Estimation of the effect of SLCO1B1 polymorphisms on lopinavir plasma concentration in HIV-Infected Adults

Background—The organic anion transporting polypeptides (OATP)/SLCO family represents an important class of hepatic drug uptake transporters that mediate the sodium independent transport of a diverse range of amphipathic organic compounds, including the protease inhibitors. The SLCO1B1 521T>C (rs4149056) single nucleotide polymorphism (SNP) has been consistently associated with reduced transport activity in vivo, and we previously showed an association of this polymorphism with lopinavir plasma concentrations. The aim of this study was to develop a population pharmacokinetic (PK) model to quantify the impact of 521T>C. Methods—A population PK analysis was performed with 594 plasma samples from 375 patients receiving lopinavir/ritonavir. Non-linear mixed effects modelling was applied to explore the effects of SLCO1B1 521T>C and patient demographics. Simulations of the lopinavir concentration profile were performed with different dosing regimens considering the different alleles. Results—A one-compartment model with first-order absorption best described the data. Population clearance was 5.67 L/h with inter-patient variability of 37%. Body weight was the only demographic factor influencing clearance, which increased 0.5 L/h for every 10 kg increase. Homozygosity for the C allele was associated with a 37% lower clearance, and 14% for heterozygosity, which were statistically significant. Conclusion—These data show an association between SLCO1B1 521T>C and lopinavir clearance. The association is likely to be mediated through reduced uptake by hepatocytes leading to higher plasma concentrations of lopinavir. Further studies are now required to confirm the association and to assess the influence of other polymorphisms in the SLCO family on lopinavir PK

Vitamin D deficiency in Malawian adults with pulmonary tuberculosis : risk factors and treatment outcomes

The study was supported by a Wellcome Trust (London, UK) Clinical PhD Fellowship awarded to DS (086757/Z/08/A) and the Malawi Liverpool Wellcome Trust (MLW) Core grant from the Wellcome Trust.SETTING: Vitamin D deficiency is common in African adults with tuberculosis (TB), and may be exacerbated by the metabolic effects of anti-tuberculosis drugs and antiretroviral therapy (ART). It is unclear whether vitamin D deficiency influences response to antituberculosis treatment. OBJECTIVES : To describe risk factors for baseline vitamin D deficiency in Malawian adults with pulmonary TB, assess the relationship between serum 25-hydroxy vitamin D (25[OH]D) concentration and treatment response, and evaluate whether the administration of anti-tuberculosis drugs and ART is deleterious to vitamin D status during treatment. DESIGN: A prospective longitudinal cohort study. RESULTS : The median baseline 25(OH)D concentration of the 169 patients (58% human immunodeficiency virus [HIV] infected) recruited was 57 nmol/l; 47 (28%) had vitamin D deficiency (<50 nmol/l). Baseline 25(OH)D concentrations were lower during the cold season (P < 0.001), with food insecurity (P = 0.034) or in patients who consumed alcohol (P = 0.019). No relationship between vitamin D status and anti-tuberculosis treatment response was found. 25(OH)D concentrations increased during anti-tuberculosis treatment, irrespective of HIV status or use of ART. CONCLUSIONS : Vitamin D deficiency is common among TB patients in Malawi, but this does not influence treatment response. Adverse metabolic effects of drug treatment may be compensated by the positive impact of clinical recovery preventing exacerbation of vitamin D deficiency during anti-tuberculosis treatment.Publisher PDFPeer reviewe

Co-existing structures in 105Ru

New positive-parity states, having a band-like structure, were observed in 105Ru. The nucleus was produced in induced fission reaction and the prompt gamma-rays, emitted from the fragments, were detected by the EUROBALL III multi-detector array. The partial scheme of excited 105Ru levels is analyzed within the Triaxial-Rotor-plus-Particle approach

A New Parameterization for the Lagrangian Density of Relativistic Mean Field Theory

A new parameterization for an effective non-linear Lagrangian density of relativistic mean field (RMF) theory is proposed, which is able to provide an excellent description not only for the properties of stable nuclei but also for those far from the valley of beta-stability. In addition recently measured superdeformed mimima in the Hg-region are reproduced with high accuracy.Comment: 8 pages, Latex, 1 ps figur

Route to nonlocality and observation of accessible solitons

We develop a general theory of spatial solitons in a liquid crystalline medium exhibiting a nonlinearity with an arbitrary degree of effective nonlocality. The model accounts the observability of "accessible solitons" and establishes an important link with parametric solitons.Comment: 4 pages, 2 figure

Boron Nitride Monolayer: A Strain-Tunable Nanosensor

The influence of triaxial in-plane strain on the electronic properties of a hexagonal boron-nitride sheet is investigated using density functional theory. Different from graphene, the triaxial strain localizes the molecular orbitals of the boron-nitride flake in its center depending on the direction of the applied strain. The proposed technique for localizing the molecular orbitals that are close to the Fermi level in the center of boron nitride flakes can be used to actualize engineered nanosensors, for instance, to selectively detect gas molecules. We show that the central part of the strained flake adsorbs polar molecules more strongly as compared with an unstrained sheet.Comment: 20 pages, 9 figure

Decay modes of 250No

The Fragment Mass Analyzer at the ATLAS facility has been used to unambiguously identify the mass number associated with different decay modes of the nobelium isotopes produced via 204Pb(48Ca,xn)(252-x)No reactions. Isotopically pure (>99.7%) 204Pb targets were used to reduce background from more favored reactions on heavier lead isotopes. Two spontaneous fission half-lives (t_1/2 = 3.7+1.1-0.8 us and 43+22-15 us) were deduced from a total of 158 fission events. Both decays originate from 250No rather than from neighboring isotopes as previously suggested. The longer activity most likely corresponds to a K-isomer in this nucleus. No conclusive evidence for an alpha branch was observed, resulting in upper limits of 2.1% for the shorter lifetime and 3.4% for the longer activity.Comment: RevTex4, 10 pages, 5 figures, submitted to PR

Localized Excitons and Breaking of Chemical Bonds at III-V (110) Surfaces

Electron-hole excitations in the surface bands of GaAs(110) are analyzed using constrained density-functional theory calculations. The results show that Frenkel-type autolocalized excitons are formed. The excitons induce a local surface unrelaxation which results in a strong exciton-exciton attraction and makes complexes of two or three electron-hole pairs more favorable than separate excitons. In such microscopic exciton &quot;droplets&quot; the electron density is mainly concentrated in the dangling orbital of a surface Ga atom whereas the holes are distributed over the bonds of this atom to its As neighbors thus weakening the bonding to the substrate. This finding suggests the microscopic mechanism of a laser-induced emission of neutral Ga atoms from GaAs and GaP (110) surfaces.Comment: submitted to PRL, 10 pages, 4 figures available upon request from: [email protected]

Spectroscopy of 194^{194}Po

Prompt, in-beam $\gamma$ rays following the reaction $^{170}$Yb + 142 MeV $^{28}$Si were measured at the ATLAS facility using 10 Compton-suppressed Ge detectors and the Fragment Mass Analyzer. Transitions in $^{194}$Po were identified and placed using $\gamma$-ray singles and coincidence data gated on the mass of the evaporation residues. A level spectrum up to J$\approx$10$\hbar$ was established. The structure of $^{194}$Po is more collective than that observed in the heavier polonium isotopes and indicates that the structure has started to evolve towards the more collective nature expected for deformed nuclei.Comment: 8 pages, revtex 3.0, 4 figs. available upon reques