Lorazepam-valproate interaction: studies in normal subjects and isolated perfused rat liver

Valproate (VPA) has been shown to interact with all the major antiepileptic drugs (AEDs) through two mechanisms of action: displacement from albumin binding sites and inhibition of drug metabolism. More recently, evidence showed that VPA inhibits the elimination of drugs metabolized by glucuronide conjugation. Lorazepam (LZP), which is primarily eliminated by conjugation with glucuronic acid, is administered concurrently with VPA both in treatment of epilepsy and in patients treated with VPA for psychiatric disorders. Therefore, a significant drug interaction is likely. We investigated such interaction both in in vitro isolated perfused rat liver (IPRL) and in normal subjects. LZP [2 mg, intravenous (i.v.) bolus] was administered to 8 normal volunteers before and after chronic dosing with VPA. In 6 of 8 subjects, VPA significantly decreased LZP plasma clearance by an average of 40% (p < 0.05) and increased LZP concentrations by decreasing formation clearance of the LZP glucuronide. In the IPRL studies, VPA also significantly decreased formation of LZP glucuronide (from 0.72 +/- 0.14 to 0.22 +/- 0.15 ml/h/kg, p < 0.05), indicating that IPRL is a useful tool for evaluation of the effect of VPA on drugs eliminated by glucuronide conjugation.     

The role of occlusion in the perception of depth, lightness, and opacity.

A theory is presented that explains how the visual system infers the lightness, opacity, and depth of surfaces from stereoscopic images. It is shown that the polarity and magnitude of image contrast play distinct roles in surface perception, which can be captured by 2 principles of perceptual inference. First, a contrast depth asymmetry principle articulates how the visual system computes the ordinal depth and lightness relationships from the polarity of local, binocularly matched image contrast. Second, a global transmittance anchoring principle expresses how variations in contrast magnitudes are used to infer the presence of transparent surfaces. It is argued that these principles provide a unified explanation of how the visual system computes the 3-D surface structure of opaque and transparent surfaces. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A new adaptation of mapping method to study mixing of multiphase flows in mixers with complex geometries

The main objective of the present work is to modify the traditional mapping method for the simulation of distributive mixing of multiphase flows in geometries involving moving parts such as, internal mixers or twin-screw extruders without a limitation on their geometrical periodicity. The periodicity condition, limits the results of traditional mapping method to tracking mapping mesh between specific discrete time intervals or distances for that geometry is repeated, hence, result is only for fixed orientation of rotors. Imaginary domain method is introduced to track mapping mesh from one state to the next free of geometrical periodicity limitations. In this work the method is introduced and its applicability and accuracy is discussed in details. A two-dimensional (2D) simulation of mixing of two Newtonian fluids with different viscosities in an intermeshing internal mixer is used as a test case study. In this example the key issues of ability to predict mixing state in details for all orientations of rotors is presented. To reduce diffusion errors of mapping method in the boundaries of the rotors, mapping mesh refinement technique that relies upon one single reference mesh is also presented.     

Alpha 2 mRNA of Na+K+ ATPase is increased in astroctyes of rat hippocampus after treatment with kainic acid

The Na+K+ ATPase (Na+ pump) plays a central role in regulating cation homeostasis and is thought to have an important role in cell proliferation. The multitude of subunit isoforms comprising the functional Na+K+ ATPase has raised the possibility that specific subunit isoform combinations may be involved in different cellular processes. We have investigated the involvement of the specific isoforms in neurons and glia at the site of a CNS lesion. Intracerebroventricular injection of kainic acid was used to induce neuronal cell loss and reactive gliosis in rat hippocampus and levels of Na+K+ ATPase subunit isoform mRNA levels were determined in cells of rat hippocampus using in situ hybridization. alpha 2 mRNA levels increased 35-40% in CA1 and CA3 astrocytes between 1-3 weeks after KA injection with no significant change in other subunit isoform mRNA levels. In addition alpha 3 mRNA levels in CA1 pyramidal neurons were decreased by approx. 35%. Small neurons in the CA1 and CA3 region showed no changes in mRNA levels for any of the Na+K+ ATPase subunit isoforms. These results may indicate a possible role for alpha 2 subunit isoform in the conversion of glial cells from a normal phenotype to the reactive phenotype characteristic in this model of CNS injury.     

The domain composition method applied to Poisson's equation in two dimensions

Domain composition, a recently described method for formulating continuum field problems, removes certain restrictions on the construction of finite element models such that it is possible to solve a finite element problem without using a global compatible mesh. The domain composition method couples or otherwise constrains meshes in local regions to obtain a solution equivalent to that produced by conventional finite element methods. In particular, the domain composition method enables finite element models to be formulated with overlapping elements. Several advantages come from this, including an ability to automatically generate a finite element model from a solid geometric model, an ability to use a variety of element types in a single finite element model and an ability to exactly match element boundaries to the local geometry. This paper shows in detail a finite element formulation of Poisson's equation using domain composition and presents certain key algorithms that incorporate the domain composition method into well-established finite element procedures.     

Prenatal diagnosis: update addresses technological advances

This is the second in a series of articles provided to the readers of PENNSYLVANIA MEDICINE as an update from researchers and clinicians in this cutting-edge medical field. The series is partially sponsored through a grant from the Pennsylvania Department of Health to the University of Pittsburgh Department of Human Genetics.     

Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia

We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon alpha (IFNalpha) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNalpha-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNalpha therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNalpha therapy far better than the cytogenetic response.     

An epidemiologic, clinical, and therapeutic study of childhood Guillain-Barré syndrome in Kuwait: is it related to the oral polio vaccine?

We studied Guillain-Barré syndrome, affecting children 12 years old or less, throughout Kuwait, in the period between January 1, 1992, and March 31, 1997. Nineteen children had the diagnostic criteria of Guillain-Barré syndrome, with an overall annual incidence rate of 0.95/100,000 population at risk. Female patients outnumbered male patients with a sex ratio of 1.4:1. There was a clustering of cases in winter and spring and in the year 1996. The disease symptoms were relatively severe in our patients because only 16% (3 of 19) of them were able to walk at the height of their illness, whereas the rest were bed or chair bound or needed assisted ventilation. Two patients had the electrodiagnostic features of axonal neuropathy and both had residual deficits on follow-up, whereas the rest recovered fully. All the patients received intravenous immunoglobulin. The mean time to walk unaided was 23.5 days (range, 2-84 days) after intravenous immunoglobulin and excluding the two patients with axonal neuropathy, and full recovery was achieved in a mean time of 103 days (range, 30-300 days). Contrary to previous studies, we found no correlation between oral polio vaccine administration and Guillain-Barré syndrome in 2 successive years (1995 and 1996) during a nationwide campaign targeting children less than 5 years old.     

The formalization and analysis of a communications protocol

The MSMIE protocol [SBC89] allows processors in a distributed system to communicate via shared memory. It was designed to meet the reliability and efficiency needs of applications such as nuclear safety systems. We present a formal model of the MSMIE protocol expressed in the notation CCS. Desirable properties of the protocol are expressed in the modal mu-calculus, an expressive modal logic. We show that the protocol lacks an important liveness property. In actual operation, additional operating constraints are checked to avoid potential problems. We present a modified protocol and show that it possesses the liveness property even without checking operating constraints. We also show how parts of the analysis were automated with the Concurrency Workbench.