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

AdViSHE: A Validation-Assessment Tool of Health-Economic Models for Decision Makers and Model Users

Background: A trade-off exists between building confidence in health-economic (HE) decision models and the use of scarce resources. We aimed to create a practical tool provid

Quality of service at the computer networks based on internet

А framework for the emerging computer networks quality of Internet service is presented. Two important components of the framework are considered: integrated service and differentiated service. They are described and problems related to their implementation are discussed. Two broadly classified algorithms are investigated: scheduling and queue management algorithms. The model of the average time delay for the type packet is presented.Запропоновано структуру забезпечення якості надання послуг Internet. Розглянуто два важливі компоненти цієї структури: інтегроване та диференційоване обслуговування, їх реалізацію та пов’язані з нею проблеми. Досліджено два алгоритма: планування і управління чергою. Запропоновано модель даних, яка базується на теорії масового обслуговування.Предложена структура обеспечения качества предоставления услуг Internet. Рассмотрены два важных компонента этой структуры: интегрированное и дифференцированное обслуживание, их реализация и связанные с ней проблемы. Исследованы два алгоритма: планирования и управления очередью. Предложена модель данных, базирующаяся на теории массового обслуживания

The Missing Stakeholder Group: Why Patients Should be Involved in Health Economic Modelling

Evaluations of healthcare interventions, e.g. new drugs or other new treatment strategies, commonly include a cost-effectiveness analysis (CEA) that is based on the application of health economic (HE) models. As end users, patients are important stakeholders regarding the outcomes of CEAs, yet their knowledge of HE model development and application, or their involvement therein, is absent. This paper considers possible benefits and risks of patient involvement in HE model development and application for modellers and patients. An exploratory review of the literature has been performed on stakeholder-involved modelling in various disciplines. In addition, Dutch patient experts have been interviewed about their experience in, and opinion about, the application of HE models. Patients have little to no knowledge of HE models and are seldom involved in HE model development and application. Benefits of becoming involved would include a greater understanding and possible acceptance by patients of HE model application, improved model validation, and a more direct infusion of patient expertise. Risks would include patient bias and increased costs of modelling. Patient involvement in HE modelling seems to carry several benefits as well as risks. We claim that the benefits may outweigh the risks and that patients should become involved

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

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

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

Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives:CVON eDETECT consortium

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy

Dysfunctional play and dopamine physiology in the Fischer 344 rat

Juvenile Fischer 344 rats are known to be less playful than other inbred strains, although the neurobiological substrate(s) responsible for this phenotype is uncertain. In the present study, Fischer 344 rats were compared to the commonly used outbred Sprague-Dawley strain on several behavioral and physiological parameters in order to ascertain whether the lack of play may be related to compromised activity of brain dopamine (DA) systems. As expected, Fischer 344 rats were far less playful than Sprague-Dawley rats, with Fischer 344 rats less likely to initiate playful contacts with a playful partner and less likely to respond playfully to these contacts. We also found that Fischer 344 rats showed less of a startle response and greater pre-pulse inhibition (PPI), especially at higher prepulse intensities. The increase in PPI seen in the Fischer 344 rat could be due to reduced DA modulation of sensorimotor gating and neurochemical measures were consistent with Fischer 344 rats releasing less DA than Sprague-Dawley rats. Fast scan cyclic voltammetry (FSCV) revealed Fischer 344 rats had less evoked DA release in dorsal and ventral striatal brain slices and high-performance liquid chromatography revealed Fischer 344 rats to have less DA turnover in the striatum and prefrontal cortex. We also found DA-dependent forms of cortical plasticity were deficient in the striatum and prefrontal cortex of the Fischer 344 rat. Taken together, these data indicate that deficits in play and enhanced PPI of Fischer 344 rats may be due to reduced DA modulation of corticostriatal and mesolimbic/mesocortical circuits critical to the execution of these behaviors

Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives: CVON eDETECT consortium

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy