Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials – except those for pulmonary arterial hypertension and scleroderma-related digital ulcers – were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused

Local Data Assimilation in the Estimation of Barotropic and Baroclinic Open Boundary Conditions

The problem of data assimilation in the specification of open boundary conditions for limited area models is addressed in this paper. Optimization approaches are detailed, which are based on combining available data on an open boundary with the physics of the hydrodynamical model. In our case the physics is in terms of the flux of energy through the open boundary. These optimized boundary conditions, for both barotropic and baroclinic situations, interpreted physically as special Linearizations of the Bernoulli equation for each normal mode. Because of the complexity of decomposing variables into normal modes for open boundaries with varying bathymetry, we present two alter native approaches. The first is a simplification of the optimized baroclinic boundary condition based on normal modes. The second makes use of empirical orthogonal functions instead of normal modes. The results of testing and comparisons of these approaches are presented for coupling coarse- and fine-resolution models. In this case our approach is in assimilating values and variables from a large-scale model. (along the open boundaries of a limited area model). In the proposed coupling schemes the energy fluxes are estimated either from coarse or from fine-grid model results. With the progress of oceanographic observing systems we would like to explore ways of combining model outputs with the oceanographic measurements in order to estimate energy fluxes used in optimized open boundary conditions

The Spectroscopic Age of 47 Tuc

High signal-to-noise integrated spectra of the metal-rich globular cluster 47 Tuc, spanning the H-gamma(HR) and Fe4668 line indices, have been obtained. The combination of these indices has been suggested (Jones & Worthey 1995, ApJ, 446, L31) as the best available mechanism for cleanly separating the age-metallicity degeneracy which hampers the dating of distant, unresolved, elliptical galaxies. For the first time, we apply this technique to a nearby spheroidal system, 47 Tuc, for which independent ages, based upon more established methods, exist. Such an independent test of the technique's suitability has not been attempted before, but is an essential one before its application to more distant, unresolved, stellar populations can be considered valid. Because of its weak series of Balmer lines, relative to model spectra, our results imply a spectroscopic ``age'' for 47 Tuc well in excess of 20 Gyr, at odds with the colour-magnitude diagram age of 14+/-1 Gyr. The derived metal abundance, however, is consistent with the known value. Emission ``fill-in'' of the H-gamma line as the source of the discrepancy cannot be entirely excluded by existing data, although the observational constraints are restrictive.Comment: 17 pages, 4 figures, LaTeX, accepted for publication in The Astronomical Journal, also available at http://casa.colorado.edu/~bgibson/publications.htm

Single-phase laminar flow heat transfer from confined electron beam enhanced surfaces

An experimental investigation of the thermal-hydraulic characteristics for single-phase flow through three electron beam enhanced structures was conducted with water at mass flow rates from 0.005 kg/s to 0.045 kg/s. The structures featured copper heat transfer surfaces, approximately 28 mm wide and 32 mm long in the flow direction, with complex three-dimensional (3D) electron beam manufactured pyramid-like structures. The channel height varied depending on the height of the protrusions and the tip clearance was maintained at 0.1-0.3 mm. The average protrusion densities for the three samples S1, S2, and S3 were 13, 11, and 25 per cm2 with protrusion heights of 2.5, 2.8, and 1.6 mm, respectively. The data gathered were compared to those for a smooth channel surface operating under similar conditions. The results show an increase up to approximately three times for the average Nusselt number compared with the smooth surface. This is attributed to the surface irregularities of the enhanced surfaces, which not only increase the heat transfer area but also improve mixing, disturb the thermal and velocity boundary layers, and reduce thermal resistance. The increase in heat transfer with the enhanced surfaces was accompanied by an increase of pressure drop, which has to be considered in design.The authors would like to acknowledge Dr Anita Buxton and Dr Bruce Dance of TWI for their contribution to this project and also EPSRC and TSB for funding the EngD programme and sponsoring the ASTIA collaborative research project that helped to develop the Electron Beam enhanced surfaces respectively

Statements made about HR 923 (The Emmett Till Unsolved Civil Rights Crime Act)

Document includes text of Congressman John Lewis\u27s statement made to the House of Representatives on 20 June 2007; a letter from lead counsel John G. Brittain to House Speaker Nancy Pelosi on 18 June 2007; a letter of support to Congressmen Lewis, Dodd, Hulshof, and Leahy from Wade Henderson and Nancy Zirkin, representing the Leadership Conference on Civil Rights; a letter to Congressmen Lewis and Hulshof from Hilary O. Shelton on behalf of the NAACP

Logarithmic asymptotics for the supremum of a stochastic process

Logarithmic asymptotics are proved for the tail of the supremum of a stochastic process, under the assumption that the process satisfies a restricted large deviation principle on regularly varying scales. The formula for the rate of decay of the tail of the supremum, in terms of the underlying rate function, agrees with that stated by Duffield and O’Connell [Math. Proc. Cambridge Philos. Soc. (1995) 118 363–374]. The rate function of the process is not assumed to be convex. A number of queueing examples are presented which include applications to Gaussian processes and Weibull sojourn sources

Circular 64

Treatment of Alaska-produced food products by ionizing radiation may benefit the seafood and agricultural industries and the Alaskan consumer. A feasibility study to evaluate the potential social and economic benefits and risks as well as the costs of using the process in Alaska on Alaskan products is being coordinated by the Institute of Northern Engineering. A research and development project to determine effects on the quality o f Alaskan products could be the next phase in the introduction o f a new food-preservation technique to Alaska

Stochastic Theories of Participation

A recent mathematical model by Horvath which predicts the process of participation in group discussions is compared to several alternative models. The models can be applied to data for which the basic unit is the act and to data for which the basic unit is a continuous sequence of acts. In both cases, when statistical tests of significance are employed, most of the more restrictive models are rejected

Franchise Litigation in Texas: Analyzing Claims and Defenses Symposium - Business Tort Litigation.

Abstract Forthcoming