Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver.

We administered an adenoviral vector, Onyx-015, into the hepatic artery of patients with metastatic colorectal cancer involving the liver. Thirty-five patients enrolled in this multi-institutional phase I/II trial received up to eight arterial infusions of up to 2 x 10(12) viral particles. Hepatic toxicity was the primary dose-limiting toxicity observed in preclinical models. However, nearly 200 infusions of this adenoviral vector were administered directly into the hepatic artery without significant toxicity. Therefore, we undertook this analysis to determine the impact of repeated adenoviral exposure on hepatic function. Seventeen patients were treated at our institution, providing a detailed data set on the changes in hepatic function following repeated exposure to adenovirus. No changes in hepatic function occurred with the first treatment of Onyx-015 among these patients. Transient increases in transaminase levels occurred in one patient starting with the second infusion and transient increases in bilirubin was observed in two patients starting with the fifth treatment. These changes occurred too early to be explained by viral-mediated lysis of hepatocytes. In addition, viremia was observed starting 3-5 days after the viral infusion in half of the patient, but was not associated with hepatic toxicity. To further understand the basis for the minimal hepatic toxicity of adenoviral vectors, we evaluated the replication of adenovirus in primary hepatocytes and tumor cells in culture and the expression of the coxsackie-adenoviral receptor (CAR) in normal liver and colon cancer metastatic to the liver. We found that adenovirus replicates poorly in primary hepatocytes but replicates efficiently in tumors including tumors derived from hepatocytes. In addition, we found that CAR is localized at junctions between hepatocytes and is inaccessible to hepatic blood flow. CAR is not expressed on tumor vasculature but is expressed on tumor cells. Spatial restriction of CAR to the intercellular space in normal liver and diminished replication of adenovirus in hepatocytes may explain the minimal toxicity observed following repeated hepatic artery infusions with Onyx-015

Precision power measurements of spacecraft CW signal with microwave noise standards

Precision power measurements of spacecraft CW signal with microwave noise standard

Beyond recurrent costs: an institutional analysis of the unsustainability of donor-supported reforms in agricultural extension

International donors have spent billions of dollars over the past four decades in developing and/or reforming the agricultural extension service delivery arrangements in developing countries. However, many of these reforms, supported through short-term projects, became unsustainable once aid funding had ceased. The unavailability of recurrent funding has predominantly been highlighted in the literature as the key reason for this undesirable outcome, while little has been written about institutional factors. The purpose of this article is to examine the usefulness of taking an institutional perspective in explaining the unsustainability of donor-supported extension reforms and derive lessons for improvement. Using a framework drawn from the school of institutionalism in a Bangladeshi case study, we have found that a reform becomes unsustainable because of poor demands for extension information and advice; missing, weak, incongruent, and perverse institutional frameworks governing the exchange of extension goods (services); and a lack of institutional learning and change during the reform process. Accordingly, we have argued that strategies for sustainable extension reforms should move beyond financial considerations and include such measures as making extension goods (services) more tangible and monetary in nature, commissioning in-depth studies to learn about local institutions, crafting new institutions and/or reforming the weak and perverse institutions prevailing in developing countries. We emphasize the need to address three categories of institutions – regulative, normative, and cultural-cognitive – and call for an alignment among them. We further argue that, in order to be sustainable, a reform should take a systemic approach in institutional capacity building and, for this to be possible, adopt a long-term program approach, as opposed to a short-term project approach

Comparison of predictive scores of symptomatic intracerebral haemorrhage after stroke thrombolysis in a single centre

Peer reviewedPublisher PD

Near- to mid-infrared picosecond optical parametric oscillator based on periodically poled RbTiOAsO4

