Human pharmacology of current and new treatments for schizophrenia

The studies in this thesis together show different ways of studying human pharmacology, give an impression of the current drug development in schizophrenia, and provide examples how human pharmacology can be applied in an early stage of drug development in healthy volunteers. The investigated compounds show that the main pharmacological focus in this area has shifted from psychosis to improvement of individual negative or cognitive symptom complexes, from direct receptor inhibition to indirect receptor modulation, and from single drug strategies to combination therapies, each targeted at different symptoms. We have tried to create a pharmacological fingerprint of the investigated compounds by making use of an intensive CNS test battery to measure effects in different functional domains of the brain and additional 'tools' (i.e. positive controls, dose escalation, PK-PD modeling and pharmacological challenge tests) to improve the reliability of the tests. This diversity of drug development strategies and range of neurotransmitters in schizophrenia reflects the increasing complexity of neuropharmacological hypotheses in this field. Despite these difficulties, incremental changes in drug characteristics and treatment strategies may well lead to the introduction of new classes or combinations of drugs in the future.The publication of this thesis was financially supported by the foundation Centre for Human Drug Research (CHDR), Leiden, the NetherlandsUBL - phd migration 201

Fostering sustained teacher learning:A longitudinal assessment of the influence of vision building and goal interdependence on information sharing

To support school improvement, understanding the mechanisms that enhance teachers’ engagement in professional learning activities within schools over time is paramount. The purpose of this three-wave longitudinal study is to examine the role of workplace conditions (school leaders’ vision building and teams’ shared goals), in supporting teachers’ engagement in information sharing over time. To test the directionality of the relationships between the concepts, we analyzed survey data from 655 vocational education and training teachers in the Netherlands using a cross-lagged panel model. Results suggest that teachers’ engagement in information sharing remains stable over time, and the results are indicative of reciprocity between goal interdependence and vision building. Mostly, the results hint at the complexity of the time-based relations involved in teacher learning in support of school improvement. Recommendations for future designs and methodologies to understand this complexity are discussed

The measurement of collaborative culture in secondary schools: An informal subgroup approach

Research on teacher collaboration underlines the importance of a collaborative culture for teachers’ functioning. However, while scholars usually regard collaborative culture as a school team characteristic, this study argues that subgroups may be more meaningful units of analysis to conceptualize and assess teachers’ perceptions of collaborative culture. Based on the assumption that collaborative culture is developed, expressed, and maintained in frequent work-related interactions, this study hypothesizes that collaborative culture is not homogenously spread over the school but rather varies between informal subgroups. Data from 760 Flemish teachers were examined using social network analysis and consensus analyses. The results provided evidence that perceptions on collaborative culture are more homogeneous within informal subgroups that are characterized by frequent interactions than the entire school team. This finding stresses the importance of assessing the meaningful unit of analysis for collective-level and socially-constructed concepts, such as collaborative culture. Moreover, the benefits and potential of a social network approach to identify (socially stable) subunits within the school team are illustrated

High prevalence of penicillin-nonsusceptible Streptococcus pneumoniae at a community hospital in Oklahoma.

During 1997, Oklahoma City's Hospital A reported penicillin-nonsusceptible Streptococcus pneumoniae in almost 67% of isolates. To confirm this finding, all Hospital A S. pneumoniae isolates from October 23, 1997, through February 19, 1998, were tested for antibiotic susceptibility and repeat-tested at two other hospital laboratories. Medical records of Hospital A patients with invasive S. pneumoniae infections during 1994 through 1997 were also reviewed. These data were compared with 1998 statewide sentinel hospital surveillance data for invasive S. pneumoniae. Of 48 S. pneumoniae isolates from Hospital A during October 23, 1997, through February 19, 1998, 31 (65%) were penicillin-nonsusceptible S. pneumoniae, and 23 (48%) were highly penicillin resistant. Similar prevalences were confirmed at the other hospital laboratories; however, significant interlaboratory differences were noted in the determination of third-generation cephalosporin susceptibility. During 1994 through 1997, a trend toward increasing penicillin nonsusceptibility (p <0.05) was noted among S. pneumoniae isolates from nursing home patients. During 1998, 85 (30%) of 282 invasive isolates reported to the state surveillance system were penicillin-nonsusceptible S. pneumoniae; 33 (12%) were highly resistant. The increase in resistance observed is notable; the interlaboratory discrepancies are unexplained. To respond, a vaccination program was implemented at Hospital A, and vaccination efforts were initiated at nursing homes

Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells.

The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in breast cancer cells, resulting in a less transformed phenotype, it slows tumor growth in a xenograft model and correlates with prolonged survival in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, furthermore, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior

Real-time single-molecule imaging reveals a direct interaction between UvrC and UvrB on DNA tightropes

Nucleotide excision DNA repair is mechanistically conserved across all kingdoms of life. In prokaryotes, this multi-enzyme process requires six proteins: UvrA?D, DNA polymerase I and DNA ligase. To examine how UvrC locates the UvrB? DNA pre-incision complex at a site of damage, we have labeled UvrB and UvrC with different colored quantum dots and quantitatively observed their interactions with DNA tightropes under a variety of solution conditions using oblique angle fluorescence imaging. Alone, UvrC predominantly interacts statically with DNA at low salt. Surprisingly, however, UvrC and UvrB together in solution bind to form the previously unseen UvrBC complex on duplex DNA. This UvrBC complex is highly motile and engages in unbiased one-dimensional diffusion. To test whether UvrB makes direct contact with the DNA in the UvrBC?DNA complex, we investigated three UvrB mutants: Y96A, a b-hairpin deletion and D338N. These mutants affected the motile properties of the UvrBC complex, indicating that UvrB is in intimate contact with the DNA when bound to UvrC. Given the in vivo excess of UvrB and the abundance of UvrBC in our experiments, this newly identified complex is likely to be the predominant form of UvrC in the cell. © 2013 The Author(s)

First trimester anomaly scan using virtual reality (VR FETUS study): study protocol for a randomized clinical trial

BACKGROUND: In recent years it has become clear that fetal anomalies can already be detected at the end of the first trimester of pregnancy by two-dimensional (2D) ultrasound. This is why increasingly in developed countries the first trimester anomaly scan is being offered as part of standard care. We have developed a Virtual Reality (VR) approach to improve the diagnostic abilities of 2D ultrasound. Three-dimensional (3D) ultrasound datasets are used in VR assessment, enabling real depth perception and unique interaction. The aim of this study is to investigate whether first trimester 3D VR ultrasound is of additional value in terms of diagnostic accuracy for the detection of fetal anomalies. Health-related quality of life, cost-effectiveness and also the perspective of both patient and ultrasonographer on the 3D VR modality will be studied. METHODS: Women in the first trimester of a high risk pregnancy for a fetus with a congenital anomaly are eligible for inclusion. This is a randomized controlled trial with two intervention arms. The control group receives 'care as usual': a second trimester 2D advanced ultrasound examination. The intervention group will undergo an additional first trimester 2D and 3D VR ultrasound examination. Following each examination participants will fill in validated questionnaires evaluating their quality of life and healthcare related expenses. Participants' and ultrasonographers' perspectives on the 3D VR ultrasound will be surveyed. The primary outcom

Large-scale in vitro production, refolding and dimerization of PsbS in different microenvironments

Solid state NMR/Biophysical Organic Chemistr