Prevalence of psychoactive substances in Dutch and Belgian traffic

Objective: The purpose of this study was to compare the prevalence of psychoactive substances in general traffic in The Netherlands and Belgium. Method: Randomly selected car drivers and drivers of small vans in six police regions in The Netherlands and five police regions in Belgium were included between January 2007 and August 2009. Blood and oral fluid samples were analyzed for 23 substances, including ethanol (alcohol), by means of ultra performance liquid chromatography tandem mass spectrometry or gas chromatography mass spectrometry analysis. Samples were weighted according to the distribution of traffic over eight 6-hour periods. Substance groups were categorized in five mutually exclusive classes: single alcohol use, single illicit drug use, single medicinal drugs use, multiple drug use (including drugs from two or more separate substance groups but excluding alcohol), and drug use (either single or multiple) in combination with alcohol. Results: In total, 7,771 drivers (4,822 in The Netherlands and 2,949 in Belgium) were included in the study. In Belgium, the prevalence of single alcohol (6.4%) and single medicinal drugs (3.0%) was much higher than in The Netherlands (2.2% and 0.6%, respectively), whereas the single illicit drugs were more common in Dutch traffic (2.2%) than in Belgian traffic (0.6%). Compared with the estimated prevalence of psychoactive substances in the general driving public in Europe, the prevalence in Belgium (10.7%) was greater than the European average (7.4%), and the prevalence in The Netherlands was below the European average (5.5%). Conclusions: The observed prevalence of psychoactive substances varies largely between The Netherlands and Belgium. Probable reasons for the differences are the higher level of alcohol enforcement in The Netherlands and nonresponse bias in the Belgian study (for illicit drugs in particular). Furthermore, cultural differences and variances in prescription policy could also be influential

Cyclooxygenase-2 inhibition prevents renal toxicity but not hypertension during sunitinib treatment

Background: Anticancer angiogenesis inhibitors cause hypertension and renal injury. Previously we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and-2) was superior to low-dose aspirin (blocking COX-1 only) to prevent these side-effects during treatment with the angiogenesis inhibitor sunitinib, suggesting a role for COX-2. High-dose aspirin additionally prevented the rise in COX-derived prostacyclin (PGI2). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI2 during angiogenesis inhibition. Methods: Male WKY rats received vehicle, sunitinib ((SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day) or a PGI2 analogue (iloprost, 100 μg/kg/day) for 8 days (n = 8–9 per group). Mean arterial pressure (MAP) was measured via radiotelemetry, biochemical measurements were performed via ELISA and vascular function was assessed via wire myography. Results: SU increased MAP (17±1mmHg versus 3±1mmHg after vehicle on day 4, P &lt; 0.002), which could not be significantly blunted by celecoxib (+12±3mmHg on day 4, P = 0.247), but was temporarily attenuated by iloprost (treatment days 1 + 2 only). Urinary PGI2 (996 ± 112 versus 51 ± 11ng/24h after vehicle, P &lt; 0.001), but not circulating PGI2 increased during SU, which remained unaffected by celecoxib and iloprost. Celecoxib reduced sunitinib-induced albuminuria (0.36 ± 0.05 versus 0.58 ± 0.05mg/24h after SU, P = 0.005). Wire myography demonstrated increased vasoconstriction to endothelin-1 after SU (Emax P = 0.005 versus vehicle), which remained unaffected by celecoxib or iloprost. Conclusion: Selective COX-2 inhibition ameliorates albuminuria during angiogenesis inhibition with sunitinib, which most likely acts independently of PGI2. To combat angiogenesis inhibitor-induced hypertension, dual rather than selective COX-1/2 blockade seems preferential.</p

Loss of SLCO1B3 drives taxane resistance in prostate cancer

Background: Both taxanes, docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. Methods: Two docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-docetaxel resistance and gene expression profiles were compared. [14C]-docetaxel and [14C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. Results: Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to docetaxel and cabazitaxel. Conclusions: The SLCO1B3 determines intracellular concentrations of docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer

Repeatability of oral fluid collection methods for THC measurement

Study objectives: To determine the influence of sample collection for two different collection methods on THC concentrations and to compare THC concentrations collected by both methods. Methods: A total of 136 pairs of oral fluid samples from subjects who had recently smoked Cannabis were obtained by the non-acidic Statsure oral fluid collection device and by ordinary spit tubes. Oral fluid was analyzed for THC by LC-MS/MS. Bland-Altman plots were used for the quantitative analysis of repeatability, whereas Cohen's kappa was used for qualitative analysis to determine the consistency of the results with regard to the Belgian legal limit. Results: Repeatability of both sampling methods was very low. The Statsure device had a better rate of agreement when compared with the Belgian legal limit than the spitting method. THC concentrations of samples collected by spit tubes were on average a factor 5.9 higher than the corresponding concentrations in samples collected by the Statsure device. Conclusions: The repeatability of both the Statsure collection method and the ordinary spit tubes was low when applied to subjects who had consumed Cannabis very recently. Furthermore, THC concentrations were higher in samples obtained by spitting than samples collected with Statsure. These results may have implications for confirmation analysis in oral fluid, when applied for legal purposes. (C) 2012 Elsevier Ireland Ltd. All rights reserved

Accurate description of charge transport in organic field effect transistors using an experimentally extracted density of states

The width and shape of the density of states (DOS) are key parameters to describe the charge transport of organic semiconductors. Here we extract the DOS using scanning Kelvin probe microscopy on a self-assembled monolayer field effect transistor (SAMFET). The semiconductor is only a single monolayer which has allowed extraction of the DOS over a wide energy range, pushing the methodology to its fundamental limit. The measured DOS consists of an exponential distribution of deep states with additional localized states on top. The charge transport has been calculated in a generic variable range-hopping model that allows any DOS as input. We show that with the experimentally extracted DOS an excellent agreement between measured and calculated transfer curves is obtained. This shows that detailed knowledge of the density of states is a prerequisite to consistently describe the transfer characteristics of organic field effect transistors

Fundamental limitations for electroluminescence in organic dual-gate field-effect transistors

A dual-gate organic field-effect transistor is investigated for electrically pumped lasing. The two gates can independently accumulate electrons and holes, yielding current densities exceeding the lasing threshold. Here, the aim is to force the electrons and holes to recombine by confining the charges in a single semiconducting film. It is found that independent hole and electron accumulation is mutually exclusive with vertical recombination and light emission. © 2014 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim