Actions of A-131701, a novel, selective antagonist for alpha-1A compared with alpha-1B adrenoceptors on intraurethral and blood pressure responses in conscious dogs and a pharmacodynamic assessment of in vivo prostatic selectivity

A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b, hexahydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido [3',4': 4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione) is a novel compound previously shown to be selective for alpha-1a sites compared with alpha-1b adrenoceptors in radioligand binding studies and isolated tissue bioassays and to block canine urethral pressure (IUP) responses to exogenous alpha-1 adrenergic agonists to a greater extent than blood pressure responses. In conscious dogs in which IUP and mean arterial blood pressure (MABP) responses were measured periodically up to 24 hr, A-131701 blocked phenylephrine (PHE)-induced increases in IUP to a greater extent than MABP responses, and the blockade of the IUP effects of PHE was significantly different from control for up to 12 hr after doses greater than 0.3 mg/kg p.o., whereas blood pressure effects were of a lesser extent and duration. In addition to the weak antagonism of PHE-induced blood pressure responses, A-131701 also exhibited minimal effects on basal blood pressure in the dog, unlike terazosin, doxazosin or tamsulosin. Pharmacokinetic analysis of plasma samples from dogs indicated that A-131701 had a half-life of 0.4 to 0.8 hr and a bioavailability of 30 to 50% in dogs. Somewhat longer half-lives were observed in rat and monkey, with bioavailability values in the 25 to 30% range. Evidence of nonlinearity of pharmacokinetics was obtained in dogs and monkeys. Pharmacodynamic analysis revealed differences between A-131701 and nonselective alpha-1 adrenoceptor antagonists in selectivity for prostatic versus vascular alpha-1 adrenoceptors based on either extent or duration of blockade, which were either similar to or superior to compounds such as tamsulosin or REC 15/2739. These data demonstrate that A-131701 selectively blocks canine prostatic alpha-1 adrenoceptors for prolonged periods compared with MABP responses in vivo. Therefore, A-131701 should have clinical utility in the pharmacotherapy of benign prostatic hyperplasia.     

Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation

BACKGROUND: Transplantation of blood or bone-marrow stem cells is the treatment of choice for selected patients with chronic myeloid leukaemia (CML). Transplantation is used with increasing frequency and success, but remains associated with substantial risks of morbidity and mortality. Other treatments with satisfactory short-term outcome are available. For appropriate counselling of patients, a rapid and simple way to assess risk is needed. METHODS: Data from 3142 patients (1873 [60%] male, 1269 [40%] female; mean age 34 years, range <1-60 years) treated with allogeneic blood or marrow transplants for CML between 1989 and 1997, reported to the European Group for Blood and Marrow Transplantation (EBMT), were used to develop and test a simple risk score based on previously reported major pretransplant risk factors: histocompatibility, stage of disease at time of transplantation, age and sex of donor and recipient, and time from diagnosis to transplantation. We analysed probabilities of survival, leukaemia-free survival, transplant-related mortality, and relapse incidence with respect to these risk factors. FINDINGS: At the time of analysis, 1922 (61%) of the 3142 patients were alive-1567 (65%) of those with HLA-identical sibling donors and 417 (57%) of those with unrelated donors. 1682 (54%) were alive without relapse. 1220 (39%) patients had died, 1013 (83%) of transplant-related causes, 207 (17%) of relapse. 447 (14%) patients had relapsed. The final scoring system was highly predictive for leukaemia-free survival, survival and transplant-related mortality. Survival at 5 years was 72%, 70%, 62%, 48%, 40%, 18%, and 22% for patients with scores 0, 1, 2, 3, 4, 5, and 6, respectively. Risk of transplant-related mortality was 20%, 23%, 31%, 46%, 51%, 71%, and 73%. Data showed the same trends for HLA-identical sibling transplants and unrelated transplants for transplants done in 1989-93 and 1994-96. INTERPRETATION: Pretransplant risk factors are cumulative for individual patients with CML having blood or marrow transplantation. A simple system based on five main factors gives adequate risk assessment for counselling of patients and taking decisions.     

