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Erasmus Medical Center and Surface Oncology | Date: 2016-09-21

Disclosed herein are anti-CD47 antibody molecules, their manufacture and use in treating disorders associated with CD47 expression, for example, certain hematological cancers and solid tumors.


Greenberg S.M.,Massachusetts General Hospital | Salman R.A.S.,University of Edinburgh | Biessels G.J.,University Utrecht | van Buchem M.,Leiden University | And 6 more authors.
The Lancet Neurology | Year: 2014

Efforts are underway for early-phase trials of candidate treatments for cerebral amyloid angiopathy, an untreatable cause of haemorrhagic stroke and vascular cognitive impairment. A major barrier to these trials is the absence of consensus on measurement of treatment effectiveness. A range of potential outcome markers for cerebral amyloid angiopathy can be measured against the ideal criteria of being clinically meaningful, closely representative of biological progression, efficient for small or short trials, reliably measurable, and cost effective. In practice, outcomes tend either to have high clinical salience but low statistical efficiency, and thus more applicability for late-phase studies, or greater statistical efficiency but more limited clinical meaning. The most statistically efficient markers might be those that are potentially reversible with treatment, although their clinical significance remains unproven. Many of the candidate outcomes for cerebral amyloid angiopathy trials are probably applicable also to other small-vessel brain diseases. © 2014 Elsevier Ltd.


Austin P.C.,Institute for Clinical Evaluative science | Austin P.C.,University of Toronto | Steyerberg E.W.,Erasmus Medical Center
BMC Medical Research Methodology | Year: 2012

Background: When outcomes are binary, the c-statistic (equivalent to the area under the Receiver Operating Characteristic curve) is a standard measure of the predictive accuracy of a logistic regression model. Methods. An analytical expression was derived under the assumption that a continuous explanatory variable follows a normal distribution in those with and without the condition. We then conducted an extensive set of Monte Carlo simulations to examine whether the expressions derived under the assumption of binormality allowed for accurate prediction of the empirical c-statistic when the explanatory variable followed a normal distribution in the combined sample of those with and without the condition. We also examine the accuracy of the predicted c-statistic when the explanatory variable followed a gamma, log-normal or uniform distribution in combined sample of those with and without the condition. Results: Under the assumption of binormality with equality of variances, the c-statistic follows a standard normal cumulative distribution function with dependence on the product of the standard deviation of the normal components (reflecting more heterogeneity) and the log-odds ratio (reflecting larger effects). Under the assumption of binormality with unequal variances, the c-statistic follows a standard normal cumulative distribution function with dependence on the standardized difference of the explanatory variable in those with and without the condition. In our Monte Carlo simulations, we found that these expressions allowed for reasonably accurate prediction of the empirical c-statistic when the distribution of the explanatory variable was normal, gamma, log-normal, and uniform in the entire sample of those with and without the condition. Conclusions: The discriminative ability of a continuous explanatory variable cannot be judged by its odds ratio alone, but always needs to be considered in relation to the heterogeneity of the population. © 2012 Austin and Steyerberg; licensee BioMed Central Ltd.


Frilling A.,Imperial College London | Modlin I.M.,Yale University | Kidd M.,Yale University | Russell C.,University College London | And 12 more authors.
The Lancet Oncology | Year: 2014

Many management strategies exist for neuroendocrine liver metastases. These strategies range from surgery to ablation with various interventional radiology procedures, and include both regional and systemic therapy with diverse biological, cytotoxic, or targeted agents. A paucity of biological, molecular, and genomic information and an absence of data from rigorous trials limit the validity of many publications detailing management. This Review represents the views from an international conference, for which 15 expert working groups prepared evidence-based assessments addressing specific questions, and from which an independent jury derived final recommendations. The aim of the conference was to review the existing approaches to neuroendocrine liver metastases, assess the evidence on which management decisions were based, develop internationally acceptable recommendations for clinical practice (when evidence was available), and make recommendations for clinical and research endeavours. This report represents the final clinical statements and proposals for future research. © 2014 Elsevier Ltd.


Yokomizo T.,Erasmus Medical Center | Yokomizo T.,National University of Singapore | Dzierzak E.,Erasmus Medical Center
Development | Year: 2010

Hematopoietic cell clusters in the aorta of vertebrate embryos play a pivotal role in the formation of the adult blood system. Despite their importance, hematopoietic clusters have not been systematically quantitated or mapped because of technical limitations posed by the opaqueness of whole mouse embryos. Here, we combine an approach to make whole mouse embryos transparent, with multicolor marking, to allow observation of hematopoietic clusters using high-resolution 3-dimensional confocal microscopy. Our method provides the first complete map and temporal quantitation of all hematopoietic clusters in the mouse embryonic vasculature. We show that clusters peak in number at embryonic day 10.5, localize to specific vascular subregions and are heterogeneous, indicating a basal endothelial to non-basal (outer cluster) hematopoietic cell transition. Clusters enriched with the c-Kit+CD31 +SSEA1- cell population contain functional hematopoietic progenitors and stem cells. Thus, three-dimensional cartography of transparent mouse embryos provides novel insight into the vascular subregions instrumental in hematopoietic progenitor/stem cell development, and represents an important technological advancement for comprehensive in situ hematopoietic cluster analysis. © 2010. Published by The Company of Biologists Ltd.


Austin P.C.,Institute for Clinical Evaluative science | Austin P.C.,University of Toronto | Steyerberg E.W.,Erasmus Medical Center
Statistics in Medicine | Year: 2013

The change in c-statistic is frequently used to summarize the change in predictive accuracy when a novel risk factor is added to an existing logistic regression model. We explored the relationship between the absolute change in the c-statistic, Brier score, generalized R2, and the discrimination slope when a risk factor was added to an existing model in an extensive set of Monte Carlo simulations. The increase in model accuracy due to the inclusion of a novel marker was proportional to both the prevalence of the marker and to the odds ratio relating the marker to the outcome but inversely proportional to the accuracy of the logistic regression model with the marker omitted. We observed greater improvements in model accuracy when the novel risk factor or marker was uncorrelated with the existing predictor variable compared with when the risk factor has a positive correlation with the existing predictor variable. We illustrated these findings by using a study on mortality prediction in patients hospitalized with heart failure. In conclusion, the increase in predictive accuracy by adding a marker should be considered in the context of the accuracy of the initial model. © 2012 John Wiley & Sons, Ltd.


De Bruin A.M.,Academical Medical Center | Libregts S.F.,Academical Medical Center | Libregts S.F.,Sanquin Research and Landsteiner Laboratory | Valkhof M.,Erasmus Medical Center | And 4 more authors.
Blood | Year: 2012

Steady-state hematopoiesis is altered on infection, but the cellular and molecular mechanisms driving these changes are largely unknown. Modulation of hematopoiesis is essential to increase the output of the appropriate type of effector cell required to combat the invading pathogen. In the present study, we demonstrate that the pro-inflammatory cytokine IFNγ is involved in orchestrating inflammation-induced myelopoiesis. Using both mouse models and in vitro assays, we show that IFNγ induces the differentiation of monocytes over neutrophils at the level of myeloid progenitors. Infection with lymphocytic choriomeningitis virus induces monopoiesis in wild-type mice, but causes increased neutrophil production in IFNγ -/- mice. We demonstrate that IFNγ enhances the expression of the monopoiesis-inducing transcription factors IRF8 and PU.1 in myeloid progenitor cells, whereas it reduces G-CSF-driven neutrophil differentiation via a SOCS3- dependent inhibition of STAT3 phosphorylation. These results establish a critical role for IFNγ in directing monocyte versus neutrophil development during immune activation. © 2012 by The American Society of Hematology.


Ketelslegers I.A.,Erasmus Medical Center | Neuteboom R.F.,Erasmus Medical Center | Boon M.,University of Groningen | Catsman-Berrevoets C.E.,Erasmus MC Sophia Childrens Hospital | Hintzen R.Q.,Erasmus Medical Center
Neurology | Year: 2010

Background: Brain MRI is a useful tool for diagnosing inflammatory demyelinating disorders in children. However, it remains unclear which are the most reliable criteria for distinguishing multiple sclerosis (MS) from monophasic disorders such as acute disseminated encephalomyelitis (ADEM). We therefore compared the 4 current sets of MRI criteria in our Dutch pediatric cohort and determined which are the most useful in clinical practice for distinguishing ADEM from MS. Methods: We included 49 children who had had a demyelinating event and an MRI scan within 2 months of their first clinical attack. Twenty-one patients had ADEM and remained relapse-free after at least 2 years of follow-up. Twenty-eight patients had a definitive diagnosis of MS. We assessed the sensitivity and specificity of the following MRI criteria: Barkhof criteria, KIDMUS criteria, Callen MS-ADEM criteria, and Callen diagnostic MS criteria. Results: The Callen MS-ADEM criteria had the best combination of sensitivity (75%) and specificity (95%). The KIDMUS criteria had higher specificity (100%), but much lower sensitivity (11%). The Barkhof criteria had a sensitivity of 61% and a specificity of 91%. The Callen diagnostic MS criteria were the most sensitive (82%), but were only 52% specific for distinguishing a first attack of MS from ADEM. Conclusions: The results in our cohort demonstrate that the new Callen criteria for multiple sclerosis-acute disseminated encephalomyelitis (MS-ADEM) are the most useful for differentiating a first attack of MS from monophasic ADEM. Although the Callen diagnostic MS criteria are more sensitive, they lack the specificity necessary to differentiate MS from ADEM. Copyright © 2010 by AAN Enterprises, Inc.


Loeb S.,New York University | Bruinsma S.M.,Erasmus Medical Center | Nicholson J.,New York University | Briganti A.,Urological Research Institute | And 6 more authors.
European Urology | Year: 2015

Context Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of progression while on AS are debated. Objective To review primary data on markers, genetic factors, and risk stratification for patient selection and predictors of progression during AS. Evidence acquisition Electronic searches were conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 2014 for original articles on biomarkers and risk stratification for AS. Evidence synthesis Patient factors associated with AS outcomes in some studies include age, race, and family history. Multiple studies provide consistent evidence that a lower percentage of free prostate-specific antigen (PSA), a higher Prostate Health Index (PHI), a higher PSA density (PSAD), and greater biopsy core involvement at baseline predict a greater risk of progression. During follow-up, serial measurements of PHI and PSAD, as well as repeat biopsy results, predict later biopsy progression. While some studies have suggested a univariate relationship between urinary prostate cancer antigen 3 (PCA3) and transmembrane protease, serine 2-v-ets avian erythroblastosis virus E26 oncogene homolog gene fusion (TMPRSS2:ERG) with adverse biopsy features, these markers have not been consistently shown to independently predict AS outcomes. No conclusive data support the use of genetic tests in AS. Limitations of these studies include heterogeneous definitions of progression and limited follow-up. Conclusions There is a growing body of literature on patient characteristics, biopsy features, and biomarkers with potential utility in AS. More data are needed on practical applications such as combining these tests into multivariable clinical algorithms and long-term outcomes to further improve AS in the future. Patient summary Several PSA-based tests (free PSA, PHI, PSAD) and the extent of cancer on biopsy can help to stratify the risk of progression during active surveillance. Investigation of several other markers is under way. © 2014 European Association of Urology. All rights reserved.


Janssen S.F.,Royal Netherlands Academy of Arts and science KNAW | Gorgels T.G.M.F.,Royal Netherlands Academy of Arts and science KNAW | Ramdas W.D.,Erasmus Medical Center | Klaver C.C.W.,Erasmus Medical Center | And 3 more authors.
Progress in Retinal and Eye Research | Year: 2013

Primary open angle glaucoma (POAG) is a complex progressive optic nerve neuropathy triggered by both environmental and genetic risk factors. Several ocular tissues, including the ciliary body, trabecular meshwork and optic nerve head, and perhaps even brain tissues, are involved in a chain of pathological events leading to POAG.Genetic risk evidence for POAG came from family linkage-studies implicating a small number of disease genes (MYOC, OPTN, WDR36). Recent Genome Wide Association Studies (GWAS) identified a large number of new POAG loci and disease genes, such as CAV1, CDKN2B and GAS7. In the current study, we reviewed over 120 family and GWA studies. We selected in total 65 (candidate) POAG disease genes and proceeded to assess their function, mRNA expression in POAG relevant eye tissues and possible changes in disease state. We found that the proteins corresponding to these 65 (candidate) POAG disease genes take part in as few as four common functional molecular networks. Functions attributed to these 4 networks were developmental (dys)function, lipid metabolism, and inflammatory processes. For the 65 POAG disease genes, we reviewed the available (transgenic) mouse models of POAG, which may be useful for future functional studies. Finally, we showed that the 65 (candidate) POAG genes substantially increased the specificity and sensitivity of a discriminative POAG risk test. This suggests that personal risk assessment and personalized medicine for POAG are on the horizon. Taken together, the data presented are essential to comprehend the role of genetic variation in POAG, and may provide leads to understand the pathophysiology of POAG as well as other neurodegenerative disorders, such as Alzheimer's disease. © 2013 Elsevier Ltd.


Klop B.,Center for Diabetes and Vascular Medicine | Hazes J.M.W.,Erasmus Medical Center | Cabezas M.C.,Center for Diabetes and Vascular Medicine
Atherosclerosis | Year: 2013

Patients with rheumatoid arthritis (RA) carry an excess risk for cardiovascular disease, which is comparable to the risk in patients with type 2 diabetes mellitus. The mechanisms involved are partly related to traditional cardiovascular risk factors, disease-associated inflammation and undertreatment of traditional cardiovascular disease (CVD) risk factors. Since atherosclerosis is an inflammatory disease, the auto-immune mediated inflammation observed in RA patients contributes to increased endothelial dysfunction, oxidative stress and activation and vascular migration of leukocytes. This concept is underscored by the CVD risk reduction that is seen by anti-inflammatory disease modifying anti-rheumatic drugs such as methotrexate and TNFα inhibitors. The evidence for underdiagnosis and undertreatment of traditional CVD risk factors in RA strengthens the potential benefit of structured CVD risk management in these patients. Current cardiovascular guidelines recommend screening and treatment of CVD risk factors in RA patients, without well defined treatment targets. At present, there is a lack of scientific evidence to establish treatment targets for CVD risk factors in RA. Therefore, expanding research regarding screening and treatment of traditional CVD risk factors in RA patients is needed. © 2013 Elsevier Ireland Ltd.


Roy A.,University of Groningen | Oldehinkel A.J.,University of Groningen | Verhulst F.C.,Erasmus Medical Center | Ormel J.,University of Groningen | Hartman C.A.,University of Groningen
Journal of Clinical Psychiatry | Year: 2014

Objective: The progression to depression in children with attention-deficit/hyperactivity disorder (ADHD) is not clearly understood. To clarify this relationship, we tested the following hypotheses in a population-based study: (1) children with ADHD have a higher risk of developing depression than children without ADHD; (2) the pathway from ADHD to depression is mediated (partly) through anxiety and disruptive behavior disorders; and (3) mediation through anxiety is more prevalent in girls, and mediation through disruptive behavior disorders is more prevalent in boys. Method: From October 2008 to September 2010, the Composite International Diagnostic Interview was used to assess ADHD, major depressive episodes, anxiety disorders, and disruptive behavior disorders in 1,584 participants from the TRacking Adolescents' Individual Lives Survey (TRAILS) cohort. Cox regression was used to model the effects of ADHD, anxiety, and disruptive behaviors on depression. Risk of and pathways to depression were studied in both children with ADHD and children with subthreshold ADHD. Results: Comorbid depression was present in 36% of children with a diagnosis of ADHD, 24% of children with subthreshold ADHD, and 14% of children with no ADHD. Anxiety and disruptive behaviors mediated 32% of depression in ADHD. Pathways through anxiety and disruptive behavior disorders were independent of gender. Disruptive behavior disorder was a stronger mediator than anxiety for both genders (all P < .01). Conclusions: These findings may help forewarn of impending depression and therefore allow opportunities for interventions when comorbid anxiety and/or disruptive behavior disorders are present in a child with ADHD. © Copyright 2014 Physicians Postgraduate Press, Inc.


Akoudad S.,Erasmus Medical Center | Portegies M.L.P.,Erasmus Medical Center | Koudstaal P.J.,Erasmus Medical Center | Ikram M.A.,Erasmus Medical Center
Circulation | Year: 2015

Background-Cerebral microbleeds are highly prevalent in people with clinically manifest cerebrovascular disease and have been shown to increase the risk of stroke recurrence. Microbleeds are also frequently found in healthy elderly, a population in which the clinical implication of microbleeds is unknown. Methods and Results-In the population-based Rotterdam Study, the presence, number, and location of microbleeds were assessed at baseline on brain MRI of 4759 participants aged ≥45 years. Participants were followed for incident stroke throughout the study period (2005-2013). We used Cox proportional hazards to investigate if people with microbleeds were at increased risk of stroke in comparison with those without microbleeds, adjusting for demographic, genetic, and cardiovascular risk, and cerebrovascular imaging markers. Microbleed prevalence was 18.7% (median count 1 [1-111]). During mean follow-up of 4.9 years (standard deviation, 1.6) 93 strokes occurred (72 ischemic, 11 hemorrhagic, and 10 unspecified). Microbleed presence was associated with an increased risk of all strokes (hazard ratio, 1.93; 95% confidence interval, 1.25-2.99). The risk increased with greater microbleed count. In comparison with those without microbleeds, participants with microbleeds in locations suggestive of cerebral amyloid angiopathy (lobar with or without cerebellar microbleeds) were at increased risk of intracerebral hemorrhage (hazard ratio, 5.27; 95% confidence interval, 1.38-20.23). Microbleeds at other locations were associated with an increased risk of both ischemic stroke and intracerebral hemorrhage. Conclusions-Microbleeds on MRI are associated with an increased risk of stroke in the general population. Our results strengthen the notion that microbleeds mark progression of cerebrovascular pathology and represent a precursor of stroke. © 2015 American Heart Association, Inc.


Van Spaendonck-Zwarts K.Y.,University of Groningen | Van Tintelen J.P.,University of Groningen | Van Veldhuisen D.J.,University of Groningen | Van Der Werf R.,University of Groningen | And 4 more authors.
Circulation | Year: 2010

BACKGROUND-: Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that some cases of PPCM are part of the spectrum of familial DCM, presenting in the peripartum period. METHODS AND RESULTS-: We reviewed our database of 90 DCM families, focusing specifically on the presence of PPCM patients. Then, in a reverse approach, we reviewed 10 PPCM patients seen in our clinic since the early 1990s and performed cardiological screening of the first-degree relatives of 3 PPCM patients who did not show a full recovery. Finally, we analyzed the genes known to be most commonly involved in DCM in the PPCM patients. We identified a substantial number (5 of 90, 6%) of DCM families with PPCM patients. Second, cardiological screening of first-degree relatives of 3 PPCM patients who did not show full recovery revealed undiagnosed DCM in all 3 families. Finally, genetic analyses revealed a mutation (c.149A>G, p.Gln50Arg) in the gene encoding cardiac troponin C (TNNC1) segregating with disease in a DCM family with a member with PPCM, supporting the genetic nature of disease in this case. CONCLUSIONS-: Our findings strongly suggest that a subset of PPCM is an initial manifestation of familial DCM. This may have important implications for cardiological screening in such families. © 2010 American Heart Association, Inc.


van der Pas M.H.G.M.,VU University Amsterdam | Haglind E.,Sahlgrenska Universitetssjukhuset | Cuesta M.A.,VU University Amsterdam | Furst A.,Caritas Krankenhaus St Josef | And 3 more authors.
The Lancet Oncology | Year: 2013

Background: Laparoscopic surgery as an alternative to open surgery in patients with rectal cancer has not yet been shown to be oncologically safe. The aim in the COlorectal cancer Laparoscopic or Open Resection (COLOR II) trial was to compare laparoscopic and open surgery in patients with rectal cancer. Methods: A non-inferiority phase 3 trial was undertaken at 30 centres and hospitals in eight countries. Patients (aged ≥18 years) with rectal cancer within 15 cm from the anal verge without evidence of distant metastases were randomly assigned to either laparoscopic or open surgery in a 2:1 ratio, stratified by centre, location of tumour, and preoperative radiotherapy. The study was not masked. Secondary (short-term) outcomes-including operative findings, complications, mortality, and results at pathological examination-are reported here. Analysis was by modified intention to treat, excluding those patients with post-randomisation exclusion criteria and for whom data were not available. This study is registered with ClinicalTrials.gov, number NCT00297791. Findings: The study was undertaken between Jan 20, 2004, and May 4, 2010. 1103 patients were randomly assigned to the laparoscopic (n=739) and open surgery groups (n=364), and 1044 were eligible for analyses (699 and 345, respectively). Patients in the laparoscopic surgery group lost less blood than did those in the open surgery group (median 200 mL [IQR 100-400] vs 400 mL [200-700], p<0·0001); however, laparoscopic procedures took longer (240 min [184-300] vs 188 min [150-240]; p<0·0001). In the laparoscopic surgery group, bowel function returned sooner (2·0 days [1·0-3·0] vs 3·0 days [2·0-4·0]; p<0·0001) and hospital stay was shorter (8·0 days [6·0-13·0] vs 9·0 days [7·0-14·0]; p=0·036). Macroscopically, completeness of the resection was not different between groups (589 [88%] of 666 vs 303 [92%] of 331; p=0·250). Positive circumferential resection margin (<2 mm) was noted in 56 (10%) of 588 patients in the laparoscopic surgery group and 30 (10%) of 300 in the open surgery group (p=0·850). Median tumour distance to distal resection margin did not differ significantly between the groups (3·0 cm [IQR 2·0-4·8] vs 3·0 cm [1·8-5·0], respectively; p=0·676). In the laparoscopic and open surgery groups, morbidity (278 [40%] of 697 vs 128 [37%] of 345, respectively; p=0·424) and mortality (eight [1%] of 699 vs six [2%] of 345, respectively; p=0·409) within 28 days after surgery were similar. Interpretation: In selected patients with rectal cancer treated by skilled surgeons, laparoscopic surgery resulted in similar safety, resection margins, and completeness of resection to that of open surgery, and recovery was improved after laparoscopic surgery. Results for the primary endpoint-locoregional recurrence-are expected by the end of 2013. Funding: Ethicon Endo-Surgery Europe, Swedish Cancer Foundation, West Gothia Region, Sahlgrenska University Hospital. © 2013 Elsevier Ltd.


Van Doorn P.A.,Erasmus Medical Center | Brusse E.,Erasmus Medical Center
Neurology | Year: 2012

Objective: Achieving long-term remission after a limited more intense treatment period would prevent prolonged use of corticosteroids or IV immunoglobulin (IVIg) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In this prospective cohort study we present long-term follow-up data on patients included in a multicenter randomized controlled trial comparing 6 monthly pulses of dexamethasone with 8 months of daily prednisolone. Methods: Treatment effect was assessed with the Inflammatory Neuropathy Cause and Treatment disability scale and the Rivermead Mobility Index and was categorized using the CIDP Disease Activity Status (CDAS) scale. Results: By March 2011, 39 out of 40 patients were included with a median follow-up of 4.5 years. Cure (>5 years off treatment) or remission according to the CDAS criteria after 1 or 2 courses of pulsed dexamethasone or daily prednisolone was achieved in 10 out of 39 patients (26%). Half of the patients who were in remission after initial treatment experienced a relapse (median treatment-free interval: 17.5 months for dexamethasone, 11 months for prednisolone). Alternative diagnosis was made in 7 out of 12 (58%) who did not respond to any therapy and in none of the treatment-responsive patients. Conclusions: Cure or long-term remission can be achieved in about one-quarter of patients with CIDP after 1 or 2 courses of pulsed dexamethasone or 8-month daily prednisolone. In treatmentnonresponsive patients, the diagnosis CIDP should be reconsidered. Classification of Evidence: This study provides Class IV evidence that pulsed dexamethasone or 8-month daily prednisolone can lead to long-term remission in CIDP. Copyright © 2012 by AAN Enterprises, Inc.


Heppe D.H.M.,Erasmus Medical Center | Medina-Gomez C.,Erasmus Medical Center | Rivadeneira F.,Erasmus Medical Center | Jaddoe V.W.V.,Erasmus Medical Center
American Journal of Clinical Nutrition | Year: 2013

Background: Maternal diet during pregnancy has been suggested to influence bone health in later life. Objective: We assessed the association of maternal first-trimester dietary intake during pregnancy with childhood bone mass. Design: In a prospective cohort study in 2819 mothers and their children, we measured first-trimester daily energy, protein, fat, carbohydrate, calcium, phosphorus, and magnesium intakes by using a food-frequency questionnaire and homocysteine, folate, and vitamin B-12 concentrations in venous blood. We measured childhood total body bone mass by using dual-energy X-ray absorptiometry at the median age of 6.0 y. Results: Higher first-trimester maternal protein, calcium, and phosphorus intakes and vitamin B-12 concentrations were associated with higher childhood bone mass, whereas carbohydrate intake and homocysteine concentrations were associated with lower childhood bone mass (all P-trend < 0.01). Maternal fat, magnesium intake, and folate concentrations were not associated with childhood bone mass. In the fully adjusted regression model that included all dietary factors significantly associated with childhood bone mass, maternal phosphorus intake and homocysteine concentrations moststrongly predicted childhood bone mineral content (BMC) [β = 2.8 (95% CI: 1.1, 4.5) and β = 21.8 (95% CI: 23.6, 0.1) g per SD increase, respectively], whereas maternal protein intake and vitamin B-12 concentrations most strongly predicted BMC adjusted for bone area [β = 2.1 (95% CI: 0.7, 3.5) and β = 1.8 (95% CI: 0.4, 3.2) g per SD increase, respectively]. Conclusion: Maternal first-trimester dietary factors are associated with childhood bone mass, suggesting that fetal nutritional exposures may permanently influence bone development. Copyright © 2013 American Society for Nutrition.


Juni R.P.,Maastricht University | Duckers H.J.,Erasmus Medical Center | Virmani R.,CVPath Institute Inc. | Moens A.L.,Maastricht University
Journal of the American College of Cardiology | Year: 2013

Oxidative stress greatly influences the pathogenesis of various cardiovascular disorders. Coronary interventions, including balloon angioplasty and coronary stent implantation, are associated with increased vascular levels of reactive oxygen species in conjunction with altered endothelial cell and smooth muscle cell function. These alterations potentially lead to restenosis, thrombosis, or endothelial dysfunction in the treated artery. Therefore, the understanding of the pathophysiological role of reactive oxygen species (ROS) generated during or after coronary interventions, or both, is essential to improve the success rate of these procedures. Superoxide O2 ·- anions, whether derived from uncoupled endothelial nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, xanthine oxidase, or mitochondria, are among the most harmful ROS. O2 ·- can scavenge nitric oxide, modify proteins and nucleotides, and induce proinflammatory signaling, which may lead to greater ROS production. Current innovations in stent technologies, including biodegradable stents, nitric oxide donor-coated stents, and a new generation of drug-eluting stents, therefore address persistent oxidative stress and reduced nitric oxide bioavailability after percutaneous coronary interventions. This review discusses the molecular mechanisms of ROS generation after coronary interventions, the related pathological events - including restenosis, endothelial dysfunction, and stent thrombosis - and possible therapeutic ways forward. © 2013 American College of Cardiology Foundation.


Hilgenkamp T.I.M.,Erasmus Medical Center | Van Wijck R.,University of Groningen | Evenhuis H.M.,Erasmus Medical Center
Journal of Intellectual and Developmental Disability | Year: 2012

Background: Physical fitness is relevant for wellbeing and health, but knowledge on the feasibility and reliability of instruments to measure physical fitness for older adults with intellectual disability is lacking. Methods: Feasibility and testretest reliability of a physical fitness test battery (Box and Block Test, Response Time Test, walking speed, grip strength, 30-s chair stand, 10-m Incremental Shuttle Walking Test and the Extended Modified Back-Saver Sit-and-Reach Test) were investigated in older adults with ID in a convenience sample of 36 older adults (mean 65.9, range 5089 years), with differing levels of intellectual disability and mobility. Results and conclusion: All tests to measure physical fitness in older adults with ID had moderate to excellent feasibility and had sufficient testretest reliability (ICCs .63.96). No statistically significant learning effects were found. © 2012 Australasian Society for the Study of Intellectual Disability, Inc.


van Leeuwen R.W.F.,Erasmus Medical Center | van Gelder T.,Erasmus Medical Center | Mathijssen R.H.J.,Erasmus Medical Center | Jansman F.G.A.,Deventer Hospital | Jansman F.G.A.,University of Groningen
The Lancet Oncology | Year: 2014

In the past decade, many tyrosine-kinase inhibitors have been introduced in oncology and haemato-oncology. Because this new class of drugs is extensively used, serious drug-drug interactions are an increasing risk. In this Review, we give a comprehensive overview of known or suspected drug-drug interactions between tyrosine-kinase inhibitors and other drugs. We discuss all haemato-oncological and oncological tyrosine-kinase inhibitors that had been approved by Aug 1, 2013, by the US Food and Drug Administration or the European Medicines Agency. Various clinically relevant drug interactions with tyrosine-kinase inhibitors have been identified. Most interactions concern altered bioavailability due to altered stomach pH, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval. To guarantee the safe use of tyrosine-kinase inhibitors, a drugs review for each patient is needed. This Review provides specific recommendations to guide haemato-oncologists, oncologists, and clinical pharmacists, through the process of managing drug-drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice. © 2014 Elsevier Ltd.


Sijmons R.H.,University of Groningen | Hofstra R.M.W.,Erasmus Medical Center
DNA Repair | Year: 2016

Inherited mutations of the DNA Mismatch repair genes MLH1, MSH2, MSH6 and PMS2 can result in two hereditary tumor syndromes: the adult-onset autosomal dominant Lynch syndrome, previously referred to as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and the childhood-onset autosomal recessive Constitutional Mismatch Repair Deficiency syndrome. Both conditions are important to recognize clinically as their identification has direct consequences for clinical management and allows targeted preventive actions in mutation carriers. Lynch syndrome is one of the more common adult-onset hereditary tumor syndromes, with thousands of patients reported to date. Its tumor spectrum is well established and includes colorectal cancer, endometrial cancer and a range of other cancer types. However, surveillance for cancers other than colorectal cancer is still of uncertain value. Prophylactic surgery, especially for the uterus and its adnexa is an option in female mutation carriers. Chemoprevention of colorectal cancer with aspirin is actively being investigated in this syndrome and shows promising results. In contrast, the Constitutional Mismatch Repair Deficiency syndrome is rare, features a wide spectrum of childhood onset cancers, many of which are brain tumors with high mortality rates. Future studies are very much needed to improve the care for patients with this severe disorder. © 2016.


Polinder S.,Erasmus Medical Center | Haagsma J.A.,Erasmus Medical Center | Toet H.,Consumer Safety Institute | Van Beeck E.F.,Erasmus Medical Center
British Journal of Surgery | Year: 2012

Background: The impact of trauma on population health is underestimated because comprehensive overviews of the entire severity spectrum of injuries are scarce. The aim of this study was to measure the total health impact of fatal and non-fatal unintentional injury in the Netherlands. Methods: Epidemiological data for the four levels of the injury pyramid (general practitioner (GP) registry, emergency department (ED) registers, hospital discharge and mortality data) were obtained for the whole country. For all levels, the incidence and years of life lost (YLL) owing to premature death, years lived with disability (YLD) and disability-adjusted life-years (DALYs) were calculated. Results: Unintentional injury resulted in 67 547 YLL and 161 775 YLD respectively, amounting to 229 322 DALYs (14·1 per 1000 inhabitants). Home and leisure, and traffic injuries caused most DALYs. Minor injury (GP and ED treatment) contributed 37·3 per cent (85 504 DALYs; 5·2 per 1000) to the total burden of injury, whereas injuries requiring hospital admission contributed 33·3 per cent (76 271 DALYs; 4·7 per 1000) and fatalities contributed 29·5 per cent (67 547 DALYs; 4·1 per 1000). Men aged 15-65 years had the greatest burden of injury, resulting in a share of 39·6 per cent for total DALYs owing to unintentional injury. The highest individual burden resulted from death (19 DALYs per patient). Conclusion: Trauma causes a major burden to society. For priority setting in public health and the identification of opportunities for prevention it is important that burden-of-injury estimates cover the entire spectrum of injuries, ranging from minor injury to death. Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.


Marcus M.W.,University of Groningen | De Vries M.M.,University of Groningen | Junoy Montolio F.G.,University of Groningen | Jansonius N.M.,University of Groningen | Jansonius N.M.,Erasmus Medical Center
Ophthalmology | Year: 2011

Objective: To determine the association between myopia and open-angle glaucoma. Design: Systematic review and meta-analysis of observational studies. Participants: Thirteen studies involving 48 161 individuals. Methods: Articles published between 1994 and 2010 were identified in PubMed, Embase, and reference lists. Study-specific odds ratios (ORs) were pooled using a random effects model. Main Outcome Measures: Odds ratios with 95% confidence intervals (CIs) of myopia as a risk factor for open-angle glaucoma. Results: Data from 11 population-based cross-sectional studies were included in the main analyses. The pooled OR of the association between myopia and glaucoma based on 11 risk estimates was 1.92 (95% CI, 1.542.38). On the basis of 7 risk estimates, the pooled ORs of the associations between low myopia (myopia up to -3 D) and glaucoma and between high myopia (≤-3 D myopic) and glaucoma were 1.65 (1.262.17) and 2.46 (1.933.15), respectively. There was considerable heterogeneity among studies that reported an association between any myopia and glaucoma (I2=53%) and low myopia and glaucoma (I2=29%), but not for high myopia and glaucoma (I2=0%). After omitting studies that contributed significantly to the heterogeneity, the pooled ORs were 1.88 (1.602.20) for any myopia and glaucoma and 1.77 (1.412.23) for low myopia and glaucoma. Conclusions: Individuals with myopia have an increased risk of developing open-angle glaucoma. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. © 2011 American Academy of Ophthalmology.


Struik F.M.,University of Groningen | Sprooten R.T.M.,Maastricht University | Kerstjens H.A.M.,University of Groningen | Bladder G.,University of Groningen | And 5 more authors.
Thorax | Year: 2014

Introduction The effectiveness of non-invasive positive pressure ventilation (NIV) in COPD patients with prolonged hypercapnia after ventilatory support for acute respiratory failure (ARF) remains unclear. We investigated if nocturnal NIV in these patients prolongs the time to readmission for respiratory causes or death ( primary endpoint) in the following 12 months. Methods 201 COPD patients admitted to hospital with ARF and prolonged hypercapnia >48 h after termination of ventilatory support were randomised to NIV or standard treatment. Secondary outcomes were daytime arterial blood gasses, transcutaneous PCO2 during the night, lung function, health-related quality-of-life (HRQL), mood state, daily activities and dyspnoea. Results 1 year after discharge, 65% versus 64% of patients (NIV vs standard treatment) were readmitted to hospital for respiratory causes or had died; time to event was not different ( p=0.85). Daytime PaCO2 was significantly improved in NIV versus standard treatment (PaCO2 0.5 kPa (95% CI 0.04 to 0.90, p=0.03)) as was transcutaneous PCO2 during the night. HRQL showed a trend (p=0.054, Severe Respiratory Insufficiency questionnaire) in favour of NIV. Number of exacerbations, lung function, mood state, daily activity levels or dyspnoea was not significantly different. Discussions We could not demonstrate an improvement in time to readmission or death by adding NIV for 1 year in patients with prolonged hypercapnia after an episode of NIV for ARF. There is no reason to believe the NIV was not effective since daytime PaCO2 and night-time PCO2 improved. The trend for improvement in HRQL favouring NIV we believe nevertheless should be explored further.


Spanier B.W.M.,Rijnstate Hospital | Bruno M.J.,Erasmus Medical Center | Dijkgraaf M.G.W.,Clinical Research Unit
World Journal of Gastroenterology | Year: 2013

AIM: To analyze trends in incidence and mortality of acute pancreatitis (AP) and chronic pancreatitis (CP) in the Netherlands and for international standard populations. METHODS: A nationwide cohort is identified through record linkage of hospital data for AP and CP, accumulated from three nationwide Dutch registries: the hospital discharge register, the population register, and the death certificate register. Sex- and age-group specific incidence rates of AP and CP are defined for the period 2000-2005 and mortality rates of AP and CP for the period 1995-2005. Additionally, incidence and mortality rates over time are reported for Dutch and international (European and World Health Organization) standard populations. RESULTS: Incidence of AP per 100000 persons per year increased between 2000 and 2005 from 13.2 (95%CI: 12.6-13.8) to 14.7 (95%CI: 14.1-15.3). Incidence of AP for males increased from 13.8 (95%CI: 12.9-14.7) to 15.2 (95%CI: 14.3-16.1), for females from 12.7 (95%CI: 11.9-13.5) to 14.2 (95%CI: 13.4-15.1). Irregular patterns over time emerged for CP. Overall mean incidence per 100000 persons per year was 1.77, for males 2.16, and for females 1.4. Mortality for AP fluctuated during 1995-2005 between 6.9 and 11.7 per million persons per year and was almost similar for males and females. Concerning CP, mortality for males fluctuated between 1.1 (95%CI: 0.6-2.3) and 4.0 (95%CI: 2.8-5.8), for females between 0.7 (95%CI: 0.3-1.6) and 2.0 (95%CI: 1.2-3.2). Incidence and mortality of AP and CP increased markedly with age. Standardized rates were lowest for World Health Organization standard population. CONCLUSION: Incidence of AP steadily increased while incidence of CP fluctuated. Mortality for both AP and CP remained fairly stable. Patient burden and health care costs probably will increase because of an ageing Dutch population. © 2013 Baishideng. All rights reserved.


Van Lier M.G.F.,Erasmus Medical Center | Wagner A.,Rotterdam University | Van Leerdam M.E.,Erasmus Medical Center | Kuipers E.J.,Erasmus Medical Center
American Journal of Gastroenterology | Year: 2011

Objectives: Peutz-Jeghers syndrome (PJS) is characterized by gastrointestinal hamartomas. The hamartomas are located predominantly in the small intestine and may cause intussusceptions. We aimed to assess the characteristics, risk, and onset of intussusception in a large cohort of PJS patients to determine whether enteroscopy with polypectomy should be incorporated into surveillance recommendations. Methods: All PJS patients from two academic hospitals were included in this cohort study (prospective follow-up between 1995 and July 2009). We obtained clinical data by interview and chart review. Deceased family members with PJS were included retrospectively. Cumulative intussusception risks were calculated by Kaplan-Meier analysis. Results: We included 110 PJS patients (46% males) from 50 families. In all, 76 patients (69%) experienced at least one intussusception (range 1-6), at a median age of 16 (3-50) years at first occurrence. The intussusception risk was 50% at the age of 20 years (95% confidence interval 17-23 years) and the risk was independent of sex, family history, and mutation status. The intussusceptions occurred in the small intestine in 95% of events, and 80% of all intussusceptions (n128) presented as an acute abdomen. Therapy was surgical in 92.5% of events. Based on 37 histology reports, the intussusceptions were caused by polyps with a median size of 35 mm (range 15-60 mm). Conclusions: PJS patients carry a high cumulative intussusception risk at young age. Intussusceptions are generally caused by polyps 15 mm and treatment is mostly surgical. These results support the approach of enteroscopic surveillance, with removal of small-intestinal polyps 10-15 mm to prevent intussusceptions. The effect of such an approach on the incidence of intussusception remains to be established in prospective trials. © 2011 by the American College of Gastroenterology.


Dabiri Abkenari L.,Erasmus Medical Center | Boersma L.V.A.,St Antonius Hospital | Maass A.H.,University of Groningen | Van Oostrom A.J.H.H.M.,St Antonius Hospital | And 2 more authors.
Journal of the American College of Cardiology | Year: 2012

Objectives: The purpose of the study was to evaluate the efficacy and safety of the entirely subcutaneous implantable cardioverter-defibrillator (S-ICD). Background: A new entirely S-ICD has been introduced, that does not require lead placement in or on the heart. The authors report the largest multicenter experience to date with the S-ICD with a minimum of 1-year follow-up in the first 118 Dutch patients who were implanted with this device. Methods: Patients were selected if they had a class I or IIa indication for primary or secondary prevention of sudden cardiac death. All consecutive patients from 4 high-volume centers in the Netherlands with an S-ICD implanted between December 2008 and April 2011 were included. Results: A total of 118 patients (75% males, mean age 50 years) received the S-ICD. After 18 months of follow-up, 8 patients experienced 45 successful appropriate shocks (98% first shock conversion efficacy). No sudden deaths occurred. Fifteen patients (13%) received inappropriate shocks, mainly due to T-wave oversensing, which was mostly solved by a software upgrade and changing the sensing vector of the S-ICD. Sixteen patients (14%) experienced complications. Adverse events were more frequent in the first 15 implantations per center compared with subsequent implantations (inappropriate shocks 19% vs. 6.7%, p = 0.03; complications 17% vs. 10%, p = 0.10). Conclusions: This study demonstrates that the S-ICD is effective in terminating ventricular arrhythmias. There is, however, a considerable percentage of ICD related adverse events, which decreases as the therapy evolves and experience increases. © 2012 American College of Cardiology Foundation.


Oldehinkel A.J.,University of Groningen | Ormel J.,University of Groningen | Verhulst F.C.,Erasmus Medical Center | Nederhof E.,University of Groningen
Development and Psychopathology | Year: 2014

Childhood adversities have been proposed to modify later stress sensitivity and risk of depressive disorder in several ways: by stress sensitization, stress amplification, and stress inoculation. Combining these models, we hypothesized that childhood adversities would increase risk of early, but not later, onsets of depression (Hypothesis 1). In those without an early onset, childhood adversities were hypothesized to predict a relatively low risk of depression in high-stress conditions (Hypothesis 2a) and a relatively high risk of depression in low-stress conditions (Hypothesis 2b), compared to no childhood adversities. These hypotheses were tested in 1,584 participants of the Tracking Adolescents' Individual Lives Survey, a prospective cohort study of adolescents. Childhood adversities were assessed retrospectively at ages 11 and 13.5, using self-reports and parent reports. Lifetime DSM-IV major depressive episodes were assessed at age 19, by means of the Composite International Diagnostic Interview. Stressful life events during adolescence were established using interview-based contextual ratings of personal and network events. The results provided support for all hypotheses, regardless of the informant and timeframe used to assess childhood adversities and regardless of the nature (personal vs. network, dependent vs. independent) of recent stressful events. These findings suggest that age at first onset of depression may be an effective marker to distinguish between various types of reaction patterns. Copyright © Cambridge University Press 2014.


Schreuders E.H.,Erasmus Medical Center | Ruco A.,Sunnybrook Research Institute | Rabeneck L.,Institute for Clinical Evaluative science | Rabeneck L.,University of Toronto | And 4 more authors.
Gut | Year: 2015

Colorectal cancer (CRC) ranks third among the most commonly diagnosed cancers worldwide, with wide geographical variation in incidence and mortality across the world. Despite proof that screening can decrease CRC incidence and mortality, CRC screening is only offered to a small proportion of the target population worldwide. Throughout the world there are widespread differences in CRC screening implementation status and strategy. Differences can be attributed to geographical variation in CRC incidence, economic resources, healthcare structure and infrastructure to support screening such as the ability to identify the target population at risk and cancer registry availability. This review highlights issues to consider when implementing a CRC screening programme and gives a worldwide overview of CRC burden and the current status of screening programmes, with focus on international differences.


Cheng J.M.,Erasmus Medical Center | Akkerhuis K.M.,Erasmus Medical Center | Battes L.C.,Erasmus Medical Center | Van Vark L.C.,Erasmus Medical Center | And 4 more authors.
European Journal of Heart Failure | Year: 2013

Aims Heart failure with normal ejection fraction (HFNEF) is a major and growing public health problem, currently representing half of the heart failure burden. Although many studies have investigated the diagnostic and prognostic value of new biomarkers in heart failure, limited data are available on biomarkers other than natriuretic peptides inHFNEF.We performed a systematic review of epidemiological studies on the associations of biomarkers with the occurrence of HFNEF and with the prognosis of HFNEF patients. Methods and results Biomarkers examined most extensively in HFNEF include biomarkers of myocyte stress, inflammation, and extracellular matrix remodelling. Some biomarkers have been shown to be increased to a different extent in HFNEF compared with heart failure with reduced ejection fraction (HFREF). Several biomarkers, including biomarkers of myocyte stress, inflammation, extracellular matrix remodelling, growth differentiation factor 15 (GDF-15), cystatin C, resistin, and galectin-3, were associated with development of HFNEF and with clinical outcomes of HFNEF patients in terms of morbidity and mortality. Conclusion Several biomarkers, including biomarkers of myocyte stress, inflammation, extracellular matrix remodelling, GDF-15, cystatin C, resistin, and galectin-3, appeared to be promising diagnostic and prognostic tools in patients with HFNEF. Investigation of the incremental diagnostic and prognostic value of these biomarkers, or a combination thereof, over established clinical covariates and imaging techniques in large, prospective studies is warranted. © The Author 2013.


Luppino F.S.,Leiden University | De Wit L.M.,VU University Amsterdam | Bouvy P.F.,Erasmus Medical Center | Stijnen T.,Leiden University | And 5 more authors.
Archives of General Psychiatry | Year: 2010

Context: Association between obesity and depression has repeatedly been established. For treatment and prevention purposes, it is important to acquire more insight into their longitudinal interaction. Objective: To conduct a systematic review and meta-analysis on the longitudinal relationship between depression, overweight, and obesity and to identify possible influencing factors. Data Sources: Studies were found using PubMed, PsycINFO, and EMBASE databases and selected on several criteria. Study Selection: Studies examining the longitudinal bidirectional relation between depression and overweight (body mass index 25-29.99) or obesity (body mass index ≥30) were selected. Data Extraction: Unadjusted and adjusted odds ratios (ORs) were extracted or provided by the authors. Data Synthesis: Overall, unadjusted ORs were calculated and subgroup analyses were performed for the 15 included studies (N=58 745) to estimate the effect of possible moderators (sex, age, depression severity). Obesity at baseline increased the risk of onset of depression at follow-up (unadjusted OR, 1.55; 95% confidence interval [CI], 1.22-1.98; P<.001). This association was more pronounced among Americans than among Europeans (P=.05) and for depressive disorder than for depressive symptoms (P=.05). Overweight increased the risk of onset of depression at follow-up (unadjusted OR, 1.27; 95% CI, 1.07-1.51; P<.01). This association was statistically significant among adults (aged 20-59 years and ≥60 years) but not among younger persons (aged<20 years). Baseline depression (symptoms and disorder) was not predictive of overweight over time. However, depression increased the odds for developing obesity (OR, 1.58; 95% CI, 1.33-1.87; P<.001). Subgroup analyses did not reveal specific moderators of the association. Conclusions: This meta-analysis confirms a reciprocal link between depression and obesity. Obesity was found to increase the risk of depression, most pronounced among Americans and for clinically diagnosed depression. In addition, depression was found to be predictive of developing obesity. ©2010 American Medical Association. All rights reserved.


Schultz M.J.,Leica | Groeneveld A.B.J.,Erasmus Medical Center
Critical Care Medicine | Year: 2016

Objective: Passive leg raising creates a reversible increase in venous return allowing for the prediction of fluid responsiveness. However, the amount of venous return may vary in various clinical settings potentially affecting the diagnostic performance of passive leg raising. Therefore we performed a systematic meta-analysis determining the diagnostic performance of passive leg raising in different clinical settings with exploration of patient characteristics, measurement techniques, and outcome variables. Data Sources: PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and citation tracking of relevant articles. Study Selection: Clinical trials were selected when passive leg raising was performed in combination with a fluid challenge as gold standard to define fluid responders and non-responders. Data Extraction: Trials were included if data were reported allowing the extraction of sensitivity, specificity, and area under the receiver operating characteristic curve. Data Synthesis: Twenty-three studies with a total of 1,013 patients and 1,034 fluid challenges were included. The analysis demonstrated a pooled sensitivity of 86% (95% CI, 79-92), pooled specificity of 92% (95% CI, 88-96), and a summary area under the receiver operating characteristic curve of 0.95 (95% CI, 0.92-0.98). Mode of ventilation, type of fluid used, passive leg raising starting position, and measurement technique did not affect the diagnostic performance of passive leg raising. The use of changes in pulse pressure on passive leg raising showed a lower diagnostic performance when compared with passive leg raising-induced changes in flow variables, such as cardiac output or its direct derivatives (sensitivity of 58% [95% CI, 44-70] and specificity of 83% [95% CI, 68-92] vs sensitivity of 85% [95% CI, 78-90] and specificity of 92% [95% CI, 87-94], respectively; p < 0.001). Conclusions: Passive leg raising retains a high diagnostic performance in various clinical settings and patient groups. The predictive value of a change in pulse pressure on passive leg raising is inferior to a passive leg raising-induced change in a flow variable.


Van De Stolpe A.,HIGH-TECH | Pantel K.,Universitatsklinikum Hamburg Eppendorf | Sleijfer S.,Erasmus Medical Center | Terstappen L.W.,University of Twente | Den Toonder J.M.J.,HIGH-TECH
Cancer Research | Year: 2011

From February 7-11, 2011, the multidisciplinary Lorentz Workshop Circulating Tumor Cell (CTC) Isolation and Diagnostics: Toward Routine Clinical Use was held in Leiden (The Netherlands) to discuss progress and define challenges and potential solutions for development of clinically useful circulating tumor cell (CTC) diagnostics. CTCs, captured as "liquid biopsy" from blood, for counting and characterization using pathology and molecular assays, are expected to replace metastatic tissue biopsies to be used to predict drug response and resistance and to monitor therapy response and cancer recurrence. CTCs are highly heterogeneous; therefore, cancer type-specific isolation technologies, as well as complex clinical interpretation software, are required. ©2011 AACR.


Stegers-Jager K.M.,Erasmus Medical Center | Cohen-Schotanus J.,University of Groningen | Themmen A.P.N.,Erasmus Medical Center
Medical Education | Year: 2012

Context Medical schools wish to better understand why some students excel academically and others have difficulty in passing medical courses. Components of self-regulated learning (SRL), such as motivational beliefs and learning strategies, as well as participation in scheduled learning activities, have been found to relate to student performance. Although participation may be a form of SRL, little is known about the relationships among motivational beliefs, learning strategies, participation and medical school performance. Objectives This study aimed to test and cross-validate a hypothesised model of relationships among motivational beliefs (value and self-efficacy), learning strategies (deep learning and resource management), participation (lecture attendance, skills training attendance and completion of optional study assignments) and Year1 performance at medical school. Methods Year1 medical students in the cohorts of 2008 (n=303) and 2009 (n=369) completed a questionnaire on motivational beliefs and learning strategies (sourced from the Motivated Strategies for Learning Questionnaire) and participation. Year1 performance was operationalised as students' average Year1 course examination grades. Structural equation modelling was used to analyse the data. Results Participation and self-efficacy beliefs were positively associated with Year1 performance (β=0.78 and β=0.19, respectively). Deep learning strategies were negatively associated with Year1 performance (β=-0.31), but positively related to resource management strategies (β=0.77), which, in turn, were positively related to participation (β=0.79). Value beliefs were positively related to deep learning strategies only (β=0.71). The overall structural model for the 2008 cohort accounted for 47% of the variance in Year1 grade point average and was cross-validated in the 2009 cohort. Conclusions This study suggests that participation mediates the relationships between motivation and learning strategies, and medical school performance. However, participation and self-efficacy beliefs also made unique contributions towards performance. Encouraging participation and strengthening self-efficacy may help to enhance medical student performance. Discuss ideas arising from this article at '' © Blackwell Publishing Ltd 2012.


Hendriks A.E.J.,Erasmus Medical Center | Drop S.L.S.,Erasmus Medical Center | Laven J.S.E.,Erasmus Medical Center | Boot A.M.,University of Groningen
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: High-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life. Objective: The aim was to study the effect of estrogen dose on fertility outcome of these women. Design/Setting: We conducted a retrospective cohort study of university hospital patients. Patients: We studied 125 tall women aged 20-42 yr, of whom 52 women had been treated with 100 μg and 43 with 200 μg of ethinyl estradiol (EE) in adolescence. Main Outcomes: Time to first pregnancy, treatment for infertility, and live birth rate were measured. Results: The time to first pregnancy was increased in treated women. Of untreated women, 80% conceived within 1 yr vs. 69% of women treated with 100 μg EE and 59% of women treated with 200 μg EE. This trend of increased time to pregnancy with increasing estrogen dose was significant (log rank trend test, P = 0.01). Compared with untreated women, fecundability was reduced in women treated with both 100 μg EE [hazard ratio = 0.42; 95% confidence interval (CI), 0.19-0.95] and 200 μg EE (hazard ratio = 0.30; 95% CI, 0.13-0.72). We also observed a significant trend in the incidence of treatment for infertility with increased estrogen dose (P = 0.04). Fecundity was affected in women treated with 200 μg EE who had reduced odds of achieving at least one live birth (odds ratio = 0.13; 95% CI, 0.02-0.81), but not in women treated with 100 μg EE. Conclusions: We report a dose-response relationship between fertility in later life and estrogen dose used for the treatment of tall stature in adolescent girls; a higher estrogen dose is associated with increased infertility. Copyright © 2012 by The Endocrine Society.


Oosterhof N.,Erasmus Medical Center | Boddeke E.,University of Groningen | van Ham T.J.,Erasmus Medical Center
GLIA | Year: 2015

A major question in research on immune responses in the brain is how the timing and nature of these responses influence physiology, pathogenesis or recovery from pathogenic processes. Proper understanding of the immune regulation of the human brain requires a detailed description of the function and activities of the immune cells in the brain. Zebrafish larvae allow long-term, noninvasive imaging inside the brain at high-spatiotemporal resolution using fluorescent transgenic reporters labeling specific cell populations. Together with recent additional technical advances this allows an unprecedented versatility and scope of future studies. Modeling of human physiology and pathology in zebrafish has already yielded relevant insights into cellular dynamics and function that can be translated to the human clinical situation. For instance, in vivo studies in the zebrafish have provided new insight into immune cell dynamics in granuloma formation in tuberculosis and the mechanisms involving treatment resistance. In this review, we highlight recent findings and novel tools paving the way for basic neuroimmunology research in the zebrafish. © 2014 The Authors.


De Kuijper G.,Intellectual Disability Center | Evenhuis H.,Erasmus Medical Center | Minderaa R.B.,University of Groningen | Hoekstra P.J.,University of Groningen
Journal of Intellectual Disability Research | Year: 2014

Background: Antipsychotics are frequently and often long-term used for challenging behaviour in persons with intellectual disability (ID), but the evidence base for this is meagre. As these agents may cause harmful side effects, discontinuation should be considered. Previous studies regarding discontinuation of long-term used antipsychotics mostly were uncontrolled and involved small numbers. The primary objective was to investigate the effects of controlled discontinuation of antipsychotics prescribed for challenging behaviour. Secondary objectives were to compare the results of two discontinuation time schedules, to compare groups of participants who had and had not achieved complete discontinuation, and to identify patient and medication characteristics that might predict the outcomes. Our hypothesis was that discontinuation of antipsychotics used for behavioural symptoms would not lead to worsening in behaviour. Methods: This was a multi-centre parallel-group study comparing two discontinuation schedules of 14 and 28 weeks. Allocation to the two discontinuation schedules took place in a 1:1 ratio. Antipsychotics were tapered off every 2 or 4 weeks with approximately 12.5% of the initial dosage. Follow-up was 12 weeks after the scheduled complete discontinuation, that is, 26 or 40 weeks after the first dose reduction, respectively. Discontinuation was stopped in case of significant behavioural worsening. Participants were 98 residents with ID of three care providing organisations in the Netherlands, aged 15-66 year, who had used for more than 1 year one or more of the six most frequently prescribed antipsychotics for challenging behaviour. Main outcome measure was the total score of the Aberrant Behaviour Checklist (ABC); also ABC sub-scales were used. Results: Of 98 participants, 43 achieved complete discontinuation; at follow-up 7 had resumed use of antipsychotics. Mean ABC ratings improved significantly for those who achieved complete discontinuation (directly after discontinuation, P<0.01 and at follow-up, P=0.03), and at follow-up (P=0.03) for those who had not achieved complete discontinuation. Similar results were found with respect to most ABC sub-scales, including the 'irritability' sub-scale. There were no significant differences in improvement of ABC ratings between both discontinuation schedules. Higher ratings of extrapyramidal and autonomic symptoms at baseline were associated with less improvement of behavioural symptoms after discontinuation; higher baseline ABC rating predicted higher odds of incomplete discontinuation. Conclusions: Discontinuation of antipsychotics prescribed for challenging behaviour in patients with ID is associated with improved behavioural functioning. There is no need to taper off in a time frame longer than 14 weeks. © 2012 John Wiley & Sons Ltd, MENCAP & IASSIDD.


Gaillard R.,Erasmus Medical Center | Steegers E.A.,Erasmus Medical Center | Jaddoe V.W.,Erasmus Medical Center
Journal of Hypertension | Year: 2011

Objective: We examined the associations of maternal prepregnancy BMI and gestational weight gain with SBP and DBP in different trimesters of pregnancy and the risks of pregnancy-induced hypertension and preeclampsia in a population-based prospective cohort study among 6902 mothers. Methods: Information about maternal weight just before pregnancy was obtained by questionnaires. Maternal anthropometrics and blood pressure were measured in each trimester. Information about gestational hypertensive disorders was available from medical records. Results: As compared to mothers with a normal weight, maternal obesity (BMI 30-34.9 kg/m) and morbid obesity (BMI â‰1 35 kg/m) were associated with higher first trimester SBP [differences for obese women and morbidly obese women: 10.80 mmHg (95% confidence interval: 9.44-12.17) and 13.07 mmHg (95% confidence interval: 10.91-15.23), respectively] and DBP [differences for obese women and morbidly obese women: 8.69 mmHg (95% confidence interval: 7.63-9.74) and 13.12 mmHg (95% confidence interval: 11.44-14.79), respectively]. Similar differences were observed during second and third trimester. The risks of pregnancy-induced hypertension and preeclampsia were increased among obese mothers [odds ratio 4.67 (95% confidence interval: 3.07-7.09) and odds ratio 2.49 (95% confidence interval: 1.29-4.78), respectively] and morbidly obese mothers [odds ratio 11.34 (95% confidence interval: 6.80-18.86) and odds ratio 3.40 (95% confidence interval: 1.39-8.28), respectively]. Maternal weight gain was associated with the risk of pregnancy-induced hypertension. Conclusion: Maternal obesity and morbid obesity are strongly associated with blood pressure in each trimester, and increased risks of gestational hypertensive disorders. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Rock A.W.,Innsbruck Medical University | Dur A.,University of Innsbruck | Van Oven M.,Erasmus Medical Center | Parson W.,Innsbruck Medical University | Parson W.,Pennsylvania State University
Forensic Science International: Genetics | Year: 2013

The assignment of haplogroups to mitochondrial DNA haplotypes contributes substantial value for quality control, not only in forensic genetics but also in population and medical genetics. The availability of Phylotree, a widely accepted phylogenetic tree of human mitochondrial DNA lineages, led to the development of several (semi-)automated software solutions for haplogrouping. However, currently existing haplogrouping tools only make use of haplogroup-defining mutations, whereas private mutations (beyond the haplogroup level) can be additionally informative allowing for enhanced haplogroup assignment. This is especially relevant in the case of (partial) control region sequences, which are mainly used in forensics. The present study makes three major contributions toward a more reliable, semi-automated estimation of mitochondrial haplogroups. First, a quality-controlled database consisting of 14,990 full mtGenomes downloaded from GenBank was compiled. Together with Phylotree, these mtGenomes serve as a reference database for haplogroup estimates. Second, the concept of fluctuation rates, i.e. a maximum likelihood estimation of the stability of mutations based on 19,171 full control region haplotypes for which raw lane data is available, is presented. Finally, an algorithm for estimating the haplogroup of an mtDNA sequence based on the combined database of full mtGenomes and Phylotree, which also incorporates the empirically determined fluctuation rates, is brought forward. On the basis of examples from the literature and EMPOP, the algorithm is not only validated, but both the strength of this approach and its utility for quality control of mitochondrial haplotypes is also demonstrated. © 2013 The Authors.


van de Mheen L.,Erasmus Medical Center
American journal of obstetrics and gynecology | Year: 2014

OBJECTIVE: The objective of the study was to assess in trichorionic triplet pregnancies the effectiveness of elective reduction to twins.STUDY DESIGN: This was a nationwide retrospective cohort study. We compared the time to delivery and perinatal mortality in trichorionic triplet pregnancies electively reduced to twins with ongoing trichorionic triplets and primary dichorionic twins.RESULTS: We identified 86 women with reduced trichorionic triplet pregnancies, 44 with ongoing trichorionic triplets, and 824 with primary twins. Reduced triplets had a median gestational age at delivery of 36.1 weeks (interquartile range [IQR], 33.3-37.5 weeks) vs 33.3 (IQR, 28.1-35.2) weeks for ongoing triplets and 37.1 (IQR, 35.3-38.1) weeks for primary twins (P < .001). The total number of surviving children in the reduced group was 155 (90%) vs 114 (86%) in the ongoing triplet group. After reduction, 75 of women (87%) had all their fetuses surviving, compared with 36 (82%) (relative risk [RR], 1.3; 95% confidence interval [CI], 0.72-2.3) for ongoing triplets and 770 (93%) (RR, 0.91; 95% CI, 0.82-1) for primary twins. There were 6 women without any surviving children (7%) after reduction vs 5 (11.4%) (RR, 0.81; 95% CI, 0.47-1.4) among women with ongoing triplets and 32 (3.9%) (RR, 1.7; 95% CI, 0.8-3.7) in women with primary twins.CONCLUSION: In women with a triplet pregnancy, fetal reduction increases gestational age at birth with 3 weeks as compared with ongoing triplets. However, there the impact on neonatal survival is limited. Copyright © 2014 Elsevier Inc. All rights reserved.


Heidenreich A.,RWTH Aachen | Bastian P.J.,Klinikum Golzheim | Bellmunt J.,University of the Sea | Bolla M.,C.H.U. Grenoble | And 6 more authors.
European Urology | Year: 2014

Context The most recent summary of the European Association of Urology (EAU) guidelines on prostate cancer (PCa) was published in 2011. Objective To present a summary of the 2013 version of the EAU guidelines on screening, diagnosis, and local treatment with curative intent of clinically organ-confined PCa. Evidence acquisition A literature review of the new data emerging from 2011 to 2013 has been performed by the EAU PCa guideline group. The guidelines have been updated, and levels of evidence and grades of recommendation have been added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews. Evidence synthesis A full version of the guidelines is available at the EAU office or online (www.uroweb.org). Current evidence is insufficient to warrant widespread population-based screening by prostate-specific antigen (PSA) for PCa. Systematic prostate biopsies under ultrasound guidance and local anesthesia are the preferred diagnostic method. Active surveillance represents a viable option in men with low-risk PCa and a long life expectancy. A biopsy progression indicates the need for active intervention, whereas the role of PSA doubling time is controversial. In men with locally advanced PCa for whom local therapy is not mandatory, watchful waiting (WW) is a treatment alternative to androgen-deprivation therapy (ADT), with equivalent oncologic efficacy. Active treatment is recommended mostly for patients with localized disease and a long life expectancy, with radical prostatectomy (RP) shown to be superior to WW in prospective randomized trials. Nerve-sparing RP is the approach of choice in organ-confined disease, while neoadjuvant ADT provides no improvement in outcome variables. Radiation therapy should be performed with ≥74 Gy in low-risk PCa and 78 Gy in intermediate- or high-risk PCa. For locally advanced disease, adjuvant ADT for 3 yr results in superior rates for disease-specific and overall survival and is the treatment of choice. Follow-up after local therapy is largely based on PSA and a disease-specific history, with imaging indicated only when symptoms occur. Conclusions Knowledge in the field of PCa is rapidly changing. These EAU guidelines on PCa summarize the most recent findings and put them into clinical practice. Patient summary A summary is presented of the 2013 EAU guidelines on screening, diagnosis, and local treatment with curative intent of clinically organ-confined prostate cancer (PCa). Screening continues to be done on an individual basis, in consultation with a physician. Diagnosis is by prostate biopsy. Active surveillance is an option in low-risk PCa and watchful waiting is an alternative to androgen-deprivation therapy in locally advanced PCa not requiring immediate local treatment. Radical prostatectomy is the only surgical option. Radiation therapy can be external or delivered by way of prostate implants. Treatment follow-up is based on the PSA level. © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.


Head S.J.,Erasmus Medical Center | Holmes Jr. D.R.,Mayo Medical School | Mack M.J.,Heart Health | Serruys P.W.,Erasmus Medical Center | And 4 more authors.
JACC: Cardiovascular Interventions | Year: 2012

Background: The aim of this study was to evaluate the use of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in "real-world" patients unsuitable for the alternative treatment. No data are available on the risk profile and outcomes of patients that can only undergo PCI or CABG. Methods: In the SYNTAX (Synergy between PCI with TAXUS and Cardiac Surgery) trial, a multidisciplinary Heart Team reached a consensus on whether PCI and CABG could result in clinical equipoise; if so, the patient was randomized. If not, the patient was enrolled in a CABG-ineligible PCI registry or PCI-ineligible CABG registry. A proportion (60%) of patients in the CABG registry was randomly assigned to be followed up for 5 years. No statistical comparisons were performed between randomized and registry patients. Major adverse cardiac or cerebrovascular event (MACCE) rates are presented as observational only. Results: A total of 3,075 patients were treated in the SYNTAX trial; 198 (6.4%) and 1,077 (35.0%) patients were included in PCI and CABG registries, respectively. The main reason for inclusion in the CABG registry was too complex coronary anatomy (70.9%), and the main reason for inclusion in the PCI registry was too high-risk for surgery (70.7%). Three-year MACCE was 38.0% after PCI and 16.4% after CABG. Stratification by SYNTAX score terciles demonstrated a step-wise increase of MACCE rates in both PCI and CABG registries. Conclusions: The SYNTAX Heart Team concluded that PCI and CABG remained the only treatment options for 6.4% and 35.0% of patients, respectively. Inoperable patients with major comorbidities that underwent PCI had high MACCE rates. In patients not suitable for PCI, surgical results were excellent. (SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries, NCT00114972). © 2012 American College of Cardiology Foundation.


Mayerl S.,Leibniz Institute for Age Research | Visser T.J.,Erasmus Medical Center | Darras V.M.,Catholic University of Leuven | Horn S.,Leibniz Institute for Age Research | Heuer H.,Leibniz Institute for Age Research
Endocrinology | Year: 2012

Organic anion-transporting polypeptide 1c1 (Oatp1c1) (also known as Slco1c1 and Oatp14) belongs to the family of Oatp and has been shown to facilitate the transport of T 4. In the rodent brain, Oatp1c1 is highly enriched in capillary endothelial cells and choroid plexus structures where it may mediate the entry of T 4 into the central nervous system. Here, we describe the generation and first analysis of Oatp1c1-deficient mice. Oatp1c1 knockout (KO) mice were born with the expected frequency, were not growth retarded, and developed without any overt neurological abnormalities. Serum T 3 and T 4 concentrations as well as renalandhepatic deiodinase type 1 expression levels were indistinguishable between Oatp1c1 KO mice and control animals. Hypothalamic TRH and pituitaryTSH mRNA levels were not affected, but brain T 4 and T 3 content was decreased in Oatp1c1-deficient animals. Moreover, increased type 2 and decreased type 3 deiodinase activities indicate a mild hypothyroid situation in the brain of Oatp1c1 KO mice. Consequently, mRNA expression levels of gene products positively regulated by T 3 in the brain were down-regulated. This central nervous system-specific hypothyroidism is presumably caused by an impaired passage of T 4 across the blood-brain barrier and indicates a unique function of Oatp1c1 in facilitating T 4 transport despite the presence of other thyroid hormone transporters such as Mct8. Copyright © 2012 by The Endocrine Society.


van der Worp H.,University of Groningen | van den Akker-Scheek I.,University of Groningen | van Schie H.,Erasmus Medical Center | van Schie H.,University Utrecht | Zwerver J.,University of Groningen
Knee Surgery, Sports Traumatology, Arthroscopy | Year: 2013

Purpose: The general consensus that tendinopathy, at least in the chronic stage, is mainly a degenerative condition and inflammation plays a minor role has led to a shift from treatments that target inflammation towards treatment options that promote regeneration. One of these treatments is extracorporeal shockwave therapy (ESWT), a physical therapy modality that uses pressure waves to treat tendinopathy. This review was undertaken to give an overview of the literature concerning this treatment, and special attention is given to the differences between focused and radial ESWT. Methods: A narrative description of wave characteristics, generation methods and in vitro effects of ESWT is given. The literature on ESWT as a treatment for one common tendinopathy, patellar tendinopathy, was systematically reviewed. Results: Waves that are generated for focused and radial ESWT have very different physical characteristics. It is unclear how these characteristics are related to clinical effectiveness. Studies into the biological effects of ESWT have mainly used focused shockwave therapy, showing a number of effects of shockwaves on biological tissue. The systematic review of studies into the clinical effects of ESWT for patellar tendinopathy showed conflicting evidence for its effectiveness. Conclusion: Physical characteristics of focused and radial waves differ substantially, but effect on clinical effectiveness is unclear. Whereas in vitro studies often show the effects of ESWT on tendon tissue, results of clinical studies are inconsistent. Based on the review of the literature, suggestions are given for the use of ESWT in clinical practice regarding timing and treatment parameters. Level of evidence: IV. © 2012 The Author(s).


Yokomizo T.,Erasmus Medical Center | Yokomizo T.,National University of Singapore | Yamada-Inagawa T.,Erasmus Medical Center | Yzaguirre A.D.,University of Pennsylvania | And 3 more authors.
Nature Protocols | Year: 2012

We describe a three-dimensional (3D) confocal imaging technique to characterize and enumerate rare, newly emerging hematopoietic cells located within the vasculature of whole-mount preparations of mouse embryos. However, the methodology is broadly applicable for examining the development and 3D architecture of other tissues. Previously, direct whole-mount imaging has been limited to external tissue layers owing to poor laser penetration of dense, opaque tissue. Our whole-embryo imaging method enables detailed quantitative and qualitative analysis of cells within the dorsal aorta of embryonic day (E) 10.5-11.5 embryos after the removal of only the head and body walls. In this protocol we describe the whole-mount fixation and multimarker staining procedure, the tissue transparency treatment, microscopy and the analysis of resulting images. A typical two-color staining experiment can be performed and analyzed in ∼6 d. © 2012 Nature America, Inc. All rights reserved.


Brusse E.,Rotterdam University | Brusse-Keizer M.G.J.,Spectrum | Duivenvoorden H.J.,Erasmus Medical Center | Van Swieten J.C.,Rotterdam University
Neurology | Year: 2011

Objective: To identify the prevalence and severity of fatigue and predicting factors for severe fatigue in autosomal dominant spinocerebellar ataxia (SCA). Methods: We studied a cross-section of 123 patients with SCA. Six functional scales were used in a self-assessment: the Fatigue Severity Scale (FSS); the Beck Depression Inventory (BDI); the Rotterdam Handicap Scale (RHS); the Short Form-36 health survey, distinguishing a norm-based physical and mental component score (Nb-PCS and Nb-MCS); the Pittsburgh Sleep Quality Index (PSQI); and the Epworth Sleepiness Scale (ESS). A subset of 58 patients was clinically evaluated, measuring severity of ataxia with the Scale for the Assessment and Rating of Ataxia and cognitive functioning with the Mini-Mental State Examination. Results: Severe fatigue (FSS ≥5) was present in 69% of patients and FSS value correlated with the scores on RHS, Nb-PCS, Nb-MCS, BDI, PSQI, and ESS. There was no relation with disease duration, gender, or medication use. Multivariate analysis revealed that Nb-PCS and BDI were the best independent predictors for severe fatigue. Interestingly, the presence of visual symptoms was related to FSS value in the clinically evaluated subgroup. Conclusion: Fatigue is a severe and disabling symptom in adult patients with SCA, even early in the course of disease. Physical functioning and depression are the strongest predictors of fatigue. In treatment strategies, all treatable factors for fatigue should be addressed, especially depression, visual symptoms, and sleeping disorders. © 2011 by AAN Enterprises, Inc. All rights reserved.


Hilgenkamp T.I.M.,Erasmus Medical Center | van Wijck R.,University of Groningen | Evenhuis H.M.,Erasmus Medical Center
Research in Developmental Disabilities | Year: 2010

A certain level of physical fitness is a prerequisite for independent functioning and self-care, but the level of physical fitness declines with ageing. This applies to older adult with intellectual disabilities too, but very little is known about their actual level of physical fitness. This lack of knowledge is partly caused by a lack of suitable instruments to measure physical fitness in this group, but the search for and choice of instruments depends on the operationalisation of the concept physical fitness for specific this target population. In this article the advantages of two known definitions of physical fitness are combined, leading to a combination of seven components to describe physical fitness in older adults with intellectual disabilities: coordination, reaction time, balance, muscular strength, muscular endurance, flexibility and cardio-respiratory endurance.A literature search for all instruments to measure any of these components resulted in a large number of available instruments. These instruments were evaluated according criteria of functionality, reliability and feasibility in this target population. The aim of this article was to propose a selection of instruments which complied with these criteria and creates possibilities for widespread use and sharing and/or pooling of data. The proposed selection of tests to measure physical fitness in older adults with intellectual disabilities is: Box and Block test, Reaction time test with an auditive and visual signal, Berg balance scale, Walking speed comfortable and fast, Grip strength with a hand dynamometer, 30. s chair stand, modified back saver sit and reach and the 10. m incremental shuttle walking test. © 2010 Elsevier Ltd.


Nimonkar A.V.,University of California at Davis | Genschel J.,Duke University | Kinoshita E.,Erasmus Medical Center | Polaczek P.,California Institute of Technology | And 5 more authors.
Genes and Development | Year: 2011

Repair of dsDNA breaks requires processing to produce 3′-terminated ssDNA. We biochemically reconstituted DNA end resection using purified human proteins: Bloom helicase (BLM); DNA2 helicase/nuclease; Exonuclease 1 (EXO1); the complex comprising MRE11, RAD50, and NBS1 (MRN); and Replication protein A (RPA). Resection occurs via two routes. In one, BLM and DNA2 physically and specifically interact to resect DNA in a process that is ATP-dependent and requires BLM helicase and DNA2 nuclease functions. RPA is essential for both DNA unwinding by BLM and enforcing 5′ → 3′ resection polarity by DNA2. MRN accelerates processing by recruiting BLM to the end. In the other, EXO1 resects the DNA and is stimulated by BLM, MRN, and RPA. BLM increases the affinity of EXO1 for ends, and MRN recruits and enhances the processivity of EXO1. Our results establish two of the core machineries that initiate recombinational DNA repair in human cells. © 2011 by Cold Spring Harbor Laboratory Press.


Kuipers E.J.,Erasmus Medical Center | Rosch T.,University of Hamburg | Bretthauer M.,University of Oslo
Nature Reviews Clinical Oncology | Year: 2013

The first evidence that screening for colorectal cancer (CRC) could effectively reduce mortality dates back 20 years. However, actual population screening has, in many countries, halted at the level of individual testing and discussions on differences between screening tests. With a wealth of new evidence from various community-based studies looking at test uptake, screening-programme organization and the importance of quality assurance, population screening for CRC is now moving into a new realm, promising better results in terms of reducing CRC-specific morbidity and mortality. Such a shift in the paradigm requires a change from opportunistic, individual testing towards organized population screening with comprehensive monitoring and full-programme quality assurance. To achieve this, a combination of factors - including test characteristics, uptake, screenee autonomy, costs and capacity - must be considered. Thus, evidence from randomized trials comparing different tests must be supplemented by studies of acceptance and uptake to obtain the full picture of the effectiveness (in terms of morbidity, mortality and cost) the different strategies have. In this Review, we discuss a range of screening modalities and describe the factors to be considered to achieve a truly effective population CRC screening programme. © 2013 Macmillan Publishers Limited. All rights reserved.


Nation R.L.,Monash Institute of Pharmaceutical Sciences | Li J.,Monash Institute of Pharmaceutical Sciences | Cars O.,Uppsala University | Couet W.,University of Poitiers | And 8 more authors.
The Lancet Infectious Diseases | Year: 2015

In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics. © 2015 Elsevier Ltd.


Loeb S.,New York University | Carter H.B.,Brady Urological Institute | Moul J.W.,Duke University | Schroder F.H.,Erasmus Medical Center
European Urology | Year: 2012

Context: Prostate cancer screening is highly controversial, including the age to begin prostate-specific antigen (PSA) testing. Several studies have evaluated the usefulness of baseline PSA measurements at a young age. Objective: Review the literature on baseline PSA testing at a young age (≤60 yr) for the prediction of prostate cancer risk and prognosis. Evidence acquisition: PubMed was searched for English-language publications on baseline PSA and prostate cancer for the period ending April 2011. Evidence synthesis: In most published series, median PSA levels in the general male population range from approximately 0.4 to 0.7 ng/ml in men in their 40s and from approximately 0.7 to 1.0 ng/ml in men in their 50s. Evidence from both nonscreening and screening populations has demonstrated the predictive value of a single baseline PSA measurement for prostate cancer risk assessment. Specifically, men with baseline PSA levels above the age-group-specific median have a greater risk of prostate cancer diagnosis during the next 20-25 yr. Additional studies confirmed that higher baseline PSA levels at a young age are also associated with a greater risk of aggressive disease, metastasis, and disease-specific mortality many years later. Conclusions: Baseline PSA measurements at a young age are significant predictors of later prostate cancer diagnosis and disease-specific outcomes. Thus baseline PSA testing may be used for risk stratification and to guide screening protocols. © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.


Den Exter P.L.,Leiden University | Klok F.A.,Leiden University | Kroft L.J.,Leiden University | Kruip M.J.H.A.,Erasmus Medical Center | And 2 more authors.
Blood | Year: 2013

The clinical significance of subsegmental pulmonary embolism (SSPE) remains to be determined. This study aimed to investigate whether SSPE forms a distinct subset of thromboembolic disease compared with more proximally located pulmonary embolism (PE). We analyzed 3728 consecutive patients with clinically suspected PE. SSPE patients were contrasted to patients with more proximal PE and to patients in whom suspected PE was ruled out, in regards of the prevalence of thromboembolic risk factors and the 3-month risks of recurrent venous thromboembolism (VTE) and mortality. PE was confirmed in 748 patients, of whom 116(16%) had SSPE; PE was ruled out in 2980 patients. No differences were seen in the prevalence of VTE risk factors, the 3-monthriskofrecurrent VTE(3.6%vs2.5%; P = .42), and mortality(10.7%vs6.5%; P = .17) between patients with SSPE and those with more proximal PE. When compared with patients without PE, aged >60 years, recent surgery, estrogen use, and male gender were found to be independent predictors for SSPE, and patients with SSPE were at an increased risk of VTE during follow-up (hazard ratio: 3.8; 95% CI: 1.3-11.1). This study indicates that patients with SSPE mimic those with more proximally located PE in regards to their risk profile and clinical outcome. © 2013 by The American Society of Hematology.


Pagliarulo V.,University of Bari | Eisenberger M.A.,Johns Hopkins University | Schroder F.H.,Erasmus Medical Center | Sternberg C.N.,San Camillo Forlanini Hospital | Studer U.E.,University of Bern
European Urology | Year: 2012

Context: Androgen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk-benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease. Objective: Review the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds. Evidence acquisition: A comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated. Evidence synthesis: Data from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72 Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone-releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality. Conclusions: Although ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72 Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk-benefit ratio. © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.


Dall'Era M.A.,University of California at Davis | Albertsen P.C.,University of Connecticut Health Center | Bangma C.,Erasmus Medical Center | Carroll P.R.,University of California at San Francisco | And 7 more authors.
European Urology | Year: 2012

Context: Prostate cancer (PCa) remains an increasingly common malignancy worldwide. The optimal management of clinically localized, early-stage disease remains unknown, and profound quality of life issues surround PCa interventions. Objective: To systematically summarize the current literature on the management of low-risk PCa with active surveillance (AS), with a focus on patient selection, outcomes, and future research needs. Evidence acquisition: A comprehensive search of the PubMed and Embase databases from 1980 to 2011 was performed to identify studies pertaining to AS for PCa. The search terms used included prostate cancer and active surveillance or conservative management or watchful waiting or expectant management. Selected studies for outcomes analysis had to provide a comprehensive description of entry characteristics, criteria for surveillance, and indicators for further intervention. Evidence synthesis: Data from seven large AS series were reviewed. Inclusion criteria for surveillance vary among studies, and eligibility therefore varies considerably (4-82%). PCa-specific mortality remains low (0-1%), with the longest published median follow-up being 6.8 yr. Up to one-third of patients receive secondary therapy after a median of about 2.5 yr of surveillance. Surveillance protocols and triggers for intervention vary among institutions. Most patients are treated for histologic reclassification (27-100%) or prostate-specific antigen doubling time <3 yr (13-48%), while 7-13% are treated with no evidence of progression. Repeat prostate biopsy with a minimum of 12 cores appears to be important for monitoring patients for changes in tumor histology over time. Conclusions: AS for PCa offers an opportunity to limit intervention to patients who will likely benefit the most from radical treatment. This approach confers a low risk of disease-specific mortality in the short to intermediate term. An early, confirmatory biopsy is essential for limiting the risk of underestimating tumor grade and amount. © 2012 European Association of Urology.


Kluin-Nelemans H.C.,University of Groningen | Doorduijn J.K.,Erasmus Medical Center
Seminars in Hematology | Year: 2011

Treatment of elderly patients with a mantle cell lymphoma (MCL) is a challenge. High-dose cytarabine and autologous transplantation, both important components of the treatment in younger patients, are not feasible for most elderly patients. However, in fit elderly patients long progression-free survival and molecular remissions are possible. The regimen most commonly used is rituximab combined with an anthracycline-combination therapy, ie, R-CHOP. An alternative is rituximab combined with a purine analogue-containing regimen, ie, fludarabine with cyclophosphamide (R-FC). The results of a large randomized study comparing these two regimens are expected soon. Maintenance therapy with rituximab after induction improves progression-free survival. Relapse of lymphoma will occur in all patients, as cure of MCL is not yet achieved with standard therapy. Second-line treatment regimens with reasonable results are described. Treatment of the frail elderly patient and of patients after first relapse should aim at reducing symptoms and maintaining quality of life. It therefore should be individualized, and benefits and possible side effects should be carefully balanced. It is advised to include patients with MCL in clinical trials to obtain a better understanding of the value of different treatment options and new developments. © 2011 Elsevier Inc.


Pond G.R.,McMaster University | Sonpavde G.,Comprehensive Cancer Center | De Wit R.,Erasmus Medical Center | Eisenberger M.A.,Johns Hopkins University | And 2 more authors.
European Urology | Year: 2014

The presence of visceral metastases is adversely prognostic in men with metastatic castration-resistant prostate cancer (mCRPC), but the prognostic impact of the site of visceral metastasis is unclear. Men with mCRPC in the TAX 327 phase 3 trial receiving docetaxel or mitoxantrone every 3 wk or weekly docetaxel, each with prednisone, were analyzed retrospectively to study the impact of the site of visceral metastasis on overall survival (OS). Patients were assessed for OS by site of metastases: liver with or without other sites, lung with or without bone or lymph nodes, bone plus lymph nodes, bone only, and lymph nodes only. Cox proportional hazards regression, adjusted for treatment and stratification factors, was performed. Men with liver metastases with or without other metastases had shorter median OS (10.0 mo; 95% confidence interval [CI], 5.4-11.5) than men with lung metastases with or without bone or nodal metastases (median OS: 14.4 mo; 95% CI, 11.5-22.4). Men with lymph node-only disease had the best median OS (26.7 mo; 95% CI, 22.3-34.2), followed by men with bone-only metastases (median OS: 19.0 mo; 95% CI, 18.2-20.7) and bone-plus-node disease (median OS: 15.7 mo; 95% CI, 14.4-17.2). Thus, pattern of spread including site of visceral metastasis confers a differential prognostic impact. These data require validation and may inform trial design and therapy. © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.


Tjon A.S.W.,Erasmus Medical Center | Van Gent R.,Erasmus Medical Center | Kwekkeboom J.,Erasmus Medical Center
Frontiers in Immunology | Year: 2015

Intravenous immunoglobulin (IVIg) is a therapeutic preparation of polyspecific human IgGs purified from plasma pooled from thousands of individuals. When administered at a high dose, IVIg inhibits inflammation and has proven efficacy in the treatment of various autoimmune and systemic inflammatory diseases. Importantly, IVIg therapy can ameliorate both auto-antibody-mediated and T-cell mediated immune pathologies. In the last few decades, extensive research in murine disease models has resulted in the elucidation of two novel anti-inflammatory mechanisms-of-action of IVIg: induction of Fc?RIIB expression by sialylated Fc, and stimulation of regulatory T cells. Whereas controversial findings in mice studies have recently inspired intense scientific debate regarding the validity of the sialylated Fc-Fc?RIIB model, the most fundamental question is whether these anti-inflammatory mechanisms of IVIg are operational in humans treated with IVIg. In this review, we examine the evidence for the involvement of these anti-inflammatory mechanisms in the therapeutic effects of IVIg in humans. We demonstrate that although several elements of both immune-modulatory pathways of IVIg are activated in humans, incorrect extrapolations from mice to men have been made on the molecular and cellular components involved in these cascades that warrant for critical re-evaluation of these anti-inflammatory mechanisms of IVIg in humans. © 2015 Tjon, van Gent, Geijtenbeek and Kwekkeboom.


Bakker J.,Erasmus Medical Center | Nijsten M.W.N.,University of Groningen | Jansen T.C.,Erasmus Medical Center
Annals of Intensive Care | Year: 2013

Increased blood lactate levels (hyperlactataemia) are common in critically ill patients. Although frequently used to diagnose inadequate tissue oxygenation, other processes not related to tissue oxygenation may increase lactate levels. Especially in critically ill patients, increased glycolysis may be an important cause of hyperlactataemia. Nevertheless, the presence of increased lactate levels has important implications for the morbidity and mortality of the hyperlactataemic patients. Although the term lactic acidosis is frequently used, a significant relationship between lactate and pH only exists at higher lactate levels. The term lactate associated acidosis is therefore more appropriate. Two recent studies have underscored the importance of monitoring lactate levels and adjust treatment to the change in lactate levels in early resuscitation. As lactate levels can be measured rapidly at the bedside from various sources, structured lactate measurements should be incorporated in resuscitation protocols. © 2013 Bakker et al.; licensee Springer.


