Effects of combined administration of FK 506 and the purine biosynthesis inhibitors mizoribine or mycophenolic acid on lymphocyte DNA synthesis and T cell activation molecule expression in human mixed lymphocyte cultures

Our objective was to obtain new information on the in vitro antilymphocytic action of the cytokine synthesis inhibitor FK 506 and the purine biosynthesis inhibitors mycophenolic acid (MPA; the active moiety of RS61443) and mizoribine (MZB) when used alone or in combination. When added at the initiation of six-day human mixed lymphocyte cultures (MLC), FK 506, MPA or MZB exhibited dose-dependent inhibition of T-lymphocyte DNA synthesis. FK 506, however, was 100-fold more potent than MPA, and 10000-fold more potent than MZB. Combination of FK 506 with either MPA or MZB, each at suboptional concentrations, produced no more than additive inhibitory effects on 3H thymidine incorporation. Two-colour flow cytometric analysis of lymphocytes revealed that none of the drugs affected cell surface activation molecule expression (CD25 = IL-2R 55 kD α-chain, HLA-DR or CD71 = transferrin receptor [TR]) on allostimulated CD4+ or CD8+ cells harvested at three days of culture. By day six, however, all three agents, at levels which markedly inhibited proliferation, suppressed the expression of activation markers on both CD4+ and CD8+ cells. Also at day six, inhibition of activation molecule expression on CD4+ cells was achieved with the combination of FK 506 and either MPA or MZB at concentrations which, on their own, were ineffective. These data provide new, additional information on the in vitro antilymphocytic action of FK 506, MPA and MZB when used alone and in combination. © 1993

Traceable measurement and imaging of the complex permittivity of a multiphase mineral specimen at micron scales using a microwave microscope

This paper describes traceable measurements of the dielectric permittivity and loss tangent of a multiphase material (particulate rock set in epoxy) at micron scales using a resonant Near-Field Scanning Microwave Microscope (NSMM) at 1.2 GHz. Calibration and extraction of the permittivity and loss tangent is via an image charge analysis which has been modified by the use of the complex frequency to make it applicable for high loss materials. The results presented are obtained using a spherical probe tip, 0.1 mm in diameter, and also a conical probe tip with a rounded end 0.01 mm in diameter, which allows imaging with higher resolution (≈10 µm). The microscope is calibrated using approach-curve data over a restricted range of gaps (typically between 1% and 10% of tip diameter) as this is found to give the best measurement accuracy. For both tips the uncertainty of scanned measurements of permittivity is estimated to be±10% (at coverage factor k=2) for permittivity ⪝10. Loss tangent can be resolved to approximately 0.001. Subject to this limit, the uncertainty of loss tangent measurements is estimated to be±20% (at k=2). The reported measurements inform studies of how microwave energy interacts with multiphase materials containing microwave absorbent phases

Precision Measurement of PArity Violation in Polarized Cold Neutron Capture on the Proton: the NPDGamma Experiment

The NPDGamma experiment at the Los Alamos Neutron Science Center (LANSCE) is dedicated to measure with high precision the parity violating asymmetry in the $\gamma$ emission after capture of spin polarized cold neutrons in para-hydrogen. The measurement will determine unambiguously the weak pion-nucleon-nucleon ($\pi NN$) coupling constant {\it f$^1_{\pi}$}Comment: Proceedings of the PANIC'05 Conference, Santa Fe, NM, USA, October 24-28, 2005, 3 pages, 2 figure

Indirect Dark Matter Detection from Dwarf Satellites: Joint Expectations from Astrophysics and Supersymmetry

