Effect of P-glycoprotein modulation with cyclosporin A on cerebrospinal fluid penetration of doxorubicin in non-human primates

PURPOSE: P-glycoprotein (Pgp) is a transmembrane drug efflux pump that is expressed in multidrug-resistant cancer cells and in a variety of normal tissues, including brain capillary endothelial cells which comprise the blood-brain barrier. We studied the effects of the Pgp inhibitor, cyclosporin A (CsA), on the cerebrospinal fluid (CSF) penetration of the Pgp substrate, doxorubicin, in non-human primates. METHODS: The animals received doxorubicin alone (2.0 mg/kg i.v. over 60 min) or doxorubicin (1 mg/kg i.v. over 60 min) and CsA (loading dose 4.0 mg/kg i.v. over 2 h, followed by continuous infusion of 12 mg/kg per day over 48 h). Plasma and CSF were collected over 48 h and the doxorubicin concentration was measured by reverse-phase high-pressure liquid chromatography (HPLC) with fluorescence detection (detection limit 5 nM). A two-compartment model was fitted to the plasma concentration-time data. RESULTS: Pgp was demonstrated to be present in the epithelium of the choroid plexus by immunohistochemical methods, indicating that CSF drug penetration could be used as a surrogate for blood-brain barrier penetration. Steady state whole blood CsA concentrations, which were measured with a fluorescence-polarization immunoassay (TDX) that detects both CsA and its metabolites, ranged from 551-1315 microg/l at 24 h. The clearance of doxorubicin in four animals was reduced by 34%, 38%, 45% and 49% when given with CsA. The doxorubicin concentration in the CSF was <5 nM in all animals, both after doxorubicin alone and doxorubicin with CsA. CONCLUSIONS: The Pgp inhibitor, CsA, at a concentration that alters systemic clearance of doxorubicin, does not appear to significantly increase the CSF penetration of doxorubicin

Orientations of the lamellar phase of block copolymer melts under oscillatory shear flow

We develop a theory to describe the reorientation phenomena in the lamellar phase of block copolymer melt under reciprocating shear flow. We show that similar to the steady-shear, the oscillating flow anisotropically suppresses fluctuations and gives rise to the parallel-perpendicular orientation transition. The experimentally observed high-frequency reverse transition is explained in terms of interaction between the melt and the shear-cell walls.Comment: RevTex, 3 pages, 1 figure, submitted to PR

Secret sharing MPC on FPGAs in the datacenter

Multi-Party Computation (MPC) is a technique enabling data from several sources to be used in a secure computation revealing only the result while protecting the orig- inal data, facilitating shared utilization of data sets gathered by different entities. The presence of Field Programmable Gate Array (FPGA) hardware in datacenters can provide accelerated computing as well as low latency, high bandwidth communication that bolsters the performance of MPC and lowers the barrier to using MPC for many applications. In this work, we propose a Secret Sharing FPGA design based on the protocol described by Araki et al. [1]. We compare our hardware design to the original authors’ software implementations of Secret Sharing and to work accelerating MPC protocols based on Garbled Circuits with FPGAs. Our conclusion is that Secret Sharing in the datacenter is competitive and when implemented on FPGA hardware was able to use at least 10× fewer computer resources than the original work using CPUs.Accepted manuscrip

Density functional theory of spin-polarized disordered quantum dots

Using density functional theory, we investigate fluctuations of the ground state energy of spin-polarized, disordered quantum dots in the metallic regime. To compare to experiment, we evaluate the distribution of addition energies and find a convolution of the Wigner-Dyson distribution, expected for noniteracting electrons, with a narrower Gaussian distribution due to interactions. The tird moment of the total distribution is independent of interactions, and so is predicted to decrease by a factor of 0.405 upon application of a magnetic field which transforms from the Gaussian orthogonal to the Gaussian unitary ensemble.Comment: 13 pages, 2 figure

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .)

Classes of exact Einstein-Maxwell solutions

We find new classes of exact solutions to the Einstein-Maxwell system of equations for a charged sphere with a particular choice of the electric field intensity and one of the gravitational potentials. The condition of pressure isotropy is reduced to a linear, second order differential equation which can be solved in general. Consequently we can find exact solutions to the Einstein-Maxwell field equations corresponding to a static spherically symmetric gravitational potential in terms of hypergeometric functions. It is possible to find exact solutions which can be written explicitly in terms of elementary functions, namely polynomials and product of polynomials and algebraic functions. Uncharged solutions are regainable with our choice of electric field intensity; in particular we generate the Einstein universe for particular parameter values.Comment: 16 pages, To appear in Gen. Relativ. Gravi