)F and W5.43(194)A mutants resulted in complete elimination of downstream signaling, suggesting that W5.43(194) was essential for the full activation of CB2. These results indicate that both aromatic interaction and hydrogen bonding are involved in ligand binding for the residue W5.43(194), and the mutations of this tryptophan site may affect the conformation of the ligand binding pocket and therefore control the active conformation of the wild type CB2 receptor. W5.43(194)Y/F/A mutations also displayed noticeable enhancement of the constitutive activation probably attributed to the receptor conformational changes resulted from the mutations.

Are there accurate predictors of long-term vital and functional outcomes in cardiac surgical patients requiring prolonged intensive care?

BACKGROUND AND OBJECTIVE: The decision to maintain intensive treatment in cardiac surgical patients with poor initial outcome is mostly based on individual experience. The risk scoring systems used in cardiac surgery have no prognostic value for individuals. This study aims to assess (a) factors possibly related to poor survival and functional outcomes in cardiac surgery patients requiring prolonged (> or = 5 days) intensive care unit (ICU) treatment, (b) conditions in which treatment withdrawal might be justified, and (c) the patient's perception of the benefits and drawbacks of long intensive treatments. METHODS: The computerized data prospectively recorded for every patient in the intensive care unit over a 3-year period were reviewed and analyzed (n=1859). Survival and quality of life (QOL) outcomes were determined in all patients having required > or =5 consecutive days of intensive treatment (n=194/10.4%). Long-term survivors were interviewed at yearly intervals in a standardized manner and quality of life was assessed using the dependency score of Karnofsky. No interventions or treatments were given, withhold, or withdrawn as part of this study. RESULTS: In-hospital, 1-, and 3-year cumulative survival rates reached 91.3%, 85.6%, and 75.1%, respectively. Quality of life assessed 1 year postoperatively by the score of Karnofsky was good in 119/165 patients, fair in 32 and poor in 14. Multivariate logistic regression analysis of 19 potential predictors of poor outcome identified dialysis as the sole factor significantly (p=0.027) - albeit moderately - reducing long-term survival, and sustained neurological deficit as an inconstant predictor of poor functional outcome (p=0.028). One year postoperatively 0.63% of patients still reminded of severe suffering in the intensive station and 20% of discomfort. Only 7.7% of patients would definitely refuse redo surgery. CONCLUSIONS: This study of cardiac surgical patients requiring > or =5 days of intensive treatment did not identify factors unequivocally justifying early treatment limitation in individuals. It found that 1-year mortality and disability rates can be maintained at a low level in this subset of patients, and that severe suffering in the ICU is infrequent.

Art. 194 - 196 ZPO (Rechtshilfe zwischen schweizerische Gerichten)

Der Kurzkommentar zur ZPO erlaubt in handlicher Form einen schnellen Zugriff auf das schweizerische Zivilverfahrensrecht. In knapper und übersichtlicher Darstellung werden die wesentlichen Fragestellungen analysiert und die wichtigsten Argumente und Gegenargumente zu umstrittenen Punkten für die Praxis verfügbar gemacht. Zur Neuauflage Für die 2. Auflage wurde der Kommentar umfassend aktualisiert und überarbei- tet. Die Nutzerinnen und Nutzer erhalten damit ein kompaktes Arbeitsmittel auf dem Stand Frühjahr 2013. Berücksichtigt werden insbesondere: − das neue Erwachsenenschutzrecht − die am 1.5.2013 in Kraft getretenen neuen Protokollierungsvorschriften für die Zeugeneinvernahme − die inzwischen schon zahlreichen Weichenstellungen in der Rechtsprechung zur schweizerischen Zivilprozessordnung − die seit 2011 erschienene praxisrelevante neue Literatur (inkl. Neuauflage des BSK ZPO

A catalog of high-impact windstorms in Switzerland since 1859

In recent decades, extremely hazardous windstorms have caused enormous losses to buildings, infrastructure and forests in Switzerland. This has increased societal and scientific interest in the intensity and frequency of historical high-impact storms. However, high-resolution wind data and damage statistics mostly span recent decades only. For this study, we collected quantitative (e.g., volumes of windfall timber, losses relating to buildings) and descriptive (e.g., forestry or insurance reports) information on the impact of historical windstorms. To define windstorm severity, normalized and declustered quantitative data were processed by extreme value statistics. Descriptive information was classified using a conceptual guideline. Validation with independent damage information, as well as comparison with wind measurements and a reanalysis, indicates that the most hazardous winter storms are captured, while too few moderate windstorms are detected. Strong storms in the wind measurements and reanalysis are thus added to the catalog. The final catalog encompasses approximately 240 high-impact windstorms in Switzerland since 1859. It features three robust severity classes and contains eight extreme windstorms. Evidence of high winter storm activity in the early and late 20th century compared to the mid-20th century in both damage and wind data indicates a co-variability of hazard and related damage on decadal timescales.