Neuropharmacology of novel dopamine modulators

De neurotransmitter dopamine speelt een essenti_le rol in diverse neurofysiologische functies en is betrokken bij de pathofysiologie van diverse neuropsychiatrische aandoeningen, waaronder de ziekte van Parkinson, schizofrenie, drugsverslaving en hyperprolactinemie. De huidige farmacotherapeutische methoden om dopaminerge neurotransmissie te be_nvloeden, hebben slechts een beperkt effect op de symptomen, terwijl hinderlijke bijwerkingen kunnen optreden. Derhalve heeft verbetering van de farmacotherapie van deze ziekten een hoge prioriteit. De bevindingen van studies in dit proefschrift en followup studies tonen aan dat verbetering van de kinetiek van het geneesmiddel ter plaatse van de receptor en verbetering van de selectiviteit van het geneesmiddel veelbelovende strategie_n zijn. De resultaten van be_nvloeding van de controle mechanismen door tachykinines en gaba lijken vooralsnog minder therapeutisch nut op te leveren, maar geven wel indicaties voor biologische effecten die verder onderzoek verdienen. Deze onderzoekslijnen geven aan dat, ondanks de grote verscheidenheid aan beschikbare dopamine agonisten en antagonisten, de therapeutische mogelijkheden om dopamine neurotransmissie te be_nvloeden nog lang niet verzadigd zijnUBL - phd migration 201

Extrapulmonary Tuberculosis by Nationality, the Netherlands, 1993–2001

The growth of the number of inhabitants with a non-Western ethnic background most likely explains the growth of extrapulmonary TB in the Netherlands

Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces

Contains fulltext : 89590.pdf (publisher's version ) (Open Access)BACKGROUND: Many newly detected point mutations are located in protein-coding regions of the human genome. Knowledge of their effects on the protein's 3D structure provides insight into the protein's mechanism, can aid the design of further experiments, and eventually can lead to the development of new medicines and diagnostic tools. RESULTS: In this article we describe HOPE, a fully automatic program that analyzes the structural and functional effects of point mutations. HOPE collects information from a wide range of information sources including calculations on the 3D coordinates of the protein by using WHAT IF Web services, sequence annotations from the UniProt database, and predictions by DAS services. Homology models are built with YASARA. Data is stored in a database and used in a decision scheme to identify the effects of a mutation on the protein's 3D structure and function. HOPE builds a report with text, figures, and animations that is easy to use and understandable for (bio)medical researchers. CONCLUSIONS: We tested HOPE by comparing its output to the results of manually performed projects. In all straightforward cases HOPE performed similar to a trained bioinformatician. The use of 3D structures helps optimize the results in terms of reliability and details. HOPE's results are easy to understand and are presented in a way that is attractive for researchers without an extensive bioinformatics background

ODoSE: a webserver for genome-wide calculation of adaptive divergence in prokaryotes

This is the final version of the article. Available from the publisher via the DOI in this record.Quantifying patterns of adaptive divergence between taxa is a major goal in the comparative and evolutionary study of prokaryote genomes. When applied appropriately, the McDonald-Kreitman (MK) test is a powerful test of selection based on the relative frequency of non-synonymous and synonymous substitutions between species compared to non-synonymous and synonymous polymorphisms within species. The webserver ODoSE (Ortholog Direction of Selection Engine) allows the calculation of a novel extension of the MK test, the Direction of Selection (DoS) statistic, as well as the calculation of a weighted-average Neutrality Index (NI) statistic for the entire core genome, allowing for systematic analysis of the evolutionary forces shaping core genome divergence in prokaryotes. ODoSE is hosted in a Galaxy environment, which makes it easy to use and amenable to customization and is freely available at www.odose.nl.MWJvP is funded by the Netherlands Organization for Scientific Research (NWO) via a VENI grant. TtB and MAvD are funded by the BioAssist/BRS programme of the Netherlands Bioinformatics Centre, which is supported by the Netherlands Genomics Initiative. This work is part of the programme of BiG Grid, the Dutch e-Science Grid, which is financially supported by the NWO. MV is supported by investment from the European Regional Development Fund and the European Social Fund Convergence Programme for Cornwall and the Isles of Scilly to the European Centre for the Environment and Human Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The Role of the Noradrenergic System in the Exploration–Exploitation Trade-Off: A Psychopharmacological Study