Vlaar P.J.,University of Groningen | Mahmoud K.D.,University of Groningen | Holmes Jr. D.R.,Mayo Medical School | Van Valkenhoef G.,University of Groningen | And 4 more authors.
Journal of the American College of Cardiology | Year: 2011

Objectives: The purposes of this study were to investigate whether, in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD), percutaneous coronary intervention (PCI) should be confined to the culprit or also nonculprit vessels and, when performing PCI for nonculprit vessels, whether it should take place during primary PCI or staged procedures. Background: A significant percentage of STEMI patients have MVD. However, the best PCI strategy for nonculprit vessel lesions is unknown. Methods: Pairwise and network meta-analyses were performed on 3 PCI strategies for MVD in STEMI patients: 1) culprit vessel only PCI strategy (culprit PCI), defined as PCI confined to culprit vessel lesions only; 2) multivessel PCI strategy (MV-PCI), defined as PCI of culprit vessel as well as <1 nonculprit vessel lesions; and 3) staged PCI strategy (staged PCI), defined as PCI confined to culprit vessel, after which <1 nonculprit vessel lesions are treated during staged procedures. Prospective and retrospective studies were included when research subjects were patients with STEMI and MVD undergoing PCI. The primary endpoint was short-term mortality. Results: Four prospective and 14 retrospective studies involving 40,280 patients were included. Pairwise meta-analyses demonstrated that staged PCI was associated with lower short- and long-term mortality as compared with culprit PCI and MV-PCI and that MV-PCI was associated with highest mortality rates at both short- and long-term follow-up. In network analyses, staged PCI was also consistently associated with lower mortality. Conclusions: This meta-analysis supports current guidelines discouraging performance of multivessel primary PCI for STEMI. When significant nonculprit vessel lesions are suitable for PCI, they should only be treated during staged procedures. © 2011 American College of Cardiology Foundation.


Burke M.C.,University of Chicago | Gold M.R.,Medical University of South Carolina | Knight B.P.,Northwestern University | Barr C.S.,Russells Hall Hospital | And 8 more authors.
Journal of the American College of Cardiology | Year: 2015

Abstract Background The entirely subcutaneous implantable cardioverter-defibrillator (S-ICD) is the first implantable defibrillator that avoids placing electrodes in or around the heart. Two large prospective studies (IDE [S-ICD System IDE Clinical Investigation] and EFFORTLESS [Boston Scientific Post Market S-ICD Registry]) have reported 6-month to 1-year data on the S-ICD. Objectives The objective of this study was to evaluate the safety and efficacy of the S-ICD in a large diverse population. Methods Data from the IDE and EFFORTLESS studies were pooled. Shocks were independently adjudicated, and complications were measured with a standardized classification scheme. Enrollment date quartiles were used to assess event rates over time. Results Eight hundred eighty-two patients who underwent implantation were followed for 651 ± 345 days. Spontaneous ventricular tachyarrhythmia (VT)/ventricular fibrillation (VF) events (n = 111) were treated in 59 patients; 100 (90.1%) events were terminated with 1 shock, and 109 events (98.2%) were terminated within the 5 available shocks. The estimated 3-year inappropriate shock rate was 13.1%. Estimated 3-year, all-cause mortality was 4.7% (95% confidence interval: 0.9% to 8.5%), with 26 deaths (2.9%). Device-related complications occurred in 11.1% of patients at 3 years. There were no electrode failures, and no S-ICD-related endocarditis or bacteremia occurred. Three devices (0.3%) were replaced for right ventricular pacing. The 6-month complication rate decreased by quartile of enrollment (Q1: 8.9%; Q4: 5.5%), and there was a trend toward a reduction in inappropriate shocks (Q1: 6.9% Q4: 4.5%). Conclusions The S-ICD demonstrated high efficacy for VT/VF. Complications and inappropriate shock rates were reduced consistently with strategic programming and as operator experience increased. These data provide further evidence for the safety and efficacy of the S-ICD. (Boston Scientific Post Market S-ICD Registry [EFFORTLESS]; NCT01085435; S-ICD® System IDE Clinical Study; NCT01064076). © 2015 by the American College of Cardiology Foundation.


Mesman E.,University Utrecht | Hillegers M.H.J.,University Utrecht | Ambree O.,University of Munster | Arolt V.,University of Munster | And 2 more authors.
Bipolar Disorders | Year: 2015

Objectives: There is increasing evidence that both immune and neurochemical alterations are involved in the pathogenesis of bipolar disorder; however, their precise role remains unclear. In this study, we aimed to evaluate neuro-immune changes in a prospective study on children of patients with bipolar disorder. Methods: Bipolar offspring, from the prospective Dutch bipolar offspring study (n = 140), were evaluated cross-sectionally within a longitudinal context at adolescence, young adulthood, and adulthood. We examined the expression of 44 inflammation-related genes in monocytes, the cytokines pentraxin 3 (PTX3), chemokine ligand 2 (CCL2), and interleukin-1β (IL-1β), and brain-derived neurotrophic factor (BDNF) and S100 calcium binding protein B (S100B) in the serum of bipolar offspring and healthy controls. Results: During adolescence, bipolar offspring showed increased inflammatory gene expression in monocytes, high serum PTX3 levels, but normal CCL2 levels. BDNF levels were decreased, while S100B levels were normal. During young adulthood, monocyte activation remained, although to a lesser degree. Serum PTX3 levels remained high, and signs of monocyte migration became apparent through increased CCL2 levels. BDNF and S100B levels were not measured. At adulthood, circulating monocytes had lost their activation state, but CCL2 levels remained increased. Both BDNF and S100B were now increased. Abnormalities were independent of psychopathology state at all stages. Conclusions: This study suggests an aberrant neuro-immune state in bipolar offspring, which followed a dynamic course from adolescence into adulthood and was present irrespective of lifetime or future mood disorders. We therefore assumed that the aberrant neuro-immune state reflects a general state of vulnerability for mood disorders rather than being of direct predictive value. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Lamers B.H.C.,Erasmus Medical Center | Milani A.L.,Reinier Of Graaf Group
International Urogynecology Journal and Pelvic Floor Dysfunction | Year: 2011

Pessaries have been used to treat women with pelvic organ prolapse (POP) since the beginning of recorded history. This review aims to assess the effect of pessary treatment on the disease-specific, health-related quality of life in women with pelvic organ prolapse. After a Medline search using the Mesh term 'pessary' and critical appraisal, 41 articles were selected and used in this review. Pessaries are widely used to treat pelvic organ prolapse. It is minimally invasive and appears to be safe. Although there is evidence that the use of pessaries in the treatment of pelvic organ prolapse is effective in alleviating symptoms and that patient satisfaction is high, the follow-up in many published papers is short, and the use of validated urogynaecological questionnaires is limited. Comparison with surgical treatment of pelvic organ prolapse is rare and not assessed in a randomised controlled trial. © The Author(s) 2011.


Roozen H.G.,Erasmus Medical Center | De Waart R.,Center for Addiction | Van Der Kroft P.,Erasmus Medical Center
Addiction | Year: 2010

Aims: Many individuals with substance use disorders are opposed to seeking formal treatment, often leading to disruptive relationships with concerned significant others (CSOs). This is disturbing, as untreated individuals are often associated with a variety of other addiction-related problems. Community Reinforcement and Family Training (CRAFT) provides an option to the more traditional treatment and intervention approaches. The objective of this systematic review was to compare CRAFT with the Alcoholics Anonymous/Narcotics Anonymous (Al-Anon/Nar-Anon) model and the Johnson Institute intervention in terms of its ability to engage patients in treatment and improve the functioning of CSOs. Methods: The electronic databases PubMed, PsycINFO, EMBASE, CINAHL and the Cochrane Library were consulted. Four high-quality randomized controlled trials were identified, with a total sample of 264 CSOs. Data were synthesized to quantify the effect with 95% confidence intervals, using the random effects model. Results: CRAFT produced three times more patient engagement than Al-Anon/Nar-Anon relative risk (RR) 3.25, 95% confidence interval (CI) 2.11-5.02, P < 0.0001; numbers needed to treat (NNT) = 2 and twice the engagement of the Johnson Institute intervention (RR 2.15, 95% CI 1.28-3.62, P = 0.004; NNT = 3). Overall, CRAFT encouraged approximately two-thirds of treatment-resistant patients to attend treatment, typically for four to six CRAFT sessions. CSOs showed marked psychosocial and physical improvements whether they were assigned to CRAFT, Al-Anon/Nar-Anon or the Johnson Institute intervention within the 6-month treatment window. Conclusion: CRAFT has been found to be superior in engaging treatment-resistant substance-abusing individuals compared with the traditional programmes. © 2010 Society for the Study of Addiction.


De Bruin J.L.,Medical Center | Baas A.F.,University Utrecht | Buth J.,Catharina Hospital | Prinssen M.,University Utrecht | And 6 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: For patients with large abdominal aortic aneurysms, randomized trials have shown an initial overall survival benefit for elective endovascular repair over conventional open repair. This survival difference, however, was no longer significant in the second year after the procedure. Information regarding the comparative outcome more than 2 years after surgery is important for clinical decision making. METHODS: We conducted a long-term, multicenter, randomized, controlled trial comparing open repair with endovascular repair in 351 patients with an abdominal aortic aneurysm of at least 5 cm in diameter who were considered suitable candidates for both techniques. The primary outcomes were rates of death from any cause and reintervention. Survival was calculated with the use of Kaplan-Meier methods on an intentionto-treat basis. RESULTS: We randomly assigned 178 patients to undergo open repair and 173 to undergo endovascular repair. Six years after randomization, the cumulative survival rates were 69.9% for open repair and 68.9% for endovascular repair (difference, 1.0 percentage point; 95% confidence interval [CI], -8.8 to 10.8; P=0.97). The cumulative rates of freedom from secondary interventions were 81.9% for open repair and 70.4% for endovascular repair (difference, 11.5 percentage points; 95% CI, 2.0 to 21.0; P=0.03). CONCLUSIONS: Six years after randomization, endovascular and open repair of abdominal aortic aneurysm resulted in similar rates of survival. The rate of secondary interventions was significantly higher for endovascular repair. Copyright © 2010 Massachusetts Medical Society.


Dewailly D.,Lille University of Science and Technology | Lujan M.E.,Cornell University | Carmina E.,University of Palermo | Cedars M.I.,University of California at San Francisco | And 3 more authors.
Human Reproduction Update | Year: 2014

Background: The diagnosis of polycystic ovary syndrome (PCOS) relies on clinical, biological and morphological criteria. With the advent of ultrasonography, follicle excess has become the main aspect of polycystic ovarian morphology (PCOM). Since 2003, most investigators have used a threshold of 12 follicles (measuring 2-9 mm in diameter) per whole ovary, but that now seems obsolete. An increase in ovarian volume (OV) and/or area may also be considered accurate markers of PCOM, yet their utility compared with follicle excess remains unclear. Methods: Published peer-reviewed medical literature about PCOM was searched using PubMed.gov online facilities and was submitted to critical assessment by a panel of experts. Studies reporting antral follicle counts (AFC) or follicle number per ovary (FNPO) using transvaginal ultrasonography in healthy women of reproductive age were also included. Only studies that reported the mean or median AFC or FNPO of follicles measuring 2-9 mm, 2-10 mm or <10 mm in diameter, or visualized all follicles, were included. Results: Studies addressing women recruited from the general population and studies comparing control and PCOS populations with appropriate statistics were convergent towards setting the threshold for increased FNPO at ≥25 follicles, in women aged 18-35 years. These studies suggested maintaining the threshold for increased OV at ≥10 ml. Critical analysis of the literature showed that OV had less diagnostic potential for PCOM compared with FNPO. The review did not identify any additional diagnostic advantage for other ultrasound metrics such as specific measurements of ovarian stroma or blood flow. Even though serum concentrations of anti-Müllerian hormone (AMH) showed a diagnostic performance for PCOM that was equal to or better than that of FNPO in some series, the accuracy and reproducibility issues of currently available AMH assays preclude the establishment of a threshold value for its use as a surrogate marker of PCOM. PCOM does not associate with significant consequences for health in the absence of other symptoms of PCOS but, because of the use of inconsistent definitions of PCOM among studies, this question cannot be answered with absolute certainty. Conclusions: The Task Force recommends using FNPO for the definition of PCOM setting the threshold at ≥25, but only when using newer technology that affords maximal resolution of ovarian follicles (i.e. transducer frequency ≥8 MHz). If such technology is not available, we recommend using OV rather than FNPO for the diagnosis of PCOM for routine daily practice but not for research studies that require the precise full characterization of patients. The Task Force recognizes the still unmet need for standardization of the follicle counting technique and the need for regularly updating the thresholds used to define follicle excess, particularly in diverse populations. Serum AMH concentration generated great expectations as a surrogate marker for the follicle excess of PCOM, but full standardization of AMH assays is needed before they can be routinely used for clinical practice and research. Finally, the finding of PCOM in ovulatory women not showing clinical or biochemical androgen excess may be inconsequential, even though some studies suggest that isolated PCOM may represent the milder end of the PCOS spectrum. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Mulder I.M.,Erasmus Medical Center | La Chapelle C.F.,Leiden University | Lange J.F.,Erasmus Medical Center
British Journal of Surgery | Year: 2012

Background: Broad implementation of laparoscopic surgery has made trocar-related complications clinically important. Trocar-site hernia (TSH) is an uncommon, but potentially serious, complication that occasionally requires emergency surgery. This systematic review was conducted to establish the prevalence and risk factors for TSH. Methods: The review was conducted according to the PRISMA guidelines. MEDLINE, Embase, Web of Science and the Cochrane Library were searched to 7 June 2010 for studies on TSH. Results: Twenty-two articles were included. One study was a randomized clinical trial, five were prospective cohort studies and 16 were retrospective cohort studies. The prevalence of TSH is low, with a median pooled estimate of 0·5 (range 0-5·2) per cent. No meta-analysis on risk factors could be performed. Pyramidal trocars, 12-mm trocars and a long duration of surgery were identified as the most important technical risk factors for TSH. Older age and a higher body mass index were observed to be patient-related risk factors. Conclusion: TSH is an uncommon complication of laparoscopic surgery. The most important technical risk factors are the design and size of the trocars. The scientific evidence for recommendations to avoid TSH is sparse. Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.


Kunst A.E.,University of Amsterdam | Amiri M.,Erasmus Medical Center | Amiri M.,Shahrekord University of Medical Sciences | Janssen F.,University of Groningen
Stroke | Year: 2011

Background and Purpose-This article aims to make projections of future trends in stroke mortality in the Year 2030 based on recent trends in stroke mortality in 7 Western European countries. Methods-Mortality data were obtained from national cause of death registries. Annual rates of decline in stroke mortality of 1980 to 2005 were determined for men and women in the United Kingdom, France, the Netherlands, and 4 Nordic countries on the basis of regression analysis. Estimated rates of decline were extrapolated until 2030. Cause-elimination life tables were used to determine the effect of stroke in 2030 in terms of potential gain in life expectancy. The absolute numbers of stroke deaths in 2030 were estimated using national population projections of Eurostat. Results-In all countries, stroke mortality rates declined incessantly until 2005 among both men and women. If these trends were to continue, age-adjusted mortality rates would decline by approximately half between 2005 and 2030 with larger declines in France (approximately two thirds) and smaller declines in the Netherlands, Denmark, and Sweden (approximately one fourth). Similar rates of decline would be observed in terms of potential gain in life expectancy. Because of population aging, the absolute number of stroke deaths would decline slowly in the United Kingdom and France and stabilize or even increase in other countries. Conclusions-In the near future, stroke may lose much of its effects on life expectancy but remain a frequent cause of death among elderly populations. The prevention of stroke-related disability instead of mortality may become increasingly more important. © 2011 American Heart Association, Inc.


Heuer H.,Leibniz Institute for Age Research | Visser T.J.,Erasmus Medical Center
Biochimica et Biophysica Acta - General Subjects | Year: 2013

Background: As a prerequisite for thyroid hormone (TH) metabolism and action TH has to be transported into cells where TH deiodinases and receptors are located. The trans-membrane passage of TH is facilitated by TH transporters of which the monocarboxylate transporter MCT8 has been most intensively studied. Inactivating mutations in the gene encoding MCT8 are associated with a severe form of psychomotor retardation and abnormal serum TH levels (Allan-Herndon-Dudley syndrome). In order to define the underlying pathogenic mechanisms, Mct8 knockout mice have been generated and intensively studied. Most surprisingly, Mct8 ko mice do not show any neurological symptoms but fully replicate the abnormal serum thyroid state. Scope of review: We will summarize the findings of these mouse studies that shed light on various aspects of Mct8 deficiency and unambiguously demonstrated the pivotal role of Mct8 in mediating TH transport in various tissues. These studies have also revealed the presence of the complex interplay between different pathogenic mechanisms that contribute to the generation of the abnormal TH serum profile. Major conclusions: Most importantly, studies of Mct8 ko mice indicated the presence of additional TH transporters that act in concert with Mct8. Interesting candidates for such a function are the L-type amino acid transporters Lat1 and Lat2 as well as the organic anion transporting polypeptide Oatp1c1. General significance: Overall, the analysis of Mct8 deficient mice has greatly expanded our knowledge about the (patho-) physiological function of this transporter and established a sound basis for the characterization of additional TH transporter candidates. This article is part of a Special Issue entitled Thyroid hormone signalling. © 2012 Elsevier B.V. All rights reserved.


News Article | October 12, 2016
Site: www.nature.com

No sample-size estimate was calculated before the study was executed. The experiments were not randomized. The investigators were not blinded to allocation during experiments and outcome assessment. Endoscopic, colorectal and duodenal biopsy samples were obtained from individuals of different ages that had been admitted for suspected inflammation. One individual (donor 1) showed no inflammation during colonoscopy, but was later diagnosed with microscopic colitis. The other individuals were found to be healthy based on standard histological examination. Endoscopic biopsies were performed at the University Medical Center Utrecht and the Wilhelmina Children’s Hospital. The patients’ informed consent was obtained and this study was approved by the ethical committee of University Medical Center Utrecht. Additionally, normal tissue was isolated from resected colon segments at >5 cm distance from a tumour in three colorectal cancer patients (donors 3, 4 and 19). The colonic tissues were obtained at The Diakonessen Hospital Utrecht with informed consent and the study was approved by the ethical committee. Liver biopsies (0.5–1 cm3) were obtained from donor livers during transplantations performed at the Erasmus Medical Center, Rotterdam. Both liver and colon biopsies were obtained from donor 18. The Medical Ethical Council of the Erasmus MC approved the use of this material for research purposes, and informed consent was provided by all donors and/or relatives. Dissociated colon and small intestinal crypts were isolated from the biopsies and cultured for 1 - 2 weeks under conditions that are optimal for stem-cell proliferation, as previously described5. Liver cells were isolated from human liver biopsies and cultured as previously described3. From these cultures, single cells were sorted by flow cytometry and clonally expanded (Extended Data Fig. 1a). Clonal ASC cultures were subsequently established by manual picking of individual organoids derived from single cells and in vitro expansion for a period of ~6 weeks. DNA libraries for Illumina sequencing were generated using standard protocols (Illumina) from 200 ng - 1 μg of genomic DNA isolated from the clonally expanded ASC cultures with genomic tips (Qiagen). The libraries were sequenced with paired-end (2 × 100 bp) runs using Illumina HiSeq 2500 sequencers to a minimal depth of 30× base coverage. Samples of donors 1, 2, 3, 4, 10, 12, 13, 15, 16, 18 and 19 were sequenced using Illumina HiSeq X Ten sequencers to equal depth. The reference samples, blood or biopsy, were sequenced similarly. Sequence reads were mapped against human reference genome GRCh37 using Burrows–Wheeler Aligner v0.5.9 mapping tool27 with settings ‘bwa mem -c 100 –M’. Sequence reads were marked for duplicates using Sambamba v0.4.7 (ref. 28) and realigned per donor using Genome Analysis Toolkit (GATK) IndelRealigner v2.7.2 and sequence read-quality scores were recalibrated with GATK BaseRecalibrator v2.7.2. Alignments from different libraries of the same ASC culture were combined into a single BAM file. Raw variants were multi-sample (per donor) called using the GATK UnifiedGenotyper v2.7.2 (ref. 29) and GATK-Queue v2.7.2 with default settings and additional option ‘EMIT_ALL_CONFIDENT_SITES’. The quality of variant and reference positions was evaluated using GATK VariantFiltration v2.7.2 with options ‘–filterExpression “MQ0 ≥4 && ((MQ0 / (1.0 * DP)) > 0.1)”–filterName “HARD_TO_VALIDATE”–filterExpression “QUAL < 30.0 “–filterName “VeryLowQual”–filterExpression “QUAL > 30.0 && QUAL < 50.0 “–filterName “LowQual”–filterExpression “QD < 1.5 “–filterName “LowQD”’. To obtain high-quality catalogues of somatic point mutations, we applied a comprehensive filtering procedure (Extended Data Fig. 1b). We considered variants that were passed by VariantFiltration and had a GATK phred-scaled quality score ≥100. Subsequently, for each ASC culture, we considered the positions with a base coverage of at least 20× in both the culture and the reference sample (blood or biopsy). Furthermore, we only regarded variants at autosomal chromosomes. We excluded variant positions that overlapped with single-nucleotide polymorphisms (SNPs) in the SNP database (dbSNP) v137.b37 (ref. 30). Furthermore, we excluded all positions that were found to be variable in at least two of three unrelated individuals (that is, donor 5, 6 and X (not in study)) to exclude recurrent sequencing artefacts. To obtain somatic point mutations, we filtered out all variants with any evidence of the alternative allele in the reference sample. We validated the clonal origin of the sequenced ASC cultures by analysing the variant allele frequencies (VAFs) of the somatic mutations. Two cultures (donor 14, cell b and donor 17, cell c) showed a shift in the peak of the somatic heterozygous mutations to the left, indicating that they did not arise from a single stem cell, and were therefore excluded from the analysis (Extended Data Fig. 2). Finally, for all cultures we excluded point mutations with a VAF < 0.3 to exclude mutations that were potentially induced in vitro after the (first) clonal step (Extended Data Fig. 1b–d). The number of mutations that passed each filtering step for the samples of donor 5 and 6 is depicted in Extended Data Fig. 1c. The overlap of the point mutations between ASCs of the same donor is depicted in Extended Data Fig. 4d. We evaluated our mutation filtering procedure by independent validations of 374 pre-selected positions that were either discarded or passed during filtering using amplicon-based next-generation sequencing. To this end, primers were designed ~250 nucleotides 5′ and 3′ from the candidate point mutations to obtain amplicons of ~500 bp (primer sequences available upon request). These regions were PCR-amplified for both the organoid cultures and reference samples of donor 5 and 6, using 5 ng genomic DNA, 1× PCR Gold Buffer (Life Technologies), 1.5 mM MgCl , 0.2 mM of each dNTP and 1 unit of AmpliTaq Gold (Life Technologies) in a final volume of 10 μl. This which was held at 94 °C for 60 s followed by 15 cycles at 92 °C for 30 s, 65 °C for 30 s (with a decrement of 0.2 °C per cycle) and 72 °C for 60 s; followed by 30 cycles of 92 °C for 30 s, 58 °C for 30 s and 72 °C for 60 s; with a final extension at 72 °C for 180 s. The PCR products were pooled and barcoded per culture. Illumina sequence libraries were generated according to the manufacturer’s protocol. Subsequently, the libraries were pooled and sequenced using the MiSeq platform (2 × 250 bp) to an average depth of ~100×. Alignment and variant-calling was performed as described above. For each ASC we evaluated those positions with at least 20× coverage for both culture and reference sample, and defined positive positions as those with a call in culture, with a VAF ≥ 0.3 and no call in the reference sample. Subsequently, we determined the number of confirmed negatives of the positions that were filtered out for each filter step (Extended Data Fig. 1d). Moreover, we determined the number of confirmed positive of the positions that passed all filters (Extended Data Fig. 1e, f). We expanded 10 initial clonal organoid cultures from small intestine and liver for a further 3–5 months (equivalent to ~20 weekly passages), upon which we isolated single cells and subjected them to clonal expansion to obtain sufficient DNA for WGS (Extended Data Fig. 6a). This approach allowed us to catalogue the mutations that accumulated in single ASCs during the culturing period between the two clonal steps. To this end, we selected the somatic point mutations that were unique to the sub-clonal cultures and not present in the corresponding original clonal cultures and therefore acquired during the in vitro expansion. We evaluated the specificity of our mutation-discovery procedure by determining the confirmation rate of the mutations identified in the original clone in the corresponding subclone. Only positions that had a coverage of ≥20× in both the original clonal and corresponding subclonal culture as well as in the reference sample were evaluated. On average, 91.1% ± 4.87 (mean ± s.d). of these point mutations were confirmed in the subclonal cultures (Extended Data Fig. 3). The surveyed area per ASC was calculated as the number of positions coverage ≥20× in both culture and the reference sample. The percentage of the whole non-N autosomal genome (GCRh37: 2,682,655,440 bp) that is surveyed in each ACS is depicted in Extended Data Table 1. For each ASC the total number of identified somatic point mutations was extrapolated to the whole non-N autosomal genome using its surveyed area. Subsequently, a linear mixed-effects regression model was fitted to estimate the effect of age on the number of somatic point mutations for each tissue using the nlme R package31, 32, in which ‘donor’ is modelled as a random effect to resolve the non-independence that results from having multiple measurements per donor. A two-tailed t-test was performed to test whether the slope is significantly different from zero (that is to say, whether the fixed age effect in the linear mixed model is statistically significant). The intercept of the regression lines with the y axis represents the somatic mutations present at birth (that have accumulated in the tissue lineage during prenatal development) plus the noise levels in the data and the mutations that have accumulated during the first week(s) of culturing proceeding the clonal step (see above). Since all cells were assessed in a similar manner, noise levels will be comparable and therefore will not bias the mutation rate (slope) estimates. The slope of the regression line was used to estimate the fixed age effect on somatic point mutation rate per tissue. To exclude the possibility that differences in surveyed areas between ASCs bias our results, we performed the age correlation and spectrum analyses on a subset of mutations that are located in genomic regions that are surveyed (≥20×) in all samples in this study. This consensus surveyed area comprises 38.2% of the autosomal non-N genome and both the mutation rate and spectra were highly similar to those in Fig. 1c (Extended Data Fig. 4a–c), indicating that the differences in surveyed areas between the clones do not bias our conclusions. To generate a conserved DNA replication timing profile for the human genome, we downloaded 16 Repli-seq data sets from the ENCODE project33 at the University of California, SantaCruz (UCSC) genome browser34 (GRCh37/hg19). The data consisted of Wavelet-smoothed values per 1-kb bin throughout the genome for 15 different cell lines (BJ, BG02ES, GM06990, GM12801, GM12812, GM12813, GM12878, HeLa-S3, HepG2, HUVEC, IMR90, K562, MCF-7, NHEK and SK-N-SH). We considered the median values of all cell lines per bin, thereby excluding cell-specific values. We arbitrarily divided the genome into early- (≥60), intermediate- (>33 & <60) and late- (≤33) replicating bins (Fig. 3b). To generate a conserved chromatin-association profile for the human genome, we downloaded data containing the H3K9me3 signal per 25-nucleotide bin throughout the genome for 22 different cell lines (A549, AG04450, DND41, GM12878, H1-hESC, HeLa-S3, HepG2, HMEC, HSMM, HSMMt, HUVEC, K562, monocytes-CD14+_RO1746, NH-A, NHDF-Ad, NHEK, NHLF, osteoblasts, MCF-7, NT2-D1, PBMC and U2OS) and the H3K27ac signal for 9 different cell lines (CD20+_RO01794, DND41, H1-hESC, HeLa-S3, HSMM, monocytes-CD14+_RO1746, NH-A, NHDF and osteoblasts). Data were downloaded from the ENCODE project33 at the UCSC browser34 (GRCh37/hg19) and the median values of all cell lines per bin were calculated. Next, we determined the distribution of the fractions of all bins (genome-wide). According to the shape of the resulting graph, we considered bins with an H3K9me3 value ≥4, or an H3K27ac value ≥2, as associated with that chromatin mark. Finally, exonic sequences were defined as all exonic regions reported in Ensembl v75 (GCRh37)35. We determined whether somatic point mutations were enriched or depleted in the genomic regions described above. To this end, we determined how many point mutations were observed in each genomic region for each donor. Next, we calculated the number of bases that were surveyed in each genomic region and calculated the expected number of point mutations by multiplying this surveyed length with the genome-wide point-mutation frequency. The log (observed/expected) of the mutations in the genomic regions was used as a measure of the effect size of the depletion or enrichment. One-tailed binomial tests were performed to calculate the statistical significance of deviations from the expected number of mutations in the genomic regions using pbinom31; P < 0.05 was considered significant. The occurrences of all 96-trinucleotide changes were counted for each ASC and averaged per donor. Three mutational signatures were extracted using NMF36. To determine the replication bias of signatures, we determined whether the point mutations were located in an intermediate, early or late replicating region (as defined above) using GenomicRanges37 and repeated the NMF on a 288 count matrix (96 trinucleotides × 3 replication timing regions). Similarly, we looked at transcriptional strand bias by performing NMF on a 192 count matrix (96 trinucleotides × 2 strands). To this end, we selected all point mutations that fall within gene bodies and checked whether the mutated C or T was located on the transcribed or non-transcribed strand. We defined the transcribed units of all protein coding genes based on Ensembl v75 (GCRh37)35 and included introns and untranslated regions. The dN/dS ratio was determined as described previously18. In brief, we used 192 rates, one for each of the possible trinucleotide changes in both strands. For each substitution type, we counted the number of potential synonymous and non-synonymous mutations in the protein-coding sequences of the human genome, using the longest DNA coding sequence as the reference sequence for each gene. Poisson regression was used to obtain maximum-likelihood estimates and confidence intervals of the normalized ratio of non-synonymous versus synonymous mutations (dN/dS ratio). The dN/dS ratio was tested against neutrality (dN/dS = 1) using a likelihood-ratio test. Intestinal ASCs were isolated from the proximal part of the small intestine of randomly chosen ~2-year-old mice (one male and one female) carrying the Lgr5-EGFP-Ires-CreERT2 allele (mice were C57BL/6 background) by sorting for GFPhigh cells. Subsequently, three Lgr5-positive cells per animal were clonally expanded as described4. All experiments were approved by the Animal Care Committee of the Royal Dutch Academy of Sciences according to the Dutch legal ethical guidelines. DNA isolated from the intestinal ASC cultures isolated from mouse 1 were sequenced with paired-end (75 and 35 bp) runs using SOLiD 5500 sequencers (Life Technologies) to an average depth of ~18× base coverage. Intestinal ASC cultures of mouse 2 were sequenced using Illumina HiSeq 2500 sequencers as described above. Sequence reads were aligned using Burrows–Wheeler Aligner to the mouse reference genome (NCBIM37) and point mutations were called using the GATK UnifiedGenotyper v2.7.2 as described above. Post-processing filters for the intestinal ASCs of mouse 1 (analysed by SOLiD sequencing) were as follows: a minimum depth of 10×, variant uniquely called in one intestinal stem cell without more than one alternative allele found at the same position in the other ASCs of the same mouse, a GATK a phred-scaled quality score ≥100, variant absent in mouse 2, variant position absent in the dbSNP (build 128) and a VAF ≥ 0.25. Post-processing filters for the intestinal ASCs of mouse 2 (analysed by Illumina sequencing) were as described above for the human mutation data. Mutations identified in the indicated genes in colorectal or liver cancers were downloaded from cBioPortal (http://www.cbioportal.org/). Only point mutations that resulted in a missense, nonsense or splice-site mutation were considered. To detect copy-number variations (CNVs), BAM files were analysed for read-depth variations by CNVnator v0.2.7 (ref. 39) with a bin size of 1 kb and Control-FREEC v6.740 with a bin size of 5 kb. Highly variable regions, defined as harbouring germline CNVs in at least three control samples, were excluded from the analysis. To obtain somatic CNVs, we excluded CNVs for which there was evidence in the reference sample (blood/biopsy) of the same individual. Resulting candidate CNV regions were assessed for additional structural variants on the paired-end and split-read level through DELLY v0.3.3 (ref. 41). Based on these results, we excluded five candidate CNV regions as mapping artefacts on the read-depth level and acquired base-pair accuracy of the involved breakpoints for the other events. This also revealed the tandem orientation of the duplication events and the complex structural variation in the colon sample. Reported gene definitions (Extended Data Table 2) are based on Ensembl v75 (GCRh37)35. Common fragile sites overlapping the events were detected using existing definitions42. LINE/SINE elements within 100 bp of the breakpoints were determined with the repeat element annotation43 from the UCSC genome browser34 GCRh37 (retrieved 26 October 2015). All code and filtered vcf files are freely available under a MIT License at https://wgs11.op.umcutrecht.nl/mutational_patterns_ASCs/ and https://github.com/CuppenResearch/MutationalPatterns/.


News Article | November 17, 2016
Site: www.prnewswire.co.uk

Publikation im Journal of Clinical Virology demonstriert Effektivität und einfache Handhabung für Routinetests AUSTIN, Texas, 17. November 2016 /PRNewswire/ -- Die Luminex Corporation (NASDAQ: LMNX) gab heute bekannt, dass die international renommierte Abteilung für Virologie im Erasmus Medical Center in Rotterdam, Niederlande, das ARIES® System und Flu A/B & RSV CE-IVD Assay für klinische Tests in einer kürzlich veröffentlichten Studie evaluiert hat. Das Erasmus MC ist ein Konsultationszentrum zu viralen Infektionen für die Weltgesundheitsorganisation und dient ebenfalls in den Niederlanden als nationales Referenzzentrum für Influenza und aufkommende Infektionen. In der Studie zeigten die ARIES® Plattform und das Flu A/B & RSV Assay eine hohe klinische Spezifizität und Sensitivität, die mit laborentwickelten RT-PCR Assays vergleichbar sind, sowie bessere Ergebnisse in diesem Zusammenhang als jene von etablierten Assays, wie z. B. immunchromatographische Tests und direkte Immunfluoreszenz-Tests. Die Anwenderfreundlichkeit ist laut Studie mit anderen schnellen molekularen Testplattformen gleichzusetzen. Die ARIES® Plattform ist insofern einzigartig, da man mit ihr ebenfalls intern entwickelte Assays in Echtzeit mit generischen ARIES® Kassetten durchführen kann. „Wir sind sehr stolz, dass eines der führenden medizinischen Zentren für klinische Virologie nach einer sorgfältigen Beurteilung die Effektivität und leichte Handhabung von ARIES festgestellt hat", sagte Thomas Pracht, Managing Director für EMEIA bei der Luminex Corporation. „Die Erasmus-Studie zeigt die Qualität und Leistung der ARIES® Plattform und den Nutzen des Systems für Molekulardiagnose-Labore, die MDx-Testverfahren „außerhalb des Takts" durchführen wollen – in anderen Worten, außerhalb der offiziellen Dienstzeiten für Tests oder beispielsweise Statistiktests zwischen den Testläufen während der offiziellen Dienstzeiten im Labor. Die Studie unterstreicht ebenfalls die Bedeutung der Tests mit Direktauswirkung, bei denen die Resultate zu unmittelbaren Folgen für die Patientenbehandlung und die klinische Entscheidungsfindung führen – selbst außerhalb der normalen Dienstzeiten." Lesen Sie die komplette Studie „Performance evaluation of a rapid molecular diagnostic, MultiCode based, sample-to-answer assay for the simultaneous detection of Influenza A, B and respiratory syncytial viruses", veröffentlicht im Journal of Clinical Virology, Dezember 2016, Volume 85, Seiten 65-70. Über die Luminex Corporation Luminex hat sich das Ziel gesetzt, Labore bei der Suche nach zuverlässigen, zeitnahen und umsetzbaren Antworten zu unterstützen, um letztlich zur Förderung der Gesundheit beizutragen. Wir bieten ein breites Spektrum von Lösungen, die in verschiedenen Märkten eingesetzt werden können, unter anderem in den Bereichen klinische Diagnostik, pharmazeutische Wirkstoffentwicklung, Genom- und Proteomikforschung, biologische Abwehrforschung und Lebensmittelsicherheit. Unser Unternehmen stellt Antworten schneller bereit, vereinfacht gleichzeitig die Komplexität und verschafft sichere Erkenntnisse auf der Grundlage einer nahtlosen Anwendererfahrung. Weitere Informationen über Luminex erhalten Sie, wenn Sie luminexcorp.com aufrufen. Aussagen in dieser Pressemitteilung, welche die Absichten, Pläne, Überzeugungen, Erwartungen oder Prognosen von Luminex bzw. der Geschäftsführung von Luminex zu zukünftigen Ereignissen ausdrücken, sind sogenannte vorausschauende Aussagen. Zu den vorausschauenden Aussagen in dieser Pressemitteilung gehören Aussagen über die Entwicklung und die Prüfungsfortschritte unserer Pipeline-Produkte sowie über deren regulatorische Zulassung. Begriffe wie „glauben", „erwarten", „beabsichtigen", „prognostizieren", „überzeugt", „werden", „könnten", „sollten" und ähnliche Ausdrücke weisen auf derartige vorausschauende Aussagen im Sinne des Private Securities Litigation Reform Act von 1995 hin und machen sie kenntlich. In diesem Zusammenhang wird ausdrücklich darauf hingewiesen, dass sich die tatsächlichen Ergebnisse oder Leistungen des Unternehmens wesentlich von jenen unterscheiden könnten, die in solchen vorausschauenden Aussagen prognostiziert werden. Zu den Faktoren, die dazu führen könnten, dass die tatsächlichen Ergebnisse oder Leistungen von Luminex erheblich abweichen, gehören Risiken und Unwägbarkeiten u. a. im Zusammenhang mit unserer Fähigkeit, Produkte zeitnah auf dem Markt einzuführen, mit dem zeitlichen Ablauf regulatorischer Zulassungen und dem Ergebnis klinischer Studien ebenso wie die im Abschnitt „Risikofaktoren" in den von Luminex bei der Securities and Exchange Commission auf den Formularen 10-K und 10-Q eingereichten und erörterten Risiken. Die hier enthaltenen vorausschauenden Aussagen geben die Einschätzung von Luminex zum Zeitpunkt der Veröffentlichung dieser Pressemitteilung wieder und Luminex lehnt ausdrückliche jede Absicht, Verpflichtung oder Zusicherung ab, öffentlich Aktualisierungen oder Berichtigungen an vorausschauenden Aussagen vorzunehmen, um Änderungen der Erwartungen von Luminex in diesem Zusammenhang oder Änderungen aufgrund von Ereignissen, Bedingungen oder Umständen, auf denen vorausschauenden Aussagen basieren, widerzuspiegeln.


News Article | November 17, 2016
Site: www.prnewswire.co.uk

Journal of Clinical Virology Publication Demonstrates Effectiveness and Ease of Use for Routine Testing AUSTIN, Texas, Nov. 17, 2016 /PRNewswire/ -- Luminex Corporation (NASDAQ: LMNX) today announced that the internationally renowned Department of Viroscience at Erasmus Medical Center in Rotterdam, The Netherlands, has evaluated the ARIES® System and Flu A/B & RSV CE-IVD Assay for clinical testing in a recently published study. Erasmus MC is a consultation center for the World Health Organization on viral infections, as well as serving as the National Reference Center for Influenza and Emerging Infections in The Netherlands. In the study, the ARIES® platform and Flu A/B & RSV Assay showed a high clinical specificity and sensitivity, comparable to laboratory developed RT-PCR assays, and better than those of established assays such as immunochromatographic tests and direct immunofluorescence assays. Ease of use was found to be comparable to other rapid molecular test platforms. The ARIES® platform is unique in that it can also run in-house developed real-time assays with generic ARIES® cassettes. "We are proud that after thorough evaluation, ARIES has been found to be effective and easy to use by one of the world's leading medical centers for clinical virology," said Thomas Pracht, Managing Director, EMEIA, at Luminex Corporation. "The Erasmus study demonstrates the quality and performance of the ARIES® platform and the value of the system for molecular diagnostic labs that want to perform 'out of sync' MDx testing — in other words, outside of office hours testing or stat testing during office hours in between runs. The study also underlines the importance of 'point of impact' tests, where results have an immediate impact on patient care and clinical decision making, even outside normal office hours." Read the complete study, "Performance evaluation of a rapid molecular diagnostic, MultiCode based, sample-to-answer assay for the simultaneous detection of Influenza A, B and respiratory syncytial viruses," published in the Journal of Clinical Virology, December 2016, Volume 85, Pages 65–70. About Luminex Corporation At Luminex, our mission is to empower labs to obtain reliable, timely, and actionable answers, ultimately advancing health. We offer a wide range of solutions applicable in diverse markets including clinical diagnostics, pharmaceutical drug discovery, biomedical research, genomic and proteomic research, biodefense research, and food safety. We accelerate reliable answers while simplifying complexity, and deliver certainty with a seamless experience. To learn more about Luminex, please visit us at luminexcorp.com. Statements made in this release that express Luminex's or management's intentions, plans, beliefs, expectations or predictions of future events are forward-looking statements. Forward-looking statements in this release include statements regarding the development and testing progress of our pipeline products, and the regulatory approvals thereof. The words "believe", "expect", "intend", "anticipates", "confident", "will", "could", "should", and similar expressions are intended to further identify such forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. It is important to note that the Company's actual results or performance could differ materially from those anticipated in such forward-looking statements. Factors that could cause Luminex's actual results or performance to differ materially include risks and uncertainties relating to, among others, our ability to launch products on time, the timing of regulatory approvals, the outcome of clinical trials as well as the risks discussed under the heading "Risk Factors" in Luminex's Reports on Forms 10-K and 10-Q, as filed with the Securities and Exchange Commission. The forward-looking statements contained herein represent the judgment of Luminex as of the date of this press release, and Luminex expressly disclaims any intent, obligation or undertaking to release publicly any updates or revisions to any forward-looking statements to reflect any change in Luminex's expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.


News Article | February 15, 2017
Site: www.eurekalert.org

GAINESVILLE, Fla. -- A two-drug cocktail provided better protection against diabetes-related vision loss than a single drug during testing in rat models, a team of University of Florida Health and Dutch researchers has found. Researchers say the drug combination is a promising and unique potential treatment for patients with diabetic retinopathy, a major cause of vision loss in middle-age diabetes patients. Diabetic retinopathy damages blood vessels in the retina at the back of the eye, leading to distorted vision or blindness. There were 4.2 million cases of diabetic retinopathy among people ages 40 and over in the United States, according to a 2016 estimate by the American Academy of Ophthalmology. Now, researchers from UF and the Erasmus Medical Center in the Netherlands have shown that the two drugs were more effective than a single drug at reducing the symptoms of diabetic retinopathy within the animals' retinas. The findings were published recently in the journal Investigative Ophthalmology & Visual Science. During the 12-week study, the two-drug treatment reduced capillary loss by 68 percent compared with 43 percent with the single drug. Known as angiotensin receptor neprilysin inhibitor, or ARNI, the cocktail is a combination of irbesartin (an angiotensin receptor blocker) -- a medication already being used to treat high blood pressure -- and the anti-diarrhea compound thiorphan, a neprilysin inhibitor. In the laboratory, its effectiveness was compared with using irbesartin alone. The two drugs did not completely reverse the effects of diabetic retinopathy, but they slowed it in the animal models, said Tuhina Prasad, Ph.D., a postdoctoral associate in the UF College of Medicine's department of ophthalmology research and a co-author of the paper. Most significantly, Prasad said the two drugs were much more effective at decreasing inflammation, which is one of the main symptoms of diabetic retinopathy. "If you can decrease that inflammation, it protects the retinal cells and delays the progression of the disease," Prasad said. The two-drug combination was also more effective than the lone drug at reducing cell death in the retina after 12 weeks in the rat models. The two drugs produced a 51 percent reduction in cell death, while the single drug showed only a 25 percent reduction, according to the findings. That is potentially significant in the development of drugs to treat diabetic retinopathy because the disease is strongly associated with prolonged diabetes in patients, the researchers noted. Before a treatment can be brought to patients, researchers still have some work ahead: The possible chronic side effects of the neprilysin enzyme inhibitor on the eye have yet to be studied. Likewise, the long-term effects of giving that inhibitor are still unknown. Still, Prasad said, the newly discovered compound may someday be a promising option for the millions of people living with diabetic retinopathy. Funding for the research was provided by grants from the National Institutes of Health, the American Diabetes Association and the Bright Focus Foundation. Other support was provided by the National Eye Institute and Research to Prevent Blindness.


