26 research outputs found

    On the toxicity and transport mechanisms of cisplatin in kidney tissues in comparison to a gold-based cytotoxic agent

    Get PDF
    Mechanisms of toxicity and cellular transport of anticancer metallodrugs, including platinum-based agents, have not yet been fully elucidated. Here, we studied the toxic effects and accumulation mechanisms of cisplatin in healthy rat kidneys ex vivo, using the Precision Cut Tissue Slices (PCTS) method. In addition, for the first time, we investigated the nephrotoxic effects of an experimental anticancer cyclometallated complex [Au(pyb-H)(PTA)Cl]PF6 (PTA = 1,3,5-triazaphosphaadamantane). The viability of the kidney slices after metallodrug treatment was evaluated by ATP content determination and histomorphology analysis. A concentration dependent decrease in viability of PCKS was observed after exposure to cisplatin or the Au(III) complex, which correlated with the increase in slice content of Pt and Au, respectively. Metal accumulation in kidney slices was analysed by ICP-MS. The involvement of OCTs and MATE transporters in the accumulation of both metal compounds in kidneys was evaluated co-incubating the tissues with cimitedine, inhibitor of OCT and MATE. Studies of mRNA expression of the markers KIM-1, villin, p53 and Bax showed that cisplatin damages proximal tubules, whereas the Au(III) complex preferentially affects the distal tubules. However, no effect of cimetidine on the toxicity or accumulation of cisplatin and the Au(III) complex was observed. The effect of temperature on metallodrug accumulation in kidneys suggests the involvement of a carrier-mediated uptake process, other than OCT2, for cisplatin; while carrier-mediated excretion was suggested in the cases of the Au(III) complex

    The Netherlands study of depression in older persons (NESDO); a prospective cohort study

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>To study late-life depression and its unfavourable course and co morbidities in The Netherlands.</p> <p>Methods</p> <p>We designed the Netherlands Study of Depression in Older Persons (NESDO), a multi-site naturalistic prospective cohort study which makes it possible to examine the determinants, the course and the consequences of depressive disorders in older persons over a period of six years, and to compare these with those of depression earlier in adulthood.</p> <p>Results</p> <p>From 2007 until 2010, the NESDO consortium has recruited 510 depressed and non depressed older persons (≥ 60 years) at 5 locations throughout the Netherlands. Depressed persons were recruited from both mental health care institutes and general practices in order to include persons with late-life depression in various developmental and severity stages. Non-depressed persons were recruited from general practices. The baseline assessment included written questionnaires, interviews, a medical examination, cognitive tests and collection of blood and saliva samples. Information was gathered about mental health outcomes and demographic, psychosocial, biological, cognitive and genetic determinants. The baseline NESDO sample consists of 378 depressed (according to DSM-IV criteria) and 132 non-depressed persons aged 60 through 93 years. 95% had a major depression and 26.5% had dysthymia. Mean age of onset of the depressive disorder was around 49 year. For 33.1% of the depressed persons it was their first episode. 41.0% of the depressed persons had a co morbid anxiety disorder. Follow up assessments are currently going on with 6 monthly written questionnaires and face-to-face interviews after 2 and 6 years.</p> <p>Conclusions</p> <p>The NESDO sample offers the opportunity to study the neurobiological, psychosocial and physical determinants of depression and its long-term course in older persons. Since largely similar measures were used as in the Netherlands Study of Depression and Anxiety (NESDA; age range 18-65 years), data can be pooled thus creating a large longitudinal database of clinically depressed persons with adequate power and a large set of neurobiological, psychosocial and physical variables from both younger and older depressed persons.</p

    Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

    Get PDF
    Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts

    Androgen deprivation therapy for androgen receptor-positive advanced salivary duct carcinoma: A nationwide case series of 35 patients in The Netherlands

    Get PDF
    Background: Salivary duct carcinoma, an aggressive subtype of salivary gland cancer, is mostly androgen receptor-positive. Only limited data are available on androgen deprivation therapy (ADT). Methods: Patients with advanced androgen receptor-positive salivary duct carcinoma treated with first-line ADT were retrospectively evaluated for clinical benefit (ie, partial response [PR] and stable disease, progression-free survival [PFS] and overall survival [OS]). The OS was compared with patients with advanced salivary duct carcinoma who received best supportive care. Results: Thirty-four of 35 patients who were ADT-treated were evaluable: 6 patients had a PR (18%) and 11 had stable disease (32%) leading to a clinical benefit ratio of 50%. The median PFS for the ADT-treated patients was 4 months and the median duration of clinical benefit was 11 months. The median OS was 17 months versus 5 months in 43 patients receiving best supportive care (P=.02). Conclusion: We recommend ADT in advanced androgen receptor-positive salivary duct carcinoma given its response and clinical benefit

    Predictive factors for surgical treatment in preterm neonates with necrotizing enterocolitis: a multicenter case-control study

    Get PDF
    Necrotizing enterocolitis (NEC) is one of the most common and lethal gastrointestinal diseases in preterm infants. Early recognition of infants in need for surgical intervention might enable early intervention. In this multicenter case-control study, performed in nine neonatal intensive care units, preterm born infants (= IIA) between October 2014 and August 2017 were divided into two groups: (1) medical (conservative treatment) and (2) surgical NEC (sNEC). Perinatal, clinical, and laboratory parameters were collected daily up to clinical onset of NEC. Univariate and multivariate logistic regression analyses were applied to identify potential predictors for sNEC. In total, 73 preterm infants with NEC (41 surgical and 32 medical NEC) were included. A low gestational age (p value, adjusted odds ratio [95%CI]; 0.001, 0.91 [0.86-0.96]), no maternal corticosteroid administration (0.025, 0.19 [0.04-0.82]), early onset of NEC (0.003, 0.85 [0.77-0.95]), low serum bicarbonate (0.009, 0.85 [0.76-0.96]), and a hemodynamically significant patent ductus arteriosus for which ibuprofen was administered (0.003, 7.60 [2.03-28.47]) were identified as independent risk factors for sNEC. Conclusions: Our findings may support the clinician to identify infants with increased risk for sNEC, which may facilitate early decisive management and consequently could result in improved prognosis. What is Known: In 27-52% of the infants with NEC, a surgical intervention is indicated during its disease course. Absolute indication for surgical intervention is bowel perforation, whereas fixed bowel loop or clinical deterioration highly suggestive of bowel perforation or necrosi, is a relative indication. What is New: Lower gestational age, early clinical onset, and no maternal corticosteroids administration are predictors for surgical NEC. Low serum bicarbonate in the 3 days prior clinical onset and patent ductus arteriosus for which ibuprofen was administered predict surgical NEC
    corecore