Animal research and computational modeling have indicated an important role for the neuromodulatory locus coeruleus–norepinephrine (LC–NE) system in the control of behavior. According to the adaptive gain theory, the LC–NE system is critical for optimizing behavioral performance by regulating the balance between exploitative and exploratory control states. However, crucial direct empirical tests of this theory in human subjects have been lacking. We used a pharmacological manipulation of the LC–NE system to test predictions of this theory in humans. In a double-blind parallel-groups design (N = 52), participants received 4 mg reboxetine (a selective norepinephrine reuptake inhibitor), 30 mg citalopram (a selective serotonin reuptake inhibitor), or placebo. The adaptive gain theory predicted that the increased tonic NE levels induced by reboxetine would promote task disengagement and exploratory behavior. We assessed the effects of reboxetine on performance in two cognitive tasks designed to examine task (dis)engagement and exploitative versus exploratory behavior: a diminishing-utility task and a gambling task with a non-stationary pay-off structure. In contrast to predictions of the adaptive gain theory, we did not find differences in task (dis)engagement or exploratory behavior between the three experimental groups, despite demonstrable effects of the two drugs on non-specific central and autonomic nervous system parameters. Our findings suggest that the LC–NE system may not be involved in the regulation of the exploration–exploitation trade-off in humans, at least not within the context of a single task. It remains to be examined whether the LC–NE system is involved in random exploration exceeding the current task context

WIWS: a protein structure bioinformatics Web service collection

The WHAT IF molecular-modelling and drug design program is widely distributed in the world of protein structure bioinformatics. Although originally designed as an interactive application, its highly modular design and inbuilt control language have recently enabled its deployment as a collection of programmatically accessible web services. We report here a collection of WHAT IF-based protein structure bioinformatics web services: these relate to structure quality, the use of symmetry in crystal structures, structure correction and optimization, adding hydrogens and optimizing hydrogen bonds and a series of geometric calculations. The freely accessible web services are based on the industry standard WS-I profile and the EMBRACE technical guidelines, and are available via both REST and SOAP paradigms. The web services run on a dedicated computational cluster; their function and availability is monitored daily

226Ra determination via the rate of 222Rn ingrowth with the Radium Delayed Coincidence Counter (RaDeCC)