News Article | November 22, 2016
Site: www.newscientist.com

Bird flu is back, and it’s got nastier – for birds, at least. The H5N8 virus has spread into Europe and is killing wild birds as well as invading poultry farms – a major worry for farmers in the run-up to the festive season. So far the virus doesn’t seem to infect humans, but it is evolving. The current strain is descended from the H5N1 virus, which started killing poultry in China in 1996, and then people too. H5N1 exploded across east Asia in 2004 with the poultry trade, and then spread into Europe and Africa in 2006, thanks to migrating birds. Since then, the virus has lurked mainly in poultry, especially flu-vaccinated chickens in Asia that can carry the virus while being immune to it. So far, 452 people have died after catching it from poultry. But viruses like H5N1 have also been moving with migrating dabbling ducks like mallards, which are usually immune to it. Birds from all over Eurasia mingle in north-central Asia during the summer, swap viruses, then disperse back to Africa, Asia and Europe for the winter. This has recently allowed H5N1 to hybridise with other kinds of flu. “We do not know what is driving the plethora of H5s,” although changes in climate and migration may be involved, says Julio Pinto at the UN Food and Agriculture Organization in Rome. As Europe’s poultry farmers fatten up their geese and turkeys for Christmas, one hybrid of H5N1 is now giving them sleepless nights. H5N8 appeared in China in 2014, before spreading with migrating ducks into Japan, Korea and across Russia into north-western Europe, including the UK. It also reached Canada and the US, devastating poultry farms until it was stamped out. It now seems to be gone from North America, says David Swayne at the US National Poultry Research Center in Athens, Georgia. It appeared to cause few deaths in wild birds in 2014, and failed to reappear in Eurasia the following winter. But in June, H5N8 caused a mass die-off of wild birds in the Uvs-Nuur basin between Russia and Mongolia, a protected biodiversity hotspot. This time round H5N8 has spread west along northern and southern migration routes into India, the Middle East and Europe, as birds have escaped colder weather in recent weeks. The virus is expected to spread further as lakes freeze and ducks keep searching for open water. Dozens of farms in Denmark, Switzerland and Germany are now infected. Free-range poultry such as geese have now been moved indoors, away from wild birds. Turkeys are extremely susceptible to the virus, and 9000 turkeys were killed last week on an infected farm in Hungary, a country that produces many turkeys and geese for Christmas. Unlike the 2014 strain, the virus is also killing wild birds, including swans, gulls, grebes and tufted ducks. Ron Fouchier at the Erasmus Medical Center in Rotterdam, the Netherlands, says H5N8 has picked up new genes from flu strains in wild birds, which could be making it deadly to more species. The Friedrich Löffler Institute in Insel Riems, Germany, is now testing different species for susceptibility to the virus. While humans have so far escaped infection, the World Health Organization says the risk “cannot be excluded”. “You can’t be complacent about these viruses,” says Ab Osterhaus, head of the newly launched Research Center for Emerging Infections and Zoonoses in Hannover, Germany. Osterhaus’s team found that the 2014 H5N8 strain could infect ferrets, the mammal used to model human flu. And he points to the seemingly harmless H7N7 bird flu outbreak in the Netherlands in 2003 that infected hundreds and killed a vet. “We need to learn much more about the ecology of these viruses,” he says. “They might just die out in wild birds if they don’t sometimes spill over into big poultry populations.” Farmers fattening turkeys and geese for year-end feasts are hoping this week that they won’t be the ones to suffer the next spill-over. Read more: Five easy mutations to make bird flu a lethal pandemic


News Article | October 31, 2016
Site: www.eurekalert.org

NEW YORK, NY (Oct. 31) -- A major international study has found that drug-eluting stents, a less-invasive alternative to bypass surgery, are as effective as surgery for many patients with a blockage in the left main coronary artery. Findings from the EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial were published this morning online in the New England Journal of Medicine and presented at the annual Transcatheter Cardiovascular Therapeutics conference in Washington, DC. The trial research team included interventional cardiologists and cardiac surgeons from 126 centers in 17 countries. Coronary artery bypass graft (CABG) surgery has long been considered the definitive treatment for patients with left main coronary artery disease (LMCAD), in which the artery that supplies oxygen-rich blood to most of the heart muscle is clogged with atherosclerotic plaque. About two-thirds of all LMCAD patients have mild to moderate disease in the remainder of the coronary arteries. "Our study has shown that many patients with left main coronary artery disease who prefer a minimally invasive approach can now rest assured that a stent is as effective as bypass surgery for at least 3 years, and is initially safer, with fewer complications from the procedure," said first author Gregg W. Stone, MD, professor of medicine at Columbia University Medical Center and director of cardiovascular research and education at the Center for Interventional Vascular Therapy at NewYork-Presbyterian/Columbia. Stents, which are placed into the diseased artery via a catheter that is inserted through a small opening in a blood vessel in the groin, arm, or neck, are a less-invasive treatment option for many people with coronary artery disease. However, coronary artery bypass surgery (CABG) has long been considered the definitive treatment for patients with LMCAD, which affects a large portion of the heart muscle. Previously, randomized clinical trials suggested that first-generation drug-eluting stents, which release antiproliferative medications to prevent the artery from becoming re-occluded after stent placement, might be appropriate for patients with LMCAD without extensive blockages in the remainder of the heart arteries. The trial results, however, were inconclusive. "Since that time, stents have gotten better, and so has cardiac bypass surgery," said Dr. Stone. "That required us to take a fresh look at the relative safety and effectiveness of the two approaches." In the current study, 1,905 patients with LMCAD and low or intermediate coronary artery disease complexity (as determined by the SYNTAX score, an angiographic tool for measuring disease severity) were randomized to receive a drug-eluting stent that releases the antiproliferative agent everolimus (XIENCE, made by Abbott Vascular of Santa Clara, CA) or bypass surgery. The patients were followed for at least two years, with a median follow-up of three years. "We found that approximately 15 percent of patients in both groups had a heart attack, stroke, or died within three years," said Dr. Stone, lead author of the paper. "In other words, stents were equally effective as bypass surgery." The researchers also analyzed what happened to the patients in the first 30 days after treatment, when serious complications are most likely to occur. Within that period, stent patients had a significantly lower incidence (4.9 percent) of death, stroke, heart attack, or revascularization than those who had bypass surgery (7.9 percent). In addition, fewer stent patients had major bleeding, infections, kidney failure, or severe abnormal heart rhythms compared to those treated with surgery. The researchers reported that bypass surgery should still be considered standard therapy for those with LMCAD and extensive blockages in the remainder of the heart arteries, although the study did not include patients with severe disease. "Our study establishes stents as an acceptable or preferred alternative for patients with LMCAD and low or moderate disease complexity in the other 3 coronary arteries--about two-thirds of all LMCAD patients," said Dr. Stone. "While bypass is still considered a more durable repair, patients and doctors may prefer a percutaneous treatment approach, which is associated with better upfront results, fewer complications, and quicker recovery." Coronary artery disease (CAD), the most common form of heart disease in the US, results from the buildup of atherosclerotic plaques in the arteries that supply oxygenated blood to the heart. CAD frequently leads to strokes or heart attacks, killing more than 370,000 people annually, according to the Centers for Disease Control and Prevention. The left main artery, the primary supply of blood to the heart, is affected in about 10 percent of people with CAD. The study is titled, "Comparison of Everolimus-Eluting Stents and Bypass Graft Surgery in Selected Patients with Left Main Coronary Artery Disease." The other contributors are: Joseph F. Sabik (Cleveland Clinic Foundation, Cleveland, OH); Patrick W. Serruys (International Centre for Circulatory Health, NHLI, Imperial College London, London, UK); Charles A. Simonton (Abbott Vascular, Santa Clara, CA); Philippe Généreux, Erick Schampaert, and Pierre Pagé (Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada); John Puskas and Roxana Mehran (Mount Sinai Hospital, New York, NY); Nicholas Lembo, David E. Kandzari, and W. Morris Brown, III (Piedmont Hospital, Atlanta, GA); Marie-Claude Morice (Générale de Santé, Hopital Privé Jacques Cartier, Massy, France); David Taggart and Adrian Banning (John Radcliffe Hospital, Oxford, UK); Béla Merkely and Ferenc Horkay (Semmelweis University, Budapest, Hungary); Piet W. Boonstra and Ad Johannes van Boven (Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands); Imre Ungi and Gabor Bogáts (University of Szeged, Szeged, Hungary); Samer Mansour and Nicolas Noiseux (Hôpital Hôtel-Dieu de Montréal, Montréal, Québec, Canada); Manel Sabaté and Jose Pomar (Hospital Clinic, Barcelona, Spain); Mark Hickey and Anthony Gershlick (University Hospitals of Leicester NHS Trust, Leicester, UK); Pawel Buszman and Andrzej Bochenek (Medical University of Silesia, Katowice, Poland and American Heart of Poland, Ustron, Poland); Ovidiu Dressler (Cardiovascular Research Center, New York, NY); Ioanna Kosmidou (NewYork-Presbyterian, New York, NY); Stuart J. Pocock (London School of Hygiene and Tropical Medicine, London, UK); and Arie Pieter Kappetein (Erasmus Medical Center, Rotterdam, The Netherlands). The study was sponsored and funded by Abbott Vascular, Santa Clara, CA. Additional authors' disclosures are included in the article. Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org. NewYork-Presbyterian is one of the nation's most comprehensive healthcare delivery networks, focused on providing innovative and compassionate care to patients in the New York metropolitan area and throughout the globe. In collaboration with two renowned medical school partners, Weill Cornell Medicine and Columbia University College of Physicians & Surgeons, NewYork-Presbyterian is consistently recognized as a leader in medical education, groundbreaking research and clinical innovation. NewYork-Presbyterian has four major divisions: NewYork-Presbyterian Hospital is ranked #1 in the New York metropolitan area by U.S. News and World Report and repeatedly named to the magazine's Honor Roll of best hospitals in the nation; NewYork-Presbyterian Regional Hospital Network is comprised of leading hospitals in and around New York and delivers high-quality care to patients throughout the region; NewYork-Presbyterian Physician Services connects medical experts with patients in their communities; and NewYork-Presbyterian Community and Population Health features the hospital's ambulatory care network sites and operations, community care initiatives and healthcare quality programs, including NewYork Quality Care, established by NewYork-Presbyterian, Weill Cornell and Columbia. NewYork-Presbyterian is one of the largest healthcare providers in the U.S. Each year, nearly 29,000 NewYork-Presbyterian professionals deliver exceptional care to more than 2 million patients. For more information, visit http://www. and find us on Facebook, Twitter and YouTube.


Diamant Z.,Erasmus Medical Center | Spina D.,King's College London
Pulmonary Pharmacology and Therapeutics | Year: 2011

Roflumilast is a selective once daily, oral phosphodiesterase-4 inhibitor that has recently been registered in all European Union countries as novel targeted therapy for COPD, while FDA approval for the USA market is expected in 2011. In several phase III trials in patients with moderate to (very) severe COPD and in patients with symptoms of chronic bronchitis and recurrent exacerbations, roflumilast showed sustained clinical efficacy by improving lung function and by reducing exacerbation rates. These beneficial effects have also been demonstrated when added to long-acting bronchodilators (both LABA and LAMA), underscoring the anti-inflammatory activity of roflumilast in COPD. Pooled data analysis showed overall mild to moderate, mostly self-limiting adverse events, mainly consisting of nausea, diarrhea and weight loss. In this review we discuss the results of the 4 registration studies showing promising effects of roflumilast in COPD and provide an overview of the topics that still need to be addressed. © 2011 Elsevier Ltd.


Manenschijn L.,Erasmus Medical Center | Van Kruysbergen R.G.P.M.,Arbo Unie Nijverdal | De Jong F.H.,Erasmus Medical Center | Koper J.W.,Erasmus Medical Center | Van Rossum E.F.C.,Erasmus Medical Center
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Background: The incidence of obesity and other features of the metabolic syndrome is increased in shift workers. This may be due to a misalignment between the internal circadian rhythm and the behavioral rhythm. The stress hormone cortisol could play a role in this phenomenon because it is secreted in a circadian rhythm, and long-term elevated cortisol leads to components of the metabolic syndrome. We compared cortisol levels in scalp hair of shift and day workers to study changes in long-term cortisol due to shift work. Methods: Hair samples were collected from 33 shift workers and 89 day workers. Cortisol was extracted from the hair samples with methanol, and cortisol levels were measured using ELISA. Height and weight were measured, and body mass index (BMI) was calculated. Results: Shift workers had higher hair cortisol levels than day workers: 47.32 pg/mg hair [95% confidence interval (CI) = 38.37-58.21] vs. 29.72 pg/mg hair (95% CI = 26.18-33.73) (P < 0.001). When divided in age groups based on the median age, elevated cortisol levels were present only in younger shift workers: 48.53 pg/mg hair (95% CI = 36.56-64.29) vs. 26.42 pg/mg hair (95% CI =22.91-30.55) (P < 0.001). BMI was increased in younger shift workers as well: 27.2 (95% CI =25.5-28.8) vs. 23.7 (95% CI = 22.8-24.7) in young day workers (P = 0.001). Hair cortisol and BMI were positively correlated (β = 0.262; P = 0.005). Conclusion: Shift work at a young adultage is associated with elevated long-term cortisol levelsand increased BMI. Elevated cortisol levels and BMI may contribute to the increased cardiovascular risk found in shift workers. Copyright © 2011 by The Endocrine Society.


van der Sluis S.,Medical Center | Posthuma D.,Medical Center | Posthuma D.,Erasmus Medical Center | Dolan C.V.,University of Amsterdam | Dolan C.V.,VU University Amsterdam
PLoS Genetics | Year: 2013

To date, the genome-wide association study (GWAS) is the primary tool to identify genetic variants that cause phenotypic variation. As GWAS analyses are generally univariate in nature, multivariate phenotypic information is usually reduced to a single composite score. This practice often results in loss of statistical power to detect causal variants. Multivariate genotype-phenotype methods do exist but attain maximal power only in special circumstances. Here, we present a new multivariate method that we refer to as TATES (Trait-based Association Test that uses Extended Simes procedure), inspired by the GATES procedure proposed by Li et al (2011). For each component of a multivariate trait, TATES combines p-values obtained in standard univariate GWAS to acquire one trait-based p-value, while correcting for correlations between components. Extensive simulations, probing a wide variety of genotype-phenotype models, show that TATES's false positive rate is correct, and that TATES's statistical power to detect causal variants explaining 0.5% of the variance can be 2.5-9 times higher than the power of univariate tests based on composite scores and 1.5-2 times higher than the power of the standard MANOVA. Unlike other multivariate methods, TATES detects both genetic variants that are common to multiple phenotypes and genetic variants that are specific to a single phenotype, i.e. TATES provides a more complete view of the genetic architecture of complex traits. As the actual causal genotype-phenotype model is usually unknown and probably phenotypically and genetically complex, TATES, available as an open source program, constitutes a powerful new multivariate strategy that allows researchers to identify novel causal variants, while the complexity of traits is no longer a limiting factor. © 2013 van der Sluis et al.


Atzberger C.,European Commission - Joint Research Center Ispra | Eilers P.H.C.,Erasmus Medical Center
International Journal of Remote Sensing | Year: 2011

Time series of vegetation indices like NDVI are used in numerous applications ranging from ecology to climatology and agriculture. Often, these time series have to be filtered before application. The smoothing removes noise introduced by undetected clouds and poor atmospheric conditions. Ground reference measurements are usually difficult to obtain due to the medium/coarse resolution of the imagery. Hence, new filter algorithms are typically only (visually) assessed against the existing smoother. The present work aims to propose a range of quality indicators that could be useful to qualify filter performance in the absence of ground-based reference measurements. The indicators comprise (i) plausibility checks, (ii) distance metrics and (iii) geostatistical measures derived from variogram analysis. The quality measures can be readily derived from any imagery. For illustration, a large SPOT VGT dataset (1999-2008) covering South America at 1km spatial resolution was filtered using the Whittaker smoother. © 2011 Taylor & Francis.


Scher H.I.,Sloan Kettering Cancer Center | Fizazi K.,University Paris - Sud | Saad F.,University of Montréal | Taplin M.-E.,Dana-Farber Cancer Institute | And 16 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. METHODS: In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. RESULTS: The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide. CONCLUSIONS: Enzalutamide significantly prolonged the survival of men with metastatic castrationresistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.) Copyright © 2012 Massachusetts Medical Society.


Crellin N.K.,Genentech | Trifari S.,Genentech | Kaplan C.D.,Genentech | Cupedo T.,Erasmus Medical Center | Spits H.,Genentech
Journal of Experimental Medicine | Year: 2010

Lymphoid tissue inducer (LTi) cells are required for lymph node formation during fetal development, and recent evidence implies a role in mucosal immunity in the adult. LTi cells share some phenotypic features of conventional natural killer (NK; cNK) cells; however, little is known to date about the relationship between these two cell types. We show that lineage- (Lin-) CD127+RORC+ LTi-like cells in human tonsil are precursors to CD56+CD127+RORC+NKp46+ cells, which together comprise a stable RORC+ lineage. We find that LTi-like cells and their CD56+ progeny can be expanded and cloned ex vivo without loss of function and without conversion into cNK cells. Clonal analysis reveals heterogeneity of cytokine production within the CD127+ LTi-like population. Furthermore, we identify within the tonsil a cNK precursor population that is characterized as Lin-CD117+CD161 +CD127- cells. Overall, we propose that CD127 +RORC+ cells, although they share some characteristics with cNK cells, represent a functionally and developmentally distinct lineage. © 2010 Crellin et al.


Maas A.I.R.,University of Antwerp | Roozenbeek B.,University of Antwerp | Roozenbeek B.,Erasmus Medical Center | Manley G.T.,University of California at San Francisco
Neurotherapeutics | Year: 2010

In this article, we review past and current experience in clinical trials of traumatic brain injuries (TBIs), we discuss limitations and challenges, and we summarize current directions. The focus is on severe and moderate TBIs. A systematic literature search of the years from 1980 to 2009 revealed 27 large phase III trials in TBI; we were aware of a further 6 unpublished trials. Analysis of these 33 trials yielded interesting observations:•There was a peak incidence of trial initiations that occurred in the mid-1990s with a sharp decline during the period from 2000 to 2004.•Most trials that reported a significant treatment effect were studies on a therapeutic strategy (e.g., decompressive craniectomy, hypothermia), and these were single-center studies.•Increasingly, studies have been shifting toward the Far East. The currently existing trial registries permit insight into ongoing or recently conducted trials. Compared with the past decade, the number of studies on neuroprotective agents taken forward into efficacy-oriented studies is low. In contrast, the number of studies on therapeutic strategies appears to be increasing again. The disappointing results in trials on neuroprotective agents in TBI have led to a critical reappraisal of clinical trial methodology. This has resulted in recommendations for preclinical workup and has triggered extensive analysis on approaches to improve the design and analysis of clinical trials in TBI. An interagency initiative toward standardization on selection and coding of data elements across the broad spectrum of TBI is ongoing, and will facilitate comparison of research findings across studies and encourage high-quality meta-analysis of individual patient data in the future. © 2010 The American Society for Experimental NeuroTherapeutics, Inc.


Luis T.C.,Erasmus Medical Center | Luis T.C.,Leiden University | Ichii M.,Oklahoma Medical Research Foundation | Brugman M.H.,Leiden University | And 3 more authors.
Leukemia | Year: 2012

A strict balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) is required in order to maintain homeostasis, as well as to efficiently respond to injury and infections. Numbers and fate decisions made by progenitors derived from HSC must also be carefully regulated to sustain large-scale production of blood cells. The complex Wnt family of molecules generally is thought to be important to these processes, delivering critical signals to HSC and progenitors as they reside in specialized niches. Wnt proteins have also been extensively studied in connection with malignancies and are causatively involved in the development of several types of leukemias. However, studies with experimental animal models have produced contradictory findings regarding the importance of Wnt signals for normal hematopoiesis and lymphopoiesis. Here, we will argue that dose dependency of signaling via particular Wnt pathways accounts for much, if not all of this controversy. We conclude that there seems little doubt that Wnt proteins are required to sustain normal hematopoiesis, but are likely to be presented in carefully controlled gradients in a tissue-specific manner. © 2012 Macmillan Publishers Limited All rights reserved.


Pieters M.,North West University South Africa | de Maat M.P.M.,Erasmus Medical Center
Blood Reviews | Year: 2015

Dietary factors are known to influence cardiovascular disease risk. They can do so via several mechanisms, including effects on blood lipids, antioxidant status, blood pressure, body composition and also haemostasis. Dietary factors influence the haemostatic system through several pathways related to different haemostatic components namely platelets, coagulation and fibrinolysis. This review provides a comprehensive overview on the inter-relations of dietary factors with all three components of the haemostatic system. Dietary factors reviewed include energy intake, alcohol consumption, dietary fat (quantity and composition), carbohydrates, micronutrients and miscellaneous food items. This review also provides information on the relationship of diet with fibrin network structure and genetics of haemostasis. In conclusion, diet has a clear impact on the various components of the haemostatic process. © 2014 Elsevier Ltd.


Li Y.,Erasmus Medical Center | Li Y.,Shanghai JiaoTong University | de Haar C.,Erasmus Medical Center | Peppelenbosch M.P.,Erasmus Medical Center | van der Woude C.J.,Erasmus Medical Center
Cytokine and Growth Factor Reviews | Year: 2012

Inflammatory bowel disease (IBD) has unclear pathogenesis and it is related to the increasing risk of developing colorectal cancer (CRC). Recent studies have uncovered the molecular mechanism of intracellular signaling pathways of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6. The major transcription factors including STAT3 have been shown to play a major role in transmitting inflammatory cytokine signals to the nucleus. The suppressors of cytokine signaling (SOCS) 3 protein is the key physiological regulators of cytokine-mediated STAT3 signaling. As such it influences the development of inflammatory and malignant disorders like this associated with IBD. Here we review the complex function of SOCS3 in innate and adaptive immunity, different cell types (macrophages, neutrophils, dendritic cells, B cells, T cells and intestinal epithelial cells) and the role of SOCS3 on the pathogenesis of inflammatory bowel disease (IBD) and IBD-related cancer. Finally, we explore how this knowledge may open novel avenues for the rational treatment of IBD and IBD-related cancer. © 2012 Elsevier Ltd.


Brenner H.,German Cancer Research Center | Altenhofen L.,Central Research Institute of Ambulatory Health Care in Germany | Katalinic A.,University of Lübeck | Lansdorp-Vogelaar I.,Erasmus Medical Center | Hoffmeister M.,German Cancer Research Center
American Journal of Epidemiology | Year: 2011

The sojourn time of preclinical colorectal cancer is a critical parameter in modeling effectiveness and cost-effectiveness of colorectal cancer screening. For ethical reasons, it cannot be observed directly, and available estimates are based mostly on relatively small historic data sets that do not include differentiation by age and sex. The authors derived sex-and age-specific estimates (age groups: 55-59, 60-64, 65-69, 70-74, 75-79, and ≥80 years) of mean sojourn time, combining data from the German national screening colonoscopy registry (based on 1.88 million records) and data from population-based cancer registries (population base: 37.9 million people) for the years 2003-2006. Estimates of mean sojourn time were similar for both sexes and all age groups and ranged from 4.5 years (95% confidence interval: 4.1, 4.8) to 5.8 years (95% confidence interval: 5.3, 6.3) for the subgroups assessed. Sensitivity analyses indicated that mean sojourn time might be approximately 1.5 years longer if colorectal cancer prevalence in nonparticipants of screening colonoscopy is 20% lower than prevalence in participants or 1 year shorter if it exceeds the prevalence in participants by 20%. This study provides, for the first time, precise estimates of sojourn time by age and sex, and it suggests that sojourn times are remarkably consistent across age groups and in both sexes. © 2011 The Author.


Van Den Bergh R.C.N.,University Utrecht | Ahmed H.U.,University College London | Bangma C.H.,Erasmus Medical Center | Cooperberg M.R.,University of California at San Francisco | And 2 more authors.
European Urology | Year: 2014

Context Active surveillance (AS) is an alternative to initial radical treatment of low-risk prostate cancer (PCa). Current criteria for selection and follow-up incorrectly exclude some patients eligible for AS and misclassify some who actually harbour significant disease. Better prediction of cancer behaviour at diagnosis would allow less strict monitoring and may improve acceptance of AS. Objective To review and critically analyse the literature on the value of novel clinical tools for patient selection and monitoring on AS. Evidence acquisition A comprehensive search of the PubMed database until July 10, 2013, was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis statement guidelines. Studies assessing novel markers and diagnostics for patient selection for AS and follow-up during AS were included. Studies analysing only classic clinical parameters used in current protocols (prostate-specific antigen, prostate volume, number of (positive) prostate biopsies, percentage malignant tissue, Gleason score) were excluded. This review focuses only on the AS setting and not on predicting insignificant disease in general. Evidence synthesis Of 787 studies on AS, 30 were included in this review: 14 on magnetic resonance imaging (MRI), 5 on serum markers, 5 on urinary markers, 4 on histopathology markers, and 2 on germline genetic markers. Several of these markers improve the prediction of tumour volume, tumour grade, or time to active treatment. MRI has a high specificity for low-risk PCa; new serum markers are associated with unfavourable disease. In none of the studies was the new marker used as the primary decision tool. Long-term outcome measures such as mortality were not assessed. The definition of indolent PCa is disputable. Conclusions Imaging and serum markers may improve future patient selection for AS and follow-up during AS. Prospective studies should aim to further evaluate the clinical utility of these new markers with respect to longer term outcomes of AS. Patient summary We searched the literature for articles reporting new ways to safely monitor low-risk prostate cancer for patients who have not had radical treatment. We found 30 articles. The most promising tools appear to be magnetic resonance imaging scans and various new blood markers. These may be used in the future within active surveillance regimens. © 2014 European Association of Urology.


Gho C.,Hair Science Institute | Neumann M.,Erasmus Medical Center
Facial Plastic Surgery | Year: 2014

Partial loss of the eyebrows can be the result of epilation, scars, and inflammatory diseases. Facial hair and eyebrows play a major role in our mimetic expression and interaction. Therefore, facial hair restoration of the eyebrows can improve the appearance and psychological well-being of patients. We report the use of partial longitudinal follicular unit transplantation (PLFUT) to restore eyebrows. A total of 10 patients (age between 18 and 59 years; mean, 39 years) have been treated with PLFUT to restore the eyebrows. The grafts were harvested from the occipital area of the scalp. Suitable grafts were impregnated with a preservative solution and implanted into the eyebrows areas. Hair growth in the donor area as well as the eyebrows was observed before treatment and at intervals of 1week, 3 months, and 1year after treatment. Evaluation of the donor area reveals no visible scars with almost all hair follicles in the donor site reproducing hairs after 1 year. All treated patients were satisfied or very satisfied with their cosmetic results. PLFUT is a reliable, patient friendly method suitable for hair restoration of eyebrows in healthy persons as well as in burn scar tissue.©2014 by Thieme Medical Publishers, Inc.


Sacchetti A.,Erasmus Medical Center | Sacchetti A.,University of Chieti Pescara
Journal of Cellular Biochemistry | Year: 2013

Among NSAIDs Celecoxib is one of the most efficient in triggering in vitro cancer cell death, and from this perspective has been subject of numerous studies. However, it is still controversial whether this in vitro-observed effect can also occur in vivo and contribute to the antitumor action of the drug. Moreover, besides common agreement on the involvement of COX-independent pathways, the mechanisms underlying Celecoxib toxicity are still unclear. In an attempt to shed light on these mechanisms, I found that cell death only occurs at insoluble concentrations of the drug, and follows irreversible binding and damage of the plasmamembrane by precipitates. This evidence strongly suggests that Celecoxib is devoid of true molecular toxicity. Moreover, since plasma levels reached during therapy are far below the threshold of toxic precipitation, direct cytotoxicity by Celecoxib is unlikely to occur on tumor cells in vivo. Thus the antitumor effect might be only due to COX inhibition, which requires significantly lower levels of the drug. Nonetheless, direct cytotoxicity might not be confined to an in vitro artifact, but contribute to the upper gastrointestinal side effects of Celecoxib. Overall, these findings represent an important basis for further studies on Celecoxib, where true molecular actions of the drug should be discriminated from the precipitate-dependent ones, and the relationship between in vitro and in vivo effects considered at the light of the precipitate-dependent model. Moreover, remarkably, this article indicates a model of critical analysis that can be extended to other poorly soluble drugs. J. Cell. Biochem. 114: 1434-1444, 2013. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.


Chaves I.,Erasmus Medical Center | Pokorny R.,University of Marburg | Byrdin M.,CNRS Institute of Pharmacology and Structural Biology | Hoang N.,University Paris - Sud | And 8 more authors.
Annual Review of Plant Biology | Year: 2011

Cryptochromes are flavoprotein photoreceptors first identified in Arabidopsis thaliana, where they play key roles in growth and development. Subsequently identified in prokaryotes, archaea, and many eukaryotes, cryptochromes function in the animal circadian clock and are proposed as magnetoreceptors in migratory birds. Cryptochromes are closely structurally related to photolyases, evolutionarily ancient flavoproteins that catalyze light-dependent DNA repair. Here, we review the structural, photochemical, and molecular properties of cry-DASH, plant, and animal cryptochromes in relation to biological signaling mechanisms and uncover common features that may contribute to better understanding the function of cryptochromes in diverse systems including in man. Copyright © 2011 by Annual Reviews. All rights reserved.


Tinmouth J.,University of Toronto | Lansdorp-Vogelaar I.,Erasmus Medical Center | Allison J.E.,University of California at San Francisco
Gut | Year: 2015

Although colorectal cancer (CRC) is a common cause of cancer-related death, it is fortunately amenable to screening with faecal tests for occult blood and endoscopic tests. Despite the evidence for the efficacy of guaiac-based faecal occult blood tests (gFOBT), they have not been popular with primary care providers in many jurisdictions, in part because of poor sensitivity for advanced colorectal neoplasms (advanced adenomas and CRC). In order to address this issue, high sensitivity gFOBT have been recommended, however, these tests are limited by a reduction in specificity compared with the traditional gFOBT. Where colonoscopy is available, some providers have opted to recommend screening colonoscopy to their patients instead of faecal testing, as they believe it to be a better test. Newer methods for detecting occult human blood in faeces have been developed. These tests, called faecal immunochemical tests (FIT), are immunoassays specific for human haemoglobin. FIT hold considerable promise over the traditional guaiac methods including improved analytical and clinical sensitivity for CRC, better detection of advanced adenomas, and greater screenee participation. In addition, the quantitative FIT are more flexible than gFOBT as a numerical result is reported, allowing customisation of the positivity threshold. When compared with endoscopy, FIT are less sensitive for the detection of advanced colorectal neoplasms when only one time testing is applied to a screening population; however, this is offset by improved participation in a programme of annual or biennial screens and a better safety profile. This review will describe how gFOBT and FIT work and will present the evidence that supports the use of FIT over gFOBT, including the cost-effectiveness of FIT relative to gFOBT. Finally, specific issues related to FIT implementation will be discussed, particularly with respect to organised CRC screening programmes.


Szczepanski T.,University of Silesia | Szczepanski T.,Erasmus Medical Center | Harrison C.J.,Northumbria University | van Dongen J.J.M.,Erasmus Medical Center
The Lancet Oncology | Year: 2010

The process of malignant transformation in paediatric acute leukaemias is complex, requiring at least two deleterious events resulting in DNA damage. This damage ranges from point-mutations to double-strand DNA breaks leading to various types of chromosomal rearrangements. In this review we summarise the most common genetic aberrations for the three main subtypes of paediatric acute leukaemia: B-cell-precursor acute lymphoblastic leukaemia, T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia. Several genetic aberrations are independent prognostic factors, and are now used in risk stratification for treatment. Molecular pathways activated by genetic aberrations could provide potential molecular targets for novel therapies. Some genetic aberrations represent sensitive targets for molecular detection of minimal residual disease. This provides hope for the development of targeted therapies, effective against leukaemic cells. © 2010 Elsevier Ltd.


Pinto R.Z.,The George Institute for Global Health | Maher C.G.,The George Institute for Global Health | Ferreira M.L.,The George Institute for Global Health | Hancock M.,Macquarie University | And 4 more authors.
Annals of Internal Medicine | Year: 2012

Background: Existing guidelines and systematic reviews provide inconsistent recommendations on epidural corticosteroid injections for sciatica. Key limitations of existing reviews are the inclusion of trials with active controls of unknown efficacy and failure to provide an estimate of the size of the treatment effect. Purpose: To determine the efficacy of epidural corticosteroid injections for sciatica compared with placebo. Data Sources: International Pharmaceutical Abstracts, PsycINFO, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL. Study Selection: Randomized, placebo-controlled trials assessing the efficacy of epidural corticosteroid injections in participants with sciatica. Data Extraction: Two independent reviewers extracted data and assessed risk of bias. Leg pain, back pain, and disability were converted to common scales from 0 (no pain or disability) to 100 (worst possible pain or disability). Thresholds for clinically important change in the range of 10 to 30 have been proposed for these outcomes. Effects were calculated for short-term (>2 weeks but ≤3 months) and long-term (≥12 months) follow-up. Data Synthesis: Data were pooled with a random-effects model, and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used in summary conclusions. Twenty-five published reports (23 trials) were included. The pooled results showed a significant, although small, effect of epidural corticosteroid injections compared with placebo for leg pain in the short term (mean difference, -6.2 [95% CI, -9.4 to -3.0]) and also for disability in the short term (mean difference, -3.1 [CI, -5.0 to -1.2]). The long-term pooled effects were smaller and not statistically significant. The overall quality of evidence according to the GRADE classification was rated as high. Limitation: The review included only English-language trials and could not incorporate dichotomous outcome measures into the analysis. Conclusion: The available evidence suggests that epidural corticosteroid injections offer only short-term relief of leg pain and disability for patients with sciatica. The small size of the treatment effects, however, raises questions about the clinical utility of this procedure in the target population. © 2012 American College of Physicians.


Background: Early diagnosis and treatment of the newborn infant with suspected sepsis are essential to prevent severe and life threatening complications. Diagnosis of neonatal sepsis is difficult because of the variable and nonspecific clinical presentation. Therefore, many newborns with nonspecific symptoms are started on antibiotic treatment before the presence of sepsis has been proven. With our recently published single-centre intervention study we were able to show that Procalcitonin determinations allowed to shorten the duration of antibiotic therapy in newborns with suspected early-onset sepsis.Methods/Design: The study is designed as randomized controlled international multicenter intervention trial on the efficacy and safety of Procalcitonin guided treatment. Term and near-term infants (gestational age ≥ 34 0/7 weeks) with suspected sepsis in the first 3 days of life requiring empiric antibiotic therapy will be included. The duration of antibiotic therapy in the standard group is based on the attending physician's assessment of the likelihood of infection (infection unlikely, possible, probable or proven). In the Procalcitonin group, if infection is considered to be unlikely or possible, antibiotic therapy is discontinued when two consecutive Procalcitonin values are within the normal range. Co-primary outcome measures are the duration of antibiotic therapy (superiority aspect of the trial) and the proportion of infants with a recurrence of infection requiring additional courses of antibiotic therapy and/or death in the first month of life (safety of study intervention, non-inferiority aspect of the trial). The number of infants to be included equals 800 per arm. With these numbers the power of the study to demonstrate superiority for duration of antibiotic therapy as well as non-inferiority regarding safety, i.e. excluding a disadvantage difference larger than 2% for the experimental arm, will both be greater than 80%.Discussion: Benefit of the study is a possible limitation of unnecessary use of antibiotics. The results of our first study suggest that there is a low risk on discontinuing antibiotic treatment too early, resulting in the development of a neonatal infection with its morbidity and mortality. © 2010 Stocker et al; licensee BioMed Central Ltd.


Gaillard R.,Erasmus Medical Center | Steegers E.A.P.,Obstetrics and Gynaecology | Tiemeier H.,Obstetrics and Gynaecology | Tiemeier H.,Erasmus Medical Center | And 2 more authors.
Circulation | Year: 2013

BACKGROUND -: Suboptimal fetal nutrition may influence early growth and cardiovascular development. We examined whether umbilical and uterine artery resistance indices, as measures of feto-placental and utero-placental vascular function, respectively, are associated with fetal and childhood growth and cardiovascular development. METHODS AND RESULTS -: This study was embedded in a population-based prospective cohort study among 6716 mothers and their children. Umbilical artery pulsatility index and uterine artery resistance index and fetal growth were measured in third trimester. Childhood growth was repeatedly assessed from birth to the age of 6 years. We measured body fat distribution, left ventricular mass, and blood pressure at the age of 6 years. Higher third trimester umbilical and uterine artery vascular resistance were associated with lower fetal length and weight growth in third trimester resulting in a smaller size at birth among boys and girls (P values < 0.05). These differences in length and weight growth became smaller from the age of 6 months onwards, but were still present at the age of 6 years. Higher third trimester umbilical artery vascular resistance, but not uterine artery vascular resistance, was associated with higher childhood body mass index, total fat mass, android/gynoid fat mass ratio, and systolic blood pressure, and with a lower left ventricular mass (P values<0.05). These associations were not explained by birth weight. Stronger associations tended to be present among girls as compared with boys. CONCLUSIONS -: Higher third trimester feto-placental vascular resistance, but not utero-placental vascular resistance, was associated with slower fetal growth rates and cardiovascular adaptations in childhood. © 2013 American Heart Association, Inc.


Goede V.,University of Cologne | Fischer K.,University of Cologne | Busch R.,TU Munich | Engelke A.,University of Cologne | And 18 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions. METHODS: We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival. RESULTS: The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P = 0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased. CONCLUSIONS: Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. Copyright © 2014 Massachusetts Medical Society.


News Article | August 25, 2016
Site: www.chromatographytechniques.com

Researchers have identified a gene that appears to curb coffee consumption. People with a DNA variation in a gene called PDSS2 tend to drink fewer cups of coffee, the study found. Experts say the findings suggest that the gene reduces the ability of cells to breakdown caffeine, causing it to stay in the body for longer. This means that a person would not need to consume as much coffee to get the same caffeine hit, the team says. The findings add to previous studies that have identified genes linked to coffee habits and shed new light on the biological mechanisms of caffeine metabolism. Researchers looked at genetic information from 370 people living in a small village in south Italy and 843 people from six villages in north-east Italy. Each of the study participants was asked to complete a survey that included a question about how many cups of coffee they drank each day. The team found that people with the DNA variation in PDSS2 tended to consume fewer cups of coffee than people without the variation. The effect was equivalent to around one fewer cup of coffee per day on average. The researchers replicated the study in a group of 1,731 people from the Netherlands. The result was similar but the effect of the gene on the number of cups of coffee consumed was slightly lower. This could be because of the different styles of coffee that are drunk in the two countries, the researchers say. In Italy, people tend to drink smaller cups such as espresso whereas in the Netherlands the preference is towards larger cups that contain more caffeine overall. The study was conducted at the Universities of Edinburgh and Trieste, the Burlo Garofolo Pediatric Institute in Italy, the Erasmus Medical Center and PolyOmica, a data analysis company based in Groningen, the Netherlands. Researchers from the Italian coffee company Illy also participated in the project though the company did not offer financial support. The study is published in the journal Scientific Reports. "The results of our study add to existing research suggesting that our drive to drink coffee may be embedded in our genes. We need to do larger studies to confirm the discovery and also to clarify the biological link between PDSS2 and coffee consumption," said Nicola Pirastu, a Chancellor's Fellow at the University of Edinburgh's Usher Institute.


Scientists have used a unique computational technique that sifts through big data to identify a subset of concussion patients with normal brain scans, who may deteriorate months after diagnosis and develop confusion, personality changes and differences in vision and hearing, as well as post-traumatic stress disorder. This finding, which is corroborated by the identification of molecular biomarkers, is paving the way to a precision medicine approach to the diagnosis and treatment of patients with traumatic brain injury. Investigators headed by scientists at UC San Francisco and its partner institution Zuckerberg San Francisco General Hospital and Trauma Center (ZSFG) analyzed an unprecedented array of data, using a machine learning tool called topological data analysis (TDA), which "visualizes" diverse datasets across multiple scales, a technique that has never before been used to study traumatic brain injury. TDA, which employs mathematics derived from topology, draws on the philosophy that all data has an underlying shape. It creates a summary or compressed representation of all the data points using algorithms that map patient data into a multidimensional space. The new research relied on a TDA platform developed by Ayasdi, an advanced analytics company based in Palo Alto, Calif. "TDA is a type of machine intelligence that provides a way to easily visualize patient differences across the full spectrum of traumatic brain injury from concussion to coma," said senior co-author, Adam Ferguson, PhD, associate professor in the Department of Neurological Surgery and a member of the UCSF Weill Institute for Neurosciences. "This has potential to transform diagnosis and predict outcome by providing a new level of precision." The study, publishing in PLOS ONE on March 1, 2017, is part of a government-funded multisite initiative called TRACK-TBI, Transforming Research and Clinical Knowledge in Traumatic Brain Injury, which was established to identify new diagnostic and prognostic markers, and to refine outcome assessments. Traumatic brain injury results in approximately 52,000 deaths, 257,000 hospitalizations and 2.2 million emergency department visits in the United States annually, according to the Centers for Disease Control and Prevention's Injury Center. These injuries can lead to widespread lesions throughout the brain's white matter, as well as a "cascade of secondary injury mechanisms that evolve over times." The heterogeneity of the manifestations of these secondary injuries is one significant obstacle that thwarts the development of new treatments, the authors note in their paper. "Traumatic brain injury lags 40 to 50 years behind cancer and heart disease in terms of progress and understanding of the actual disease process and its potential aftermath," said co-senior author Geoffrey Manley, MD, PhD, vice chair of the Department of Neurological Surgery at UCSF and chief of neurosurgery at ZFGH. "More than 30 clinical trials of potential traumatic brain injury treatments have failed, and not a single drug has been approved." In the study, so-called common data elements were collected from 586 patients with acute traumatic brain injury from trauma centers at ZSFG, University of Pittsburgh Medical Center and University Medical Center Brackenridge in Austin, Texas. These elements comprised 944 variables, including demographics, clinical presentation, imaging and psychological testing. The variables were edited by "data curators," to build a robust multivariate clinical dataset that could be harnessed by biomedical data scientists. Mapping of outcome using TDA revealed that concussion, or mild traumatic brain injury, could be stratified into multiple subgroups with diverse prognoses. Among them was a large group of patients who, despite normal brain scans, demonstrated poor recovery and a tendency to get worse, three-to-six months after the injury. These patients were likely to suffer from post-traumatic stress disorder. "These are patients with clear scans that would have been discharged from the hospital with nothing more than a recommendation to take over-the-counter medications," said Ferguson. "By recognizing these patients as a distinct subgroup, clinicians may be able to anticipate future symptoms and treat them proactively." According to first author Jessica Nielson, PhD, also of the UCSF Department of Neurological Surgery and the Weill Institute, the most challenging symptoms to treat are those that are not apparent immediately after an injury. "Eventually we hope to identify treatment targets early after injury to prevent this gradual decline and boost our ability to intervene and improve outcome for patients," she said. In addition to variants in PARP1, researchers found other biomarkers in patients' blood samples that were predictive of poor recovery, including ANKK1 and COMT. These genes are associated with signaling by the neurotransmitter dopamine and may provide critical clues to recovery and drugs' responsiveness. A future goal of TRACK-TBI is to contribute to the design of clinical trials to develop therapeutic drugs for traumatic brain injury - perhaps even tailored to a patient's blood-based biomarkers. "TDA improves upon traditional outcome prediction approaches for patients with traumatic brain injury," said Nielson, who is also affiliated with ZSFG. "By leveraging the full information provided by all outcomes, TDA has the potential to improve diagnosis and therapeutic targeting." TDA technology is already being used by banks for fraud detection and in military applications, but it has not reached the mainstream in biomedicine, according to the authors. "Potentially this could change very soon," said Ferguson. "Our proof-of-concept study demonstrates the maturity of the technology and its potential use in medical decision-making when coupled with high-quality data from electronic medical records." The study was supported by funding from the National Institutes of Health - National Institute of Neurological Disorders and Stroke. The study's co-authors are Shelly Cooper, John Yue, Tomoo Inoue, MD, PhD; and Mary Vassar of ZSFG and UCSF; Esther Yuh, MD, PhD, and Pratik Mukherjee, MD, PhD, of UCSF; Tanya Petrossian, PhD; Jesse Paquette MS, Pek Lum, PhD, and Gunnar Carlsson, PhD, of or previously of Ayasdi in Palo Alto, Calif.; Hester Lingsma, PhD, of Erasmus Medical Center in the Netherlands; Wayne Gordon, PhD, of Icahn School of Medicine at Mount Sinai in New York; Alex Valadka, MD, of Virginia Commonwealth University in Richmond; and David Okonkwo, MD, PhD, of the University of Pittsburgh.


