Coprescription of levodopa with antipsychotics in a population of 84 596 psychiatric inpatients from 1994 to 2008

Patients on levodopa therapy frequently require additional antipsychotic pharmacotherapy. However, consideration must be given to antagonistic interactions on dopamine receptors between levodopa and antipsychotics, and efficacy and safety of such combinations. We therefore aimed to explore the practice and rationale of coprescription between levodopa and antipsychotics in psychiatric patients.A descriptive retrospective study based on cross-sectional prescription data repeatedly collected from psychiatric inpatients through the international Drug Safety in Psychiatry (AMSP) program between 1994 and 2008 was undertaken.Within a population of 84 596 psychiatric patients the prevalence of levodopa therapy was 1.0% (n=886). Among those patients on levodopa therapy 59.6% (n=528) also received antipsychotics. Quetiapine coprescription increased after its first marketing in 2000 to 45.9% in 2008. Coprescription of clozapine and olanzapine decreased from up to 25 and 22%, respectively, before to less than 10% after the introduction of quetiapine. Coprescribing of other antipsychotics remained approximately stable with average prevalences between 6 and less than 1%.Quetiapine has now replaced clozapine as the most frequently coprescribed neuroleptic in psychiatric patients with levodopa therapy. This is in accordance with recent data indicating a low potential for clinically relevant interactions with levodopa and efficacy against psychosis in levodopa-treated patients. The combined use of antipsychotics other than quetiapine and clozapine with levodopa is less common and generally not supported by appropriate evidence

Impact of the provision of safe drinking water on school absence rates in Cambodia:a quasi-experimental study

Education is one of the most important drivers behind helping people in developing countries lift themselves out of poverty. However, even when schooling is available absenteeism rates can be high. Recently interest has focussed on whether or not WASH interventions can help reduce absenteeism in developing countries. However, none has focused exclusively on the role of drinking water provision. We report a study of the association between absenteeism and provision of treated water in containers into schools

The Mitotic Arrest Deficient Protein MAD2B Interacts with the Small GTPase RAN throughout the Cell Cycle

Contains fulltext : 81260.pdf (publisher's version ) (Open Access)BACKGROUND: Previously, we identified the mitotic arrest deficient protein MAD2B (MAD2L2) as a bona fide interactor of the renal cell carcinoma (RCC)-associated protein PRCC. In addition, we found that fusion of PRCC with the transcription factor TFE3 in t(X;1)(p11;q21)-positive RCCs results in an impairment of this interaction and, concomitantly, an abrogation of cell cycle progression. Although MAD2B is thought to inhibit the anaphase promoting complex (APC) by binding to CDC20 and/or CDH1(FZR1), its exact role in cell cycle control still remains to be established. METHODOLOGY/PRINCIPAL FINDINGS: Using a yeast two-hybrid interaction trap we identified the small GTPase RAN, a well-known cell cycle regulator, as a novel MAD2B binding protein. Endogenous interaction was established in mammalian cells via co-localization and co-immunoprecipitation of the respective proteins. The interaction domain of RAN could be assigned to a C-terminal moiety of 60 amino acids, whereas MAD2B had to be present in its full-length conformation. The MAD2B-RAN interaction was found to persist throughout the cell cycle. During mitosis, co-localization at the spindle was observed. CONCLUSIONS/SIGNIFICANCE: The small GTPase RAN is a novel MAD2B binding protein. This novel protein-protein interaction may play a role in (i) the control over the spindle checkpoint during mitosis and (ii) the regulation of nucleocytoplasmic trafficking during interphase

The Cdc42p effector Gic2p is targeted for ubiquitin-dependent degradation by the SCFGrr1 complex.

Cdc42p, a Rho-related GTP-binding protein, regulates cytoskeletal polarization and rearrangements in eukaryotic cells. In yeast, Gic1p and Gic2p are effectors of Cdc42p involved in actin polarization at bud emergence. Gic2p is expressed in a cell cycle-dependent manner and rapidly disappears shortly after bud emergence concomitant with the activation of the G1 cyclin-dependent kinase Cdc28p-Clnp. Here we have shown that the rapid disappearance of Gic2p results from ubiquitin-dependent proteolysis. Biochemical and genetic evidence demonstrates that degradation of Gic2p required the Skp1-cullin-F-box protein complex (SCF) components Cdc34p, Cdc53p, Skp1p and Grr1p, but not Cdc4p. Phosphorylation of several C-terminal sites of Gic2p served as part of the recognition signal for ubiquitination. In addition, binding of Gic2p to Cdc42p was a prerequisite for degradation, suggesting that specifically the active form of Gic2p is targeted for destruction. Finally, our data indicate that degradation of Gic2p may be part of a mechanism which restricts cytoskeletal polarization in the G1 phase of the cell cycle

Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C.

Metazoan cyclin C was originally isolated by virtue of its ability to rescue Saccharomyces cerevisiae cells deficient in G1 cyclin function. This suggested that cyclin C might play a role in cell cycle control, but progress toward understanding the function of this cyclin has been hampered by the lack of information on a potential kinase partner. Here we report the identification of a human protein kinase, K35 [cyclin-dependent kinase 8 (CDK8)], that is likely to be a physiological partner of cyclin C. A specific interaction between K35 and cyclin C could be demonstrated after translation of CDKs and cyclins in vitro. Furthermore, cyclin C could be detected in K35 immunoprecipitates prepared from HeLa cells, indicating that the two proteins form a complex also in vivo. The K35-cyclin C complex is structurally related to SRB10-SRB11, a CDK-cyclin pair recently shown to be part of the RNA polymerase II holoenzyme of S. cerevisiae. Hence, we propose that human K35(CDK8)-cyclin C might be functionally associated with the mammalian transcription apparatus, perhaps involved in relaying growth-regulatory signals

Adverse drug reactions following nonresponse in a depressed patient with CYP2D6 deficiency and low CYP 3A4/5 activity

A 47-year-old male taxi driver experienced multiple adverse drug reactions during therapy with clomipramine (CMI) and quetiapine for major depressive disorder, after having been unsuccessfully treated with adequate doses of mirtazapine and venlafaxine. Drug serum concentrations of CMI and quetiapine were significantly increased and pharmacogenetic testing showed a poor metabolizer status for CYP2D6, low CYP3A4/5 activity and normal CYP2C19 genotype. After reduction of the CMI dose and discontinuation of quetiapine, all ADR subsided except for the increase in liver enzymes. The latter improved but did not normalize completely, even months later, possibly due to concomitant cholelithiasis