We present a general methodology for determining the gamma-ray flux from annihilation of dark matter particles in Milky Way satellite galaxies, focusing on two promising satellites as examples: Segue 1 and Draco. We use the SuperBayeS code to explore the best-fitting regions of the Constrained Minimal Supersymmetric Standard Model (CMSSM) parameter space, and an independent MCMC analysis of the dark matter halo properties of the satellites using published radial velocities. We present a formalism for determining the boost from halo substructure in these galaxies and show that its value depends strongly on the extrapolation of the concentration-mass (c(M)) relation for CDM subhalos down to the minimum possible mass. We show that the preferred region for this minimum halo mass within the CMSSM with neutralino dark matter is ~10^-9-10^-6 solar masses. For the boost model where the observed power-law c(M) relation is extrapolated down to the minimum halo mass we find average boosts of about 20, while the Bullock et al (2001) c(M) model results in boosts of order unity. We estimate that for the power-law c(M) boost model and photon energies greater than a GeV, the Fermi space-telescope has about 20% chance of detecting a dark matter annihilation signal from Draco with signal-to-noise greater than 3 after about 5 years of observation

Orbital resonances in discs around braneworld Kerr black holes

Rotating black holes in the brany universe of the Randall-Sundrum type are described by the Kerr geometry with a tidal charge b representing the interaction of the brany black hole and the bulk spacetime. For b<0 rotating black holes with dimensionless spin a>1 are allowed. We investigate the role of the tidal charge b in the orbital resonance model of QPOs in black hole systems. The orbital Keplerian, the radial and vertical epicyclic frequencies of the equatorial, quasicircular geodetical motion are given and their radial profiles are discussed. The resonant conditions are given in three astrophysically relevant situations: for direct (parametric) resonances, for the relativistic precession model, and for some trapped oscillations of the warped discs, with resonant combinational frequencies. It is shown, how b could influence matching of the observational data indicating the 3:2 frequency ratio observed in GRS 1915+105 microquasar with prediction of the orbital resonance model; limits on allowed range of the black hole parameters a and b are established. The "magic" dimensionless black hole spin enabling presence of strong resonant phenomena at the radius where \nu_K:\nu_{\theta}:\nu_r=3:2:1 is determined in dependence on b. Such strong resonances could be relevant even in sources with highly scattered resonant frequencies, as those expected in Sgr A*. The specific values of a and b are given also for existence of specific radius where \nu_K:\nu_{\theta}:\nu_r=s:t:u with 5>=s>t>u being small natural numbers. It is shown that for some ratios such situation is impossible in the field of black holes. We can conclude that analysing the microquasars high-frequency QPOs in the framework of orbital resonance models, we can put relevant limits on the tidal charge of brany Kerr black holes.Comment: 31 pages, 19 figures, to appear in General Relativity and Gravitatio

Radioimmunotherapy of B-cell lymphoma with radiolabelled anti-CD20 monoclonal antibodies

CD20 has proven to be an excellent target for the treatment of B-cell lymphoma, first for the chimeric monoclonal antibody rituximab (Rituxan™), and more recently for the radiolabelled antibodies Y-90 ibritumomab tiuxetan (Zevalin™) and I-131 tositumomab (Bexxar™). Radiation therapy effects are due to beta emissions with path lengths of 1–5 mm; gamma radiation emitted by I-131 is the only radiation safety issue for either product. Dose-limiting toxicity for both radiolabelled antibodies is reversible bone marrow suppression. They produce response rates of 70%–90% in low-grade and follicular lymphoma and 40%–50% in transformed low-grade or intermediate-grade lymphomas. Both products produce higher response rates than related unlabelled antibodies, and both are highly active in patients who are relatively resistant to rituximab-based therapy. Median duration of response to a single course of treatment is about 1 year with complete remission rates that last 2 years or longer in about 25% of patients. Clinical trials suggest that anti- CD20 radioimmunotherapy is superior to total body irradiation in patients undergoing stem cell supported therapy for B-cell lymphoma, and that it is a safe and efficacious modality when used as consolidation therapy following chemotherapy. Among cytotoxic treatment options, current evidence suggests that one course of anti-CD20 radioimmunotherapy is as efficacious as six to eight cycles of combination chemotherapy. A major question that persists is how effective these agents are in the setting of rituximab- refractory lymphoma. These products have been underutilised because of the complexity of treatment coordination and concerns regarding reimbursement

