Chronic activation of the 5-HT(2) receptor reduces 5-HT neurite density as studied in organotypic slice cultures

The serotonin system densely innervates the brain and is implicated in psychopathological processes. Here we studied the effect of serotonin and serotonin pharmacological compounds on the outgrowth of serotonergic projections using organotypic slice co-cultures of hippocampus and dorsal raphe nuclei. Immunocytochemical analysis showed that several serotonergic neurites had grown into the target slice within 7 days in culture, after which the neurite density stabilized. These projections expressed the serotonin-synthesizing enzyme Tryptophan hydroxylase and the serotonin transporter and contained several serotonin-positive varicosities that also accumulated presynaptic markers. Chronic application of a 5-HT(2) agonist reduced the serotonergic neurite density, without effects on survival of serotonergic neurons. In contrast, application of a 5-HT(1A) agonist or the serotonin transporter inhibitor fluoxetine did not affect serotonergic neurite density. We conclude that serotonergic connectivity was reproduced in vitro and that the serotonin neurite density is inhibited by chronic activation of the 5-HT(2) receptor

The perception of teachers on usability and accessibility of programming materials for children with visual impairments

Programming education is strongly emerging in elementary and high school. Diversity and inclusion are important topics, however, insights on suited programming materials for younger learners with visual impairments are lacking. A wide range of programming materials for children exists, diverse in both what is being programmed (output) and how this is done (input), yet often relying on visual features. An understanding of the usability and accessibility aspects of these different materials is important to inform educational practice and to increase understanding of what makes programming materials suited for low vision and blind children. The aim of this study is to explore the usability and accessibility of programming materials currently used in education to low vision and blind children in the Netherlands. A focus group was conducted with six teachers or IT experts, all working with the target group in special education. The thematic analysis of the discussion of 25 materials (including unplugged lessons, robots and robotic kits, block-based and text- based languages) showed the potential of several materials, especially unplugged lessons, and the continuing search for suited materials and workforms specifically for the blind children. Furthermore, prioritizing “fun” and close connections to children’s daily life as well as careful explorations of usability at the cognitive level came forward as important factors for future research and development in programming materials for low vision and blind children. These insights can contribute to obtaining an inclusive approach to programming for young learners.Algorithms and the Foundations of Software technolog

Re-municipalization of public services: trend or hype?

Re-municipalization is part of a broader set of reverse privatization reforms. We argue the term re-municipalization lacks conceptual clarity and often confuses municipal level reversals from national ones, new service delivery from reversals, and mixed market positions (such as corporatization) from full public control. This conceptual confusion makes measurement of re-municipalization difficult. While more case studies are being discovered, studies based on quantitative time series do not show re-municipalization as an increasing trend. Much case study based research argues re-municipalization is politically transformative, but quantitative research generally finds re-municipalization to be part of a pragmatic market management process, a position confirmed by the papers in this special issue

Static versus dynamic fracturing in shallow carbonate fault zones

Moderate to large earthquakes often nucleate within and propagate through carbonates in the shallow crust. The occurrence of thick belts of low-strain fault-related breccias is relatively common within carbonate damage zones and was generally interpreted in relation to the quasi-static growth of faults. Here we report the occurrence of hundreds of meters thick belts of intensely fragmented dolostones along a major transpressive fault zone in the Italian Southern Alps. These fault rocks have been shattered in-situ with negligible shear strain accumulation. The conditions of in-situ shattering were investigated by deforming the host dolostones in uniaxial compression both under quasi-static (strain rate ∼10−5s−1) and dynamic (strain rate >50s−1) loading. Dolostones deformed up to failure under low-strain rate were affected by single to multiple discrete extensional fractures sub-parallel to the loading direction. Dolostones deformed under high-strain rate were shattered above a strain rate threshold of ∼120s−1 and peak stresses on average larger than the uniaxial compressive strength of the rock, whereas they were split in few fragments or remained macroscopically intact at lower strain rates. Fracture networks were investigated in three dimensions showing that low- and high-strain rate damage patterns (fracture intensity, aperture, orientation) were significantly different, with the latter being similar to that of natural in-situ shattered dolostones (i.e., comparable fragment size distributions). In-situ shattered dolostones were thus interpreted as the result of high energy dynamic fragmentation (dissipated strain energies >1.8 MJ/m3) similarly to pulverized rocks in crystalline lithologies. Given their seismic origin, the presence of in-situ shattered dolostones can be used in earthquake hazard studies as evidence of the propagation of seismic ruptures at shallow depths

Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines

Gemcitabine and paclitaxel are active agents in the treatment of non-small-cell lung cancer (NSCLC). To optimize treatment drug combinations, simultaneously and 4 and 24 h intervals, were studied using DNA flow cytometry and multiple drug effect analysis in the NSCLC cell lines H460, H322 and Lewis Lung. All combinations resulted in comparable cytotoxicity, varying from additivity to antagonism (combination index: 1.0–2.6). Gemcitabine caused a S (48%) and G1 (64%) arrest at IC-50 and 10 × IC-50 concentrations, respectively. Paclitaxel induced G2/M arrest (70%) which was maximal within 24 h at 10 × IC-50. Simultaneous treatment increased S-phase arrest, while at the 24 h interval after 72 h the first drug seemed to dominate the effect. Apoptosis was more pronounced when paclitaxel preceded gemcitabine (20% for both intervals) as compared to the reverse sequence (8%, P = 0.173 for the 4 h and 12%, P = 0.051 for the 24 h time interval). In H460 cells, paclitaxel increased 2-fold the accumulation of dFdCTP, the active metabolite of gemcitabine, in contrast to H322 cells. Paclitaxel did not affect deoxycytidine kinase levels, but ribonucleotide levels increased possibly explaining the increase in dFdCTP. Paclitaxel did not affect gemcitabine incorporation into DNA, but seemed to increase incorporation into RNA. Gemcitabine almost completely inhibited DNA synthesis in both cell lines (70–89%), while paclitaxel had a minor effect and did not increase that of gemcitabine. In conclusion, various gemcitabine–paclitaxel combinations did not show sequence dependent cytotoxic effects; all combinations were not more than additive. However, since paclitaxel increased dFdCTP accumulation, gemcitabine incorporation into RNA and the apoptotic index, the administration of paclitaxel prior to gemcitabine might be favourable as compared to reversed sequences. © 2000 Cancer Research Campaig

Tracheal agenesis: approach towards this severe diagnosis. Case report and review of the literature

Tracheal agenesis (TA) is a severe congenital disorder with often an unexpected emergency presentation. There is complete or partial absence of the trachea below the larynx, with presence or absence of a tracheoesophageal fistula (TOF). A neonate with TA is described, and another 48 cases found in literature are reviewed. Due to absence of a TOF, five cases were diagnosed prenatally because of congenital high airway obstruction syndrome (CHAOS). When a TOF is present, polyhydramnion and several other congenital malformations seen on the ultrasound examination should alert clinicians of potential tracheal problems. Prenatal magnetic resonance imaging (MRI) may provide a definitive diagnosis. Postnatal diagnosis is based on recognition of specific clinical signs in the newborn with TA: respiratory distress with breathing movement without appropriate air entry, no audible cry, and failed endotracheal intubation. Despite progress in surgical interventions, mortality remains high. Prenatal diagnosis of TA is possible, but only if a TOF is absent resulting in CHAOS. Prenatal diagnosis of polyhydramnion and other congenital malformation should alert clinicians of potential tracheal problems. Prenatal MRI may provide a definitive diagnosis

Agreement of general practitioners with the guideline-based stepped-care strategy for patients with osteoarthritis of the hip or knee: A cross-sectional study

Background: To improve the management of hip or knee osteoarthritis (OA), a multidisciplinary guideline-based stepped-care strategy (SCS) with recommendations regarding the appropriate non-surgical treatment modalities and optimal sequence for care has been developed. Implementation of this SCS in the general practice may be hampered by the negative attitude of general practitioners (GPs) towards the strategy. In order to develop a tailored implementation plan, we assessed the GPs' views regarding specific recommendations in the SCS and their working procedures with regard to OA. Methods. A survey was conducted among a random sample of Dutch GPs. Questions included the GP's demographical characteristics and the practice setting as well as how the management of OA was organized and whether the GPs supported the SCS recommendations. In particular, we assessed GP's views regarding the effectiveness of 14 recommended and non-recommended treatment modalities. Furthermore, we calculated their agreement with 7 statements based on the SCS recommendations regarding the sequence for care. With a linear regression model, we identified factors that seemed to influence the GPs' agreement with the SCS recommendations. Results: Four hundred fifty-six GPs (37%) aged 30-65 years, of whom 278 males (61%), responded. Seven of the 11 recommended modalities (i.e. oral Non-Steroidal Anti-Inflammatory Drugs, physical therapy, glucocorticoid intra-articular injections, education, lifestyle advice, acetaminophen, and tramadol) were considered effective by the majority of the GPs (varying between 95-60%). The mean agreement score, based on a 5-point scale, with the recommendations regarding the sequence for care was 2.8 (SD = 0.5). Ten percent of the variance in GPs' agreement could be explained by the GPs' attitudes regarding the effectiveness of the recommended and non-recommended non-surgical treatment modalities and the type of practice. Conclusion: In general, GPs support the recommendations in the SCS. Therefore, we expect that their attitudes will not impede a successful implementation in general practice. Our results provide sev

