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Horeweg N.,Erasmus University Rotterdam | Van Der Aalst C.M.,Erasmus University Rotterdam | Vliegenthart R.,University of Groningen | Zhao Y.,University of Groningen | And 11 more authors.
European Respiratory Journal | Year: 2013

Several medical associations recommended lung cancer screening by low-dose computed tomography scanning for high-risk groups. Counselling of the candidates on the potential harms and benefits and their lung cancer risk is a prerequisite for screening. In the NELSON trial, screenings are considered positive for (part) solid lung nodules with a volume >500 mm3 and for (part) solid or nonsolid nodules with a volume-doubling time >400 days. For this study, the performance of the NELSON strategy in three screening rounds was evaluated and risk calculations were made for a follow-up period of 5.5 years. 458 (6%) of the 7582 participants screened had a positive screen result and 200 (2.6%) were diagnosed with lung cancer. The positive screenings had a predictive value of 40.6% and only 1.2% of all scan results were false-positive. In a period of 5.5 years, the risk of screen-detected lung cancer strongly depends on the result of the first scan: 1.0% after a negative baseline result, 5.7%after an indeterminate baseline and 48.3% after a positive baseline. The screening strategy yielded few positive and false-positive scans with a reasonable positive predictive value. The 5.5-year lung cancer risk calculations aid clinicians in counselling candidates for lung cancer screening with low-dose computed tomography. © ERS 2013.


Van Den Bent M.J.,Erasmus University Rotterdam | Erdem-Eraslan L.,Erasmus University Rotterdam | Idbaih A.,Groupe Hospitalier Pitie Salpetriere | Spliet W.G.M.,UMCU | And 7 more authors.
Clinical Cancer Research | Year: 2013

Purpose: The long-term follow-up results from the EORTC-26951 trial showed that the addition of procarbazine, CCNU, and vincristine (PCV) after radiotherapy increases survival in anaplastic oligodendrogliomas/ oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treatment than others. Experimental Design:Weconducted genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted theCpGisland hypermethylated phenotype (CIMP) andMGMTpromoter methylation (MGMT-STP27) status. Results: We first show that methylation profiling can be conducted on archival tissues with a performance that is similar to snap-frozen tissue samples. We then conducted methylation profiling on EORTC-26951 clinical trial samples. Univariate analysis indicated that CIMP? or MGMT-STP27 methylated tumors had an improved survival compared with CIMP- and/or MGMT-STP27 unmethylated tumors [median overall survival (OS), 1.05 vs. 6.46 years and 1.06 vs. 3.8 years, both P < 0.0001 for CIMP and MGMT-STP27 status, respectively]. Multivariable analysis indicates that CIMP and MGMT-STP27 are significant prognostic factors for survival in presence of age, sex, performance score, and reviewdiagnosis in themodel. CIMP?andMGMTSTP27methylated tumors showed a clear benefit fromadjuvantPCVchemotherapy: themedianOSof CIMP? samples in the RT and RT-PCV arms was 3.27 and 9.51 years, respectively (P = 0.0033); for MGMT-STP27 methylated samples, it was 1.98 and 8.65 years. There was no such benefit for CIMP- or for MGMT-STP27 unmethylated tumors. MGMT-STP27 status remained significant in an interaction test (P = 0.003). Statistical analysis of microarray (SAM) identified 259 novel CpGs associated with treatment response. Conclusions:MGMT-STP27 may be used to guide treatment decisions in this tumor type. © 2013 American Association for Cancer Research.


Van der Heyden M.A.G.,UMCU | Stary-Weinzinger A.,University of Vienna | Sanchez-Chapula J.A.,University of Colima
Current Molecular Medicine | Year: 2013

Cardiac inward rectifier channels belong to three different classes of the KIR channel protein family. The KIR2.x proteins generate the classical inward rectifier current, IK1, while KIR3 and KIR6 members are responsible for the acetylcholine responsive and ATP sensitive inward rectifier currents IKAch and IKATP, respectively. Aberrant function of these channels has been correlated with severe cardiac arrhythmias, indicating their significant contribution to normal cardiac electrophysiology. A common feature of inward rectifier channels is their dependence on the lipid phosphatidyl-4,5-bisphospate (PIP2) interaction for functional activity. Cationic amphiphilic drugs (CADs) are one of the largest classes of pharmaceutical compounds. Several widely used CADs have been associated with inward rectifier current disturbances, and recent evidence points to interference of the channel-PIP2 interaction as the underlying mechanism of action. we will review how six of these well known drugs, used for treatment in various different conditions, interfere in cardiac inward rectifier functioning. In contrast, KIR channel inhibition by the anionic anesthetic thiopental is achieved by a different mechanism of channel-PIP2 interference. We will discuss the latest basic science insights of functional inward rectifier current characteristics, recently derived KIR channel structures and specific PIP2-receptor interactions at the molecular level and provide insight in how these drugs interfere in the structure-function relationships. © 2013 Bentham Science Publishers.