Differential thymic selection outcomes stimulated by focal structural alteration in peptide/major histocompatibility complex ligands

The T lineage repertoire is shaped by T cell receptor (TCR)-dependent positive and negative thymic selection processes. Using TCR-transgenic (N15tg) beta2-microglobulin-deficient (beta2m-/-) RAG-2(-/-) H-2(b) mice specific for the VSV8 (RGYVYQGL) octapeptide bound to Kb, we identified a single weak agonist peptide variant V4L (L4) inducing phenotypic and functional T cell maturation. The cognate VSV8 peptide, in contrast, triggers negative selection. The crystal structure of L4/Kb was determined and refined to 2.1 A for comparison with the VSV8/Kb structure at similar resolution. Aside from changes on the p4 side chain of L4 and the resulting alteration of the exposed Kb Lys-66 side chain, these two structures are essentially identical. Hence, a given TCR recognizes subtle distinctions between highly related ligands, resulting in dramatically different selection outcomes. Based on these finding and the recent structural elucidation of the N15-VSV8/Kb complex, moreover, it appears that the germ-line Valpha repertoire contributes in a significant way to positive selection.     

Contributions to Oil-Spill Detection and Analysis with Radar and Microwave Radiometry: Results of the Archimedes II Campaign

During the Archimedes II campaign in November 1985 (conducted and sponsored by JRC ISPRA) different DFVLR-instruments were flown, an X-band SLAR, an elementary L-band SAR, and microwaveradiometers at 32 and 90 GHz. The objective of these measurements was to evaluate the possibility of detection, localization, and qualification of oil pollution with microwave sensors. Examples of measurement results obtained are presented. As a main result, it can be stated that all of these microwave instruments are valuable and necessary tools for oil pollution detection andoil collection systems.     

Brookite Formation in TiO2?Ag Nanocomposites and Visible‐Light‐Induced Templated Growth of Ag Nanostructures in TiO2

TiO₂? Ag‐nanocomposites exhibit various desirable properties that make them suitable for a variety of applications, for example in photocatalysis and as bactericidal coatings. In this work, a new method for processing TiO₂? Ag nanocomposites is presented. The nanocomposite films are fabricated from one precursor solution with high silver loading of up to 50%. The resulting films exhibit a microstructure consisting of TiO₂? Ag_xO nanocomposites with a largely XRD‐amorphous TiO₂ matrix containing brookite nanocrystals. This specific microstructure absorbs in the visible range so that photoreduction of Ag ions can be accomplished by using visible light. The thin films can be patterned using simple shadow masks. The illuminated areas show a high density of self‐organized nanoparticles (SNPs) and nanorods (SNRs), which are templated by the TiO₂ porous network. The particle size can be tuned by varying the irradiation time. Most of the SNPs and SNRs form faceted crystals, which are mostly a combination of {111} and {110}. The application of these films as substrates for surface‐enhanced Raman scattering is shown. Enhancement factors as high as 4.6 × 10⁶ could be obtained using rhodamine 6G dye molecules. More applications should involve photocatalytic water purification using visible light.     

德国并不是加热欧洲太阳能市场的唯一国家

据iSuppli公司,虽然德国作为新增太阳能安装之王获得了光伏(PV)市场的王冠,但欧洲其它国家也在扩大自己的2010年及未来光伏计划.实际上,欧洲其它可以替代德国成为投资热点的地区大量涌现,意大利和法国的投资回报(ROI)就非常吸引人.iSuppli公司已经看到,大多数德国太阳能投资者涌向这些国家,以拓宽投资范围.     

Masking effect produced by Mach bands on the detection of narrow bars of random polarity

Difficulties arise in measuring masking by Mach bands because very-low-contrast signals distort the bands. [J. Opt. Soc. Am. A 17, 1147 (2000).] Adding narrow luminance increments (bright bars) in the dark Mach band widens the dark band; adding decrements (dark bars) narrows the dark band, and conversely in the bright bands. Randomizing signal polarity prevents observers from using the distortion of the Mach bands as a cue to the presence of the signal. We measured (two-alternative-forced-choice) Mach bands' masking of randomly selected bright (incremental) or dark (decremental) bars. Detection was worse in both dark and bright Mach bands than on the neighboring plateaus. Separate analysis of trials containing only one polarity signal revealed 9-cycle/deg oscillations in performance as a function of location. Oscillations in the two polarities were approximately 180 degrees out of phase.     

Effect of laser chirp on optical systems?initial tests using a 1480 nm DFB laser

Initial assessment of the effect of laser ?chirp? on optical systems is described. Measurements of the wavelength shift and its effect on the received pulse after 4 km and 80 km of dispersive fibre are presented. The results are in good agreement with simple modelling, which predicts no penalty for this system Further tests are needed to determine whether this behaviour is typical.