ISI Document Delivery No.: 278HU Times Cited: 0 Cited Reference Count: 23 Cited References: Annett AL, 2013, ANTARCT SCI, V25, P445, DOI 10.1017/S0954102012000892 Bourquin M, 2011, MAR CHEM, V126, P132, DOI 10.1016/j.marchem.2011.05.001 Burnett WC, 2006, SCI TOTAL ENVIRON, V367, P498, DOI 10.1016/j.scitotenv.2006.05.009 BUTTS J, 1988, MAR CHEM, V25, P349, DOI 10.1016/0304-4203(88)90115-6 Charette MA, 2012, LIMNOL OCEANOGR-METH, V10, P451, DOI 10.4319/lom.2012.10.451 Charette MA, 2001, LIMNOL OCEANOGR, V46, P465 Foster DA, 2004, MAR CHEM, V87, P59, DOI 10.1016/j.marchem.2004.02.003 Garcia-Solsona E, 2008, MAR CHEM, V109, P198, DOI 10.1016/j.marchem.2007.11.006 GIFFIN C, 1963, J GEOPHYS RES, V68, P1749, DOI 10.1029/JZ068i006p01749 Hsieh YT, 2011, J ANAL ATOM SPECTROM, V26, P1338, DOI 10.1039/c1ja10013k Ku TL, 2008, RADIOACTIV ENVIRONM, V13, P307, DOI 10.1016/S1569-4860(07)00009-5 KU TL, 1976, EARTH PLANET SC LETT, V32, P236, DOI 10.1016/0012-821X(76)90064-9 Moatar F, 2010, J RADIOANAL NUCL CH, V283, P3, DOI 10.1007/s10967-009-0001-2 Moore WS, 1996, J GEOPHYS RES-OCEANS, V101, P1321, DOI 10.1029/95JC03139 Moore WS, 2008, MAR CHEM, V109, P188, DOI 10.1016/j.marchem.2007.06.015 MOORE WS, 1995, GEOCHIM COSMOCHIM AC, V59, P4285, DOI 10.1016/0016-7037(95)00242-R Moore WS, 2003, BIOGEOCHEMISTRY, V66, P75, DOI 10.1023/B:BIOG.0000006065.77764.a0 Peterson RN, 2009, LIMNOL OCEANOGR-METH, V7, P196 Rama, 1996, GEOCHIM COSMOCHIM AC, V60, P4645 Rodellas V, 2012, J HYDROL, V466, P11, DOI 10.1016/j.jhydrol.2012.07.005 Sun Y, 1998, MAR CHEM, V62, P299, DOI 10.1016/S0304-4203(98)00019-X van Beek P, 2010, J ENVIRON RADIOACTIV, V101, P521, DOI 10.1016/j.jenvrad.2009.12.002 Waska H, 2008, J ENVIRON RADIOACTIV, V99, P1859, DOI 10.1016/j.jenvrad.2008.08.008 Geibert, Walter Rodellas, Valenti Annett, Amber van Beek, Pieter Garcia-Orellana, Jordi Hsieh, Yu-Te Masque, Pere Masque, Pere/B-7379-2008 Masque, Pere/0000-0002-1789-320X National Environmental Research Council through "UK Geotraces" [NE/H008497/1]; Scottish Alliance for GeoSciences and the Environment; MICINN (Spain) [AP2008-03044]; "Antarctic Science" research bursary, the British Antarctic Survey, NERC's Collaborative Gearing Scheme by the Natural Sciences and Engineering Research Council of Canada; "Antarctic Science" research bursary, the British Antarctic Survey, NERC's Collaborative Gearing Scheme by the University of Edinburgh; British Council-Egide "Alliance" scheme; prize ICREA Academia; Generalitat de Catalunya We would like to gratefully acknowledge support from funding agencies: W. G. and Y.-T. Hsieh from the National Environmental Research Council through "UK Geotraces" (NE/H008497/1); W. G. from the Scottish Alliance for GeoSciences and the Environment; V. R. for a PhD fellowship (AP2008-03044) from MICINN (Spain); A. A. from the "Antarctic Science" research bursary, the British Antarctic Survey, NERC's Collaborative Gearing Scheme, by the Natural Sciences and Engineering Research Council of Canada and by the University of Edinburgh; W. G., A. A., and P. v. B. received travel support from the British Council-Egide "Alliance" scheme; P. M. through the prize ICREA Academia, funded by the Generalitat de Catalunya. Thanks go to Gideon Henderson, Raja Ganeshram, and Michiel Rutgers van der Loeff; their contributions were essential to enable us to finish this manuscript. Three anonymous reviewers have provided helpful insights that contributed to improve the manuscript substantially. 0 AMER SOC LIMNOLOGY OCEANOGRAPHY WACO LIMNOL OCEANOGR-METHWe present a new method to determine Ra-226 in aqueous environmental samples, based on the rate of ingrowth of Rn-222 from Ra-226, using the radium delayed coincidence counter (RaDeCC). We use the same instrument setup that is used for the determination of Ra-223 and Ra-224. In contrast to methods published earlier, the approach does not require a modification of the counting equipment, counting separately for Ra-226, or waiting for radioactive equilibrium. We show that the calibration works from as low as 10 dpm (0.166 Bq) per sample, up to more than 1000 dpm (16.7 Bq). Although uncertainties are larger (typically around 10%) than reported uncertainties for gamma counting, liquid scintillation, or mass spectrometry at comparable activities, the simple setup, low cost, and robustness of the method make it a useful approach for underway measurements, combinations with short-lived radium isotopes, or monitoring purposes when limited funding or infrastructure is available

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.</p

Oncology Section EDGE Task Force on Urogenital Cancer Outcomes: Clinical Measures of Lymphedema—A Systematic Review

Background: Valid and reliable tools to assess lymphedema are necessary to accurately evaluate status and to objectively document and measure the results of interventions. Understanding the advantages and disadvantages of each measure can inform the clinician\u27s choice of the appropriate tool to be used in the clinic or research setting. Purpose: To identify reliable and valid measurement techniques that are sensitive to change for assessing edema volume or soft tissue change in the lower extremities or genital region of patients with lymphedema. Methods: A systematic review of the literature was conducted to assess the published psychometric properties and clinical feasibility of each method identified. Task Force members independently reviewed each measure using the Cancer EDGE Rating Form. Results: Both water displacement and circumferential measurement methods by tape measure were rated as Highly Recommended to quantify lower-extremity limb volume. Water displacement was determined to be the criterion standard by which all other assessments of volume are benchmarked. Both optoelectric volumetry and bioelectric impedance analysis were rated as Recommended, and ultrasound was rated Not Recommended. Conclusion: The Urogenital Cancer EDGE Task Force highly recommends water displacement and circumferential tape measurement for use as reliable methods for assessment and documentation of change of limb volume in this patient population. Early detection of subclinical lower-extremity lymphedema in this patient population remains challenging, as there is no “index” limb that can be proven to be uninvolved in a patient population with documented pelvic node dissection/irradiation. No articles were found to support valid and reliable genital lymphedema volume measurement