Wijkstra J.,UMCU
The Cochrane database of systematic reviews | Year: 2013

Evidence is limited regarding the most effective pharmacological treatment for psychotic depression: combination of an antidepressant plus an antipsychotic, monotherapy with an antidepressant or monotherapy with an antipsychotic. This is an update of a review first published in 2005 and last updated in 2009. 1. To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression: antidepressant monotherapy, antipsychotic monotherapy and the combination of an antidepressant plus an antipsychotic, compared with each other and/or with placebo.2. To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment. A search of the Cochrane Central Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (CCDANCTR) was carried out (to 12 April 2013). These registers include reports of randomised controlled trials from the following bibliographic databases: EMBASE (1970-), MEDLINE (1950-) and PsycINFO (1960-). Reference lists of all studies and related reviews were screened and key authors contacted. All randomised controlled trials (RCTs) that included participants with acute major depression with psychotic features, as well as RCTs consisting of participants with acute major depression with or without psychotic features, that reported separately on the subgroup of participants with psychotic features. Two review authors independently extracted data and assessed risk of bias in the included studies, according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. Data were entered into RevMan 5.1. We used intention-to-treat data. For dichotomous efficacy outcomes, the risk ratio (RR) with 95% confidence intervals (CIs) was calculated. For continuously distributed outcomes, it was not possible to extract data from the RCTs. Regarding the primary outcome of harm, only overall dropout rates were available for all studies. The search identified 3659 abstracts, but only 12 RCTs with a total of 929 participants could be included in the review. Because of clinical heterogeneity, few meta-analyses were possible. The main outcome was reduction of severity (response) of depression, not of psychosis.We found no evidence for the efficacy of monotherapy with an antidepressant or an antipsychotic.However, evidence suggests that the combination of an antidepressant plus an antipsychotic is more effective than antidepressant monotherapy (three RCTs; RR 1.49, 95% CI 1.12 to 1.98, P = 0.006), more effective than antipsychotic monotherapy (four RCTs; RR 1.83, 95% CI 1.40 to 2.38, P = 0.00001) and more effective than placebo (two identical RCTs; RR 1.86, 95% CI 1.23 to 2.82, P = 0.003).Risk of bias is considerable: there were differences between studies with regard to diagnosis, uncertainties around randomisation and allocation concealment, differences in treatment interventions (pharmacological differences between the various antidepressants and antipsychotics) and different outcome criteria. Psychotic depression is heavily understudied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone.


Investigation into the considerations taken into account by the central and regional disciplinary tribunals for the health service (CTG and RTG) in cases where a doctor was permanently removed from the national professional register. Retrospective study of jurisprudence and literature. A search was carried out for jurisprudential cases in which doctors were removed from the professional register during the period January 2006-December 2011, using the following sources: the websites of the disciplinary tribunals, the Dutch Government Gazette (Staatscourant) and two journals concerned with healthcare law. The verdicts were analysed, general statistical records were kept and categories for the consideration were set up on the basis of short, characteristic quotations from the verdicts. These verdicts were subsequently re-examined and divided into these categories. A total of 34 verdicts concerning 13 different physicians were found in the study period. There were 17 verdicts from the RTGs and 16 verdicts from the CTG. One verdict was pronounced by the Medical Supervisory Board (CMT). In 12 cases the final verdict was permanent removal from the professional register. In one case the CTG imposed a lower sanction than that earlier imposed by the RTG. The most common considerations taken into account by removal from the professional register were the combination of medical-technical errors, incomplete and/or inaccurate maintenance of patient records and the doctor's attitude towards his or her own actions. Removal from the professional register is rarely imposed. In most cases, an accumulation of obvious errors is involved. Improper sexual behaviour is also punished severely. Acting in accordance with professional medical standards, adequate medical record-keeping and self-reflection are important factors in the prevention of this sanction.


Van Santvoort H.C.,UMCU
Nederlands Tijdschrift voor Geneeskunde | Year: 2013

A recent meta-analysis of 57 studies investigated the diagnostic accuracy of imaging techniques in acute cholecystitis. The main findings were that abdominal ultrasound has a sensitivity of 81% and a specificity of 83%, that ultrasound seems comparable to magnetic resonance imaging (MRI), that cholescintigraphy has a sensitivity of 96% and a specificity of 90%, and that there are insufficient studies to evaluate the role of computed tomography (CT). In daily practice, ultrasound is the preferred modality as it is safe, widely available and cheap. MRI and cholescintigraphy are less available and have additional disadvantages. Patients with a negative or inconclusive ultrasound examination should undergo CT as this is in line with the general diagnostic strategy for acute abdominal pain that results in the highest sensitivity for urgent conditions and lowest exposure to radiation. Patients with clinical suspicion of acute cholecystitis but negative imaging findings should undergo prompt diagnostic laparoscopy and potentially cholecystectomy.


De Boer T.P.,UMCU | Houtman M.J.C.,UMCU | Compier M.,UMCU | Van Der Heyden M.A.G.,UMCU
Acta Physiologica | Year: 2010

Inward rectifier currents based on KIR2.x subunits are regarded as essential components for establishing a stable and negative resting membrane potential in many excitable cell types. Pharmacological inhibition, null mutation in mice and dominant positive and negative mutations in patients reveal some of the important functions of these channels in their native tissues. Here we review the complex mammalian expression pattern of KIR2.x subunits and relate these to the outcomes of functional inhibition of the resultant channels. Correlations between expression and function in muscle and bone tissue are observed, while we recognize a discrepancy between neuronal expression and function. © 2010 Scandinavian Physiological Society.


Polders D.L.,UMCU | Hoogduin J.M.,UMCU
PET Clinics | Year: 2013

Chemical exchange saturation transfer (CEST) measurements hold great promise as the next step in magnetization transfer imaging and possibly allow for in vivo quantification of many clinically relevant parameters, including pH, temperature, and amide concentration. Therefore, it is a valuable method to add to the MR imaging toolbox. The aim of this article was to review the methods for the acquisition of CEST data and necessary postprocessing. CEST research is very much a field still in development, and initial explorations in clinical applications are shown to illustrate the potential of CEST as a new contrast mechanism. © 2013 Elsevier Inc.


van Santvoort H.C.,UMCU
Nederlands tijdschrift voor geneeskunde | Year: 2013

A recent meta-analysis of 57 studies investigated the diagnostic accuracy of imaging techniques in acute cholecystitis. The main findings were that abdominal ultrasound has a sensitivity of 81% and a specificity of 83%, that ultrasound seems comparable to magnetic resonance imaging (MRI), that cholescintigraphy has a sensitivity of 96% and a specificity of 90%, and that there are insufficient studies to evaluate the role of computed tomography (CT). In daily practice, ultrasound is the preferred modality as it is safe, widely available and cheap. MRI and cholescintigraphy are less available and have additional disadvantages. Patients with a negative or inconclusive ultrasound examination should undergo CT as this is in line with the general diagnostic strategy for acute abdominal pain that results in the highest sensitivity for urgent conditions and lowest exposure to radiation. Patients with clinical suspicion of acute cholecystitis but negative imaging findings should undergo prompt diagnostic laparoscopy and potentially cholecystectomy.


Hubens L.E.G.,UMCU | Verloop W.L.,UMCU | Joles J.A.,UMCU | Blankestijn P.J.,UMCU | Voskuil M.,UMCU
Current Hypertension Reports | Year: 2013

Renal denervation has developed as a new treatment strategy for patients suffering from resistant hypertension. The success of this therapy is due to the fact that sympathetic hyperactivity is involved in the pathogenesis of elevated blood pressure. However, not only the sympathetic nervous system (SNS), but also the renin angiotensin system (RAS) is known to be involved in hypertension. In addition, RAS is involved in other sympathetic hyperactivity states, such as heart failure, chronic kidney disease, insulin resistance and obstructive sleep apnea. Moreover, renal denervation has a beneficial effect on patients suffering from these disease states. Recent research suggested that the production of reactive oxygen species (ROS) is elevated in sympathetic hyperactivity states, and that ROS are able to activate the SNS and local tissue renin angiotensin system. Therefore, this review discusses the possibility of ROS as a common trigger of SNS and RAS activity in sympathetic hyperactivity states, and the effect of renal denervation on this ROS production. © 2013 Springer Science+Business Media New York.

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