Tavares L.,University of Oxford | Dimitrova E.,Babraham Institute | Oxley D.,Babraham Institute | Webster J.,Babraham Institute | And 10 more authors.
Cell | Year: 2012

Polycomb-repressive complex 1 (PRC1) has a central role in the regulation of heritable gene silencing during differentiation and development. PRC1 recruitment is generally attributed to interaction of the chromodomain of the core protein Polycomb with trimethyl histone H3K27 (H3K27me3), catalyzed by a second complex, PRC2. Unexpectedly we find that RING1B, the catalytic subunit of PRC1, and associated monoubiquitylation of histone H2A are targeted to closely overlapping sites in wild-type and PRC2-deficient mouse embryonic stem cells (mESCs), demonstrating an H3K27me3-independent pathway for recruitment of PRC1 activity. We show that this pathway is mediated by RYBP-PRC1, a complex comprising catalytic subunits of PRC1 and the protein RYBP. RYBP-PRC1 is recruited to target loci in mESCs and is also involved in Xist RNA-mediated silencing, the latter suggesting a wider role in Polycomb silencing. We discuss the implications of these findings for understanding recruitment and function of Polycomb repressors. © 2012 Elsevier Inc.


Muller A.E.,Radboud University Nijmegen | Muller A.E.,Erasmus Medical Center | Muller A.E.,St Elisabeth Hospital | Punt N.,Medimatics | Mouton J.W.,Radboud University Nijmegen
Journal of Antimicrobial Chemotherapy | Year: 2013

Objectives: The %fT.MIC of ceftazidime has been shown to correlate with microbiological outcome of Gramnegative bacteria (GNB) in preclinical studies. However, clinical data are still lacking. We explored the relationship of ceftazidime exposure and outcome in patients with nosocomial pneumonia using data from a recent randomized, double-blind Phase 3 clinical trial. Patients and methods: Pharmacokinetic (PK) and demographic data from three clinical trials were used to construct a population PK model using non-linear mixed-effects modelling. Individual concentration-time curves and PK/pharmacodynamic indices were determined for individual patients. The MICs used in the analyses were the highest MICs for any GNB cultured at baseline or end of therapy. Results: A two-compartment model best fit the data, with creatinine clearance as covariate on clearance and age on the central compartment. Classification and regression tree analysis showed a breakpoint value of 44.9% (P,0.0001) for GNB in 154 patients. The Emax model showed a good fit (R20.93). The benefit of adequate treatment increased from an eradication rate of 0.4848 at %fT.MIC of 0% to 0.9971 at 100%. The EC50 was 46.8% and the EC90 was 95.5% for %fT.MIC. Exposure correlated significantly with both microbiological and clinical outcome at test-of-cure. Conclusions: We conclude that exposures to ceftazidime predict microbiological as well as clinical outcome, and the %fT.MIC required to result in a likely favourable outcome is.45% of the dosing interval. This value is similar to that observed in animal models and underscores the principle that adequate dosing can be predicted and is beneficial to patient care.


Tiddens H.A.W.M.,Erasmus Medical Center | Stick S.M.,Princess Margaret Hospital for Children | Davis S.,James Whitcomb Riley Hospital for Children
Paediatric Respiratory Reviews | Year: 2014

Cystic fibrosis [CF] lung disease is characterized by progressive bronchiectasis and small airways disease. To monitor CF lung disease traditionally spirometry has been the most important modality. In addition to spirometry chest radiography was used to monitor progression of structural lung abnormalities. However, the importance of chest radiography in disease management has been limited due to its poor sensitivity and specificity to detect disease progression. Over the last decade chest CT has become the gold standard for monitoring the severity and progression of bronchiectasis. Small airways disease can be monitored using spirometry, multiple breath washout techniques, and chest CT. In modern CF-care a multi-modality approach is needed to monitor CF lung disease and to personalize treatment for the needs of the patient. When state-of-the-art low dose bi-annual chest CT protocols are used radiation risk is considered to be low. In between chest CT imaging, physiologic measures are important to obtain for monitoring. Stratification of monitoring protocols based on the risk profile of the patient can help us in the future to better care for people with CF. © 2013.


Head S.J.,Erasmus Medical Center | Mokhles M.M.,Erasmus Medical Center | Osnabrugge R.L.J.,Erasmus Medical Center | Pibarot P.,Institute University Of Cardiologie | And 4 more authors.
European Heart Journal | Year: 2012

Aims Numerous studies have linked prosthesispatient mismatch (PPM) after aortic valve replacement (AVR) to adverse outcomes. Its correlation with long-term survival has been described but with contradicting results. This systematic review and meta-analysis of observational studies aims to determine the hazard of PPM after AVR. Methods and resultsThe Medline and EMBase databases were searched for English-language original publications. Two researchers independently screened studies and extracted data. Pooled estimates were obtained by random effects model. Subgroup analyses were performed to detect sources of heterogeneity. The search yielded 348 potentially relevant studies; 34 were included comprising 27 186 patients and 133 141 patient-years. Defined by the universally accredited indexed effective orifice area <0.85 cm 2/m 2, 44.2 of patients were categorized as having PPM. In 34.2 and 9.8 of patients moderate (0.650.85 cm 2/m 2) and severe (<0.65 cm 2/m 2) PPM was present, respectively. Prosthesispatient mismatch was associated with a statistically significant increase in all-cause mortality (HR 1.34, 95 CI: 1.181.51), but only a trend to an increase in cardiac-related mortality (HR 1.51, 95 CI: 0.882.60) was recognized. Analysis by severity of PPM demonstrated that both moderate and severe PPM increased all-cause mortality (HR 1.19, 95 CI: 1.071.33 and HR 1.84, 95 CI: 1.382.45) and cardiac-related mortality (HR 1.32, 95 CI: 1.021.71 and HR 6.46, 95 CI: 2.7914.97). Further analyses showed a consistent effect over separate time intervals during follow-up. Conclusion Prosthesispatient mismatch is associated with an increase in all-cause and cardiac-related mortality over long-term follow-up. We recommend that current efforts to prevent PPM should receive more emphasis and a widespread acceptance to improve long-term survival after AVR. Published on behalf of the European Society of Cardiology. © The Author 2011.


Van Hees F.,Erasmus Medical Center | Zauber A.G.,Sloan Kettering Cancer Center | Klabunde C.N.,U.S. National Cancer Institute | Goede S.L.,Erasmus Medical Center | And 2 more authors.
JAMA Internal Medicine | Year: 2014

Importance: Many Medicare beneficiaries undergo more intensive colonoscopy screening than recommended. Whether this is favorable for beneficiaries and efficient from a societal perspective is uncertain.Objective: To determine whether more intensive colonoscopy screening than recommended is favorable for Medicare beneficiaries (ie, whether it results in a net health benefit) and whether it is efficient from a societal perspective (ie, whether the net health benefit justifies the additional resources required).Design, Setting, and Participants: Microsimulation modeling study of 65-year-old Medicare beneficiaries at average risk for colorectal cancer (CRC) and with an average life expectancy who underwent a screening colonoscopy at 55 years with negative results.Interventions: Colonoscopy screening as recommended by guidelines (ie, at 65 and 75 years) vs scenarios with a shorter screening interval (5 or 3 instead of 10 years) or in which screening was continued to 85 or 95 years.Main Outcomes and Measures: Quality-adjusted life-years (QALYs) gained (measure of net health benefit); additional colonoscopies required per additional QALY gained and additional costs per additional QALY gained (measures of efficiency).Results: Screening previously screened Medicare beneficiaries more intensively than recommended resulted in only small increases in CRC deaths prevented and life-years gained. In comparison, the increases in colonoscopies performed and colonoscopy-related complications experienced were large. As a result, all scenarios of more intensive screening than recommended resulted in a loss of QALYs, rather than a gain (ie, a net harm). The only exception was shortening the screening interval from 10 to 5 years, which resulted in 0.7 QALYs gained per 1000 beneficiaries. However, this scenario was inefficient because it required no less than 909 additional colonoscopies and an additional $711 000 per additional QALY gained. Results in previously unscreened beneficiaries were slightly less unfavorable, but conclusions were identical.Conclusions and Relevance: Screening Medicare beneficiaries more intensively than recommended is not only inefficient from a societal perspective; often it is also unfavorable for those being screened. This study provides evidence and a clear rationale for clinicians and policy makers to actively discourage this practice. Copyright © 2014 American Medical Association. All rights reserved.


Witter L.,Royal Academy for Arts and science KNAW | De Zeeuw C.I.,Royal Academy for Arts and science KNAW | De Zeeuw C.I.,Erasmus Medical Center
Cerebellum | Year: 2015

The cerebellum plays an important role in the coordination and refinement of movements and cognitive processes. Recently, it has been shown that the main output neuron of the cerebellar cortex, i.e., the Purkinje cell, can show a different firing behavior dependent on its intrinsic electrophysiological properties. Yet, to what extent a different nature of mossy fiber inputs can influence the firing behavior of cerebellar cortical neurons remains to be elucidated. Here, we compared the firing rate and regularity of mossy fibers and neurons in two different regions of cerebellar cortex. One region intimately connected with the cerebral cortex, i.e., lobules VI/VII of the neocerebellum, and another one strongly connected with the vestibular apparatus, i.e., lobule X of the archaeocerebellum. Given their connections, we hypothesized that activity in neurons in lobules VI/VII and lobule X may be expected to be more phasic and tonic, respectively. Using whole-cell and cell-attached recordings in vivo in anesthetized mice, we show that the mossy fiber inputs to these functionally distinct areas of the cerebellum differ in that the irregularity and bursty character of their firing is significantly greater in lobules VI/VII than in lobule X. Importantly, this difference in mossy fiber regularity is propagated through the granule cells at the input stage to the Purkinje cells and molecular layer interneurons, ultimately resulting in different regularity of simple spikes. These data show that the firing behavior of cerebellar cortical neurons does not only reflect particular intrinsic properties but also an interesting interplay with the innate activity at the input stage. © 2015, The Author(s).


Hoorn E.J.,Erasmus Medical Center | Ellison D.H.,Oregon Health And Science University
Experimental Cell Research | Year: 2012

In the kidney, the renal tubule plays a major role in maintaining fluid and electrolyte balance. This balance is achieved by an interplay between various hormones and nerves that signal changes throughout the body and transfer these signals to transport proteins. Increased or reduced activity of these transporters helps to restore homeostasis, but can also contribute to disease (e.g. sodium retention in hypertension). In recent years, it has become clear that the signal transfer to transporters is largely mediated by kinases. Among these, WNK kinases (With No lysine. =. K) stand out, because they regulate the major sodium and potassium transporters in the distal nephron. Moreover, mutations in genes encoding WNK kinases result in an inherited form of salt-sensitive hypertension with hyperkalemia, illustrating their important role in sodium, potassium, and blood pressure regulation. More recently, WNK kinases were found to play a role in acquired forms of hypertension as well. Together, the evolving insight in the kinase regulation of ion transport is providing new insights in the longstanding question how salt and blood pressure are related. Here, we review the current models of how WNK kinases regulate the various transport proteins and which roles they play in health and disease. © 2012.


Linster M.,Erasmus Medical Center | Van Boheemen S.,Erasmus Medical Center | De Graaf M.,Erasmus Medical Center | Schrauwen E.J.A.,Erasmus Medical Center | And 10 more authors.
Cell | Year: 2014

Recently, A/H5N1 influenza viruses were shown to acquire airborne transmissibility between ferrets upon targeted mutagenesis and virus passage. The critical genetic changes in airborne A/Indonesia/5/05 were not yet identified. Here, five substitutions proved to be sufficient to determine this airborne transmission phenotype. Substitutions in PB1 and PB2 collectively caused enhanced transcription and virus replication. One substitution increased HA thermostability and lowered the pH of membrane fusion. Two substitutions independently changed HA binding preference from α2,3-linked to α2,6-linked sialic acid receptors. The loss of a glycosylation site in HA enhanced overall binding to receptors. The acquired substitutions emerged early during ferret passage as minor variants and became dominant rapidly. Identification of substitutions that are essential for airborne transmission of avian influenza viruses between ferrets and their associated phenotypes advances our fundamental understanding of virus transmission and will increase the value of future surveillance programs and public health risk assessments. © 2014 Elsevier Inc.


Kiefte-De Jong J.C.,Erasmus Medical Center | Mathers J.C.,Vitality | Franco O.H.,Erasmus Medical Center
Proceedings of the Nutrition Society | Year: 2014

Healthy longevity is a tangible possibility for many individuals and populations, with nutritional and other lifestyle factors playing a key role in modulating the likelihood of healthy ageing. Nevertheless, studies of effects of nutrients or single foods on ageing often show inconsistent results and ignore the overall framework of dietary habits. Therefore, the use of dietary patterns (e.g. a Mediterranean dietary pattern) and the specific dietary recommendations (e.g. dietary approaches to stop hypertension, Polymeal and the American Healthy Eating Index) are becoming more widespread in promoting lifelong health. A posteriori defined dietary patterns are described frequently in relation to age-related diseases but their generalisability is often a challenge since these are developed specifically for the population under study. Conversely, the dietary guidelines are often developed based on prevention of disease or nutrient deficiency, but often less attention is paid to how well these dietary guidelines promote health outcomes. In the present paper, we provide an overview of the state of the art of dietary patterns and dietary recommendations in relation to life expectancy and the risk of age-related disorders (with emphasis on cardiometabolic diseases and cognitive outcomes). According to both a posteriori and a priori dietary patterns, some key 'ingredients' can be identified that are associated consistently with longevity and better cardiometabolic and cognitive health. These include high intake of fruit, vegetables, fish, (whole) grains and legumes/pulses and potatoes, whereas dietary patterns rich in red meat and sugar-rich foods have been associated with an increased risk of mortality and cardiometabolic outcomes. © The Authors 2014.


Spijker A.T.,PsyQ the Hague | Van Rossum E.F.C.,Erasmus Medical Center
Neuroendocrinology | Year: 2012

In this review, we provide an overview of recent literature on glucocorticoid (GC) sensitivity in mood disorders. Assessing GC sensitivity is often performed by measuring the cortisol awakening rise (CAR), by challenging the hypothalamic-pituitary-adrenal (HPA) axis using a dexamethasone suppression test (DST) or a dexamethasone/cortisol-releasing hormone test (DEX/CRH); more recently by measuring cortisol as a retrospective calendar in scalp hair. The main findings in mood disorders are higher mean cortisol levels in hair samples and a higher CAR, showing a hyperactivity of the HPA axis. This is in line with the mild resistance for GCs previously observed in challenge tests during mood episodes. GC sensitivity is partly determined by polymorphisms in the genes encoding receptors and other proteins involved in the regulation of the HPA axis. We shortly discuss the glucocorticoid receptor, as well as the mineralocorticoid receptor, the cortisol-releasing hormone receptor-1, and the glucocorticoid receptor co-chaperone FKBP5. Data clearly indicate genetic changes, along with epigenetic changes which influence the set-point and regulation of the HPA axis. Early trauma, as well as influences in utero, appears to be important. Future research is necessary to further clarify the biological background and consequences of an individual's cortisol exposure in relation to mood. Copyright © 2011 S. Karger AG, Basel.


Koga S.,Kobe Design University | Rossiter H.B.,University of Leeds | Heinonen I.,University of Turku | Heinonen I.,Erasmus Medical Center | And 2 more authors.
Medicine and Science in Sports and Exercise | Year: 2014

Resolving the bases for different physiological functioning or exercise performance within a population is dependent on our understanding of control mechanisms. For example, when most young healthy individuals run or cycle at moderate intensities, oxygen uptake (V̇O2) kinetics are rapid and the amplitude of the V̇O2 response is not constrained by O 2 delivery. For this to occur, muscle O2 delivery (i.e., blood flow × arterial O2 concentration) must be coordinated superbly with muscle O2 requirements (V̇O2), the efficacy of which may differ among muscles and distinct fiber types. When the O2 transport system succumbs to the predations of aging or disease (emphysema, heart failure, and type 2 diabetes), muscle O2 delivery and O2 delivery-V̇O2 matching and, therefore, muscle contractile function become impaired. This forces greater influence of the upstream O2 transport pathway on muscle aerobic energy production, and the O2 delivery-V̇O2 relationship(s) assumes increased importance. This review is the first of its kind to bring a broad range of available techniques, mostly state of the art, including computer modeling, radiolabeled microspheres, positron emission tomography, magnetic resonance imaging, near-infrared spectroscopy, and phosphorescence quenching to resolve the O2 delivery-V̇O2 relationships and inherent heterogeneities at the whole body, interorgan, muscular, intramuscular, and microvascular/myocyte levels. Emphasis is placed on the following: 1) intact humans and animals as these provide the platform essential for framing and interpreting subsequent investigations, 2) contemporary findings using novel technological approaches to elucidate O2 delivery-V̇O 2 heterogeneities in humans, and 3) future directions for investigating how normal physiological responses can be explained by O 2 delivery-V̇O2 heterogeneities and the impact of aging/disease on these processes. © 2014 by the American college of Sports Medicine.


Zauber A.G.,Sloan Kettering Cancer Center | Winawer S.J.,Sloan Kettering Cancer Center | O'Brien M.J.,Boston University | Lansdorp-Vogelaar I.,Erasmus Medical Center | And 8 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: In the National Polyp Study (NPS), colorectal cancer was prevented by colonoscopic removal of adenomatous polyps. We evaluated the long-term effect of colonoscopic polypectomy in a study on mortality from colorectal cancer. METHODS: We included in this analysis all patients prospectively referred for initial colonoscopy (between 1980 and 1990) at NPS clinical centers who had polyps (adenomas and nonadenomas). The National Death Index was used to identify deaths and to determine the cause of death; follow-up time was as long as 23 years. Mortality from colorectal cancer among patients with adenomas removed was compared with the expected incidence-based mortality from colorectal cancer in the general population, as estimated from the Surveillance Epidemiology and End Results (SEER) Program, and with the observed mortality from colorectal cancer among patients with nonadenomatous polyps (internal control group). RESULTS: Among 2602 patients who had adenomas removed during participation in the study, after a median of 15.8 years, 1246 patients had died from any cause and 12 had died from colorectal cancer. Given an estimated 25.4 expected deaths from colorectal cancer in the general population, the standardized incidence-based mortality ratio was 0.47 (95% confidence interval [CI], 0.26 to 0.80) with colonoscopic polypectomy, suggesting a 53% reduction in mortality. Mortality from colorectal cancer was similar among patients with adenomas and those with nonadenomatous polyps during the first 10 years after polypectomy (relative risk, 1.2; 95% CI, 0.1 to 10.6). CONCLUSIONS: These findings support the hypothesis that colonoscopic removal of adenomatous polyps prevents death from colorectal cancer. (Funded by the National Cancer Institute and others.) Copyright © 2012 Massachusetts Medical Society. All rights reserved.


Eikelboom J.W.,Hamilton Health Sciences | Connolly S.J.,Hamilton Health Sciences | Brueckmann M.,Boehringer Ingelheim | Brueckmann M.,University of Heidelberg | And 14 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves. METHODS: In this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran. RESULTS: The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding. CONCLUSIONS: The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. Copyright © 2013 Massachusetts Medical Society.


Muller A.E.,Radboudumc | Muller A.E.,St Elisabeth Hospital | Punt N.,Medimatics | Moutona J.W.,Erasmus Medical Center
Antimicrobial Agents and Chemotherapy | Year: 2014

The percentage of the dosing interval that the non-protein-bound plasma concentration is above the MIC (%fT>MIC) for cephalosporins has been shown to correlate with microbiological outcomes in preclinical studies. However, clinical data are scarce. Using data from a randomized double-blind phase 3 clinical trial, we explored the relationship of ceftobiprole exposure with microbiological and clinical outcomes in patients with nosocomial pneumonia. The individual ceftobiprole exposure was determined for different pharmacokinetic (PK)/pharmacodynamic (PD) indices using individual pharmacokinetic data and a previously published population model. The MICs used in the analysis were the highest MICs for any bacterium cultured at baseline or the end of treatment (EOT). Outcomes were microbiological cure at EOT and clinical cure at test of cure (TOC). Multiple logistic regression (MLR) and classification and regression tree (CART) analyses were applied to determine the relationships among exposure, patient characteristics, and outcomes. MLR indicated that the%fT>MIC of ceftobiprole was the best predictor for both microbiological eradication and clinical cure. CART analysis showed a breakpoint value of 51.1% (n=159; P=0.0024) for clinical cure, whereas it was 62.2% (n=251; P<0.0001) for microbiological eradication. Other factors also contributed, particularly to clinical outcome. These included the difference between VAP and non-VAP patients, systemic inflammatory response syndrome (SIRS), creatinine clearance, the use of anti-Pseudomonas combination therapy, and Acute Physiology and Chronic Health Evaluation II (APACHE-II) score. There is a strong correlation between microbiological eradication and clinical cure with exposure to ceftobiprole. The%fT>MIC required to result in a favorable clinical outcome is>51% of the dosing interval, which is in line with the values found for microbiological eradication, the comparator ceftazidime, and preclinical models. © 2014, American Society for Microbiology.


Wei Z.,Hong Kong University of Science and Technology | Zheng S.,Hong Kong University of Science and Technology | Spangler S.,Erasmus Medical Center | Yu C.,Hong Kong University of Science and Technology | And 3 more authors.
Molecular Cell | Year: 2011

Liprins are highly conserved scaffold proteins that regulate cell adhesion, cell migration, and synapse development by binding to diverse target proteins. The molecular basis governing liprin/target interactions is poorly understood. The liprin-α2/CASK complex structure solved here reveals that the three SAM domains of liprin-α form an integrated supramodule that binds to the CASK kinase-like domain. As supported by biochemical and cellular studies, the interaction between liprin-α and CASK is unique to vertebrates, implying that the liprin-α/CASK interaction is likely to regulate higher-order brain functions in mammals. Consistently, we demonstrate that three recently identified X-linked mental retardation mutants of CASK are defective in binding to liprin-α. We also solved the liprin-α/liprin-β SAM domain complex structure, which uncovers the mechanism underlying liprin heterodimerizaion. Finally, formation of the CASK/liprin-α/liprin-β ternary complex suggests that liprins can mediate assembly of target proteins into large protein complexes capable of regulating numerous cellular activities. © 2011 Elsevier Inc.


Kappetein A.P.,Erasmus Medical Center | Feldman T.E.,NorthShore University Health System | MacK M.J.,Baylor Healthcare System | Morice M.-C.,Institute Cardiovasculaire Paris Sud | And 6 more authors.
European Heart Journal | Year: 2011

Aims Long-term randomized comparisons of percutaneous coronary intervention (PCI) to coronary artery bypass grafting (CABG) in left main coronary (LM) disease and/or three-vessel disease (3VD) patients have been limited. This analysis compares 3-year outcomes in LM and/or 3VD patients treated with CABG or PCI with TAXUS Express stents. Methods and resultsSYNTAX is an 85-centre randomized clinical trial (n 1800). Prospectively screened, consecutive LM and/or 3VD patients were randomized if amenable to equivalent revascularization using either technique; if not, they were entered into a registry. Patients in the randomized cohort will continue to be followed for 5 years. At 3 years, major adverse cardiac and cerebrovascular events [MACCE: death, stroke, myocardial infarction (MI), and repeat revascularization; CABG 20.2 vs. PCI 28.0, P< 0.001], repeat revascularization (10.7 vs. 19.7, P< 0.001), and MI (3.6 vs. 7.1, P 0.002) were elevated in the PCI arm. Rates of the composite safety endpoint (death/stroke/MI 12.0 vs. 14.1, P 0.21) and stroke alone (3.4 vs. 2.0, P 0.07) were not significantly different between treatment groups. Major adverse cardiac and cerebrovascular event rates were not significantly different between arms in the LM subgroup (22.3 vs. 26.8, P 0.20) but were higher with PCI in the 3VD subgroup (18.8 vs. 28.8, P< 0.001). Conclusion sAt 3 years, MACCE was significantly higher in PCI-compared with CABG-treated patients. In patients with less complex disease (low SYNTAX scores for 3VD or low/intermediate terciles for LM patients), PCI is an acceptable revascularization, although longer follow-up is needed to evaluate these two revascularization strategies. © 2011 The Author.


Poste G.,Arizona State University | Carbone D.P.,Thoracic Oncology Center | Parkinson D.R.,Nodality | Verweij J.,Erasmus Medical Center | And 2 more authors.
Clinical Cancer Research | Year: 2012

Molecular diagnostics are becoming increasingly important in clinical research to stratify or identify molecularly profiled patient cohorts for targeted therapies, to modify the dose of a therapeutic, and to assess early response to therapy or monitor patients. Molecular diagnostics can also be used to identify the pharmacogenetic risk of adverse drug reactions. The articles in this CCR Focus section on molecular diagnosis describe the development and use of markers to guide medical decisions regarding cancer patients. They define sources of preanalytic variability that need to be minimized, as well as the regulatory and financial challenges involved in developing diagnostics and integrating them into clinical practice. They also outline a National Cancer Institute program to assist diagnostic development. Molecular diagnostic clinical tests require rigor in their development and clinical validation, with sensitivity, specificity, and validity comparable to those required for the development of therapeutics. These diagnostics must be offered at a realistic cost that reflects both their clinical value and the costs associated with their development. When genome-sequencing technologies move into the clinic, they must be integrated with and traceable to current technology because they may identify more efficient and accurate approaches to drug development. In addition, regulators may define progressive drug approval for companion diagnostics that requires further evidence regarding efficacy and safety before full approval can be achieved. One way to accomplish this is to emphasize phase IV postmarketing, hypothesis-driven clinical trials with biological characterization that would permit an accurate definition of the association of low-prevalence gene alterations with toxicity or response in large cohorts. ©2012 AACR.


Van Der Wal J.B.C.,Erasmus Medical Center | Iordens G.I.T.,Erasmus Medical Center | Vrijland W.W.,Sint Fransiscus Hospital | Van Veen R.N.,IkaziaHospital Rotterdam | And 2 more authors.
Annals of Surgery | Year: 2011

Objective: The objective of the study was to determine the long-term effect of the use of a hyaluronic acid-carboxymethylcellulose membrane (Seprafilm) on the incidence of adhesions and subsequent small-bowel obstruction and chronic abdominal complaints after colorectal surgery (Hartmanns procedure). Background: Adhesions occur frequently after abdominal surgery and are the most common cause of bowel obstruction, chronic abdominal pain, and infertility. The risk for adhesion-related readmission in the first 10 years after colorectal surgery is as high as 30%. To reduce the formation of adhesions, a mechanical barrier composed of hyaluronic acid and carboxymethylcellulose was developed, to prevent adherence of tissues after abdominal surgery. Long-term results concerning the incidence of small-bowel obstruction and chronic abdominal pain are lacking. Methods: Between April 1996 and September 1998, 71 patients requiring Hartmanns procedure for sigmoid diverticulitis or obstructed rectosigmoid were randomized to either intraperitoneal placement of Seprafilm under the midline and in the pelvis or as a control. Direct visual evaluation of the incidence and severity of adhesions was performed laparoscopically in 42 patients at second-stage surgery for restoration of the continuity of the colon. The results of this study were published in 2002. In 2006, the patients general practitioners were interviewed by means of a questionnaire concerning their patients health. The patients who were still alive were interviewed and asked to fill out 2 questionnaires concerning pain and quality of life (VAS-pain score, EQ-5D, and SF-36). In 2009, the medical records of the patients were evaluated for adhesion-related hospital re-admissions. Results: Of the 42 evaluated patients, 35 (16 in the Seprafilm group, 19 in the control group) could be enrolled in the long-term follow-up. Median follow-up was 126 months (range 41-148) for the Seprafilm group and 128 months (range 49-149) months for the control group. Incidence of chronic (3 months or longer existing) abdominal complaints was significantly lower in the Seprafilm group compared with controls (35.3% vs. 77.8%, respectively; P = 0.018). Incidence of small-bowel obstruction showed no significant difference in favor of the Seprafilm group; no small-bowel obstructions occurred in the Seprafilm group, whereas in the control group 2 cases of small-bowel obstruction were found to have occurred. Evaluation of the quality of life questionnaires did not reveal significant differences between the 2 groups. Conclusions: In Hartmanns procedure, Seprafilm placement does not provide protection against small-bowel obstruction. Incidence of chronic abdominal complaints is significantly lower after use of Seprafilm. © 2011 Lippincott Williams & Wilkins.


Schoots I.G.,Erasmus Medical Center | Petrides N.,University College London | Giganti F.,University College London | Giganti F.,San Raffaele Scientific Institute | And 6 more authors.
European Urology | Year: 2015

Context There is great interest in using magnetic resonance imaging (MRI) for men on active surveillance for prostate cancer. Objective To systematically review evidence regarding the use of MRI in men with low- or intermediate-risk prostate cancer suitable for active surveillance. Evidence acquisition Ovid Medline and Embase databases were searched for active surveillance, prostate cancer, and MRI from inception until April 25, 2014 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses process. Identified reports were critically appraised according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. Evidence synthesis A lesion on MRI suspicious for prostate cancer (positive MRI) is seen in two-thirds of men otherwise suitable for active surveillance. A positive MRI makes the identification of clinically significant disease at repeat biopsy more likely, especially when biopsies are targeted to suspicious MRI lesions. Radical prostatectomy data show that positive MRI is more likely to be associated with upgrading (Gleason score >3 + 3) than a negative MRI (43% vs 27%). A positive MRI is not significantly more likely to be associated with upstaging at radical prostatectomy (>T2) than a negative MRI (10% vs 8%). Although MRI is of interest in the monitoring of men on active surveillance, robust data on the use of repeat MRI in active surveillance are lacking. Prospective studies with clear definitions of radiological significance and progression are needed before this approach can be adopted. Conclusions MRI is useful for detection of clinically significant disease at initial assessment of men considering active surveillance. To use MRI as a monitoring tool in surveillance, it will be necessary to define both radiological significance and radiological progression. Patient summary This review assesses evidence for the use of magnetic resonance imaging (MRI) in men on active surveillance for prostate cancer. MRI at the start of surveillance can detect clinically significant disease in one-third to half of men. There are few data to assess the use of MRI as a monitoring tool during surveillance, so there is a need to define significant disease on MRI and significant changes over time. © 2014 European Association of Urology. All rights reserved.


Habbema D.,Erasmus Medical Center | De Kok I.M.C.M.,Erasmus Medical Center | Brown M.L.,U.S. National Cancer Institute
Milbank Quarterly | Year: 2012

Context: This article compares cervical cancer screening intensity and cervical cancer mortality trends in the United States and the Netherlands to illustrate the potential of cross-national comparative studies. We discuss the lessons that can be learned from the comparison as well as the challenges in each country to effective and efficient screening. Methods: We used nationally representative data sources in the United States and the Netherlands to estimate the number of Pap smears and the cervical cancer mortality rate since 1950. The following questions are addressed: How do differences in intensity of Pap smear use between the countries translate into differences in mortality trends? Can population coverage rates (the proportion of eligible women who had a Pap smear within a specified period) explain the mortality trends better than the total intensity of Pap smear use? Findings: Even though three to four times more Pap smears per woman were conducted in the United States than in the Netherlands over a period of three decades, the two countries' mortality trends were quite similar. The five-year coverage rates for women aged thirty to sixty-four were quite comparable at 80 to 90 percent. Because screening in the Netherlands was limited to ages thirty to sixty, screening rates for women under thirty and over sixty were much higher in the United States. These differences had consequences for age-specific mortality trends. The relatively good coverage rate in the Netherlands can be traced back to a nationwide invitation system based on municipal population registries. While both countries followed a "policy cycle" involving evidence review, surveillance of screening practices and outcomes, clinical guidelines, and reimbursement policies, the components of this cycle were more systematically linked and implemented nationwide in the Netherlands than in the United States. To a large extent, this was facilitated by a public health model of screening in the Netherlands, rather than a medical services model. Conclusions: Cross-country studies like ours are natural experiments that can produce insights not easily obtained from other types of study. The cervical cancer screening system in the Netherlands seems to have been as effective as the U.S. system but used much less screening. Adequate coverage of the female population at risk seems to be of central importance. © 2012 Milbank Memorial Fund.


News Article | November 17, 2016
Site: www.prnewswire.com

AUSTIN, Texas, Nov. 17, 2016 /PRNewswire/ -- Luminex Corporation (NASDAQ: LMNX) today announced that the internationally renowned Department of Viroscience at Erasmus Medical Center in Rotterdam, The Netherlands, has evaluated the ARIES® System and Flu A/B & RSV CE-IVD Assay for...


DUBLIN - Nov. 14, 2016 - Medtronic plc (NYSE: MDT) today announced notable presentations of clinical studies on how endovascular treatments are furthering the treatment of core and complex aortic disease at the 43rd Annual Symposium of Vascular and Endovascular Issues (VEITHsymposium), the world's largest educational meeting specializing in vascular surgical medicine in New York from November 14 - 19, 2016. This year, Medtronic's aortic technologies will be featured in more than 30 presentations at VEITHsymposium, including new data from the ENGAGE Global Registry, the ANCHOR registry and on the Valiant(TM) Captivia(TM) system to treat dissections. Additional presentations highlighting investigational technology from Medtronic, including the Valiant(TM) Mona LSA(TM), Valiant(TM)EVO thoracic stent graft system, Valiant® TAAA stent graft system and the Valiant ascending stent graft will occur throughout the symposium. A presentation on the chimney technique for endovascular aortic repair (ChEVAR) will also take place and include data from the PROTAGORAS study. This publication looked at a standardized use of the Endurant(TM) II/IIs stent graft system with ChEVAR.* "Medtronic's Aortic business collaborates closely with physicians to provide meaningful clinical data to advance treatments for aortic disease," said Daveen Chopra, vice president and general manager of the Aortic business in Medtronic's Aortic & Peripheral Vascular division. "The breadth of data being presented at VEITHsymposium is further proof of our investment in innovation for the endovascular treatment of complex aortic disease." Notably, new sub-set analyses from the ENGAGE Global Registry will be unveiled on Tuesday, November 15 in several sessions focused on the benefits of endovascular aortic repair (EVAR) in patients with hostile necks. In these sessions, Prof. Hence Verhagen, M.D., Ph.D., chief of vascular surgery at Erasmus Medical Center in Rotterdam, the Netherlands will present a new analysis on the safety and durability of EVAR in hostile necks, and make a second presentation on long-term outcomes in patients with complex anatomies, such as angled necks, conical necks and necks with circumferential thrombus/calcium. A complementary presentation by Prof. Dittmar Böckler, M.D., University of Heidelberg, Department of Vascular Surgery in Germany will highlight data first presented at Charing Cross on the benefit of new generation EVAR devices over first generation EVAR devices. Another key set of presentations on Thursday, November 17 will include new findings from Medtronic's ANCHOR registry - a global, multi-center, multi-arm, prospective, post-market registry evaluating the real-world applicability of the Heli-FX(TM) EndoAnchor(TM) system in up to 2,000 patients. In a series of three presentations, researchers will present new data on the use of EndoAnchor implants in patients with complex aortic abdominal aneurysm (AAA) anatomy, particularly those who have hostile characteristics. A schedule of key presentations appears below in chronological order in Eastern Standard Time.  Some of the titles included in the presentations below may include investigational devices or uses. In collaboration with leading clinicians, researchers and scientists worldwide, Medtronic offers the broadest range of innovative medical technology for the interventional and surgical treatment of cardiovascular disease and cardiac arrhythmias. The company strives to offer products and services that deliver clinical and economic value to healthcare consumers and providers around the world. * In the U.S., the Endurant II/IIs stent system is approved for neck lengths >=10 mm and <=60° infra-renal angulation and it is not approved for use in chEVAR procedures . Now in its 43rd year, VEITHsymposium provides vascular surgeons, interventional radiologists, interventional cardiologists and other vascular specialists with a unique and exciting format to learn the most current information about what is new and important in the treatment of vascular disease. The 5-day event features rapid-fire presentations from world renowned vascular specialists with emphasis on the latest advances, changing concepts in diagnosis and management, pressing controversies and new techniques. Press will receive complimentary registration. Please visit www.VEITHpress.org or contact Pauline T. Mayer at +1-561-316-3330. Medtronic plc (www.medtronic.com), headquartered in Dublin, Ireland, is among the world's largest medical technology, services and solutions companies - alleviating pain, restoring health and extending life for millions of people around the world. Medtronic employs more than 88,000 people worldwide, serving physicians, hospitals and patients in approximately 160 countries. The company is focused on collaborating with stakeholders around the world to take healthcare Further, Together. Any forward-looking statements are subject to risks and uncertainties such as those described in Medtronic's periodic reports on file with the Securities and Exchange Commission. Actual results may differ materially from anticipated results.


DUBLIN - Nov. 14, 2016 - Medtronic plc (NYSE: MDT) today announced notable presentations of clinical studies on how endovascular treatments are furthering the treatment of core and complex aortic disease at the 43rd Annual Symposium of Vascular and Endovascular Issues (VEITHsymposium), the world's largest educational meeting specializing in vascular surgical medicine in New York from November 14 - 19, 2016. This year, Medtronic's aortic technologies will be featured in more than 30 presentations at VEITHsymposium, including new data from the ENGAGE Global Registry, the ANCHOR registry and on the Valiant(TM) Captivia(TM) system to treat dissections. Additional presentations highlighting investigational technology from Medtronic, including the Valiant(TM) Mona LSA(TM), Valiant(TM)EVO thoracic stent graft system, Valiant® TAAA stent graft system and the Valiant ascending stent graft will occur throughout the symposium. A presentation on the chimney technique for endovascular aortic repair (ChEVAR) will also take place and include data from the PROTAGORAS study. This publication looked at a standardized use of the Endurant(TM) II/IIs stent graft system with ChEVAR.* "Medtronic's Aortic business collaborates closely with physicians to provide meaningful clinical data to advance treatments for aortic disease," said Daveen Chopra, vice president and general manager of the Aortic business in Medtronic's Aortic & Peripheral Vascular division. "The breadth of data being presented at VEITHsymposium is further proof of our investment in innovation for the endovascular treatment of complex aortic disease." Notably, new sub-set analyses from the ENGAGE Global Registry will be unveiled on Tuesday, November 15 in several sessions focused on the benefits of endovascular aortic repair (EVAR) in patients with hostile necks. In these sessions, Prof. Hence Verhagen, M.D., Ph.D., chief of vascular surgery at Erasmus Medical Center in Rotterdam, the Netherlands will present a new analysis on the safety and durability of EVAR in hostile necks, and make a second presentation on long-term outcomes in patients with complex anatomies, such as angled necks, conical necks and necks with circumferential thrombus/calcium. A complementary presentation by Prof. Dittmar Böckler, M.D., University of Heidelberg, Department of Vascular Surgery in Germany will highlight data first presented at Charing Cross on the benefit of new generation EVAR devices over first generation EVAR devices. Another key set of presentations on Thursday, November 17 will include new findings from Medtronic's ANCHOR registry - a global, multi-center, multi-arm, prospective, post-market registry evaluating the real-world applicability of the Heli-FX(TM) EndoAnchor(TM) system in up to 2,000 patients. In a series of three presentations, researchers will present new data on the use of EndoAnchor implants in patients with complex aortic abdominal aneurysm (AAA) anatomy, particularly those who have hostile characteristics. A schedule of key presentations appears below in chronological order in Eastern Standard Time.  Some of the titles included in the presentations below may include investigational devices or uses. In collaboration with leading clinicians, researchers and scientists worldwide, Medtronic offers the broadest range of innovative medical technology for the interventional and surgical treatment of cardiovascular disease and cardiac arrhythmias. The company strives to offer products and services that deliver clinical and economic value to healthcare consumers and providers around the world. * In the U.S., the Endurant II/IIs stent system is approved for neck lengths >=10 mm and <=60° infra-renal angulation and it is not approved for use in chEVAR procedures . Now in its 43rd year, VEITHsymposium provides vascular surgeons, interventional radiologists, interventional cardiologists and other vascular specialists with a unique and exciting format to learn the most current information about what is new and important in the treatment of vascular disease. The 5-day event features rapid-fire presentations from world renowned vascular specialists with emphasis on the latest advances, changing concepts in diagnosis and management, pressing controversies and new techniques. Press will receive complimentary registration. Please visit www.VEITHpress.org or contact Pauline T. Mayer at +1-561-316-3330. Medtronic plc (www.medtronic.com), headquartered in Dublin, Ireland, is among the world's largest medical technology, services and solutions companies - alleviating pain, restoring health and extending life for millions of people around the world. Medtronic employs more than 88,000 people worldwide, serving physicians, hospitals and patients in approximately 160 countries. The company is focused on collaborating with stakeholders around the world to take healthcare Further, Together. Any forward-looking statements are subject to risks and uncertainties such as those described in Medtronic's periodic reports on file with the Securities and Exchange Commission. Actual results may differ materially from anticipated results.


DUBLIN - Nov. 14, 2016 - Medtronic plc (NYSE: MDT) today announced notable presentations of clinical studies on how endovascular treatments are furthering the treatment of core and complex aortic disease at the 43rd Annual Symposium of Vascular and Endovascular Issues (VEITHsymposium), the world's largest educational meeting specializing in vascular surgical medicine in New York from November 14 - 19, 2016. This year, Medtronic's aortic technologies will be featured in more than 30 presentations at VEITHsymposium, including new data from the ENGAGE Global Registry, the ANCHOR registry and on the Valiant(TM) Captivia(TM) system to treat dissections. Additional presentations highlighting investigational technology from Medtronic, including the Valiant(TM) Mona LSA(TM), Valiant(TM)EVO thoracic stent graft system, Valiant® TAAA stent graft system and the Valiant ascending stent graft will occur throughout the symposium. A presentation on the chimney technique for endovascular aortic repair (ChEVAR) will also take place and include data from the PROTAGORAS study. This publication looked at a standardized use of the Endurant(TM) II/IIs stent graft system with ChEVAR.* "Medtronic's Aortic business collaborates closely with physicians to provide meaningful clinical data to advance treatments for aortic disease," said Daveen Chopra, vice president and general manager of the Aortic business in Medtronic's Aortic & Peripheral Vascular division. "The breadth of data being presented at VEITHsymposium is further proof of our investment in innovation for the endovascular treatment of complex aortic disease." Notably, new sub-set analyses from the ENGAGE Global Registry will be unveiled on Tuesday, November 15 in several sessions focused on the benefits of endovascular aortic repair (EVAR) in patients with hostile necks. In these sessions, Prof. Hence Verhagen, M.D., Ph.D., chief of vascular surgery at Erasmus Medical Center in Rotterdam, the Netherlands will present a new analysis on the safety and durability of EVAR in hostile necks, and make a second presentation on long-term outcomes in patients with complex anatomies, such as angled necks, conical necks and necks with circumferential thrombus/calcium. A complementary presentation by Prof. Dittmar Böckler, M.D., University of Heidelberg, Department of Vascular Surgery in Germany will highlight data first presented at Charing Cross on the benefit of new generation EVAR devices over first generation EVAR devices. Another key set of presentations on Thursday, November 17 will include new findings from Medtronic's ANCHOR registry - a global, multi-center, multi-arm, prospective, post-market registry evaluating the real-world applicability of the Heli-FX(TM) EndoAnchor(TM) system in up to 2,000 patients. In a series of three presentations, researchers will present new data on the use of EndoAnchor implants in patients with complex aortic abdominal aneurysm (AAA) anatomy, particularly those who have hostile characteristics. A schedule of key presentations appears below in chronological order in Eastern Standard Time.  Some of the titles included in the presentations below may include investigational devices or uses. In collaboration with leading clinicians, researchers and scientists worldwide, Medtronic offers the broadest range of innovative medical technology for the interventional and surgical treatment of cardiovascular disease and cardiac arrhythmias. The company strives to offer products and services that deliver clinical and economic value to healthcare consumers and providers around the world. * In the U.S., the Endurant II/IIs stent system is approved for neck lengths >=10 mm and <=60° infra-renal angulation and it is not approved for use in chEVAR procedures . Now in its 43rd year, VEITHsymposium provides vascular surgeons, interventional radiologists, interventional cardiologists and other vascular specialists with a unique and exciting format to learn the most current information about what is new and important in the treatment of vascular disease. The 5-day event features rapid-fire presentations from world renowned vascular specialists with emphasis on the latest advances, changing concepts in diagnosis and management, pressing controversies and new techniques. Press will receive complimentary registration. Please visit www.VEITHpress.org or contact Pauline T. Mayer at +1-561-316-3330. Medtronic plc (www.medtronic.com), headquartered in Dublin, Ireland, is among the world's largest medical technology, services and solutions companies - alleviating pain, restoring health and extending life for millions of people around the world. Medtronic employs more than 88,000 people worldwide, serving physicians, hospitals and patients in approximately 160 countries. The company is focused on collaborating with stakeholders around the world to take healthcare Further, Together. Any forward-looking statements are subject to risks and uncertainties such as those described in Medtronic's periodic reports on file with the Securities and Exchange Commission. Actual results may differ materially from anticipated results.


New Studies Demonstrate Value of Gene Expression Risk Profiling to Identify Ultra-High-Risk Multiple Myeloma Patients ROTTERDAM, Netherlands and LAGUNA HILLS, California, Nov. 29, 2016 /PRNewswire/ -- SkylineDx today announced the presentation of new data that demonstrate the prognostic value of MMprofiler™ SKY92 gene signature, a gene expression profiling test for multiple myeloma (MM), as part of an integrated approach to identifying patients at ultra-high risk of MM. The data will be presented in a poster session on Monday, December 5, at the 58th annual meeting of the American Society of Hematology (ASH) in San Diego, CA. "The data being presented at the ASH meeting suggest that gene expression testing with MMprofiler, when used in combination with molecular genetic risk profiling, can enable risk stratification in multiple myeloma by elucidating patterns of survival and disease progression in high-risk and ultra-high-risk patients," said Dharminder S. Chahal, Chief Executive Officer of SkylineDx. "An integrated profiling testing strategy, with MMprofiler as a key component, may thus facilitate evaluation of risk-stratified treatment approaches in patients with multiple myeloma, and may even help identify potentially beneficial therapies for patients at ultra-high risk." In the ASH poster presentation, researchers will describe how they used MMprofiler, along with a molecular genetic risk profiling tool, to assess 221 newly diagnosed patients with MM who participated in the UK NCRI Myeloma XI trial. SKY92 is a prognostic gene signature that determines the level of risk for patients with MM by classifying them into a "high" or "standard" risk group. Included in a growing number of international treatment guidelines, MMprofiler assesses risk by measuring the activity of 92 MM-related genes that comprise SKY92, the novel, proprietary gene signature that is the lead product of SkylineDx. Patients with a high-risk classification have a poor prognosis as compared to patients with a standard risk profile, regardless of treatment. The performance of the SKY92 gene signature to risk-stratify these patients exceeds that of standard clinical parameters that include fluorescent in situ hybridization (FISH) and earlier gene expression signatures utilized in myeloma. The following posters related to SKY92 will be presented Monday, December 5, from 6:00-8:00pm PST in Hall GH of the San Diego Convention Center: Multiple myeloma (MM) is a cancer that arises from plasma cells, a type of white blood cell made in the bone marrow. In patients with MM, the plasma cells become abnormal, multiply uncontrollably, and release only one type of antibody – known as M-protein – which has no useful function. It is often through the measurement of M-protein that MM is diagnosed and monitored. Most medical problems related to MM are caused by the build-up of abnormal plasma cells in the bone marrow and the presence of the M-protein in the blood or urine. The most common symptoms of MM include bone pain, recurring infection, kidney damage, and fatigue. According to the World Cancer Research Fund International, an estimated 114,000 people around the world are diagnosed with MM annually, and the disease represents 0.8% of all cancers globally. For more information about MM, visit www.hematon.nl/myeloom (information available in Dutch only), www.themmrf.org, www.myeloma.org.uk, www.mpeurope.org, www.myeloma.org, and www.jsm.gr.jp. MMprofiler SKY92 prognostic gene signature assesses risk by measuring the activity of 92 MM-related genes that comprise SKY92, the novel, proprietary gene signature. The lead product of SkylineDx, MMprofiler is proven superior to the biomarkers currently used to risk stratify newly diagnosed and relapsed multiple myeloma patients into a "high" or "standard" risk category.1 Included in a growing number of international treatment guidelines, MMprofiler is CE-IVD registered in Europe and will be coming soon as a laboratory-developed test (LDT) in the United States. For more information, please visit www.mmprofiler.com. About SkylineDx SkylineDx is a commercial-stage biotech company based in Rotterdam, the Netherlands. Originally a spin-off of the Erasmus Medical Center in Rotterdam, the company specializes in the development and marketing of innovative gene signature-based prognostic tests to assist healthcare professionals in making personalized treatment decisions for individual patients. These tests are designed to accurately determine the type or status of the disease or to predict a patient's response to a specific treatment. Based on the test results, healthcare professionals can tailor the treatment to the individual patient. MMprofiler is the company's lead product. To learn more, please visit www.skylinedx.com. 1 Van Beers EH, et al. SKY92 GEP, iFISH, and ISS comparisons for risk stratification in multiple myeloma. Poster p661 presented at 2015 European Hematology Association Congress.


Hoye B.J.,Netherlands Institute of Ecology | Fouchier R.A.M.,Erasmus Medical Center | Klaassen M.,Netherlands Institute of Ecology | Klaassen M.,Deakin University
Proceedings of the Royal Society B: Biological Sciences | Year: 2012

Individual variation in infection modulates both the dynamics of pathogens and their impact on host populations. It is therefore crucial to identify differential patterns of infection and understand the mechanisms responsible. Yet our understanding of infection heterogeneity in wildlife is limited, even for important zoonotic host-pathogen systems, owing to the intractability of host status prior to infection. Using novel applications of stable isotope ecology and eco-immunology, we distinguish antecedent behavioural and physiological traits associated with avian influenza virus (AIV) infection in free-living Bewick's swans (Cygnus columbianus bewickii). Swans infected with AIV exhibited higher serum δ 13C (-25.3 ± 0.4) than their non-infected counterparts (-26.3±0.2). Thus, individuals preferentially foraging in aquatic rather than terrestrial habitats experienced a higher risk of infection, suggesting that the abiotic requirements of AIV give rise to heterogeneity in pathogen exposure. Juveniles were more likely to be infected (30.8% compared with 11.3% for adults), shed approximately 15-fold higher quantity of virus and exhibited a lower specific immune response than adults. Together, these results demonstrate the potential for heterogeneity in infection to have a profound influence on the dynamics of pathogens, with concomitant impacts on host habitat selection and fitness. © 2011 The Royal Society.


Simonsz H.J.,Erasmus Medical Center | Kolling G.H.,University of Heidelberg
European Journal of Paediatric Neurology | Year: 2011

Infantile esotropia (IE) is defined as an esotropia before the age of 6 months, with a large angle, latent nystagmus, dissociated vertical deviation, limitation of abduction, and reduced binocular vision, without neurological disorder. Prematurity, low birth weight, and low Apgar scores are significant risk factors for IE. US standard age of first surgery is 12-18 months, in Europe 2-3 years. The only study to date with prospectively assigned early- and late-surgery groups and evaluation according to intention-to-treat, was the European Early vs. Late Infantile Strabismus Surgery Study (ELISSS). In that study 13.5% of children operated around 20 months vs. 3.9% (P = 0.001) of those operated around 49 months had gross stereopsis (Titmus Housefly) at age 6. The reoperation rate was 28.7% in children operated early vs. 24.6% in those operated late. Unexpectedly, 8% in the early group vs. 20% in the late group had not been operated at age 6, although all had been eligible for surgery at baseline at 11 SD 3.7 months. In most of these children the angle of strabismus decreased spontaneously. In a meta-regression analysis of the ELISSS and 12 other studies we found that reoperation rates were 60-80% for children first operated around age 1 and 25% for children operated around age 4. Based on these findings, the endpoints to consider when contemplating best age for surgery in an individual child with IE should be: (1) degree of binocular vision restored or retained, (2) postoperative angle and long-term stability of the angle and (3) number of operations needed or chance of spontaneous regression. IE is characterized by lack of binocular connections in the visual cortex that cannot develop, e.g. because the eyes squint, or do not develop, e.g. after perinatal hypoxia. As the cause of IE, whether motor or sensory, is a determinant of surgical outcome, a subdivision of IE according to cause is needed. As similarities exist between IE and cerebral palsy we propose to adapt the working definition formulated by the Surveillance of Cerebral Palsy in Europe and define IE as "a group of permanent, but not unchanging, disorders with strabismus and disability of fusional vergence and binocular vision, due to a nonprogressive interference, lesion, or maldevelopment of the immature brain, the orbit, the eyes, or its muscles, that can be differentiated according to location, extent, and timing of the period of development." © 2011 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.


Giskes K.,Erasmus Medical Center | Giskes K.,Queensland University of Technology | Avendano M.,Erasmus Medical Center | Brug J.,University of Amsterdam | Kunst A.E.,Erasmus Medical Center
Obesity Reviews | Year: 2010

This Review examined socioeconomic inequalities in intakes of dietary factors associated with weight gain, overweight/obesity among adults in Europe. Literature searches of studies published between 1990 and 2007 examining socioeconomic position (SEP) and the consumption of energy, fat, fibre, fruit, vegetables, energy-rich drinks and meal patterns were conducted. Forty-seven articles met the inclusion criteria. The direction of associations between SEP and energy intakes were inconsistent. Approximately half the associations examined between SEP and fat intakes showed higher total fat intakes among socioeconomically disadvantaged groups. There was some evidence that these groups consume a diet lower in fibre. The most consistent evidence of dietary inequalities was for fruit and vegetable consumption; lower socioeconomic groups were less likely to consume fruit and vegetables. Differences in energy, fat and fibre intakes (when found) were small-to-moderate in magnitude; however, differences were moderate-to-large for fruit and vegetable intakes. Socioeconomic inequalities in the consumption of energy-rich drinks and meal patterns were relatively under-studied compared with other dietary factors. There were no regional or gender differences in the direction and magnitude of the inequalities in the dietary factors examined. The findings suggest that dietary behaviours may contribute to socioeconomic inequalities in overweight/obesity in Europe. However, there is only consistent evidence that fruit and vegetables may make an important contribution to inequalities in weight status across European regions. © 2009 International Association for the Study of Obesity.


Sugano K.,Jichi Medical University | Tack J.,Catholic University of Leuven | Kuipers E.J.,Erasmus Medical Center | Graham D.Y.,Baylor College of Medicine | And 6 more authors.
Gut | Year: 2015

Objective To present results of the Kyoto Global Consensus Meeting, which was convened to develop global consensus on (1) classification of chronic gastritis and duodenitis, (2) clinical distinction of dyspepsia caused by Helicobacter pylori from functional dyspepsia, (3) appropriate diagnostic assessment of gastritis and (4) when, whom and how to treat H. pylori gastritis. Design Twenty-three clinical questions addressing the above-mentioned four domains were drafted for which expert panels were asked to formulate relevant statements. A Delphi method using an anonymous electronic system was adopted to develop the consensus, the level of which was predefined as ≥80%. Final modifications of clinical questions and consensus were achieved at the face-to-face meeting in Kyoto. Results All 24 statements for 22 clinical questions after extensive modifications and omission of one clinical question were achieved with a consensus level of >80%. To better organise classification of gastritis and duodenitis based on aetiology, a new classification of gastritis and duodenitis is recommended for the 11th international classification. A new category of H. pylori-associated dyspepsia together with a diagnostic algorithm was proposed. The adoption of grading systems for gastric cancer risk stratification, and modern image-enhancing endoscopy for the diagnosis of gastritis, were recommended. Treatment to eradicate H. pylori infection before preneoplastic changes develop, if feasible, was recommended to minimise the risk of more serious complications of the infection. Conclusions A global consensus for gastritis was developed for the first time, which will be the basis for an international classification system and for further research on the subject. © 2015 BMJ Publishing Group Ltd & British Society of Gastroenterology.


Damhuis R.A.M.,Comprehensive Cancer Center the Netherlands | Wijnhoven B.P.L.,Erasmus Medical Center | Plaisier P.W.,Albert Schweitzer Hospital | Kirkels W.J.,Erasmus Medical Center | And 2 more authors.
British Journal of Surgery | Year: 2012

Background: Various definitions are used to calculate postoperative mortality. As variation hampers comparability between reports, a study was performed to evaluate the impact of using different definitions for several types of cancer surgery. Methods: Population-based data for the period 1997-2008 were retrieved from the Rotterdam Cancer Registry for resectional surgery of oesophageal, gastric, colonic, rectal, breast, lung, renal and bladder cancer. Postoperative deaths were tabulated as 30-day, in-hospital or 90-day mortality. Postdischarge deaths were defined as those occurring after discharge from hospital but within 30 days. Results: This study included 40 474 patients. Thirty-day mortality rates were highest after gastric (8·8 per cent) and colonic (6·0 per cent) surgery, and lowest after breast (0·2 per cent) and renal (2·0 per cent) procedures. For most tumour types, the difference between 30-day and in-hospital rates was less than 1 per cent. For bladder and oesophageal cancer, however, the in-hospital mortality rate was considerably higher at 5·1 per cent (+1·3 per cent) and 7·3 per cent (+2·8 per cent) respectively. For gastric, colonic and lung cancer, 1·0 per cent of patients died after discharge. For gastric, lung and bladder cancer, more than 3 per cent of patients died between discharge and 90 days. Conclusion: The 30-day definition is recommended as an international standard because it includes the great majority of surgery-related deaths and is not subject to discharge procedures. The 90-day definition, however, captures mortality from multiple causes; although this may be of less interest to surgeons, the data may be valuable when providing information to patients before surgery. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.


Smalberg J.H.,Rotterdam University | Arends L.R.,Erasmus University Rotterdam | Arends L.R.,Erasmus Medical Center | Valla D.C.,Service dHepatologie | And 3 more authors.
Blood | Year: 2012

Myeloproliferative neoplasms (MPNs) are the most common cause of Budd-Chiari syndrome (BCS) and nonmalignant, non-cirrhotic portal vein thrombosis (PVT). In this meta-analysis, we determined the prevalence of MPNs and their subtypes as well as JAK2V617F and its diagnostic role in these uncommon disorders. MEDLINE and EMBASE databases were searched. Prevalence of MPNs, JAK2V617F, and MPN subtypes were calculated using a random-effects model. A total of 1062 BCS and 855 PVT patients were included. In BCS, mean prevalence of MPNs and JAK2V617F was 40.9% (95% CI, 32.9%-49.5%) and 41.1% (95% CI, 32.3%-50.6%), respectively. In PVT, mean prevalence of MPNs and JAK2V617F was 31.5% (95% CI, 25.1%-38.8%) and 27.7% (95% CI, 20.8%-35.8%), respectively. JAK2V617F and MPNs were more frequent in BCS compared with PVT (P = .03 and P = .09, respectively). Polycythemia vera was more prevalent in BCS than in PVT (P = .001). JAK2V617F screening in splanchnic vein thrombosis (SVT) patients without typical hematologic MPN features identified MPN in 17.1% and 15.4% of screened BCS and PVT patients, respectively. These results demonstrate a high prevalence of MPNs and JAK2V617F in SVT patients and show differences in underlying etiology between these disorders. Furthermore, these results validate routine inclusion of JAK2V617F in the diagnostic workup of SVT patients. © 2012 by The American Society of Hematology.


Treasure T.,University College London | Takkenberg J.J.M.,Erasmus Medical Center | Pepper J.,Royal Brompton Hospital | Pepper J.,Institute of Cardiovascular Medicine and Science ICMS
Heart | Year: 2014

Elective root replacement in Marfan syndrome has improved life expectancy in affected patients. Three forms of surgery are now available: total root replacement (TRR) with a valved conduit, valve sparing root replacement (VSRR) and personalised external aortic root support (PEARS) with a macroporous mesh sleeve. TRR can be performed irrespective of aortic dimensions and a mechanical replacement valve is a secure and near certain means of correcting aortic valve regurgitation but has thromboembolic and bleeding risks. VSRR offers freedom from anticoagulation and attendant risks of bleeding but reoperation for aortic regurgitation runs at 1.3% per annum. A prospective multi-institutional study has found this to be an underestimate of the true rate of valve-related adverse events. PEARS conserves the aortic root anatomy and optimises the chance of maintaining valve function but average follow-up is under 5 years and so the long-term results are yet to be determined. Patients are on average in their 30s and so the cumulative lifetime need for reoperation, and of any valve-related complications, are consequently substantial. With lowering surgical risk of prophylactic root replacement, the threshold for intervention has reduced progressively over 30 years to 4.5 cm and so an increasing number of patients who are not destined to have a dissection are now having root replacement. In evaluation of these three forms of surgery, the number needed to treat to prevent dissection and the balance of net benefit and harm in future patients must be considered.


Onuma Y.,Erasmus Medical Center | Dudek D.,Jagiellonian University | Thuesen L.,Aarhus University Hospital | Webster M.,Aarhus University Hospital | And 4 more authors.
JACC: Cardiovascular Interventions | Year: 2013

Objectives This study sought to demonstrate the 5-year clinical and functional multislice computed tomography angiographic results after implantation of the fully resorbable everolimus-eluting scaffold (Absorb BVS, Abbott Vascular, Santa Clara, California). Background Multimodality imaging of the first-in-humans trial using a ABSORB BVS scaffold demonstrated at 2 years the bioresorption of the device while preventing restenosis. However, the long-term safety and efficacy of this therapy remain to be documented. Methods In the ABSORB cohort A trial (ABSORB Clinical Investigation, Cohort A [ABSORB A] Everolimus-Eluting Coronary Stent System Clinical Investigation), 30 patients with a single de novo coronary artery lesion were treated with the fully resorbable everolimus-eluting Absorb scaffold at 4 centers. As an optional investigation in 3 of the 4 centers, the patients underwent multislice computed tomography (MSCT) angiography at 18 months and 5 years. Acquired MSCT data were analyzed at an independent core laboratory (Cardialysis, Rotterdam, the Netherlands) for quantitative analysis of lumen dimensions and was further processed for calculation of fractional flow reserve (FFR) at another independent core laboratory (Heart Flow, Redwood City, California). Results Five-year clinical follow-up is available for 29 patients. One patient withdrew consent after 6 months, but the vital status of this patient remains available. At 46 days, 1 patient experienced a single episode of chest pain and underwent a target lesion revascularization with a slight troponin increase after the procedure. At 5 years, the ischemia-driven major adverse cardiac event rate of 3.4% remained unchanged. Clopidogrel was discontinued in all but 1 patient. Scaffold thrombosis was not observed in any patient. Two noncardiac deaths were reported, 1 caused by duodenal perforation and the other from Hodgkin's disease. At 5 years, 18 patients underwent MSCT angiography. All scaffolds were patent, with a median minimal lumen area of 3.25 mm2 (interquartile range: 2.20 to 4.30). Noninvasive FFR analysis was feasible in 13 of 18 scans, which yielded a median distal FFR of 0.86 (interquartile range: 0.82 to 0.94). Conclusions The low event rate at 5 years suggests sustained safety after the implantation of a fully bioresorbable Absorb everolimus-eluting scaffold. Noninvasive assessment of the coronary artery with an option of functional assessment could be an alternative to invasive imaging after treatment of coronary narrowing with such a polymeric bioresorbable scaffold. (ABSORB Clinical Investigation, Cohort A [ABSORB A] Everolimus-Eluting Coronary Stent System Clinical Investigation [ABSORB]; NCT00300131) © 2013 by the American College of Cardiology Foundation.


De Vries J.F.,Erasmus Medical Center | Zwaan C.M.,Sophia Childrens Hospital | De Bie M.,Erasmus Medical Center | Voerman J.S.A.,Erasmus Medical Center | And 3 more authors.
Leukemia | Year: 2012

We investigated whether the newly developed antibody (Ab) -targeted therapy inotuzumab ozogamicin (CMC-544), consisting of a humanized CD22 Ab linked to calicheamicin, is effective in pediatric primary B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells in vitro, and analyzed which parameters determine its efficacy. CMC-544 induced dose-dependent cell kill in the majority of BCP-ALL cells, although IC 50 values varied substantially (median 4.8 ng/ml, range 0.1-1000 ng/ml at 48 h). The efficacy of CMC-544 was highly dependent on calicheamicin sensitivity and CD22/CMC-544 internalization capacity of BCP-ALL cells, but hardly on basal and renewed CD22 expression. Although CD22 expression was essential for uptake of CMC-544, a repetitive loop of CD22 saturation, CD22/CMC-544 internalization and renewed CD22 expression was not required to achieve intracellular threshold levels of calicheamicin sufficient for efficient CMC-544-induced apoptosis in BCP-ALL cells. This is in contrast to studies with the comparable CD33 immunotoxin gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia (AML) patients, in which complete and prolonged CD33 saturation was required for apoptosis induction. These data suggest that CMC-544 treatment may result in higher response rates in ALL compared with response rates obtained in AML with Mylotarg, and that therefore clinical studies in ALL, preferably with multiple low CMC-544 dosages, are warranted. © 2012 Macmillan Publishers Limited All rights reserved.


Roobol M.J.,Erasmus Medical Center | Haese A.,University of Hamburg | Bjartell A.,Sk University Hospital Malm O
Acta Oncologica | Year: 2011

The serum PSA test still is the most important biomarker for the detection and follow-up of prostate cancer. PSA-based screening can reduce disease specific mortality but coinciding unnecessary testing and overdiagnosis warrant further research for more specific biomarkers. Numerous studies of both serum and urine-based prostate cancer biomarker candidates have been presented the last ten years. However, biomarkers for identifying the most aggressive subsets of this malignancy are still missing. Being non-invasive, urine-based tests might be suitable for both clinical and (mass) screening purposes, but also for prediction and to gain prognostic information. Protein-based, DNA-based and RNA-based urine biomarkers have been developed and tested. Protein markers in urine. Data on protein-based urine biomarkers (i.e. Annexin A3, matrix metalloproteinases and the urinary:serum PSA ratio) show up to now contradictory results and further studies are warranted to be able to assess their clinical value in which the cost aspect should not be overlooked. DNA markers in urine. Studies on DNA-based urine biomarkers focus on hypermethylation of gene panels with GSTP1 hypermethylation being the most promising individual marker. Larger prospective clinical studies of single markers and gene panels are however needed to validate their clinical utility. RNA markers in urine. RNA-based urine biomarkers are by far the most developed. The PCA3 test, the TMPRSS2â€"ERG fusion gene, transcript expression levels of GOLPH2, SPINK1 and their combination have been subject of many studies showing encouraging results. Conclusion. Up to now urine-based biomarkers represent a promising alternative or addition to serum-based biomarkers. Prospective studies in a multivariate setting, including larger sample sizes and avoiding attribution bias caused by preselection on the basis of serum PSA are however required. © 2011 Informa Healthcare.


Verhagen A.P.,Erasmus Medical Center | Cardoso J.R.,State University Londrina | Bierma-Zeinstra S.M.A.,Erasmus Medical Center
Best Practice and Research: Clinical Rheumatology | Year: 2012

This is a best-evidence synthesis providing an evidence-based summary on the effectiveness of aquatic exercises and balneotherapy in the treatment of musculoskeletal conditions. The most prevalent musculoskeletal conditions addressed in this review include: low back pain, osteoarthritis, fibromyalgia and rheumatoid arthritis. Over 30 years of research demonstrates that exercises in general, and specifically aquatic exercises, are beneficial for reducing pain and disability in many musculoskeletal conditions demonstrating small to moderate effect sizes ranging between 0.19 and 0.32. Balneotherapy might be beneficial, but the evidence is yet insufficient to make a definitive statement about its use. High-quality trials are needed on balneotherapy and aquatic exercises research especially in specific patient categories that might benefit most. © 2012 Elsevier Ltd. All rights reserved.


Peirano G.,University of Calgary | Van Der Bij A.K.,Erasmus Medical Center | Van Der Bij A.K.,Reinier Of Graaf Hospital | Gregson D.B.,University of Calgary | Pitout J.D.D.,University of Calgary
Journal of Clinical Microbiology | Year: 2012

A study was designed to assess the importance of sequence types among extended-spectrum β-lactamase (ESBL)-producing Escherichia coli isolates causing bacteremia over an 11-year period (2000 to 2010) in a centralized Canadian region. A total of 197 patients with incident infections were identified; the majority presented with community-onset urosepsis, with a significant increase in the prevalence of ESBL-producing E. coli during the later part of the study. The majority of E. coli isolates produced either CTX-M-15 or CTX-M-14. We identified 7 different major sequence types among 91% of isolates (i.e., the ST10 clonal complex, ST38, ST131, ST315, ST393, ST405, and ST648) and provided insight into their clinical and molecular characteristics. ST38 was the most antimicrobial-susceptible sequence type and predominated during 2000 to 2004 but disappeared after 2008. ST131 was the most antimicrobial-resistant sequence type, and the influx of a single pulsotype of this sequence type was responsible for the significant increase of ESBL-producing E. coli strains since 2007. During 2010, 49/63 (78%) of the ESBL-producing E. coli isolates belonged to ST131, and this sequence type had established itself as a major drug-resistant pathogen in Calgary, Alberta, Canada, posing an important new public health threat within our region. We urgently need well-designed epidemiological and molecular studies to understand the dynamics of transmission, risk factors, and reservoirs for E. coli ST131. This will provide insight into the emergence and spread of this multiresistant sequence type. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Baalbergen A.,Reinier Of Graaf Hospital | Helmerhorst T.J.M.,Erasmus Medical Center
International Journal of Gynecological Cancer | Year: 2014

Objective: This study aimed to review literature if therapeutic strategies in adenocarcinoma in situ of the cervix could lead to a more conservative approach. Methods: A review of the literature was conducted using a Medline search for articles published between 1966 and 2013. Results: Thirty-five studies showed that after a radical cone, 16.5% residual disease in the re-cone or uterus was found. After cone with positive margins, residual abnormalities were found in 49.3%. Thirty-seven studies showed 5% recurrence rate after conservative therapy (large loop excision transformation zone-cold knife conization. After conization with negative margins, the risk of recurrence was 3%. Conclusions: Adenocarcinoma in situ is a relatively rare premalignant but increasingly frequent lesion of the cervix. Although there is a risk of relapse (3%) with a chance of malignancy (<1%), this risk is so small that conservative treatment with negative margins by large loop excision transformation zone or cold knife conization is justified and justifiable not only for women to have children. Copyright © 2014 by IGCS and ESGO.


Giskes K.,Queensland University of Technology | van Lenthe F.,Erasmus Medical Center | Avendano-Pabon M.,Erasmus Medical Center | Brug J.,VU University Amsterdam
Obesity Reviews | Year: 2011

This study examined whether physical, social, cultural and economical environmental factors are associated with obesogenic dietary behaviours and overweight/obesity among adults. Literature searches of databases (i.e. PubMed, CSA Illumina, Web of Science, PsychInfo) identified studies examining environmental factors and the consumption of energy, fat, fibre, fruit, vegetables, sugar-sweetened drinks, meal patterns and weight status. Twenty-eight studies were in-scope, the majority (n= 16) were conducted in the USA. Weight status was consistently associated with the food environment; greater accessibility to supermarkets or less access to takeaway outlets were associated with a lower BMI or prevalence of overweight/obesity. However, obesogenic dietary behaviours did not mirror these associations; mixed associations were found between the environment and obesogenic dietary behaviours. Living in a socioeconomically-deprived area was the only environmental factor consistently associated with a number of obesogenic dietary behaviours. Associations between the environment and weight status are more consistent than that seen between the environment and dietary behaviours. The environment may play an important role in the development of overweight/obesity, however the dietary mechanisms that contribute to this remain unclear and the physical activity environment may also play an important role in weight gain, overweight and obesity. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.


Baalbergen A.,Reinier Of Graaf Hospital | Smedts F.,Reinier Of Graaf Hospital | Helmerhorst T.J.M.,Erasmus Medical Center
International Journal of Gynecological Cancer | Year: 2011

Objective: This study aimed to evaluate the treatment and follow-up in a large series of women with early cervical adenocarcinoma (AC), stages IA1 and IA2, and to perform an extensive review of the literature in an effort to ascertain whether conservative therapy is justified. Methods: Records of 59 cases of microinvasive AC diagnosed between 1987 and 2006 in the Rotterdam district, the Netherlands, were retrieved. Clinical and pathological data were reviewed and analyzed. A mesh review of all relevant literature concerning stage IA1 and IA2 was performed. Results: Of all patients, 33 had stage IA1 and 26 stage IA2 cervical AC. Also, 42 patients were treated conservatively (ie, conization or simple hysterectomy) and 17 patients were treated radically (ie, radical hysterectomy/trachelectomy with lymph node dissection). Recurrence occurred in 1 patient (1.7%) with stage IA1 disease (grade 1 adenocarcinoma, depth 1.4 mm, and width 3.8 mm, with lymph vascular space involvement [LVSI]) treated by vaginal hysterectomy. The mean follow-up was 79.9 months. From the literature, pooling all data from patients with stage IA1 and IA2 AC, the risk of recurrent disease was 1.5% after conservative therapy and 2.0% after radical therapy. Conclusions: Extensive treatment such as radical hysterectomy with pelvic lymph node dissection or trachelectomy does not prevent recurrent disease. Patients with microinvasive AC should be treated identically to patients with SCC. In stage IA1 and IA2 AC, we recommend conservative therapy (by conization). In cases with LVSI, an additional lymphadenectomy is advised. For patients with stage IA2 AC with LVSI, a trachelectomy/radical hysterectomy with lymph node dissection should be considered. Copyright © 2011 by IGCS and ESGO.


De Bekker-Grob E.W.,Erasmus Medical Center | Ryan M.,University of Aberdeen | Gerard K.,University of Southampton
Health Economics | Year: 2012

Discrete choice experiments (DCEs) have become a commonly used instrument in health economics. This paper updates a review of published papers between 1990 and 2000 for the years 2001-2008. Based on this previous review, and a number of other key review papers, focus is given to three issues: experimental design; estimation procedures; and validity of responses. Consideration is also given to how DCEs are applied and reported. We identified 114 DCEs, covering a wide range of policy questions. Applications took place in a broader range of health-care systems, and there has been a move to incorporating fewer attributes, more choices and interview-based surveys. There has also been a shift towards statistically more efficient designs and flexible econometric models. The reporting of monetary values continues to be popular, the use of utility scores has not gained popularity, and there has been an increasing use of odds ratios and probabilities. The latter are likely to be useful at the policy level to investigate take-up and acceptability of new interventions. Incorporation of interactions terms in the design and analysis of DCEs, explanations of risk, tests of external validity and incorporation of DCE results into a decision-making framework remain important areas for future research. Copyright © 2010 John Wiley & Sons, Ltd.


Colombel J.F.,University of Lille Nord de France | Sandborn W.J.,Mayo Medical School | Reinisch W.,Vienna University Hospital | Mantzaris G.J.,Evangelismos Hospital | And 9 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for Crohn's disease are unknown. METHODS: In this randomized, double-blind trial, we evaluated the efficacy of infliximab monotherapy, azathioprine monotherapy, and the two drugs combined in 508 adults with moderate-to-severe Crohn's disease who had not undergone previous immunosuppressive or biologic therapy. Patients were randomly assigned to receive an intravenous infusion of 5 mg of infliximab per kilogram of body weight at weeks 0, 2, and 6 and then every 8 weeks plus daily oral placebo capsules; 2.5 mg of oral azathioprine per kilogram daily plus a placebo infusion on the standard schedule; or combination therapy with the two drugs. Patients received study medication through week 30 and could continue in a blinded study extension through week 50. RESULTS: Of the 169 patients receiving combination therapy, 96 (56.8%) were in corticosteroid-free clinical remission at week 26 (the primary end point), as compared with 75 of 169 patients (44.4%) receiving infliximab alone (P = 0.02) and 51 of 170 patients (30.0%) receiving azathioprine alone (P<0.001 for the comparison with combination therapy and P = 0.006 for the comparison with infliximab). Similar numerical trends were found at week 50. At week 26, mucosal healing had occurred in 47 of 107 patients (43.9%) receiving combination therapy, as compared with 28 of 93 patients (30.1%) receiving infliximab (P = 0.06) and 18 of 109 patients (16.5%) receiving azathioprine (P<0.001 for the comparison with combination therapy and P = 0.02 for the comparison with infliximab). Serious infections developed in 3.9% of patients in the combination-therapy group, 4.9% of those in the infliximab group, and 5.6% of those in the azathioprine group. CONCLUSIONS: Patients with moderate-to-severe Crohn's disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy. (ClinicalTrials.gov number, NCT00094458.) Copyright © 2010 Massachusetts Medical Society.


Onuma Y.,Erasmus Medical Center | Ormiston J.,Auckland City Hospital | Serruys P.W.,Erasmus Medical Center
Circulation Journal | Year: 2011

Fully bioabsorbable scaffolds (BRS) are a novel approach that provides transient vessel support with drug delivery capability without the long-term limitations of the metallic drug-eluting stents (DES), such as permanent caging with or without malapposition. The technology has the potential to overcome many of the safety concerns associated with metallic DES, and possibly even convey further clinical benefit. Although the technology is still in its infancy, several devices have been tested in clinical trials and the initial results have been very promising. This review will discuss the emerging need for BRS, the theoretical advantages of this new technology over current generation metallic DES and review the status of the currently available BRS. In addition, we will discuss the ideal duration of bioresorption, the proven and potential clinical benefits and future perspectives of this rapidly progressing technology.


Stauffer P.R.,Thomas Jefferson University | van Rhoon G.C.,Erasmus Medical Center
International Journal of Hyperthermia | Year: 2016

Moderate temperature hyperthermia (40–45°C for 1 h) is emerging as an effective treatment to enhance best available chemotherapy strategies for bladder cancer. A rapidly increasing number of clinical trials have investigated the feasibility and efficacy of treating bladder cancer with combined intravesical chemotherapy and moderate temperature hyperthermia. To date, most studies have concerned treatment of non-muscle-invasive bladder cancer (NMIBC) limited to the interior wall of the bladder. Following the promising results of initial clinical trials, investigators are now considering protocols for treatment of muscle-invasive bladder cancer (MIBC). This paper provides a brief overview of the devices and techniques used for heating bladder cancer. Systems are described for thermal conduction heating of the bladder wall via circulation of hot fluid, intravesical microwave antenna heating, capacitively coupled radio-frequency current heating, and radiofrequency phased array deep regional heating of the pelvis. Relative heating characteristics of the available technologies are compared based on published feasibility studies, and the systems correlated with clinical requirements for effective treatment of MIBC and NMIBC. © 2016 Informa UK Limited, trading as Taylor & Francis Group.


Jansen T.C.,Erasmus Medical Center | Van Bommel J.,Erasmus Medical Center | Schoonderbeek F.J.,Ikazia Hospital | Sleeswijk Visser S.J.,Reinier Of Graaf Hospital | And 4 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: It is unknown whether lactate monitoring aimed to decrease levels during initial treatment in critically ill patients improves outcome. Objectives: To assess the effect of lactate monitoring and resuscitation directed at decreasing lactate levels in intensive care unit (ICU) patients admitted with a lactate level of greater than or equal to 3.0 mEq/L. Methods: Patients were randomly allocated to two groups. In the lactate group, treatment was guided by lactate levels with the objective to decrease lactate by 20% or more per 2 hours for the initial 8 hours of ICU stay. In the control group, the treatment team had no knowledge of lactate levels (except for the admission value) during this period. The primary outcome measure was hospital mortality. Measurements and Main Results: The lactate group received more fluids and vasodilators. However, there were no significant differences in lactate levels between the groups. In the intention-to-treat population (348 patients), hospital mortality in the control group was 43.5% (77/177) compared with 33.9% (58/171) in the lactate group (P = 0.067). When adjusted for predefined risk factors, hospital mortality was lower in the lactate group (hazard ratio, 0.61; 95% confidence interval, 0.43-0.87; P = 0.006). In the lactate group, Sequential Organ Failure Assessment scores were lower between 9 and 72 hours, inotropes could be stopped earlier, and patients could be weaned from mechanical ventilation and discharged from the ICU earlier. Conclusions: In patients with hyperlactatemia on ICU admission, lactate-guided therapy significantly reduced hospital mortality when adjusting for predefined risk factors. As this was consistent with important secondary endpoints, this study suggests that initial lactate monitoring has clinical benefit. Clinical trial registered with www.clinicaltrials.gov (NCT00270673).


Dudek D.,Jagiellonian University | Onuma Y.,Erasmus Medical Center | Ormiston J.A.,Auckland City Hospital | Thuesen L.,Aarhus University Hospital | And 2 more authors.
EuroIntervention | Year: 2012

Aims: The first-in-man ABSORB Cohort A trial demonstrated the bioresorption of the ABSORB BVS (Abbott Vascular, Santa Clara, CA, USA) at two years. This report describes the 4-year clinical outcomes. Methods and results: The ABSORB Cohort A trial enrolled 30 patients with a single de novo native coronary artery lesion. Clinical follow-up was available in 29 patients since one patient withdrew consent after the six month follow-up. At four years, the hierarchical ID-MACE of 3.4% remained unchanged. Clopidogrel therapy had been discontinued in all patients. Conclusions: Four-year clinical results demonstrate a sustained low MACE rate (3.4%) without any late complications such as stent thrombosis. © Europa Edition 2012. All rights reserved.


Van Hoeven L.,Erasmus University Rotterdam | Luime J.,Erasmus Medical Center | Han H.,Maasstadziekenhuis | Vergouwe Y.,Erasmus Medical Center | Weel A.,Maasstadziekenhuis
Arthritis Care and Research | Year: 2014

Objective To identify axial spondyloarthritis (SpA) in Dutch primary care patients with chronic low back pain (CLBP), and to design a simple referral model for general practitioners (GPs) that would identify patients at risk for axial SpA. Methods Patients (ages 20-45 years) with CLBP were identified from GP records. Assessments included inflammatory back pain questionnaires, medical interviews, physical examinations, HLA-B27, C-reactive protein level, conventional radiography, and magnetic resonance imaging. The outcome measure was axial SpA defined by the Assessment of SpondyloArthritis international Society (ASAS) criteria. Multivariable regression analysis with bootstrapping was used to develop the referral model. Results A total of 364 patients (mean ± SD age 36.3 ± 6.8 years) was recruited with a median symptom duration of 9.0 years. Eighty-six patients (24%) fulfilled the ASAS criteria for axial SpA. Of all potential determinants, the ASAS inflammatory back pain questionnaire, good response to nonsteroidal antiinflammatory drugs, family history of SpA, and symptom duration were identified as most relevant for diagnosing axial SpA by multivariable regression analysis related to axial SpA. The shrunken regression coefficients were, respectively, 1.04, 0.83, 0.73, and 0.23. The combination of these 4 items proved a useful area under the receiver operating characteristic curve of 0.75 (SE 0.03). In a simplified score model, at the suggested cutoff value of 1.5, the sensitivity was 83% and specificity was 59%. Conclusion This study shows that 1 of 4 primary care patients with CLBP was classified as having axial SpA. A preselection in primary care based on a combination of clinical items may be useful to facilitate the identification of patients at risk of axial SpA. Copyright © 2014 by the American College of Rheumatology.


Osnabrugge R.L.J.,Erasmus Medical Center | Mylotte D.,McGill University | Mylotte D.,Galway University Hospital | Head S.J.,Erasmus Medical Center | And 7 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives The purpose of this study was to evaluate the prevalence of aortic stenosis (AS) in the elderly and to estimate the current and future number of candidates for transcatheter aortic valve replacement (TAVR). Background Severe AS is a major cause of morbidity and mortality in the elderly. A proportion of these patients is at high or prohibitive risk for surgical aortic valve replacement, and is now considered for TAVR. Methods A systematic search was conducted in multiple databases, and prevalence rates of patients (>75 years) were pooled. A model was based on a second systematic literature search of studies on decision making in AS. Monte Carlo simulations were performed to estimate the number of TAVR candidates in 19 European countries and North America. Results Data from 7 studies (n = 9,723 subjects) were used. The pooled prevalence of all AS in the elderly was 12.4% (95% confidence interval [CI]: 6.6% to 18.2%), and the prevalence of severe AS was 3.4% (95% CI: 1.1% to 5.7%). Among elderly patients with severe AS, 75.6% (95% CI: 65.8% to 85.4%) were symptomatic, and 40.5% (95% CI: 35.8% to 45.1%) of these patients were not treated surgically. Of those, 40.3% (95% CI: 33.8% to 46.7%) received TAVR. Of the high-risk patients, 5.2% were TAVR candidates. Projections showed that there are approximately 189,836 (95% CI: 80,281 to 347,372) TAVR candidates in the European countries and 102,558 (95% CI: 43,612 to 187,002) in North America. Annually, there are 17,712 (95% CI: 7,590 to 32,691) new TAVR candidates in the European countries and 9,189 (95% CI: 3,898 to 16,682) in North America. Conclusions With a pooled prevalence of 3.4%, the burden of disease among the elderly due to severe AS is substantial. Under the current indications, approximately 290,000 elderly patients with severe AS are TAVR candidates. Nearly 27,000 patients become eligible for TAVR annually. © 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.


Minkovsky A.,University of California at Los Angeles | Barakat T.,Erasmus Medical Center | Sellami N.,University of California at Los Angeles | Chin M.,University of California at Los Angeles | And 3 more authors.
Cell Reports | Year: 2013

X chromosome inactivation (XCI) is a dynamically regulated developmental process with inactivation and reactivation accompanying the loss and gain of pluripotency, respectively. A functional relationship between pluripotency and lack of XCI has been suggested, whereby pluripotency transcription factors repress the master regulator of XCI, the noncoding transcript Xist, by binding to its first intron (intron 1). To test this model, we have generated intron 1 mutant embryonic stem cells (ESCs) and two independent mouse models. We found that Xist''s repression in ESCs, its transcriptional upregulation upon differentiation, and its silencing upon reprogramming to pluripotency are not dependent on intron 1. Although we observed subtle effects of intron 1 deletion on the randomness of XCI and in the absence of the antisense transcript Tsix in differentiating ESCs, these have little relevance in. vivo because mutant mice do not deviate from Mendelian ratios of allele transmission. Altogether, our findings demonstrate that intron 1 is dispensable for the developmental dynamics of Xist expression. Video Abstract: In the mouse, there is a close coupling between pluripotency and absence of Xist RNA expression: upon differentiation, Xist is upregulated to silence one X chromosome in female cells; and upon reprogramming, Xist coating is lost and the silent X chromosome reactivated. Here, Plath and colleagues refute the hypothesis that the first intron of the Xist gene is a critical genomic element for the regulation of X chromosome inactivation and reactivation in the mouse system. © 2013 The Authors.


Wishaupt J.O.,Reinier Of Graaf Hospital | Russcher A.,Reinier Of Graaf Hospital | Smeets L.C.,Reinier Of Graaf Hospital | Versteegh F.G.A.,Groene Hart Ziekenhuis | Hartwig N.G.,Erasmus Medical Center
Pediatrics | Year: 2011

OBJECTIVE: Real-time polymerase chain reaction (RT-PCR) testing is a quick sensitive method for detecting respiratory pathogens. We evaluated the diagnostic yield of RT-PCR assays and measured the effect of rapid reporting on patient care. METHODS: In a controlled clinical trial, nasal wash specimens were obtained from patients <12 years of age with suspected acute respiratory infections. In addition to the standard hospital protocol, RT-PCR assays for 17 pathogens were performed. The RT-PCR results were communicated to the clinicians within 12 to 36 hours in the intervention group and after 4 weeks in the control group. RESULTS: A total of 583 patients were included (mean age: 8.1 months [range: 0 -107.5 months]): 298 in the intervention group and 285 in the control group. Eighty-two percent of nasal wash specimens tested positive for ≥1 pathogen. Respiratory syncytial virus was the most frequently encountered (55%) pathogen. There were no significant differences between the groups with respect to hospital admissions (intervention group: 223 admissions; control group: 211 admissions; P = .825), length of hospital stay (mean ± SD: 3.68 ± 2.68 days [intervention group] and 3.96 ± 2.67 days [control group]; P = .178), or duration of antibiotic use (mean ± SD: 6.52 ± 2.15 days [intervention group] and 6.97 ± 2.86 days [control group]; P = .490), when antibiotic treatment had been initiated. CONCLUSIONS: RT-PCR testing has a high yield of viral diagnoses, but rapid communication does not lead to decreases in hospital admissions, shorter hospital stays, or less antibiotic use for children with acute respiratory infections. Copyright © 2011 by the American Academy of Pediatrics.


Brusselle G.,Ghent University | Brusselle G.,Erasmus Medical Center | Bracke K.,Ghent University
Annals of the American Thoracic Society | Year: 2014

Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic inflammatory diseases of the airways, with differences in etiology, pathogenesis, immunologic mechanisms, clinical presentation, comorbidities, prognosis, and response to treatment. In mild to moderate early-onset allergic asthma, the Th2-driven eosinophilic airway inflammation and the ensuing disease can be well controlled with maintenance treatment with inhaled corticosteroids (ICS). In real-life settings, asthma control can be improved by facilitating adherence to ICS treatment and by optimizing inhaler technique. In patients with uncontrolled severe asthma, old and novel therapies targeting specific immunologic pathways should be added according to the underlying endotype/ phenotype. In COPD, there is a high unmet need for safe and effective antiinflammatory treatments that not only prevent exacerbations but also have a beneficial impact on the course of the disease and improve survival. Although several new approaches aim to target the chronic neutrophilic pulmonary inflammation per se in patients with COPD, strategies that target the underlying causes of the pulmonary neutrophilia (e.g., smoking, chronic infection, and oxidative stress) might be more successful. In both chronic airway diseases (especially in more difficult, complex cases), the choice of the optimal treatment should be based not only on arbitrary clinical labels but also on the underlying immunopathology. Copyright © 2014 by the American Thoracic Society


Kusadasi N.,Erasmus Medical Center | Kusadasi N.,Vlietland Hospital | Groeneveld A.B.J.,Erasmus Medical Center
Shock | Year: 2013

Although a variety of disease-modifying agents have been studied as potential sepsis treatments, no beneficial effects on the course of sepsis, in terms of survival, have been observed until now. Because of their plasticity, mesenchymal stromal cells (MSCs) have been implicated as an effective novel therapy modality for various diseases and are widely used for cellular therapies and tissue engineering. The existing knowledge supports the idea that MSCs might be beneficial in sepsis treatment. Our objective was to selectively address the evidence, based on multistep processes, supporting the potential of MSC-based therapies in clinical sepsis trials. In this study, we performed a stepwise approach to defend the evaluation of MSC treatments for sepsis from the bench to the bedside. Altogether, the reviewed data postulate that the signals produced by inflamed tissues might determine the functional effects of MSCs. These effects include bacterial clearance, suppression of inflammation, antiapoptosis, or stimulation of regenerative responses. We conclude that the clinical application of MSCs is a feasible and well-tolerated approach and therefore may have benefits for patients with sepsis. Copyright © 2013 by the Shock Society.


Li V.S.W.,University Utrecht | Ng S.S.,University Utrecht | Boersema P.J.,University Utrecht | Boersema P.J.,Netherlands Proteomics Center | And 15 more authors.
Cell | Year: 2012

Degradation of cytosolic β-catenin by the APC/Axin1 destruction complex represents the key regulated step of the Wnt pathway. It is incompletely understood how the Axin1 complex exerts its Wnt-regulated function. Here, we examine the mechanism of Wnt signaling under endogenous levels of the Axin1 complex. Our results demonstrate that β-catenin is not only phosphorylated inside the Axin1 complex, but also ubiquinated and degraded via the proteasome, all within an intact Axin1 complex. In disagreement with current views, we find neither a disassembly of the complex nor an inhibition of phosphorylation of Axin1-bound β-catenin upon Wnt signaling. Similar observations are made in primary intestinal epithelium and in colorectal cancer cell lines carrying activating Wnt pathway mutations. Wnt signaling suppresses β-catenin ubiquitination normally occurring within the complex, leading to complex saturation by accumulated phospho-β-catenin. Subsequently, newly synthesized β-catenin can accumulate in a free cytosolic form and engage nuclear TCF transcription factors. © 2012 Elsevier Inc. © 2012 Elsevier Inc.


Pereboom T.C.,Universitair Medisch Centrum Utrecht | Van Weele L.J.,Universitair Medisch Centrum Utrecht | Bondt A.,Universitair Medisch Centrum Utrecht | Bondt A.,Erasmus Medical Center | MacInnes A.W.,Universitair Medisch Centrum Utrecht
Blood | Year: 2011

Dyskeratosis congenita (DC) is a bone marrow failure disorder characterized by shortened telomeres, defective stem cell maintenance, and highly heterogeneous phenotypes affecting predominantly tissues that require high rates of turnover. Here we present a mutant zebrafish line with decreased expression of nop10, one of the known H/ACA RNP complex genes with mutations linked to DC. We demonstrate that this nop10 loss results in 18S rRNA processing defects and collapse of the small ribosomal subunit, coupled to stabilization of the p53 tumor suppressor protein through small ribosomal proteins binding to Mdm2. These mutants also display a hematopoietic stem cell deficiency that is reversible on loss of p53 function. However, we detect no changes in telomere length in nop10 mutants. Our data support a model of DC whereupon in early development mutations involved in the H/ACA complex contribute to bone marrow failure through p53 deregulation and loss of initial stem cell numbers while their role in telomere maintenance does not contribute to DC until later in life. © 2011 by The American Society of Hematology.


Stratmann M.,University of Geneva | Stadler F.,University of Fribourg | Tamanini F.,Erasmus Medical Center | Van Der Horst G.T.J.,Erasmus Medical Center | Ripperger J.A.,University of Fribourg
Genes and Development | Year: 2010

The albumin D site-binding protein (DBP) governs circadian transcription of a number of hepatic detoxification and metabolic enzymes prior to the activity phase and subsequent food intake of mice. However, the behavior of mice is drastically affected by the photoperiod. Therefore, continuous adjustment of the phase of circadian Dbp expression is required in the liver. Here we describe a direct impact of CRYPTOCHROME1 (CRY1) on the phase of Dbp expression. Dbp and the nuclear receptor Rev-Erbα are circadian target genes of BMAL1 and CLOCK. Surprisingly, dynamic CRY1 binding to the Dbp promoter region delayed BMAL1 and CLOCK-mediated transcription of Dbp compared with Rev-Erbα. Extended presence of CRY1 in the nucleus enabled continuous uncoupling of the phase of Dbp from Rev-Erbα expression upon change from short to longer photoperiods. CRY1 thus maintained the peak of DBP accumulation close to the activity phase. In contrast, Rev-Erbα expression was phase-locked to the circadian oscillator and shaped by accumulation of its own gene product. Our data indicate that fine-tuning of circadian transcription in the liver is even more sophisticated than expected. © 2010 by Cold Spring Harbor Laboratory Press.


Heidenreich A.,RWTH Aachen | Bastian P.J.,Klinikum Golzheim | Bellmunt J.,University of the Sea | Bolla M.,Grenoble University Hospital Center | And 7 more authors.
European Urology | Year: 2014

Objective To present a summary of the 2013 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC). Evidence acquisition The working panel performed a literature review of the new data (2011-2013). The guidelines were updated, and levels of evidence and/or grades of recommendation were added to the text based on a systematic review of the literature that included a search of online databases and bibliographic reviews. Evidence synthesis Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). LHRH antagonists decrease testosterone without any testosterone surge, and they may be associated with an oncologic benefit compared with LHRH analogues. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation results in noninferior oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values >0.2 ng/ml following radical prostatectomy (RP) and >2 ng/ml above the nadir and after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT (SRT) at PSA levels <0.5 ng/ml and SRP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (PET/CT) are of limited importance if the PSA is <1.0 ng/ml; bone scans and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include analysis of PSA and testosterone levels, and screening for cardiovascular disease and metabolic syndrome. Treatment of CRPC includes sipuleucel-T, abiraterone acetate plus prednisone (AA/P), or chemotherapy with docetaxel at 75 mg/m2 every 3 wk. Cabazitaxel, AA/P, enzalutamide, and radium-223 are available for second-line treatment of CRPC following docetaxel. Zoledronic acid and denosumab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications. Conclusions The knowledge in the field of advanced, metastatic, and castration-resistant PCa is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or at www.uroweb.org. Patient summary We present a summary of the 2013 version of the European Association of Urology guidelines on treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC). Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). LHRH antagonists decrease testosterone without any testosterone surge, and they might be associated with an oncologic benefit compared with LHRH analogues. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation results in noninferior oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values >0.2 ng/ml following radical prostatectomy (RP) and >2 ng/ml above the nadir and after radiation therapy. Therapy for PSA relapse after RP includes salvage radiation therapy at PSA levels <0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Multiparametric magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (PET/CT) are of limited importance if the PSA is <1.0 ng/ml; bone scans, and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include analysis of PSA and testosterone levels, and screening for cardiovascular disease and metabolic syndrome. Treatment of castration-resistant CRPC includes sipuleucel-T, abiraterone acetate plus prednisone (AA/P), or chemotherapy with docetaxel 75 mg/m2 every 3 wk. Cabazitaxel, AA/P, enzalutamide, and radium-223 are available for second-line treatment of CRPC following docetaxel. Zoledronic acid and denosumab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications. The guidelines reported should be adhered to in daily routine to improve the quality of care in PCa patients. As we have shown recently, guideline compliance is only in the area of 30-40%. © 2013 European Association of Urology.


De la Croix A.,Erasmus Medical Center | Skelton J.,University of Birmingham
Medical Education | Year: 2013

Context Institutional interactions are often asymmetrical in that the professional has more control over the conversation. It is difficult to say who the professional is in simulated consultations between simulated patients (SPs) and medical students because these feature a real (educational) institutional context and a simulated (medical) institutional context. This study describes this asymmetry and makes educational recommendations based on the description. Methods One hundred assessed conversations between SPs and Year3 students were transcribed and analysed using discourse analysis (DA). We aimed to find linguistic patterns in predefined parts of the conversations (questions, topic initiations, openings, closings) that might suggest conversational dominance. Results The SP is conversationally more dominant, despite performing the role of the patient, in that he or she asks more direct questions, is more likely to initiate topics, is more likely not to follow topic changes by students, and closes the consultation. The student is likely to follow topics initiated by the SP and to seek permission to pre-close the consultation. Conclusions The apparently greater dominance of the SP indicates that the simulated consultation differs from the doctor-patient consultation in certain key aspects. It is in that sense unrealistic. We argue, however, that 'realism' ought not to be a goal of simulated consultation and that what matters is that such consultations are sufficiently realistic for their educational purpose. We discuss the educational implications that follow from this. © 2013 Blackwell Publishing Ltd.


Bonella F.,Universitatsklinikum Essen g | Wijsenbeek M.,Erasmus Medical Center | Molina-Molina M.,University of Barcelona | Duck A.,ILD | And 3 more authors.
European Respiratory Journal | Year: 2016

Patient advocacy groups play an important role in supporting patients with chronic diseases and promoting better care. The aim of this patient-physician initiative was to gather perceptions from European idiopathic pulmonary fibrosis (IPF) patient advocacy groups regarding inequalities and unmet needs in IPF care, in order to develop a Patient Charter to advocate for better care. In total, 11 European patient advocacy groups were interviewed regarding the care of patients with IPF in their countries. Interview feedback was presented to a Working Group including patient advocacy group representatives and IPF specialists; key areas of agreement were developed into the European IPF Patient Charter. The interviews identified five key themes that fed into the final Charter: the need for improved diagnosis, treatment access, holistic care, disease awareness and palliative care. The final Charter was endorsed by patient advocacy groups and presented to 26 Members of the European Parliament in September 2014. It has received >8900 signatures to date. This patient-physician initiative highlights the inequalities and unmet needs in IPF care across Europe, and demonstrates how this insight can inform the development of a Patient Charter, designed as a call to action for healthcare policymakers to drive improvement in European IPF care. Copyright © 2016 by the European Respiratory Society.


Oberg K.E.,Entrance | Reubi J.,University of Bern | Kwekkeboom D.J.,Erasmus Medical Center | Krenning E.P.,Erasmus Medical Center
Gastroenterology | Year: 2010

The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have increased in the past 20 years. GEP-NETs are heterogeneous tumors, in terms of clinical and biological features, that originate from the pancreas or the intestinal tract. Some GEP-NETs grow very slowly, some grow rapidly and do not cause symptoms, and others cause hormone hypersecretion and associated symptoms. Most GEP-NETs overexpress receptors for somatostatins. Somatostatins inhibit the release of many hormones and other secretory proteins; their effects are mediated by G proteincoupled receptors that are expressed in a tissue-specific manner. Most GEP-NETs overexpress the somatostatin receptor SSTR2; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone-related symptoms and also have antitumor effects. Long-acting formulations of somatostatin analogues stabilize tumor growth over long periods. The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP-NETs. Peptide receptor radiotherapy has significant antitumor effects, increasing overall survival times of patients with tumors that express a high density of SSTRs, particularly SSTR2 and SSTR5. The multi-receptor somatostatin analogue SOM230 (pasireotide) and chimeric molecules that bind SSTR2 and the dopamine receptor D2 are also being developed to treat patients with GEP-NETs. Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways, such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor, might be the most effective therapeutics for GEP-NETs. © 2010 by the AGA Institute.


Lacroix A.,Center Hospitalier Of Luniversite Of Montreal Chum | Feelders R.A.,Erasmus Medical Center | Stratakis C.A.,U.S. National Institutes of Health | Nieman L.K.,U.S. National Institutes of Health
The Lancet | Year: 2015

Chronic exposure to excess glucorticoids results in diverse manifestations of Cushing's syndrome, including debilitating morbidities and increased mortality. Genetic and molecular mechanisms responsible for excess cortisol secretion by primary adrenal lesions and adrenocorticotropic hormone (ACTH) secretion from corticotroph or ectopic tumours have been identified. New biochemical and imaging diagnostic approaches and progress in surgical and radiotherapy techniques have improved the management of patients. The therapeutic goal is to normalise tissue exposure to cortisol to reverse increased morbidity and mortality. Optimum treatment consisting of selective and complete resection of the causative tumour is necessay to allow eventual normalisation of the hypothalamic-pituitary-adrenal axis, maintenance of pituitary function, and avoidance of tumour recurrence. The development of new drugs offers clinicians several choices to treat patients with residual cortisol excess. However, for patients affected by this challenging syndrome, the long-term effects and comorbidities associated with hypercortisolism need ongoing care. © 2015 Elsevier Ltd.


Lambrecht B.N.,Laboratory of Immunoregulation and Mucosal Immunology | Lambrecht B.N.,Ghent University | Lambrecht B.N.,Erasmus Medical Center | Hammad H.,Laboratory of Immunoregulation and Mucosal Immunology
Annual Review of Immunology | Year: 2012

Lung dendritic cells (DCs) bridge innate and adaptive immunity, and depending on context, they also induce a Th1, Th2, or Th17 response to optimally clear infectious threats. Conversely, lung DCs can also mount maladaptive Th2 immune responses to harmless allergens and, in this way, contribute to immunopathology. It is now clear that the various aspects of DC biology can be understood only if we take into account the functional specializations of different DC subsets that are present in the lung in homeostasis or are attracted to the lung as part of the inflammatory response to inhaled noxious stimuli. Lung DCs are heavily influenced by the nearby epithelial cells, and a model is emerging whereby direct communication between DCs and epithelial cells determines the outcome of the pulmonary immune response. Here, we have approached DC biology from the perspective of viral infection and allergy to illustrate these emerging concepts. © 2012 by Annual Reviews. All rights reserved.


Duijts L.,Erasmus Medical Center | Reiss I.K.,Erasmus Medical Center | Brusselle G.,Erasmus Medical Center | Brusselle G.,Ghent University | de Jongste J.C.,Erasmus Medical Center
European Journal of Epidemiology | Year: 2014

Chronic obstructive lung diseases, like asthma and chronic obstructive pulmonary disease, have high prevalences and are a major public health concern. Chronic obstructive lung diseases have at least part of their origins in early life. Exposure to an adverse environment during critical periods in early life might lead to permanent developmental adaptations which results in impaired lung growth with smaller airways and lower lung volume, altered immunological responses and related inflammation, and subsequently to increased risks of chronic obstructive lung diseases throughout the life course. Various pathways leading from early life factors to respiratory health outcomes in later life have been studied, including fetal and early infant growth patterns, preterm birth, maternal obesity, diet and smoking, children’s diet, allergen exposure and respiratory tract infections, and genetic susceptibility. Data on potential adverse factors in the embryonic and preconception period and respiratory health outcomes are scarce. Also, the underlying mechanisms how specific adverse exposures in the fetal and early postnatal period lead to chronic obstructive lung diseases in later life are not yet fully understood. Current studies suggest that interactions between early environmental exposures and genetic factors such as changes in DNA-methylation and RNA expression patterns may explain the early development of chronic obstructive lung diseases. New well-designed epidemiological studies are needed to identify specific critical periods and to elucidate the mechanisms underlying the development of chronic obstructive lung disease throughout the life course. © 2014, Springer Science+Business Media Dordrecht.


De Ridder I.,Erasmus Medical Center | Dirks M.,Erasmus Medical Center | Niessen L.,Johns Hopkins Medical Institutions | Niessen L.,University of East Anglia | Dippel D.,Erasmus Medical Center
Stroke | Year: 2013

Background and Purpose - A recent meta-analysis showed that women with acute ischemic stroke are less likely to receive treatment with intravenous alteplase than men. The aim of this study was to assess sex differences in treatment with intravenous alteplase and to explore the reasons for these differences. Methods - We analyzed data from the Promoting Acute Thrombolysis for Ischaemic Stroke (PRACTISE) study. We applied a multiple logistic regression model and expressed the association between sex and treatment with an age-adjusted odds ratio with 95% confidence interval. Results - In total, 5515 patients were included in PRACTISE. Women were an average of 4 years older than men. The median National Institutes of Health Stroke Scale score was 6 in women and 5 in men. Fewer women were treated with intravenous alteplase (11% versus 14%; adjusted odds ratio, 0.8; 95% confidence interval, 0.7-1.0). However, fewer women arrived within 4 hours after onset (27% versus 33%; adjusted odds ratio, 0.8; 95% confidence interval, 0.7-0.9). Conclusions - Fewer women present themselves within 4 hours from stroke onset than men and consequently less often receive thrombolytic treatment. This difference may be caused by the older age of women on average and consequently women more often living alone. © 2013 American Heart Association, Inc.


Brusselle G.G.,Ghent University | Brusselle G.G.,Erasmus Medical Center | Joos G.,Ghent University
Current Opinion in Pulmonary Medicine | Year: 2014

PURPOSE OF REVIEW: Severe asthma is a heterogeneous syndrome, encompassing several distinct clinical phenotypes. Different molecular and cellular pathways or endotypes determine the type of underlying airway inflammation in patients with severe asthma, which can be categorized as eosinophilic asthma (allergic and nonallergic) or noneosinophilic asthma (neutrophilic and paucigranulocytic). In this review, we discuss the potential role of macrolides in the treatment of severe asthma in adults. RECENT FINDINGS: Maintenance treatment with low-dose macrolides such as erythromycin and azithromycin provides clinical benefit in several chronic neutrophilic airway diseases, including cystic fibrosis (CF), non-CF bronchiectasis and exacerbation-prone chronic obstructive pulmonary disease. Although several short-term studies of macrolides in mild-to-moderate asthma have failed to improve lung function, the AzIthromycin in Severe Asthma trial has demonstrated a significant reduction in the rate of exacerbations in patients with exacerbation-prone noneosinophilic severe asthma. As chronic macrolide use is associated with the risks of population antimicrobial resistance, this add-on treatment should be restricted to severe asthma patients at greatest unmet need despite optimal asthma management. SUMMARY: Further clinical, translational and basic research is needed to better phenotype patients with severe asthma, to determine the risk-benefit ratio of macrolide maintenance treatment in neutrophilic severe asthma and to elucidate the principal mechanisms of action of macrolides. © 2013 Wolters Kluwer Health.


Hammad H.,Ghent University | Plantinga M.,Ghent University | Deswarte K.,Ghent University | Pouliot P.,Ghent University | And 5 more authors.
Journal of Experimental Medicine | Year: 2010

It is unclear how Th2 immunity is induced in response to allergens like house dust mite (HDM). Here, we show that HDM inhalation leads to the TLR4/MyD88-dependent recruitment of IL-4 competent basophils and eosinophils, and of inflammatory DCs to the draining mediastinal nodes. Depletion of basophils only partially reduced Th2 immunity, and depletion of eosinophils had no effect on the Th2 response. Basophils did not take up inhaled antigen, present it to T cells, or express antigen presentation machinery, whereas a population of FceRI+ DCs readily did. Inflammatory DCs were necessary and sufficient for induction of Th2 immunity and features of asthma, whereas basophils were not required. We favor a model whereby DCs initiate and basophils amplify Th2 immunity to HDM allergen. © 2010 Hammad et al.


Kampourakis K.,Teacher Training Institute | Vayena E.,University of Zürich | Mitropoulou C.,Erasmus Medical Center | Van Schaik R.H.,Erasmus Medical Center | And 3 more authors.
EMBO Reports | Year: 2014

Recent advances in genomics and sequencing technology herald the advent of pharmacogenomics in routine clinical practice. Yet, while science and technology have progressed rapidly, legal, social and ethical challenges remain to be resolved. © 2014 The Authors.


Plantinga M.,Ghent University | Hammad H.,Ghent University | Lambrecht B.N.,Ghent University | Lambrecht B.N.,Erasmus Medical Center
European Journal of Immunology | Year: 2010

Lung DC bridge innate and adaptive immunity, and depending on the context, induce Th1, Th2 or Th17 response, to optimally clear infections. Conversely, lung DC can also prevent overt and harmful immune responses to harmless inhaled antigens via induction of Treg or via induction of neutralizing mucosal IgA antibodies. Here, we propose that these functions are not the result of a single population of DC, and instead, subsets of DC perform specialized functions. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.


Ghamari A.,Erasmus Medical Center | van de Corput M.P.C.,Erasmus Medical Center | Thongjuea S.,University of Bergen | Van Cappellen W.A.,Erasmus Medical Center | And 8 more authors.
Genes and Development | Year: 2013

Transcription steps are marked by different modifications of the C-terminal domain of RNA polymerase II (RNAPII). Phosphorylation of Ser5 and Ser7 by cyclin-dependent kinase 7 (CDK7) as part of TFIIH marks initiation, whereas phosphorylation of Ser2 by CDK9 marks elongation. These processes are thought to take place in localized transcription foci in the nucleus, known as "transcription factories," but it has been argued that the observed clusters/foci are mere fixation or labeling artifacts. We show that transcription factories exist in living cells as distinct foci by live-imaging fluorescently labeled CDK9, a kinase known to associate with active RNAPII. These foci were observed in different cell types derived from CDK9-mCherry knock-in mice. We show that these foci are very stable while highly dynamic in exchanging CDK9. Chromatin immunoprecipitation (ChIP) coupled with deep sequencing (ChIP-seq) data show that the genome-wide binding sites of CDK9 and initiating RNAPII overlap on transcribed genes. Immunostaining shows that CDK9-mCherry foci colocalize with RNAPII-Ser5P, much less with RNAPII-Ser2P, and not with CDK12 (a kinase reported to be involved in the Ser2 phosphorylation) or with splicing factor SC35. In conclusion, transcription factories exist in living cells, and initiation and elongation of transcripts takes place in different nuclear compartments. © 2013 by Cold Spring Harbor Laboratory Press.


Roffi M.,University of Geneva | Angiolillo D.J.,Florida College | Kappetein A.P.,Erasmus Medical Center
European Heart Journal | Year: 2011

Diabetic mellitus (DM) patients with coronary artery disease (CAD) are at higher risk of cardiovascular events compared with non-DM individuals. While aggressive cardiovascular prevention and adequate blood glucose control remain cornerstones of therapy, the decision when and how to proceed to coronary revascularization in an individual DM patient should be based on the extent of CAD, ischaemic burden, ventricular function, as well as comorbidities. While in patients with stable symptoms, moderate CAD on coronary angiography and preserved left ventricular function a conservative strategy may be a valuable initial strategy, in patients with acute coronary syndromes (ACS) an early invasive approach should be favoured. The revascularization strategy for DM patients with complex multivessel CAD should be discussed within a heart team consisting of cardiologists, cardiac surgeons, and anaesthesiologists. In general, the threshold for coronary artery bypass surgery (CABG) should be lower for DM than for non-DM individuals. In patients undergoing percutaneous coronary intervention, the use of drug-eluting stents (DES) andin the setting of ACSof potent platelet inhibitors, such as prasugrel or ticagrelor, should be favoured. In the near future, multiple strategies may further favourably impact the prognosis of DM patients undergoing coronary revascularization. These include alternative antiplatelet agents such as thromboxane receptor inhibitors, the broad use of second generation DES, and possibly the implantation of bioresorbable stents. Coronary artery bypass surgery outcomes may also further improve by wide implementation of arterial revascularization, reduction in perioperative stroke by avoiding clamping of the aorta, reduction in wound infection by minimally invasive techniques, and optimization of post-operative medical management. © 2011 The Author.


Kool M.,Ghent University | Kool M.,Erasmus Medical Center | Willart M.,Ghent University | van Nimwegen M.,Erasmus Medical Center | And 9 more authors.
Immunity | Year: 2011

Although deposition of uric acid (UA) crystals is known as the cause of gout, it is unclear whether UA plays a role in other inflammatory diseases. We here have shown that UA is released in the airways of allergen-challenged asthmatic patients and mice, where it was necessary for mounting T helper 2 (Th2) cell immunity, airway eosinophilia, and bronchial hyperreactivity to inhaled harmless proteins and clinically relevant house dust mite allergen. Conversely, administration of UA crystals together with protein antigen was sufficient to promote Th2 cell immunity and features of asthma. The adjuvant effects of UA did not require the inflammasome (Nlrp3, Pycard) or the interleukin-1 (Myd88, IL-1r) axis. UA crystals promoted Th2 cell immunity by activating dendritic cells through spleen tyrosine kinase and PI3-kinase δ signaling. These findings provide further molecular insight into Th2 cell development and identify UA as an essential initiator and amplifier of allergic inflammation. © 2011 Elsevier Inc.


Crowther M.J.,University of Leicester | Look M.P.,Erasmus Medical Center | Riley R.D.,University of Birmingham
Statistics in Medicine | Year: 2014

Multilevel mixed effects survival models are used in the analysis of clustered survival data, such as repeated events, multicenter clinical trials, and individual participant data (IPD) meta-analyses, to investigate heterogeneity in baseline risk and covariate effects. In this paper, we extend parametric frailty models including the exponential, Weibull and Gompertz proportional hazards (PH) models and the log logistic, log normal, and generalized gamma accelerated failure time models to allow any number of normally distributed random effects. Furthermore, we extend the flexible parametric survival model of Royston and Parmar, modeled on the log-cumulative hazard scale using restricted cubic splines, to include random effects while also allowing for non-PH (time-dependent effects). Maximum likelihood is used to estimate the models utilizing adaptive or nonadaptive Gauss-Hermite quadrature. The methods are evaluated through simulation studies representing clinically plausible scenarios of a multicenter trial and IPD meta-analysis, showing good performance of the estimation method. The flexible parametric mixed effects model is illustrated using a dataset of patients with kidney disease and repeated times to infection and an IPD meta-analysis of prognostic factor studies in patients with breast cancer. User-friendly Stata software is provided to implement the methods. © 2014 John Wiley & Sons, Ltd.


Schaap F.G.,Leiden University | Schaap F.G.,Maastricht University | French P.J.,Erasmus Medical Center | Bovee J.V.M.G.,Leiden University
Advances in Anatomic Pathology | Year: 2013

Heterozygous hotspot mutations in isocitrate dehydrogenases (IDH) IDH1 or IDH2 are frequently observed in specific types of cartilaginous tumors, gliomas, and leukemias. Mutant IDH enzyme loses its normal activity to convert isocitrate into α-ketoglutarate (αKG) and instead acquires the ability to reduce αKG to D-2-hydroxyglutarate. Through direct competition with αKG, accumulation of the oncometabolite D-2-hydroxyglutarate in IDH mutated tumors results in inhibition of αKG-dependent dioxygenases involved in DNA and histone demethylation. Apart from epigenetic alterations, perturbations in the tricarboxylic acid cycle (depletion of intermediates) and activation of the intricately linked hypoxia signaling pathway are apparent in IDH mutated cells. As molecular details are being unraveled, the emerging concept is that IDH mutations result in tumor formation by epigenetic alterations that affect gene expression and result in inhibition of cellular differentiation. Activation of hypoxic stress signaling reprograms cellular energy metabolism and promotes anabolic processes and angiogenesis, thus, providing an advantage to promote neoplastic growth. Copyright © 2012 by Lippincott Williams & Wilkins.


De Cock I.,Ghent University | Zagato E.,Ghent University | Braeckmans K.,Ghent University | Luan Y.,Erasmus Medical Center | And 3 more authors.
Journal of controlled release : official journal of the Controlled Release Society | Year: 2015

Although promising results are achieved in ultrasound mediated drug delivery, its underlying biophysical mechanisms remain to be elucidated. Pore formation as well as endocytosis has been reported during ultrasound application. Due to the plethora of ultrasound settings used in literature, it is extremely difficult to draw conclusions on which mechanism is actually involved. To our knowledge, we are the first to show that acoustic pressure influences which route of drug uptake is addressed, by inducing different microbubble-cell interactions. To investigate this, FITC-dextrans were used as model drugs and their uptake was analyzed by flow cytometry. In fluorescence intensity plots, two subpopulations arose in cells with FITC-dextran uptake after ultrasound application, corresponding to cells having either low or high uptake. Following separation of the subpopulations by FACS sorting, confocal images indicated that the low uptake population showed endocytic uptake. The high uptake population represented uptake via pores. Moreover, the distribution of the subpopulations shifted to the high uptake population with increasing acoustic pressure. Real-time confocal recordings during ultrasound revealed that membrane deformation by microbubbles may be the trigger for endocytosis via mechanostimulation of the cytoskeleton. Pore formation was shown to be caused by microbubbles propelled towards the cell. These results provide a better insight in the role of acoustic pressure in microbubble-cell interactions and the possible consequences for drug uptake. In addition, it pinpoints the need for a more rational, microbubble behavior based choice of acoustic parameters in ultrasound mediated drug delivery experiments. Copyright © 2014 Elsevier B.V. All rights reserved.


Wijnhoven B.P.L.,Erasmus Medical Center | Dejong C.H.C.,Maastricht University
British Journal of Surgery | Year: 2010

Background: The fate of papers submitted and subsequently rejected by the British Journal of Surgery (BJS) is currently unknown. The present study was designed to investigate whether, when and where these papers are published following rejection. Methods: All rejected manuscripts in the year 2006 were identified from the Manuscript Central electronic database. Between December 2008 and February 2009, a PubMed search was conducted spanning the period 2006-2009 using the corresponding author's last name and initials to identify whether and when manuscripts had been published elsewhere. Results: From the 926 manuscripts rejected by BJS, 609 (65-8 per cent) were published in 198 different journals with a mean(s.d.) time lapse of 13-8(6-5) months. Some 165 manuscripts (27-1 per cent) were published in general surgical journals, 250 (41-1 per cent) in subspecialty surgical journals and 194 (31-9 per cent) in non-surgical journals. The mean(s.d.) impact factor of the journals was 2-0(1-1). Only 14 manuscripts (2-3 per cent) were published in journals with a higher impact factor than that of BJS. Conclusion: Rejection of a manuscript by BJS does not preclude publication, but rejected manuscripts are published more often in surgical subspecialty journals and journals with a lower impact factor, although the occasional exception exists. Copyright © 2010 British Journal of Surgery Society Ltd.


de Die-Smulders C.E.M.,Maastricht University | de Wert G.M.W.R.,Maastricht University | Liebaers I.,Vrije Universiteit Brussel | Tibben A.,Leiden University | And 2 more authors.
Human Reproduction Update | Year: 2013

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative late onset disorder. This review of reproductive options aims to increase reproductive confidence and to prevent suffering in relation to family planning around HD and possibly other late onset neurodegenerative disorders. Methods: Selected relevant literature and own views and experiences as clinical geneticists, psychologists and ethicists have been used. Results: Possible options, with emphasis on prenatal diagnosis (PD) and preimplantation genetic diagnosis (PGD) to prevent the transmission of HD to the next generation, are described and discussed. They are formally presented in a decision tree, taking into account the presence or absence of a fully penetrant allele (FPA), a reduced penetrant allele (RPA) or an intermediate allele (IA). A table compares invasive and non-invasive PD and PGD. From a psychological perspective, the complex process of counselling and decision-making regarding reproductive options is discussed. Special attention is paid to the decision to avoid the transmission of the mutation and to the confrontation and coping of a mutation-free child growing up with a parent developing disease symptoms. From an ethical point of view, reflections on both PD and PGD are brought forward taking into account the difference between FPA, RPA and IA, direct testing or exclusion testing and taking into account the welfare of the child in the context of medically assisted reproduction. Conclusion: Recommendations and suggestions for good clinical practice in the reproductive care for HD families are formulated. © The Author 2013.Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.


Ulrik C.S.,Hvidovre Hospital | Diamant Z.,Erasmus Medical Center
Clinical and Experimental Allergy | Year: 2010

Rationale: Excessive airway narrowing in response to broncho-active stimuli is a predictor for severe exacerbations in asthma. Leukotriene receptor antagonists (LTRAs) have complementary properties to inhaled corticosteroids (ICS) on asthma control. Objectives: The LTRA montelukast may provide an additional protection against excessive airway narrowing. We tested the add-on effects of montelukast on the maximal response plateau and PD20 to inhaled methacholine in asthmatics on a stable dose of ICS. Methods: Thirty-one patients with allergic asthma [14M/17F, 19-50 years, forced expiratory volume in 1 s (FEV1) >70% pred., PD20 <3.9 μmol methacholine], with a twice documented response plateau to methacholine, were randomized in a double-blind (montelukast 10 mg or matching placebo once daily), 12-week parallel study. Bronchoprovocation tests with methacholine (0.03-256 μmol or ≥40% decline in FEV1) were repeated every 4 weeks and after wash-out. The main study objectives were changes from baseline in maximal FEV1 decline at the response plateau (i.e. >2 post-dose FEV 1 values within 5%) and PD20 to methacholine after 12 weeks' treatment. Results: Neither treatment affected baseline FEV1 (P=0.62). Compared with placebo, montelukast significantly decreased the maximal response plateau to methacholine (mean difference 9.4%; 95% confidence interval 3.9-15.7; P<0.005), improved the FEV1 decline (mean change in FEV1 decline was 2.1% [montelukast] and -0.8% [placebo], respectively, P<0.05), and increased PD20 methacholine (mean change in PD20 of 5.3 [montelukast] and 1.4 [placebo] doubling doses, respectively, P<0.001). Conclusion: Add-on montelukast to ICS has disease-modifying effects in adults with persistent asthma, and hence reduces the risk of excessive airway narrowing (NCT 00913328). © 2010 Blackwell Publishing Ltd.


de Graaf L.E.,Maastricht University | de Graaf L.E.,Erasmus Medical Center | Hollon S.D.,Vanderbilt University | Huibers M.J.H.,Maastricht University
Journal of Consulting and Clinical Psychology | Year: 2010

Objective: To explore pretreatment and short-term improvement variables as potential moderators and predictors of 12-month follow-up outcome of unsupported online computerized cognitive behavioral therapy (CCBT), usual care, and CCBT combined with usual care for depression. Method: Three hundred and three depressed patients were randomly allocated to (a) unsupported online CCBT, (b) treatment as usual (TAU), or (c) CCBT and TAU combined (CCBT&TAU). Potential predictors and moderators were demographic, clinical, cognitive, and short-term improvement variables. Outcomes were the Beck Depression Inventory-II score at 12 months of follow-up and reliable change. Results: Those with higher levels of extreme (positive) responding had a better outcome in CCBT compared with TAU, whereas those having a parental psychiatric history or a major depressive disorder diagnosis had a better outcome in CCBT&TAU compared with TAU. Predictors regardless of treatment type included current employment, low pretreatment illness severity, and short-term improvement on clinical variables. Conclusions: Optimistic patients, holding approach-oriented coping strategies, might benefit most from CCBT, whereas CCBT&TAU might be the most suitable option for those with more severe vulnerability characteristics. Those with the least impairment improve the most, regardless of treatment type. © 2010 American Psychological Association.


News Article | December 20, 2016
Site: www.eurekalert.org

In the third week of PLOS Medicine's ongoing special issue on cancer genomics, principal investigator Jules Meijerink of the Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands and colleagues seek to identify mechanisms underlying treatment resistance in children with T-cell acute lymphoblastic leukemia (T-ALL) by combining genomic DNA sequencing and chromosomal copy-number analyses, and suggest a new approach to therapy. Treatment of childhood leukemia has improved markedly in recent decades, with long-term cure achieved in most patients who have access to modern, highly intensive treatment regimens. However, some patients develop resistance to the steroid drugs which are a key part of combination chemotherapy treatments, which results in poor clinical outcomes. As described in their Research Article, Meijerink and colleagues studied genetic changes in leukemic cells from pediatric T-ALL patients before treatment. The researchers found specific gene mutations affecting signaling inside cells, involving the interleukin 7 receptor and downstream molecules, that were associated with steroid resistance and adverse clinical outcome. Drugs designed to target individual signaling proteins were able to restore steroid sensitivity to primary leukemic cells from patients. Discussing the research in an accompanying Perspective article, Steven Goossens and Pieter Van Vlierberghe conclude that "inhibition of MEK-ERK or PI3K/AKT/mTOR signaling could enhance steroid sensitivity in T-ALL and potentially improve patient outcomes, a notion that warrants investigation in future prospective clinical trials." Funding: YL was funded by Stichting Kinderen Kankervrij (https:/ ; KiKa-2010-082). KC-B and WKS were funded by Stichting Kinderen Kankervrij (https:/ ; KiKa-2008-029, KiKa-2013-116). EMV was funded by KWF Kanker Bestrijding (https:/ ; EMCR-KWF-2010-4691). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: RCB and GJRZ are founders and shareholders of Netherlands Translational Research Center B.V. The other authors have declared that no competing interests exist. Citation: Li Y, Buijs-Gladdines JGCAM, Canté-Barrett K, Stubbs AP, Vroegindeweij EM, Smits WK, et al. (2016) IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study. PLoS Med 13(12): e1002200. doi:10.1371/journal.pmed.1002200 Author Affiliations: Department of Pediatric Oncology/Hematology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands Department of Bioinformatics, Erasmus Medical Center, Rotterdam, The Netherlands Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands Research Institute Children's Cancer Center Hamburg, Hamburg, Germany Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Co-operative Study Group for Childhood Acute Lymphoblastic Leukemia, Hamburg, Germany Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Netherlands Translational Research Center, Oss, The Netherlands IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://journals. Funding: The authors received no funding for this work. Competing Interests: The authors have declared that no competing interests exist. IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://journals.


Chan K.Y.,Erasmus Medical Center | Vermeersch S.,University Hospitals Leuven | De Hoon J.,University Hospitals Leuven | Villalon C.M.,CINVESTAV | Maassenvandenbrink A.,Erasmus Medical Center
Pharmacology and Therapeutics | Year: 2011

Currently available drugs for the acute treatment of migraine, i.e. ergot alkaloids and triptans, are cranial vasoconstrictors. Although cranial vasoconstriction is likely to mediate-at least a part of-their therapeutic effects, this property also causes vascular side-effects. Indeed, the ergot alkaloids and the triptans have been reported to induce myocardial ischemia and stroke, albeit in extremely rare cases, and are contraindicated in patients with known cardiovascular risk factors. In view of these limitations, novel antimigraine drugs devoid of vascular (side) effects are being explored. Currently, calcitonin gene-related peptide (CGRP) receptor antagonists, which do not have direct vasoconstrictor effects, are under clinical development. Other classes of drugs, such as 5-HT 1F receptor agonists, glutamate receptor antagonists, nitric oxide synthase inhibitors, VPAC/PAC receptor antagonists and gap junction modulators, have also been proposed as potential targets for acute antimigraine drugs. Although these prospective drugs do not directly induce vasoconstriction, they may well induce indirect vascular effects by inhibiting or otherwise modulating the responses to endogenous vasoactive substances. These indirect vascular effects might contribute to the therapeutic efficacy of the previously mentioned compounds, but may alternatively also lead to vascular side-effects. As described in the current review, some of the prospective antimigraine drugs with a proposed non-vascular mechanism of action may still have direct or indirect vascular effects. © 2010 Elsevier Inc. All rights reserved.


Dhermain F.G.,CNRS Gustave Roussy Institute | Hau P.,University of Regensburg | Lanfermann H.,Hannover Medical School | Jacobs A.H.,University of Munster | And 2 more authors.
The Lancet Neurology | Year: 2010

Imaging techniques are important for accurate diagnosis and follow-up of patients with gliomas. T1-weighted MRI, with or without gadolinium, is the gold standard method. However, this technique only reflects biological activity of the tumour indirectly by detecting the breakdown of the blood-brain barrier. Therefore, especially for low-grade glioma or after treatment, T1-weighted MRI enhanced with gadolinium has substantial limitations. Development of more advanced imaging methods to improve outcomes for individual patients is needed. New imaging methods based on MRI and PET can be employed in various stages of disease to target the biological activity of the tumour cells (eg, increased uptake of aminoacids or nucleoside analogues), the changes in diffusivity through the interstitial space (diffusion-weighted MRI), the tumour-induced neovascularisation (perfusion-weighted MRI or contrast-enhanced MRI, or increased uptake of aminoacids in endothelial wall), and the changes in concentrations of metabolites (magnetic resonance spectroscopy). These techniques have advantages and disadvantages, and should be used in conjunction to best help individual patients. Advanced imaging techniques need to be validated in clinical trials to ensure standardisation and evidence-based implementation in routine clinical practice. © 2010 Elsevier Ltd.


