Total Synthesis of Shearinines†D and G: A Convergent Approach to Indole Diterpenoids.

The first total syntheses of the indole diterpenoids (+)-shearinine G and D are disclosed. The successful routes rely on late-stage coupling of two complex fragments. Formation of the challenging trans-hydrindane motif was accomplished by diastereoselective, intramolecular cyclopropanation. A one-pot sequence consisting of Sharpless dihydroxylation/Achmatowicz reaction was developed to install the dioxabicyclo[3.2.1]octane motif. The indenone subunit was accessed by Prins cyclization. Tuning the electronic nature of the substituents on the parent arylcarboxaldehyde allowed access to divergent products that were further transformed into shearinines G and D. Riley-type oxidation of a bicyclic enone yielded a surprising stereochemical outcome.

Synthesis of Photoswitchable Δ9-Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling.

The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nervous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ9-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly rectifying potassium channels, as well as adenylyl cyclase.

A cross-national comparison of incident reporting systems implemented in German and Swiss hospitals.

OBJECTIVE: This study aimed to empirically compare incident reporting systems (IRS) in two European countries and to explore the relationship of IRS characteristics with context factors such as hospital characteristics and characteristics of clinical risk management (CRM). DESIGN: We performed exploratory, secondary analyses of data on characteristics of IRS from nationwide surveys of CRM practices. SETTING: The survey was originally sent to 2136 hospitals in Germany and Switzerland. PARTICIPANTS: Persons responsible for CRM in 622 hospitals completed the survey (response rate 29%). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Differences between IRS in German and Swiss hospitals were assessed using Chi2, Fisher's Exact and Freeman-Halton-Tests, as appropriate. To explore interrelations between IRS characteristics and context factors (i.e. hospital and CRM characteristics) we computed Cramer's V. RESULTS: Comparing participating hospitals across countries, Swiss hospitals had implemented IRS earlier, more frequently and more often provided introductory IRS training systematically. German hospitals had more frequently systematically implemented standardized procedures for event analyses. IRS characteristics were significantly associated with hospital characteristics such as hospital type as well as with CRM characteristics such as existence of strategic CRM objectives and of a dedicated position for central CRM coordination. CONCLUSIONS: This study contributes to an improved understanding of differences in the way IRS are set up in two European countries and explores related context factors. This opens up new possibilities for empirically informed, strategic interventions to further improve dissemination of IRS and thus support hospitals in their efforts to move patient safety forward.

Duration of survival after peptic ulcer perforation.

BACKGROUND: The long-term course after peptic ulcer perforation is unclear, but because the ulcer population is generally older and has concomitant disease, the long-term prognosis may be expected to be poor. METHODS: In a study based on prospective data collection, all patients with peptic ulcer perforation treated at the Department of Surgery at the Heinrich-Heine-University in Dusseldorf, Germany, were documented between 1986 and 1995. In a follow-up study, the following parameters were investigated and survival rates were estimated: hospital mortality, 1-month mortality, 1-year mortality, and 5-year mortality. Significant prognostic parameters for death were worked out in univariate and multivariate analysis. RESULTS: Ninety-nine out of 108 patients with peptic ulcer perforation could be followed-up. One-month mortality was similar to hospital mortality, at 9.1%; 1-year mortality was about 20.2%; and 5-year mortality was 32.3%. Statistically significant prognostic factors for death in univariate analysis were age beyond 70 years, concomitant diseases, risk-related drugs, postinterventional complications and admission status. In multivariate analysis concomitant diseases, postoperative complications, and advanced age were significant parameters for death. CONCLUSIONS: Long-term prognosis of peptic ulcer perforation is poor. Risk factors for late mortality after peptic ulcer perforation are age, severe concomitant diseases, and postinterventional complications.

Time-trends in the epidemiology of peptic ulcer bleeding.

OBJECTIVE: Despite the introduction of effective medical treatment of peptic ulcer disease, bleeding is still a frequent complication. The aim of this study was to investigate whether the incidence and the risk profile of peptic ulcer haemorrhage have changed within a 10-year period. MATERIAL AND METHODS: In a prospective epidemiological and observational study the incidence and risk profile of peptic ulcer haemorrhage in Düsseldorf, Germany were compared between two time periods (period A: 1.3.89-28.2.90 and period B: 1.4.99-31.3.2000), involving nine hospitals with both surgical and medical departments. Patients with proven peptic ulcer haemorrhage at endoscopy or operation were included in the study; those with bleeding under defined severe stress conditions were excluded. RESULTS: No differences in bleeding ulcer incidence were observed between periods A and B (51.4 per 100,000 person-years versus 48.7), or for duodenal ulcer (24.9 versus 25.7) or for gastric ulcer bleeding (26.5 versus 23.0). A marked increase in incidence rates was observed with increasing age. In period B, patients with bleeding ulcers were older (56% versus 41% 70 years or older), were usually taking non-steroidal anti-inflammatory drugs (NSAIDs) (45% versus 27%) and were less likely to have a history of ulcer (25% versus 59%) compared with patients in period A. CONCLUSIONS: The persisting high incidence of peptic ulcer disease is a superimposing of two trends: a higher incidence in the growing population of elderly patient with a higher intake of NSAIDs and a lower incidence among younger patients due to a decrease in incidence and improved medical treatment.

Endoscopic versus operative treatment in high-risk ulcer bleeding patients - results of a randomised study.

BACKGROUND AND AIMS: The treatment of peptic ulcer bleeding is still a matter of controversy in high-risk patients with arterial bleeding or a visible vessel. Patients with recurrent bleeding during hospital stay carry an increased risk of death. Therapeutic concepts using early elective operation compete with solitary endoscopic treatment. Numerous prospective studies have contrasted comparable improvements for the different therapeutic regimens but there is still a lack of a randomised comparison. PATIENTS AND METHODS: We initiated a multicentre randomised clinical trial comparing endoscopic fibrin glue injection with early elective operation in peptic ulcer patients with arterial bleeding or a visible vessel > or =2 mm. After initial endoscopic control of bleeding, patients were randomised to repeated fibrin glue injection or early elective operation. Outcome criteria were recurrent bleeding and death. The study was terminated after a planned interim analysis. RESULTS: Due to strict inclusion and exclusion criteria 61 patients were randomised and 55 patients could be included in the per-protocol analysis, 23 in the early elective operation group and 32 in the patient group with endoscopic therapy. The type of surgery in the early elective operation group was usually gastric resection (79%). Recurrent bleeding occurred in 50% of the endoscopically treated patient group, and in the operative group in one patient (relative risk: 11.5; 95% CI: 1.6 to 80.7). There were no statistically significant differences between the two treatment groups with respect to mortality (relative risk: 0.7, 95% CI: 0.1 to 4.8). CONCLUSION: Early elective surgery is an effective procedure in bleeding peptic ulcer patients at high risk for re-bleeding. Fibrin glue injection carries a risk for re-bleeding, however, the majority of these re-bleeding episodes can be controlled by re-endoscopic treatment, but a subgroup will need an emergency operation with a fatal outcome in individual patients.