Genetic Obesity Disorders:Body Mass Index Trajectories and Age of Onset of Obesity Compared with Children with Obesity from the General Population

Objective: We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening. Study design: This longitudinal, observational study included growth measurements from birth onward of children with nonsyndromic and syndromic genetic obesity and control children with obesity from a population-based cohort. Diagnostic performance of AoO was evaluated. Results: We describe the body mass index trajectories of 62 children with genetic obesity (29 nonsyndromic, 33 syndromic) and 298 controls. Median AoO was 1.2 years in nonsyndromic genetic obesity (0.4 and 0.6 years in biallelic LEPR and MC4R; 1.7 in heterozygous MC4R); 2.0 years in syndromic genetic obesity (0.9, 2.3, 4.3, and 6.8 years in pseudohypoparathyroidism, Bardet-Biedl syndrome, 16p11.2del syndrome, and Temple syndrome, respectively); and 3.8 years in controls. The optimal AoO cut-off was ≤3.9 years (sensitivity, 0.83; specificity, 0.49; area under the curve, 0.79; P &lt; .001) for nonsyndromic and ≤4.7 years (sensitivity, 0.82; specificity, 0.37; area under the curve, 0.68; P = .001) for syndromic genetic obesity.Conclusions: Optimal AoO cut-off as single parameter to determine which children should undergo genetic testing was ≤3.9 years. In case of older AoO, additional features indicative of genetic obesity should be present to warrant genetic testing. Optimal cut-offs might differ across different races and ethnicities.</p

Exploring the Correlation Between Fibrosis Biomarkers and Clinical Disease Severity in PLN p.Arg14del Patients

Background: Pathogenic variants in phospholamban (PLN, like p. Arg14del), are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in PLN p.Arg14del carriers. During collagen synthesis and breakdown, propeptides are released into the circulation, such as procollagen type I carboxy-terminal propeptide (PICP) and C-terminal telopeptide collagen type I (ICTP). Aim: To investigate if PICP/ICTP levels in blood are correlative biomarkers for clinical disease severity and outcome in PLN p.Arg14del variant carriers. Methods: Serum and EDTA blood samples were collected from 72 PLN p.Arg14del carriers (age 50.5 years, 63% female) diagnosed with ACM (n = 12), DCM (n = 14), and preclinical variant carriers (n = 46). PICP levels were measured with an enzyme-linked immune sorbent assay and ICTP with a radio immuno-assay. Increased PICP/ICTP ratios suggest a higher collagen deposition. Clinical data including electrocardiographic, and imaging results were adjudicated from medical records. Results: No correlation between PICP/ICTP ratios and late gadolinium enhancement (LGE) was found. Moderate correlations were found between the PICP/ICTP ratio and end-diastolic/systolic volume (both r(s) = 0.40, n = 23, p = 0.06). PICP/ICTP ratio was significantly higher in patients with T wave inversion (TWI), especially in leads V4–V6, II, III, and aVF (p < 0.022) and in patients with premature ventricular contractions (PVCs) during an exercise tolerance test (p = 0.007). Conclusion: High PICP/ICTP ratios correlated with clinical parameters, such as TWI and PVCs. Given the limited size and heterogeneity of the patient group, additional studies are required to substantiate the incremental prognostic value of these fibrosis biomarkers in PLN p.Arg14del patients

Op afstand maar toch verbonden: samen voor het publieke belang

Essay voor de gemeente Rotterdam over verbonden partijen, aandeelhouderschap en publieke belangen