Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.     

Practices with technology: learning at the boundary between study and work

A study of part‐time student experience of university courses delivered using a range of technologies found that information and communication technology enabled students to move between study and work experience to the benefit of their learning in both contexts. Technology‐based study activities enabled students to participate in learning both as a student and as a member of a practice or work context. Given the increasingly pressured lives of all students in higher education and their aspirations for employment after graduation, this suggests that we would benefit from taking their relationship to work and professional practice into account more directly, in deciding how to integrate technology into their study experience. Teacher conceptions of technology as a tool primarily for information delivery and discussion need to expand to recognize that it can be used to construct learning experiences situated in roles, skills and interactive environments that enhance students' ability to make transitions across the boundaries between contexts of study and work.     

Trends and periodicities in observed temperature,precipitation and runoff in a desert catchment: case study for the Shiyang River Basin in Northwestern China

The Mann–Kendall test, wavelet analysis was used to analyse the long‐term trends and periodicities in temperature, precipitation and streamflow in China's Shiyang River Basin since 1950. The Principal components analysis (PCA) was used to quantify the impacts of climate change and human activities on water resources. The annual mean air temperature has increased, consistent with increasing global temperatures. The annual precipitation fluctuated but has generally increased since the 1990s. The air temperature and precipitation showed changes on periods ranging from 2 to 28 years. The correlation between annual runoff and precipitation variation was 0.61 (P < 0.05), indicating precipitation is the main source of the runoff. Human activities played the dominant role in the lower reaches, accounting for 58.5% of the total effect. The results have important implications for water resources management to support harmonisation of the relationship between humans and nature to combat the effect of climate.     

65—FIDIVAN—AN AUTOMATED SYSTEM FOR THE RAPID MEASUREMENT OF FIBRE DIAMETERS

A new system is described for measuring fibre diameter distributions rapidly and accurately, with minimum operator participation at any stage. It is based on the scanning of photographic images of aligned fibre snippets by a television camera connected to pulse-width-sorting circuitry, which gives an automatic print-out of the frequency distribution of fibre diameter. Results are given of measurements made with this system on IWTO standard tops that show very close agreement with accepted values.     

Neuro-otologic findings in the lightning-injured patient

To determine whether endoplasmic reticulum (ER) proliferation in hepatocytes after phenobarbital (PB) administration relates closely to cytochrome P-450 (P-450) increase, we have measured the amount of total P-450 per unit cytoplasmic volume (P-450 content) by microphotometry and estimated the area of ER per unit cytoplasmic volume (ER area) by morphometry in periportal, midzonal, and perivenular hepatocytes of mice injected daily with PB (100 mg/kg), or with PB (100 mg/kg) plus cobalt chloride (50 mg/kg) for three days. After injection of PB, the P-450 content and ER area increased in hepatocytes of the three sublobular zones. In mice treated with PB plus cobalt chloride, however, the ER area increased, but the P-450 content decreased or remained unchanged in hepatocytes of the three zones. We conclude that cobalt chloride inhibits the increase in total P-450 but has no effect on the proliferation of ER of hepatocytes in mice treated with PB, indicating a dissociation of ER proliferation and P-450 increase after administration of PB.     

Heavy oil and bitumen recovery by hot solvent injection

Thermal and miscible methods are commonly used for in situ recovery of heavy oil and bitumen. Both techniques have their own limitations and benefits. However, these methods can be combined by co-injecting solvent with steam or injecting solvent into a pre-heated reservoir. The current work was undertaken to study the performance of solvents at higher temperatures for heavy oil/bitumen recovery. Glass bead packs and Berea sandstone cores were used in the experiments to represent different types of pore structures, porosity and permeability. After saturating with heavy oil, the samples were exposed to the vapor of paraffinic solvents (propane and butane) at a temperature above the boiling point of the solvent, and a constant pressure of 1500 kPa. A mechanical convection oven was used to maintain constant temperature across the setup. The setup was designed in such a way that a reasonably long sample (up to 30 cm) can be tested to analyze the gravity effect. The oil recovered from each of these experiments was collected using a specifically designed collection system and analyzed for composition, viscosity and asphaltene content.The final amount of oil recovered in each case (recovery factor but not extraction rate) was also analyzed and the quantity and nature of asphaltene precipitated with each of the tested solvents under the prevailing temperature and pressure of the experiment was reported. Optimal conditions for each solvent type were identified for the highest ultimate recovery. It was observed that recovery decreased with increasing temperature and pressure of the system for both solvents, and that the best results were found when experimental temperature is only slightly higher than the saturation temperature of the solvent used. It was also noticed that butane diluted the oil more than propane which resulted in lower asphaltene content and viscosity of oil produced with butane as a solvent.     

Surface-bound heparin fails to reduce thrombin formation during clinical cardiopulmonary bypass

The hypothesis that heparin-coated perfusion circuits reduce thrombin formation and activity; fibrinolysis; and platelet, complement, and neutrophil activation was tested in 20 consecutive, randomized adults who had cardiopulmonary bypass. Twenty identical perfusion systems were used; in 10, all blood-contacting surfaces were coated with partially degraded heparin (Carmeda process; Medtronic Cardiopulmonary, Anaheim, Calif.). All patients received a 300 U/kg dose of heparin. Activated clotting times were maintained longer than 400 seconds. Cardiopulmonary bypass lasted 36 to 244 minutes. Blood samples for platelet count, platelet response to adenosine diphosphate, plasma beta-thromboglobulin, inactivated complement 3b, neutrophil elastase, fibrinopeptide A, prothrombin fragment F1.2, thrombin-antithrombin complex, tissue plasminogen activator, plasminogen activator inhibitor-1, plasmin alpha 2-antiplasmin complex, and D-dimer were obtained at these times: after heparin was given, 5 and 30 minutes after cardiopulmonary bypass was started, within 5 minutes after bypass was stopped, and 15 minutes after protamine was given. After cardiopulmonary bypass, tubing segments were analyzed for surface-adsorbed anti-thrombin, fibrinogen, factor XII, and von Willebrand factor by radioimmunoassay. Heparin-coated circuits significantly (p < 0.001) reduced platelet adhesion and maintained platelet sensitivity to adenosine diphosphate (p = 0.015), but did not reduce release of beta-thromboglobulin. There were no significant differences between groups at any time for fibrinopeptide A, prothrombin fragment F1.2, or thrombin-antithrombin complex or in the markers for fibrinolysis: D-dimer, tissue plasminogen activator, plasminogen activator inhibitor-1, and alpha 2-antiplasmin complex. In both groups, concentrations of prothrombin fragment F1.2 and thrombin-antithrombin complex increased progressively and significantly during cardiopulmonary bypass and after protamine was given. Concentrations of D-dimer, alpha 2-antiplasmin complex, and plasminogen activator inhibitor-1 also increased significantly during bypass in both groups. Fibrinopeptide A levels did not increase during bypass but in both groups increased significantly after protamine was given. No significant differences were observed between groups for levels of inactivated complement 3b or neutrophil elastase. Radioimmunoassay showed a significant increase in surface-adsorbed antithrombin on coated circuits but no significant differences between groups for other proteins. We conclude that heparin-coated circuits used with standard doses of systemic heparin reduce platelet adhesion and improve platelet function but do not produce a meaningful anticoagulant effect during clinical cardiopulmonary bypass. The data do not support the practice of reducing systemic heparin doses during cardiac operations with heparin-coated extracorporeal perfusion circuitry.     

Integrilin prevents prolonged bleeding times after cardiopulmonary bypass

BACKGROUND: Cardiopulmonary bypass reduces platelet number and function, increases postoperative bleeding time, and is the major, unsolved cause of nonsurgical bleeding after open heart operations. Temporary inhibition of platelet function during cardiopulmonary bypass (platelet anesthesia) protects platelets and reduces postoperative bleeding time and bleeding. METHODS: Integrilin, a short-acting, reversible platelet glycoprotein IIb/IIIa inhibitor was studied in 28 baboons that had 60 minutes of normothermic cardiopulmonary bypass using peripheral cannulas. A control group, two groups that received different doses of Integrilin, and a group that received a combination of Integrilin and low-dose Iloprost were studied. Blood samples for platelet count, aggregation to adenosine diphosphate, beta-thromboglobulin, prothrombin fragment F1.2, thrombin-antithrombin complex, and fibrinopeptide A were obtained at seven time points. Template bleeding times were measured before and at five intervals after cardiopulmonary bypass. RESULTS: Both doses of Integrilin and the combination of Integrilin and Iloprost significantly protected platelet number, inhibited the response to adenosine diphosphate, and reduced postoperative bleeding times, but they did not reduce beta-thromboglobulin release except in the high-dose Integrilin group. Thrombin formation and activity were qualitatively, but not significantly, reduced in all treatment groups. Bleeding times were not significantly different from baseline at the time protamine was given in the combination group and 60 minutes after protamine administration in all treatment groups. CONCLUSIONS: Integrilin alone or in combination with Iloprost significantly reduces platelet activation during cardiopulmonary bypass and produces normal or near-normal bleeding times at the time protamine is given.