We describe a Ti:sapphire-pumped picosecond optical parametric oscillator based on periodically poled RbTiOAsO4 that is broadly tunable in the near to mid infrared. A 4.5-mm single-grating crystal at room temperature in combination with pump wavelength tuning provided access to a continuous-tuning range from 3.35 to 5 mu m, and a pump power threshold of 90 mW was measured. Average mid-infrared output powers in excess of 100 mW and total output powers of 400 mW in similar to 1-ps pulses were obtained at 33% extraction efficiency. (C) 1998 Optical Society of America.</p

Theory of Nonequilibrium Spin Transport and Spin Transfer Torque in Superconducting-Ferromagnetic Nanostructures

Spin transport currents and the spin-transfer torques in voltage-biased superconducting-ferromagnetic nanopillars (SFNFS point contacts) are computed. We develop and implement an algorithm based on the Ricatti formulation of the quasiclassical theory of superconductivity to solve the time-dependent boundary conditions for the nonequilibrium Green's functions for spin transport through the ferromagnetic interfaces. A signature of the nonequilibrium torque is a component perpendicular to the plane spanned by the two ferromagnetic moments. The perpendicular component is absent in normal-metal-ferromagnetic nanopillars (NFNFN) contacts, but is shown to have the same order of magnitude as the in-plane torque for non-equilibrium SFNFS contacts. The out-of-plane torque is due to the rotation of quasiparticle spin by the exchange fields of the ferromagnetic layers. In the ballistic limit the equilibrium torque is related to the spectrum of spin-polarized Andreev bound states, while the {\sl ac} component, for small bias voltages, is determined by the nearly adiabatic dynamics of the Andreev bound states. The nonlinear voltage dependence of the non-equilibrium torque, including the subharmonic gap structure and the high-voltage asymptotics, is attributed to the interplay between multiple Andreev reflections, spin filtering and spin mixing. These properties of spin angular momentum transport may be exploited to control the state of nanomagnets.Comment: 15 pages, 14 figure

Characterization of 40-Gbit/s pulses generated using a lithium niobate modulator at 1550 nm using frequency resolved optical gating

The characteristics of 40-Gbit/s pulses generated by exploiting the nonlinear characteristics of a Mach-Zender Lithium Niobate modulator are presented. A high spectral resolution frequency resolved optical gating apparatus has been developed to allow for the complete characterization of the intensity and phase of these pulses. The use of these measurements to simplify the design and optimization of an 80-Gbit/s pulse source, based on this 40-Gbit/s source followed by a nonlinear fiber compressor and multiplexer, is also demonstrated

Building leadership capacity and future leaders in operational research in low-income countries: why and how?

Very limited operational research (OR) emerges from programme settings in low-income countries where the greatest burden of disease lies. The price paid for this void includes a lack of understanding of how health systems are actually functioning, not knowing what works and what does not, and an inability to propose adapted and innovative solutions to programme problems. We use the National Tuberculosis Control Programme as an example to advocate for strong programme-level leadership to steer OR and build viable relationships between programme managers, researchers and policy makers. We highlight the need to create a stimulating environment for conducting OR and identify some of the main practical challenges and enabling factors at programme level. We focus on the important role of an OR focal point within programmes and practical approaches to training that can deliver timely and quantifiable outputs. Finally, we emphasise the need to measure successful OR leadership development at programme level and we propose parameters by which this can be assessed. This paper 1) provides reasons why programmes should take the lead in coordinating and directing OR, 2) identifies the practical challenges and enabling factors for implementing, managing and sustaining OR and 3) proposes parameters for measuring successful leadership capacity development in OR

EPR entanglement strategies in two-well BEC

Criteria suitable for measuring entanglement between two different potential wells in a Bose- Einstein condensation (BEC) are evaluated. We show how to generate the required entanglement, utilizing either an adiabatic two-mode or dynamic four-mode interaction strategy, with techniques that take advantage of s-wave scattering interactions to provide the nonlinear coupling. The dynamic entanglement method results in an entanglement signature with spatially separated detectors, as in the Einstein-Podolsky-Rosen (EPR) paradox.Comment: 4 pages, 4 figure