Superior activity of a thromboxane receptor antagonist as compared with aspirin in rat models of arterial and venous thrombosis

We determined the effects of aspirin and a novel thromboxane A2/prostaglandin endoperoxide (TP)-receptor antagonist, BMS-180291, on thrombosis and bleeding times in skin and mesenteric arteries. In anesthetized rats, occlusive thrombosis was induced in the carotid artery by topical application of ferrous chloride and in the vena cava by blood flow stasis combined with either infusion of thromboplastin or hypotonic saline. Aspirin (1, 10, and 50 mg/kg) did not reduce arterial or venous thrombus weight significantly. BMS 180,291 (150 micrograms/kg/min) decreased arterial thrombus weight and hypotonic saline-induced caval thrombus weight by 58 and 57%, respectively. BMS-180291 lacked antithrombotic activity at a lower dose (50 micrograms/kg/min) and failed to inhibit thromboplastin-induced caval thrombosis. BMS-180291 (150 micrograms/kg/min) significantly reduced arterial thrombus weight by 40% when plasma epinephrine concentration was increased to 5 ng/ml. BMS-180291 and aspirin produced increases of only < or = 30% in bleeding times. These results demonstrate that BMS-180291 has antithrombotic activity in experimental aspirin-resistant arterial and venous thrombosis. Both aspirin and BMS-180291 have only modest effects on small artery hemostasis in rats.     

Cell-Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit

The ubiquitin-proteasome system (UPS) is an established therapeutic target for approved drugs to treat selected hematologic malignancies. While drug discovery targeting the UPS focuses on irreversibly binding epoxyketones and slowly-reversibly binding boronates, optimization of novel covalent-reversibly binding warheads remains largely unattended. We previously reported α-ketoamides to be a promising reversible lead motif, yet the cytotoxic activity required further optimization. This work focuses on the lead optimization of phenoxy-substituted α-ketoamides combining the structure-activity relationships from the primed and the non-primed site of the proteasome β5 subunit. Our optimization strategy is accompanied by molecular modeling, suggesting occupation of P1′ by a 3-phenoxy group to increase β5 inhibition and cytotoxic activity in leukemia cell lines. Key compounds were further profiled for time-dependent inhibition of cellular substrate conversion. Furthermore, the α-ketoamide lead structure 27 does not affect escape response behavior in Danio rerio embryos, in contrast to bortezomib, which suggests increased target specificity.     

Alpine infrastructure in Central Europe: integral evaluation of wastewater treatment systems at mountain refuges

Planning, construction and operation of onsite wastewater treatment systems at mountain refuges is a challenge. Energy supply, costly transport, limited water resources, unfavourable climate and load variations are only some of the problems that have to be faced. Additionally, legal regulations are different between and even within countries of the Alps. To ensure sustainability, integrated management of the alpine infrastructure management is needed. The energy and water supply and the wastewater and waste disposal systems and the cross-relations between them were analysed for 100 mountain refuges. Wastewater treatment is a main part of the overall 'mountain refuge' system. The data survey and first analyses showed the complex interaction of the wastewater treatment with the other infrastructure. Main criteria for reliable and efficient operation are training, technical support, user friendly control and a relatively simple system set up. Wastewater temperature, alkalinity consumption and high peak loads have to be considered in the planning process. The availability of power in terms of duration and connexion is decisive for the choice of the system. Further, frequency fluctuations may lead to damages to the installed aerators. The type of water source and the type of sanitary equipment influence the wastewater quantity and quality. Biosolids are treated and disposed separately or together with primary or secondary sludge from wastewater treatment dependent on the legal requirements.     

Secondary organic aerosol formation by irradiation of 1,3,5-trimethylbenzene-NOx-H2O in a new reaction chamber for atmospheric chemistry and physics

A new environmental reaction smog chamber was built to simulate particle formation and growth similar to that expected in the atmosphere. The organic material is formed from nucleation of photooxidized organic compounds. The chamber is a 27 m3 fluorinated ethylene propylene (FEP) bag suspended in a temperature-controlled enclosure. Four xenon arc lamps (16 kW total) are used to irradiate primary gas components for experiments lasting up to 24 h. Experiments using irradiations of 1,3,5-trimethylbenzene-NOx-H2O at similar input concentrations without seed particles were used to determine particle number and volume concentration wall loss rates of 0.209+/-0.018 and 0.139+/-0.070 h(-1), respectively. The particle formation was compared with and without propene.     