Heavy quarkonium: progress, puzzles, and opportunities

A golden age for heavy quarkonium physics dawned a decade ago, initiated by the confluence of exciting advances in quantum chromodynamics (QCD) and an explosion of related experimental activity. The early years of this period were chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in 2004, which presented a comprehensive review of the status of the field at that time and provided specific recommendations for further progress. However, the broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles could only be partially anticipated. Since the release of the YR, the BESII program concluded only to give birth to BESIII; the $B$-factories and CLEO-c flourished; quarkonium production and polarization measurements at HERA and the Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the deconfinement regime. All these experiments leave legacies of quality, precision, and unsolved mysteries for quarkonium physics, and therefore beg for continuing investigations. The plethora of newly-found quarkonium-like states unleashed a flood of theoretical investigations into new forms of matter such as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the spectroscopy, decays, production, and in-medium behavior of c\bar{c}, b\bar{b}, and b\bar{c} bound states have been shown to validate some theoretical approaches to QCD and highlight lack of quantitative success for others. The intriguing details of quarkonium suppression in heavy-ion collisions that have emerged from RHIC have elevated the importance of separating hot- and cold-nuclear-matter effects in quark-gluon plasma studies. This review systematically addresses all these matters and concludes by prioritizing directions for ongoing and future efforts.Comment: 182 pages, 112 figures. Editors: N. Brambilla, S. Eidelman, B. K. Heltsley, R. Vogt. Section Coordinators: G. T. Bodwin, E. Eichten, A. D. Frawley, A. B. Meyer, R. E. Mitchell, V. Papadimitriou, P. Petreczky, A. A. Petrov, P. Robbe, A. Vair

Strategic positioning:an integrated decision process for manufacturers

Purpose – This paper describes research that has sought to create a formal and rational process that guides manufacturers through the strategic positioning decision. Design/methodology/approach – The methodology is based on a series of case studies to develop and test the decision process. Findings – A decision process that leads the practitioner through an analytical process to decide which manufacturing activities they should carryout themselves. Practical implications – Strategic positioning is concerned with choosing those production related activities that an organisations should carry out internally, and those that should be external and under the ownership and control of suppliers, partners, distributors and customers. Originality/value – This concept extends traditional decision paradigms, such as those associated with “make versus buy” and “outsourcing”, by looking at the interactions between manufacturing operations and the wider supply chain networks associated with the organisation

Towards optimal use of antithrombotic therapy of people with cancer at the end of life: a research protocol for the development and implementation of the SERENITY shared decision support tool Thrombosis Research

Background: Even though antithrombotic therapy has probably little or even negative effects on the well-being of people with cancer during their last year of life, deprescribing antithrombotic therapy at the end of life is rare in practice. It is often continued until death, possibly resulting in excess bleeding, an increased disease burden and higher healthcare costs. Methods: The SERENITY consortium comprises researchers and clinicians from eight European countries with specialties in different clinical fields, epidemiology and psychology. SERENITY will use a comprehensive approach combining a realist review, flash mob research, epidemiological studies, and qualitative interviews. The results of these studies will be used in a Delphi process to reach a consensus on the optimal design of the shared decision support tool. Next, the shared decision support tool will be tested in a randomised controlled trial. A targeted implementation and dissemination plan will be developed to enable the use of the SERENITY tool across Europe, as well as its incorporation in clinical guidelines and policies. The entire project is funded by Horizon Europe.Results: SERENITY will develop an information-driven shared decision support tool that will facilitate treatment decisions regarding the appropriate use of antithrombotic therapy in people with cancer at the end of life. Conclusions: We aim to develop an intervention that guides the appropriate use of antithrombotic therapy, prevents bleeding complications, and saves healthcare costs. Hopefully, usage of the tool leads to enhanced empowerment and improved quality of life and treatment satisfaction of people with advanced cancer and their care givers