Influence of base material,tempered condition and hardening pattern on the residual stress profile of induction hardened gears

Forschung im Ingenieurwesen - This paper discusses influences of the base material, pre-heat treatment and hardening pattern on the residual stresses of induction hardened gears with module 2 and...     

Measurements of OVOCs and NMHCs in a Swiss highway tunnel for estimation of road transport emissions

Eighteen oxygenated volatile organic compounds (OVOCs) and eight nonmethane hydrocarbons (NMHCs) were measured continuously during a two-week campaign in 2004 in the Gubrist highway tunnel (Switzerland). The study aimed to estimate selected OVOC and NMHC emissions of the current vehicle fleet under highway conditions. For the measured OVOCs the highest EFs were found for ethanol (9.7 mg/km), isopropanol (3.2 mg/km), and acetaldehyde (2.5 mg/km), followed by acetone, benzaldehyde, and acrolein. Formaldehyde, the most abundant OVOC measured in other studies, was not measured by the method applied. Relative emissions of the measured OVOCs were estimated to contribute approximately 6 and 4% to the total road traffic VOC emissions from Switzerland and Europe, respectively. Results are compared with those from previous studies from the same tunnel performed in 1993 and 2002, and from campaigns in other tunnels. A continuous reduction in the emission factors (EFs) was determined for all measured compounds from 1993 until 2004. The relative contributions of light-duty vehicles (LDV) and heavy-duty vehicles (HDV) to the total emissions indicated that OVOCs were mainly produced by the HDVs, whereas LDVs dominated the production of the NMHCs.     

Observations of long-lived anthropogenic halocarbons at the high-Alpine site of Jungfraujoch (Switzerland) for assessment of trends and European sources

Anthropogenic halocarbons, such as chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs), hydrofluorocarbons (HFCs), bromocarbons (halons) and long-lived chlorinated solvents have been measured continuously at the high-Alpine site of Jungfraujoch (Switzerland) since January 2000. Chloro- and bromo-containing halocarbons are responsible for the stratospheric ozone depletion and will be globally banned from usage within the next years. With the exception of the stable CFC-12 (CF2 Cl2), all major CFCs and chlorinated solvents show a negative trend in recent years in their background concentrations at Jungfraujoch. HCFCs, as their first-generation substitute, are still increasing with a few percent per year. However, the frequency and the strength of HCFCs pollution events, which are caused by regional European emissions, are already declining. This can be seen as a sign of the impending ban of these gases within the next years in Europe. On the other hand, HFCs as the second-generation substitutes, are increasing with relative rates of at least 10% per year (e.g. almost 5 ppt per year for HFC-134a). An allocation of European sources was attempted by combining measured concentrations with trajectories of air masses reaching the Jungfraujoch during pollution events. Potential source regions could be detected in Italy, France, Spain and Germany.     

Material influence on mechanical properties of gears with alternative microstructures

Case hardening represents the most important heat treatment process to increase the load carrying capacity of gear components. Beside predominantly martensitic surface layers with low proportion of retained austenite, there were investigated material structures with differing properties in preceding research work.

In a previous publication, the results of three variants made of the material 20MnCr5, which is typically used for gears, were presented. The reference heat treatment was a conventional carburizing with subsequent case hardening. The second variant was also gas carburized, but with a high proportion of retained austenite. The last presented variant had a bainitic structure in the surface layer. The second and the third variant showed a similar tooth root bending strength compared to the reference. The numbers of the pitting resistance were significantly higher than for the reference variant.

This paper presents the results of further investigations on the influence of different microstructures on the gear load carrying capacity. For this purpose, gears made of 18CrNiMo7‑6 were tested with regard to their load carrying capacity. 18CrNiMo7‑6 is a case hardening steel like 20MnCr5, too, which is often applied in big gear components. The tooth root bending strength was approximately constant, whereas the pitting resistance decreased compared to the corresponding variants of the material 20MnCr5. In comparison to the carburized 20MnCr5 reference variant, only the 18CrNiMo7‑6 variant with a large proportion of retained austenite showed a higher pitting resistance.

The tooth root bending strength investigations took place in the cycle regime of limited life as well in the high cycle fatigue regime. The pitting resistance was only determined in the cycle regime of limited life.