Berns E.M.J.J.,Erasmus Medical Center | Bowtell D.D.,Peter MacCallum Cancer Center | Bowtell D.D.,University of Melbourne
Cancer Research | Year: 2012

The classification of epithelial ovarian cancer has been substantially revised, with an increased appreciation of the cellular origins and molecular aberrations of the different histotypes. Distinct patterns of signaling-pathway disruption are seen between and within histotypes. Large-scale genomic studies of high-grade serous cancer, the most common histotype, have identified novel molecular subtypes that are associated with distinct biology and clinical outcome. High-grade serous cancers are characterized by few driver point mutations but abundant DNA copy number aberrations. Inactivation of genes associated withDNAdamage repair underlies responses to platinum and PARP inhibitors. Here we review these recent developments. ©2012 AACR.


Bleeker F.E.,Neurosurgical Center Amsterdam | Molenaar R.J.,University of Amsterdam | Leenstra S.,Erasmus Medical Center
Journal of Neuro-Oncology | Year: 2012

Glioblastoma is the most common and most aggressive primary brain tumor. Despite maximum treatment, patients only have a median survival time of 15 months, because of the tumor's resistance to current therapeutic approaches. Thus far, methylation of the O 6-methylguanine-DNA methyltransferase (MGMT) promoter has been the only confirmed molecular predictive factor in glioblastoma. Novel "genome-wide" techniques have identified additional important molecular alterations as mutations in isocitrate dehydrogenase 1 (IDH1) and its prognostic importance. This review summarizes findings and techniques of genetic, epigenetic, transcriptional, and proteomic studies of glioblastoma. It provides the clinician with an up-to-date overview of current identified molecular alterations that should ultimately lead to new therapeutic targets and more individualized treatment approaches in glioblastoma. © 2012 The Author(s).


Aerts J.G.,Erasmus Medical Center | Aerts J.G.,Amphia Hospital | Hegmans J.P.,Erasmus Medical Center
Cancer Research | Year: 2013

There is growing evidence that activation of the immune system may be an effective treatment for patients with either small cell lung cancer or non-small cell lung cancer (NSCLC). Immunomodulatory antibodies directed against cytotoxic T cell-associated antigen 4 (CTLA-4/CD152) and programmed cell death ligand 1 (PDL1/ CD274) showed clinical efficacy in patients with lung cancer. The key immune cells responsible for antitumor activity are the CTLs. The presence of these tumor-directed CTLs, both in number and functionality, is a prerequisite for the immune system to attack cancer cells. Immunomodulatory agents attempt to increase the efficacy of CTL activity. Thus, the limited number of patients who benefit from immunomodulatory antibodies may be caused by either an inadequate number or the impairment of CTL activity by the hostile environment created by the tumor. In this review, we discuss tumor-induced impairment of CTLs and experimental treatments that can stimulate T-cell responses and optimize specific CTL function. We discuss 2 types of immune cells with known suppressive capacity on CTLs that are of pivotal importance in patients with lung cancer: regulatory T cells and myeloid-derived suppressor cells. Cancer Res; 73(8); 2381-8. © 2013 American Association for Cancer Research.


Eggenhofer E.,University of Regensburg | Hoogduijn M.J.,Erasmus Medical Center
Transplantation Research | Year: 2012

Mesenchymal stem cells (MSC) mediate their immunosuppressive effects via a variety of mechanisms. One of these mechanisms involves the induction of macrophages with immunomodulatory capacities. This effect of MSC may be exploited when MSC are used as a cell therapeutic product. Furthermore, MSC are resident in tissues where they may locally target infiltrating macrophages to adapt more regulatory properties. The present review discusses the interaction between MSC and macrophages, the induction of MSC-educated macrophages, how these cells position between other immune regulatory cells, and how they may be used in the clinic. © 2012 Eggenhofer and Hoogduijn; licensee BioMed Central Ltd.


Quanjer P.H.,Erasmus Medical Center | Pretto J.J.,John Hunter Hospital | Pretto J.J.,University of Newcastle | Brazzale D.J.,Austin Hospital | And 2 more authors.
European Respiratory Journal | Year: 2014

The objective of this study was to redesign the current grading of obstructive lung disease so that it is clinically relevant and free of biases related to age, height, sex and ethnic group. Spirometric records from 17 880 subjects (50.4% female) from hospitals in Australia and Poland, and 21 191 records (53.0% female) from two epidemiological studies (age range 18-95 years) were analysed. We adopted the American Thoracic Society(ATS)/European Respiratory Society (ERS) criteria for airways obstruction based on an forced expiratory volume in 1 s (FEV1)/(forced) vital capacity ((F)VC) ratio below the fifth percentile and graded the severity of pulmonary function impairment using z-scores for FEV1, which signify how many standard deviations a result is from the mean predicted value. Using the lower limit of normal for FEV1/(F)VC and z-scores for FEV1 of -2, -2.5, -3 and -4 to delineate severity grades of airflow limitation leads to close agreement with ATS/ERS severity classifications and removes age, sex and height related bias. The new classification system is simple, easily memorised and clinically valid. It retains previously established associations with clinical outcomes and avoids biases due to the use of per cent predicted FEV1. Combined with the Global Lung Function prediction equations it provides a worldwide diagnostic standard, free of bias due to age, height, sex and ethnic group. Copyright © ERS 2014.


Slagt C.,Zaans Medical Center | Malagon I.,University of Manchester | Groeneveld A.B.J.,Erasmus Medical Center
British Journal of Anaesthesia | Year: 2014

SummaryThe FloTrac/Vigileo™, introduced in 2005, uses arterial pressure waveform analysis to calculate cardiac output (CO) and stroke volume variation (SVV) without external calibration. The aim of this systematic review is to evaluate the performance of the system. Sixty-five full manuscripts on validation of CO measurements in humans, published in English, were retrieved; these included 2234 patients and 44 592 observations. Results have been analysed according to underlying patient conditions, that is, general critical illness and surgery as normodynamic conditions, cardiac and (post)cardiac surgery as hypodynamic conditions, and liver surgery and sepsis as hyperdynamic conditions, and subsequently released software versions. Eight studies compared SVV with other dynamic indices. CO, bias, precision, %error, correlation, and concordance differed among underlying conditions, subsequent software versions, and their interactions, suggesting increasing accuracy and precision, particularly in hypo- and normodynamic conditions. The bias and the trending capacity remain dependent on (changes in) vascular tone with most recent software. The SVV only moderately agreed with other dynamic indices, although it was helpful in predicting fluid responsiveness in 85% of studies addressing this. Since its introduction, the performance of uncalibrated FloTrac/Vigileo™ has improved particularly in hypo- and normodynamic conditions. A %error at or below 30% with most recent software allows sufficiently accurate and precise CO measurements and trending for routine clinical use in normo- and hypodynamic conditions, in the absence of large changes in vascular tone. © The Author [2013].


Bellardita L.,Fondazione IRCCS Instituto Nazionale Dei Tumori | Valdagni R.,Fondazione IRCCS Instituto Nazionale Dei Tumori | Van Den Bergh R.,University Utrecht | Randsdorp H.,Europa Uomo Europa Uomo | And 4 more authors.
European Urology | Year: 2015

Context The optimal management of screen-detected, localised prostate cancer remains controversial, related to overtreatment issues of screening and the nonrandomised evidence base. Active surveillance (AS) aims to delay or avoid curative therapy but may potentially harm patients' well-being through living with untreated prostate cancer. Objective To systematically review the literature on quality of life (QoL) in patients undergoing AS. Evidence acquisition Embase, Medline, Psychinfo, Cochrane Central, Web of Science, and PubMed databases were searched in May 2014 using quality of life, active surveillance, prostate cancer, their synonyms, and targeted manual searches. The psychological dimensions related to health-related QoL (HRQoL) outcomes were anxiety and depression, distress, decisional conflict, and mental health. Evidence synthesis Ten clinical and research-based AS studies worldwide measured HRQoL and related psychological facets in six cross-sectional studies and four cohorts (follow-up: 9-36 mo; published: 2006-2014). Six studies were linked to published AS cohorts. In total, 966 men undergoing AS (mean: 102 per study) were assessed (mean age: 66 yr). AS patients had good overall HRQoL scores, which were comparable or better than those of patients undergoing postradical treatment (comparator group in four studies), men's partners (one study) and population-based data (three studies). Anxiety and depression scores were favourable. Selection bias may be present, as none were randomised comparisons. Decreased psychological well-being may be partly predicted by AS patients' baseline and clinical characteristics. Conclusions Patients undergoing AS reported good QoL and did not appear to suffer major negative psychological impacts. Longer follow-up is required as well as investigation into which patients are predisposed to negative impact and leaving AS prematurely. Patient summary We reviewed the published evidence for quality-of-life impact on men with prostate cancer being monitored by active surveillance. The men who were on active surveillance usually reported good levels of well-being and did not appear to suffer major negative psychological impacts. The research findings suggest little presence of anxiety and depression and high overall quality of life related to their disease. However, there are few long-term studies, so more high-quality research is needed to make definitive recommendations. © 2014 European Association of Urology. All rights reserved.


Lievense L.A.,Erasmus Medical Center | Bezemer K.,Erasmus Medical Center | Aerts J.G.J.V.,Erasmus Medical Center | Aerts J.G.J.V.,Amphia Hospital | Hegmans J.P.J.J.,Erasmus Medical Center
Lung Cancer | Year: 2013

Tumor-associated macrophages (TAMs) can be abundantly present in numerous cancer types. Under influence of various stimuli in the tumor microenvironment TAMs develop into a tumor-inhibitory (M1) or tumor-promoting (M2) phenotype. Recently, the role of TAMs in tumor biology and their prognostic value in cancer has become a major topic of interest. In this review we will discuss the importance of TAMs in the pathogenesis and clinical outcome of lung cancer and mesothelioma patients. In addition, the potential of TAMs as therapeutic targets will be discussed. © 2013 Elsevier Ireland Ltd.


Muller M.,Rockefeller University | Mentel M.,Comenius University | Van Hellemond J.J.,Erasmus Medical Center | Henze K.,Heinrich Heine University Düsseldorf | And 6 more authors.
Microbiology and Molecular Biology Reviews | Year: 2012

Major insights into the phylogenetic distribution, biochemistry, and evolutionary significance of organelles involved in ATP synthesis (energy metabolism) in eukaryotes that thrive in anaerobic environments for all or part of their life cycles have accrued in recent years. All known eukaryotic groups possess an organelle of mitochondrial origin, mapping the origin of mitochondria to the eukaryotic common ancestor, and genome sequence data are rapidly accumulating for eukaryotes that possess anaerobic mitochondria, hydrogenosomes, or mitosomes. Here we review the available biochemical data on the enzymes and pathways that eukaryotes use in anaerobic energy metabolism and summarize the metabolic end products that they generate in their anaerobic habitats, focusing on the biochemical roles that their mitochondria play in anaerobic ATP synthesis. We present metabolic maps of compartmentalized energy metabolism for 16 well-studied species. There are currently no enzymes of core anaerobic energy metabolism that are specific to any of the six eukaryotic supergroup lineages; genes present in one supergroup are also found in at least one other supergroup. The gene distribution across lineages thus reflects the presence of anaerobic energy metabolism in the eukaryote common ancestor and differential loss during the specialization of some lineages to oxic niches, just as oxphos capabilities have been differentially lost in specialization to anoxic niches and the parasitic lifestyle. Some facultative anaerobes have retained both aerobic and anaerobic pathways. Diversified eukaryotic lineages have retained the same enzymes of anaerobic ATP synthesis, in line with geochemical data indicating low environmental oxygen levels while eukaryotes arose and diversified. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Wakkee M.,Erasmus Medical Center | Herings R.M.C.,Institute for Drug Outcome Research | Herings R.M.C.,Erasmus Medical Center | Nijsten T.,Erasmus Medical Center
Journal of Investigative Dermatology | Year: 2010

Although psoriasis has been associated with components of the metabolic syndrome, its association with myocardial infarction is less clear. A cohort study was conducted using hospital and pharmacy records of 2.5 million Dutch residents between 1997 and 2008. The risk of ischemic heart disease (IHD) hospitalizations was compared between psoriasis patients and a matched reference cohort. Additional adjustments were made for healthcare consumption and use of cardiovascular drugs. A total of 15,820 psoriasis patients and 27,577 reference subjects were included, showing an incidence rate of 611 and 559 IHD per 100,000 person-years, respectively (P=0.066). The age-and gender-adjusted risk of IHD was comparable between both cohorts (hazard ratio (HR)=1.10, 95% confidence interval 0.99-1.23). Before cohort entry, psoriasis patients used more antihypertensive, antidiabetic, and lipid-lowering drugs and were more often hospitalized. Adjusting for these confounders decreased the HR for IHD, but it remained comparable between both populations. There was no different risk of IHD between the subgroup of patients who only used topicals versus those who received systemic therapies or inpatient care for their psoriasis. This study, therefore, suggests that psoriasis is not a clinically relevant risk factor for IHD hospitalizations on the population level. © 2010 The Society for Investigative Dermatology.


Miller M.R.,Queen Elizabeth Hospital Birmingham | Quanjer P.H.,Erasmus Medical Center | Swanney M.P.,Christchurch Hospital | Ruppel G.,Saint Louis University | Enright P.L.,University of Arizona
Chest | Year: 2011

Background: Differences in COPD classification have been shown in population data sets when using fifth percentiles as the lower limit of normal (LLN) vs the current GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines of FEV1/FVC <0.70 for detecting airway obstruction and an FEV 1 of 80% predicted for detecting and classifying the severity of COPD (GOLD/PP). Many lung function laboratories use 80% predicted to determine whether results are abnormal. Misclassification of the full range of lung diseases in large patient groups when using GOLD/PP criteria instead of the LLN has not been explored previously. Methods: We determined the discrepancy rates in pulmonary function test interpretation between the GOLD/PP and LLN methods on prebronchodilator lung function results from a large number of adult patients from the United Kingdom, New Zealand, and the United States. Results: In 11,413 patients, the GOLD/PP method misclassified 24%. Ten percent of patients who had normal lung function were falsely classified with a disease category, and 7% of patients were falsely attributed with emphysema. The GOLD/PP method gave false-positive classifications for airflow obstruction and restrictive defects to significantly more men(P<.01) and older patients (P<.0001) and also missed airflow obstruction and restrictive defects in younger patients (P<.0001). Conclusions: Using lung function tests on their own with 80% predicted and fixed cut points to determine whether a test is abnormal could misdiagnose >20% of patients referred for pulmonary function tests. The GOLD/PP method introduces clinically important biases in assessing disease status that could affect allocation to treatment groups. This misclassification is avoided by using the LLN based on the fifth-percentile values. © 2011 American College of Chest Physicians.


Robin C.,Erasmus Medical Center | Durand C.,University Pierre and Marie Curie
International Journal of Developmental Biology | Year: 2010

During mouse ontogeny, the first adult-type hematopoietic stem cells (HSC) are autonomously generated at mid-gestation in the AGM (Aorta-Gonad-Mesonephros) region. Successively present in different anatomical sites where they will expand, HSCs will finally colonize the bone marrow (BM) where they will reside during the entire adult life. In the bone marrow, both HSC self-renewal and differentiation are controlled at cellular and molecular levels by interactions with the stromal microenvironment. So far, very little is known about the extracellular factors involved in the regulation of embryonic HSC emergence, survival and expansion. In the present review, we outline the BMP and IL-3 signaling pathways that are critical for the growth and potential of embryonic HSCs. We will also discuss how these pathways might be integrated with the ones of Notch and Mpl/thrombopoietin, also identified as important key regulators of AGM HSC activity. © 2010 UBC Press.


Finzsch M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Schreiner S.,Friedrich - Alexander - University, Erlangen - Nuremberg | Kichko T.,Friedrich - Alexander - University, Erlangen - Nuremberg | Reeh P.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 4 more authors.
Journal of Cell Biology | Year: 2010

Mutations in the transcription factor SOX10 cause neurocristopathies, including Waardenburg-Hirschsprung syndrome and peripheral neuropathies in humans. This is partly attributed to a requirement for Sox10 in early neural crest for survival, maintenance of pluripotency, and specification to several cell lineages, including peripheral glia. As a consequence, peripheral glia are absent in Sox10-deficient mice. Intriguingly, Sox10 continues to be expressed in these cells after specification. To analyze glial functions after specification, we specifically deleted Sox10 in immature Schwann cells by conditional mutagenesis. Mutant mice died from peripheral neuropathy before the seventh postnatal week. Nerve alterations included a thinned perineurial sheath, increased lipid and collagen deposition, and a dramatically altered cellular composition. Nerve conduction was also grossly aberrant, and neither myelinating nor non-myelinating Schwann cells formed. Instead, axons of different sizes remained unsorted in large bundles. Schwann cells failed to develop beyond the immature stage and were unable to maintain identity. Thus, our study identifies a novel cause for peripheral neuropathies in patients with SOX10 mutations. © 2010 Finzsch et al.


Nijsten T.,Erasmus Medical Center | Stern R.S.,Beth Israel Deaconess Medical Center
Journal of Investigative Dermatology | Year: 2012

Epidemiology literally means the study of what is upon the people. It puts the individual's condition in a population context and is the path to disease prevention. In the first part of this review, important aspects of epidemiology are discussed. Fundamentals of epidemiologic research include the measurement of occurrence of an event (prevalence and incidence) and the identification of factors that are associated with this event. The main study designs in observational studies are cohort, case-control, and cross-sectional studies, all of which have intrinsic strengths and limitations. These limitations include a variety of biases, which can be regrouped into selection bias, information bias, and confounding. The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist is an important tool to further improve the reporting and quality of epidemiologic studies, and it is introduced. In the second part of this review, practical examples are presented, illustrating how dermatoepidemiology has contributed to an improved understanding of skin diseases and patient care, specifically in the case of melanoma therapy, serious cutaneous adverse reactions, Lyme disease, long-term safety of psoralin plus UVA (PUVA), teratogenicity of isotretinoin, and comorbidities in psoriasis. © 2012 The Society for Investigative Dermatology.


Pijnenburg M.W.,Erasmus Medical Center | Szefler S.,University of Colorado at Denver
Paediatric Respiratory Reviews | Year: 2015

Personalized medicine for children with asthma aims to provide a tailored management of asthma, which leads to faster and better asthma control, has less adverse events and may be cost saving. Several patient characteristics, lung function parameters and biomarkers have been shown useful in predicting treatment response or predicting successful reduction of asthma medication. As treatment response to the main asthma therapies is partly genetically determined, pharmacogenetics may open the way for personalized medicine in children with asthma. However, the number of genes identified for the various asthma drug response phenotypes remains small and randomized controlled trials are lacking.Biomarkers in exhaled breath or breath condensate remain promising but did not find their way from bench to bedside yet, except for the fraction of exhaled nitric oxide.E-health will most likely find its way to clinical practice and most interventions are at least non-inferior to usual care. More studies are needed on which interventions will benefit most individual children. © 2014 Elsevier Ltd.


Eggenhofer E.,University of Regensburg | Luk F.,Erasmus Medical Center | Dahlke M.H.,University of Regensburg | Hoogduijn M.J.,Erasmus Medical Center
Frontiers in Immunology | Year: 2014

Mesenchymal stem cells (MSC) are present throughout the body and are thought to play a role in tissue regeneration and control of inflammation. MSC can be easily expanded in vitro and their potential as a therapeutic option for degenerative and inflammatory disease is therefore intensively investigated. Whilst it was initially thought that MSC would replace dysfunctional cells and migrate to sites of injury to interact with inflammatory cells, experimental evidence indicates that the majority of administered MSC get trapped in capillary networks and have a short life span. In this review, we discuss current knowledge on the migratory properties of endogenous and exogenous MSC and confer on how culture-induced modifications of MSC may affect these properties. Finally, we will discuss how, despite their limited survival, administered MSC can bring about their therapeutic effects. © 2014 Eggenhofer, Luk, Dahlke and Hoogduijn.


Kuo W.,Erasmus Medical Center | Ciet P.,Erasmus Medical Center | Ciet P.,Beth Israel Deaconess Medical Center | Tiddens H.A.W.M.,Erasmus Medical Center | And 3 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Computed tomography (CT) is a sensitive technique to monitor structural changes related to cystic fi brosis (CF) lung disease. It detects structural pulmonary abnormalities such as bronchiectasis and trapped air, at an early stage, before they become apparent with other diagnostic tests. Clinical decisions may be in fl uenced by knowledge of these abnormalities. CT imaging, however, comes with risk related to ionizing radiation exposure. The aim of this review is to discuss the risk of routine CT imaging in patients with CF, using current models of radiation-induced cancer, and to put this risk in perspective with other medical and nonmedical risks. The magnitude of the risk is a complex, controversial matter. Risk analyses have largely been based on a linear no-threshold model, and excess relative and excess absolute risk estimates have been derived mainly from atomic bomb survivors. The estimates have large confidence intervals. Our risk estimates are in concordance with previously reported estimates. A large proportion of radiation to which humans are exposed is from natural background sources and varies widely depending on geographical location. The risk differences due to variation in background radiation can be larger than the risks associated with CF lung disease monitoring by CT. We conclude that the risk related to routine usage of CT in clinical care is small. In addition, a life-limiting disease, such as CF, lowers the risk of radiation-induced cancer. Nonetheless, the use of CT should always be justi fi ed and the radiation dose should be kept as low as reasonably achievable. Copyright © 2014 by the American Thoracic Society.


Jungwirth A.,EMCO Private Clinic | Giwercman A.,Skåne University Hospital | Tournaye H.,Free University of Brussels | Diemer T.,Justus Liebig University | And 3 more authors.
European Urology | Year: 2012

Context: New data regarding the diagnosis and treatment of male infertility have emerged and led to an update of the European Association of Urology (EAU) guidelines for Male Infertility. Objective: To review the new EAU guidelines for Male Infertility. Evidence acquisition: A comprehensive work-up of the literature obtained from Medline, the Cochrane Central Register of Systematic Reviews, and reference lists in publications and review articles was developed and screened by a group of urologists and andrologists appointed by the EAU Guidelines Committee. Previous recommendations based on the older literature on this subject were taken into account. Levels of evidence and grade of guideline recommendations were added, modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence. Evidence summary: These EAU guidelines are a short comprehensive overview of the updated guidelines of male infertility as recently published by the EAU (http://www.uroweb.org/guidelines/online-guidelines/), and they are also available in the National Guideline Clearinghouse (http://www.guideline.gov/). © 2012 European Association of Urology.


Bain C.C.,University of Glasgow | Scott C.L.,University of Glasgow | Uronen-Hansson H.,Lund University | Gudjonsson S.,Skåne University Hospital | And 7 more authors.
Mucosal Immunology | Year: 2013

Macrophages (mφ) are essential for intestinal homeostasis and the pathology of inflammatory bowel disease (IBD), but it is unclear whether discrete mφ populations carry out these distinct functions or if resident mφ change during inflammation. We show here that most resident mφ in resting mouse colon express very high levels of CX3CR1, are avidly phagocytic and MHCIIhi, but are resistant to Toll-like receptor (TLR) stimulation, produce interleukin 10 constitutively, and express CD163 and CD206. A smaller population of CX3CR1int cells is present in resting colon and it expands during experimental colitis. Ly6ChiCCR2+ monocytes can give rise to all mφ subsets in both healthy and inflamed colon and we show that the CX3CR1 int pool represents a continuum in which newly arrived, recently divided monocytes develop into resident CX3CR1hi mφ. This process is arrested during experimental colitis, resulting in the accumulation of TLR-responsive pro-inflammatory mφ. Phenotypic analysis of human intestinal mφ indicates that analogous processes occur in the normal and Crohn's disease ileum. These studies show for the first time that resident and inflammatory mφ in the intestine represent alternative differentiation outcomes of the same precursor and targeting these events could offer routes for therapeutic intervention in IBD.


Atteia A.,Aix - Marseille University | Van Lis R.,Aix - Marseille University | Tielens A.G.M.,Erasmus Medical Center | Martin W.F.,Heinrich Heine University Düsseldorf
Biochimica et Biophysica Acta - Bioenergetics | Year: 2013

Anaerobic metabolic pathways allow unicellular organisms to tolerate or colonize anoxic environments. Over the past ten years, genome sequencing projects have brought a new light on the extent of anaerobic metabolism in eukaryotes. A surprising development has been that free-living unicellular algae capable of photoautotrophic lifestyle are, in terms of their enzymatic repertoire, among the best equipped eukaryotes known when it comes to anaerobic energy metabolism. Some of these algae are marine organisms, common in the oceans, others are more typically soil inhabitants. All these species are important from the ecological (O2/CO2 budget), biotechnological, and evolutionary perspectives. In the unicellular algae surveyed here, mixed-acid type fermentations are widespread while anaerobic respiration, which is more typical of eukaryotic heterotrophs, appears to be rare. The presence of a core anaerobic metabolism among the algae provides insights into its evolutionary origin, which traces to the eukaryote common ancestor. The predicted fermentative enzymes often exhibit an amino acid extension at the N-terminus, suggesting that these proteins might be compartmentalized in the cell, likely in the chloroplast or the mitochondrion. The green algae Chlamydomonas reinhardtii and Chlorella NC64 have the most extended set of fermentative enzymes reported so far. Among the eukaryotes with secondary plastids, the diatom Thalassiosira pseudonana has the most pronounced anaerobic capabilities as yet. From the standpoints of genomic, transcriptomic, and biochemical studies, anaerobic energy metabolism in C. reinhardtii remains the best characterized among photosynthetic protists. This article is part of a Special Issue entitled: The evolutionary aspects of bioenergetic systems. © 2012 Elsevier B.V.


Rugge M.,University of Padua | Capelle L.G.,Erasmus Medical Center | Cappellesso R.,University of Padua | Nitti D.,University of Padua | Kuipers E.J.,Erasmus Medical Center
Best Practice and Research: Clinical Gastroenterology | Year: 2013

Gastric cancer is the final step in a multi-stage cascade triggered by long-standing inflammatory conditions (particularly Helicobacter pylori infection) resulting in atrophic gastritis and intestinal metaplasia: these lesions represent the cancerization field in which (intestinal-type) gastric cancer develops. Intraepithelial neoplasia is consistently recognized as the phenotypic bridge between atrophic/metaplastic lesions and invasive cancer. This paper addresses the epidemiology, pathology, molecular profiling, and clinical management of advanced precancerous gastric lesions. © 2013 Elsevier Ltd. All rights reserved.


Sharma S.,University of Toronto | Carballo M.,International Center for Migration | Feld J.J.,University of Toronto | Janssen H.L.A.,University of Toronto | Janssen H.L.A.,Erasmus Medical Center
Journal of Hepatology | Year: 2015

WHO estimates reveal that the global prevalence of viral hepatitis may be as high as 500 million, with an annual mortality rate of up to 1.3 million individuals. The majority of this global burden of disease is borne by nations of the developing world with high rates of vertical and iatrogenic transmission of HBV and HCV, as well as poor access to healthcare. In 2013, 3.2% of the global population (231 million individuals) migrated into a new host nation. Migrants predominantly originate from the developing countries of the south, into the developed economies of North America and Western Europe. This mass migration of individuals from areas of high-prevalence of viral hepatitis poses a unique challenge to the healthcare systems of the host nations. Due to a lack of universal standards for screening, vaccination and treatment of viral hepatitis, the burden of chronic liver disease and hepatocellular carcinoma continues to increase among migrant populations globally. Efforts to increase case identification and treatment among migrants have largely been limited to small outreach programs in urban centers, such that the majority of migrants with viral hepatitis continue to remain unaware of their infection. This review summarizes the data on prevalence of viral hepatitis and burden of chronic liver disease among migrants, current standards for screening and treatment of immigrants and refugees, and efforts to improve the identification and treatment of viral hepatitis among migrants. © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Paiva B.,University of Navarra | Van Dongen J.J.M.,Erasmus Medical Center | Orfao A.,University of Salamanca
Blood | Year: 2015

Assessment of minimal residual disease (MRD) is becoming standard diagnostic care for potentially curable neoplasms such as acute lymphoblastic leukemia. In multiple myeloma (MM), the majority of patients will inevitably relapse despite achievement of progressively higher complete remission (CR) rates.Novel treatment protocols with inclusion of antibodies and small molecules might well be able to further increase remission rates and potentially also cure rates. Therefore,MRD diagnostics becomes essential to assess treatment effectiveness. This review summarizes reports from the past 2 decades, which demonstrate that persistentMRD by multiparameter flow cytometry, polymerase chain reaction, next-generation sequencing, and positron emission tomography/ computed tomography, predicts significantly inferior survival among CR patients. We describe the specific features of currently available techniques for MRD monitoring and outline the arguments favoring new criteria for response assessment that incorporate MRD levels. Extensive data indicate that MRD information can potentially be used as biomarker to evaluate the efficacy of different treatment strategies, help on treatment decisions, and act as surrogate for overall survival. The time has come to address within clinical trials the exact role of baseline risk factors and MRD monitoring for tailored therapy in MM, which implies systematic usage of highly sensitive, cost-effective, readily available, and standardized MRD techniques. © 2015 by The American Society of Hematology.


Lansdorp-Vogelaar I.,Erasmus Medical Center | Kuntz K.M.,University of Minnesota | Knudsen A.B.,Massachusetts General Hospital | Wilschut J.A.,Erasmus Medical Center | And 2 more authors.
Annals of Internal Medicine | Year: 2010

Background: The Centers for Medicare & Medicaid Services considered whether to reimburse stool DNA testing for colorectal cancer screening among Medicare enrollees. Objective: To evaluate the conditions under which stool DNA testing could be cost-effective compared with the colorectal cancer screening tests currently reimbursed by the Centers for Medicare & Medicaid Services. Design: Comparative microsimulation modeling study using 2 independently developed models. Data Sources: Derived from literature. Target Population: A cohort of persons aged 65 years. A sensitivity analysis was also conducted, in which a cohort of persons aged 50 years was studied. Time Horizon: Lifetime. Perspective: Third-party payer. Intervention: Stool DNA test every 3 or 5 years in comparison with currently recommended colorectal cancer screening strategies. Outcome Measures: Life expectancy, lifetime costs, incremental cost-effectiveness ratios, and threshold costs. Results of Base-Case Analysis: Assuming a cost of $350 per test, strategies of stool DNA testing every 3 or 5 years yielded fewer life-years and higher costs than the currently recommended colorectal cancer screening strategies. Screening with the stool DNA test would be cost-effective at a per-test cost of $40 to $60 for stool DNA testing every 3 years, depending on the simulation model used. There were no levels of sensitivity and specificity for which stool DNA testing would be cost-effective at its current cost of $350 per test. Stool DNA testing every 3 years would be costeffective at a cost of $350 per test if the relative adherence to stool DNA testing were at least 50% better than that with other screening tests. Results of Sensitivity Analysis: None of the results changed substantially when a cohort of persons aged 50 years was considered. Limitation: No pathways other than the traditional adenoma-carcinoma sequence were modeled. Conclusion: Stool DNA testing could be a cost-effective alternative for colorectal cancer screening if the cost of the test substantially decreased or if its availability would entice a large fraction of otherwise unscreened persons to receive screening. Primary Funding Source: Agency for Healthcare Research and Quality. © 2010 American College of Physicians.


Stern G.,University of Bern | De Jongste J.,Erasmus Medical Center | Van Der Valk R.,Erasmus Medical Center | Baraldi E.,University of Padua | And 3 more authors.
Journal of Allergy and Clinical Immunology | Year: 2011

Background: Fraction of exhaled nitric oxide (Feno), a marker of airway inflammation, has been proposed to be useful for asthma management, but conclusions are inconsistent. This might be due to the failure of mean statistics to characterize individual variability in Feno values, which is possibly a better indicator of asthma control than single measurements. Objective: We characterized fractal fluctuations in daily Feno values over time and the relationship between Feno values and symptom scores. We investigated whether these are associated with asthma severity, control, and exacerbation risk. Methods: Daily Feno values and symptom scores over 192 days in 41 atopic asthmatic children from the Childhood Asthma Respiratory Inflammatory Status Monitoring study were analyzed. Two methods of time-series analysis were used: detrended fluctuation analysis to quantify fractal patterns in fluctuations in daily Feno values (α value) and cross-correlation to quantify the strength of the relationship between daily Feno values and symptom scores. The associations of α values and cross-correlation with markers of asthma severity and control were assessed by means of regression analysis. Results: Daily fluctuations in Feno values exhibited fractal-type long-range correlations. Those subjects receiving higher doses of inhaled corticosteroids at study entry had a significantly lower α value, corresponding to more random fluctuations in Feno values in those with greater inhaled corticosteroid need. The cross-correlation between Feno values and symptom scores was significantly higher in those subjects who had exacerbations. Conclusions: Fluctuation in Feno values and their cross-correlation to symptom scores contains information on asthma severity and control. Methods that quantify the complexity of asthma over time might assist in identifying asthmatic subjects with concordance between eosinophilic inflammation and symptoms and thus increased exacerbation risk. © 2011 American Academy of Allergy, Asthma & Immunology.


Perencevich M.,Harvard University | Ojha R.P.,St Jude Childrens Research Hospital | Steyerberg E.W.,Erasmus Medical Center | Syngal S.,Harvard University | Syngal S.,Dana-Farber Cancer Institute
Gastroenterology | Year: 2013

Background & Aims Individuals with a family history of colorectal cancer (CRC) have a higher risk of developing CRC than the general population, and studies have shown that they are more likely to undergo CRC screening. We assessed the overall and race- and ethnicity-specific effects of a family history of CRC on screening. Methods We analyzed data from the 2009 California Health Interview Survey to estimate overall and race- and ethnicity-specific odds ratios (ORs) for the association between family history of CRC and CRC screening. Results The unweighted and weighted sample sizes were 23,837 and 8,851,003, respectively. Individuals with a family history of CRC were more likely to participate in any form of screening (OR, 2.3; 95% confidence limit [CL], 1.7, 3.1) and in colonoscopy screening (OR, 2.7; 95% CL, 2.2, 3.4) than those without a family history, but this association varied among racial and ethnic groups. The magnitude of the association between family history and colonoscopy screening was highest among Asians (OR, 6.1; 95% CL, 3.1, 11.9), lowest among Hispanics (OR, 1.4; 95% CL, 0.67, 2.8), and comparable between non-Hispanic whites (OR, 3.1; 95% CL, 2.6, 3.8) and non-Hispanic blacks (OR 2.6; 95% CL, 1.2, 5.7) (P for interaction <.001). Conclusions The effects of family history of CRC on participation in screening vary among racial and ethnic groups, and have the lowest effects on Hispanics, compared with other groups. Consequently, interventions to promote CRC screening among Hispanics with a family history should be considered. © 2013 by the AGA Institute.


Oom D.M.J.,Erasmus Medical Center | West R.L.,Sint Franciscus Hospital | Schouten W.R.,Erasmus Medical Center | Steensma A.B.,Erasmus Medical Center
Diseases of the Colon and Rectum | Year: 2012

BACKGROUND: Endoanal ultrasound is widely used for the detection of external and internal anal sphincter defects in patients with fecal incontinence. Recently, 3-dimensional transperineal ultrasound has been introduced as a noninvasive imaging method for the detection of these sphincter defects. OBJECTIVE: This study was designed to assess agreement between 3-dimensional transperineal ultrasound and 2-dimensional endoanal ultrasound regarding the detection of anal sphincter defects in women with fecal incontinence. DESIGN: This study was designed as a prospective observational study. SETTINGS: The study took place in a university hospital. PATIENTS: Between October 2008 and June 2009, all women with concerns of fecal incontinence underwent 2-dimensional endoanal ultrasound as well as 3-dimensional transperineal ultrasound. MAIN OUTCOME MEASURES: The main outcome measures are the presence of external and internal anal sphincter defects. RESULTS: Fifty-five patients were included. External and internal anal sphincter defects were observed with 2-dimensional endoanal ultrasound in 27 (49%) and 15 (27%) patients. Three-dimensional transperineal ultrasound detected an external and internal sphincter defect in 19 (35%) and 16 (29%) patients. The Cohen κ coefficient for the detection of external (κ = 0.63) and internal (κ = 0.78) anal sphincter defects was good. LIMITATIONS: This study's limitations include the absence of a surgical examination as the reference standard in the determination of sphincter defects. CONCLUSION: This study shows good agreement between 3-dimensional transperineal ultrasound and 2-dimensional endoanal ultrasound regarding the detection of anal sphincter defects. Based on these data, 3-dimensional transperineal ultrasound might be considered as a valuable alternative noninvasive investigation method. © The ASCRS 2012.


Henikoff S.,Fred Hutchinson Cancer Research Center | Grosveld F.,Erasmus Medical Center
Epigenetics and Chromatin | Year: 2013

On 11 to 13 March 2013, BioMed Central will be hosting its inaugural conference, Epigenetics & Chromatin: Interactions and Processes, at Harvard Medical School, Cambridge, MA, USA. Epigenetics & Chromatin has now launched a special article series based on the general themes of the conference. © 2013 Henikoff and Grosveld; licensee BioMed Central Ltd.


Etzioni R.,Fred Hutchinson Cancer Research Center | Durand-Zaleski I.,Sante Publique URCEco APHP | Lansdorp-Vogelaar I.,Erasmus Medical Center
Journal of the National Cancer Institute - Monographs | Year: 2013

Cancer interventions often disseminate in the population before evidence of their effectiveness is available. Population disease trends provide a natural experiment for assessing the characteristics of the disease and the potential impact of the intervention. We review models for extracting information from population data for use in economic evaluations of cancer screening interventions. We focus particularly on prostate-specific antigen (PSA) screening for prostate cancer and describe approaches that can be used to project the likely costs and benefits of competing screening policies. Results indicate that the lifetime probability of biopsy-detectable prostate cancer is 33%, the chance of clinical diagnosis without screening is 13%, and the average time from onset to clinical diagnosis is 14 years. Less aggressive screening policies that screen less often and use more conservative criteria (e.g., higher PSA thresholds) for biopsy referral may dramatically reduce PSA screening costs with modest impact on benefit. © The Author 2013. Published by Oxford University Press. All rights reserved.


Holmes Jr. D.R.,Mayo Medical School | Kereiakes D.J.,Christ Hospital Heart | Garg S.,Erasmus Medical Center | Serruys P.W.,Erasmus Medical Center | And 5 more authors.
Journal of the American College of Cardiology | Year: 2010

Intense investigation continues on the pathobiology of stent thrombosis (ST) because of its morbidity and mortality. Because little advance has been made in outcomes following ST, ongoing research is focused on further understanding predictive factors as well as ST frequency and timing in various patient subsets, depending upon whether a drug-eluting stent or bare-metal stent has been implanted. Although the preventive role of antiplatelet therapies remains unchallenged, new data on genomics and variability in response to antiplatelet therapy, as well as the effects of novel therapeutic agents and duration of therapy, have become available. The goal remains identification of patients at particularly increased risk of ST so that optimal prevention strategies can be developed and employed. © 2010 American College of Cardiology Foundation.


Laperriere N.,University of Toronto | Weller M.,University of Zürich | Stupp R.,University of Lausanne | Perry J.R.,University of Toronto | And 3 more authors.
Cancer Treatment Reviews | Year: 2013

Median age at diagnosis in patients with glioblastoma (GB) is slowly increasing with an aging population in Western countries, and was 64. years in 2006. The number of patients age 65 and older with GB will double in 2030 compared with 2000. Survival in this older cohort of patients is significantly less than seen in younger patients. This may in part be related to more aggressive biology of tumor, reduced use of standard management approaches, increased toxicity of available therapies, and increased presence of comorbidities in this older patient population. Limited data do support the use of more extensive resection in these patients. Randomized data support the use of post-operative radiotherapy (RT) versus supportive care, but do not demonstrate a benefit for the use of the standard 6. weeks course of RT over hypofractionated RT given over 3. weeks. Preliminary data of randomized studies raise the possibility of temozolomide alone as an option for these patients. The use of 6. weeks of RT with concurrent and adjuvant temozolomide has been associated with reasonably good survival in several uncontrolled small series of selected older patients; however, this better outcome may be related to the selection of better prognosis patients rather than the specific therapy utilized. The current National Cancer Institute of Canada (NCIC) and European Organization for Research and Treatment of Cancer (EORTC) CE.6/26062/22061 randomized study of short course RT with or without concurrent and adjuvant temozolomide will help determine the optimal therapy for this older cohort with currently available therapies. © 2012 Elsevier Ltd.


Su S.,Ohio State University | White T.,Erasmus Medical Center | Schmidt M.,Erasmus Medical Center | Kao C.-Y.,Ohio State University | And 2 more authors.
Human Brain Mapping | Year: 2013

Human brains are highly convoluted surfaces with multiple folds. To characterize the complexity of these folds and their relationship with neurological and psychiatric conditions, different techniques have been developed to quantify the folding patterns, also known as the surface complexity or gyrification of the brain. In this study, the authors propose a new geometric approach to measure the gyrification of human brains from magnetic resonance images. This approach is based on intrinsic 3D measurements that relate the local brain surface area to the corresponding area of a tightly wrapped sheet. The authors also present an adaptation of this technique in which the geodesic depth is incorporated into the gyrification computation. These gyrification measures are efficiently and accurately computed by solving geometric partial differential equations. The presentation of the geometric framework is complemented with experimental results for brain complexity in typically developing children and adolescents. Using this novel approach, the authors provide evidence for a gradual decrease in brain surface complexity throughout childhood and adolescence. These developmental differences occur earlier in the occipital lobe and move anterior as children progress into young adulthood. © 2011 Wiley Periodicals, Inc.


Rugge M.,University of Padua | Capelle L.G.,Erasmus Medical Center | Fassan M.,University of Padua
Best Practice and Research: Clinical Gastroenterology | Year: 2014

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide and it mostly develops in long-standing inflammatory conditions, and Helicobacter pylori-gastritis, in particular. Despite the increasing understanding of both the phenotypic alterations and the molecular mechanisms occurring during GC multi-step carcinogenesis, no reliable biomarker is available to be reliably implemented into GC secondary prevention strategies. Multidisciplinary diagnostic approaches integrating endoscopy, serology, histology and molecular profiling currently appears as the most appropriate approach for patients' stratification into different GC risk classes. © 2014 Elsevier Ltd. All rights reserved.


Estey E.,University of Washington | Estey E.,Fred Hutchinson Cancer Research Center | Levine R.L.,Sloan Kettering Cancer Center | Lowenberg B.,Erasmus Medical Center
Blood | Year: 2015

A fundamental difficulty in testing "targeted therapies" in acute myeloid leukemia (AML) is the limitations of preclinical models in capturing inter- and intrapatient genomic heterogeneity. Clinical trials typically focus on single agents despite the routine emergence of resistant subclones and experience in blast-phase chronic myeloid leukemia and acute promyelocytic leukemia arguing against this strategy. Inclusion of only relapsed-refractory, or unfit newly diagnosed, patients risks falsely negative results. There is uncertainty as to whether eligibility should require demonstration of the putative target and regarding therapeutic end points. Although use of in vivo preclinical models employing primary leukemic cells is first choice, newer preclinical models including "organoids" and combinations of pharmacologicandgenetic approaches may better align models with human AML. We advocate earlier inclusion of combinations ± chemotherapy and of newly diagnosed patients into clinical trials. When a drug plausibly targets a pathway uniquely related to a specific genetic aberration, eligibility should begin with this subset, including patients with other malignancies, with subsequent extension to other patients. In other cases, a more open-minded approach to initial eligibility would facilitate quicker identification of responsive subsets. Complete remission without minimal residual disease seems a particularly useful short-term end point. Genotypic and phenotypic studies should be prespecified and performed routinely to distinguish responders from nonresponders. © 2015 by The American Society of Hematology.


Reperant L.A.,Princeton University | Fuckar N.S.,Princeton University | Osterhaus A.D.M.E.,Erasmus Medical Center | Dobson A.P.,Princeton University | Kuiken T.,Erasmus Medical Center
PLoS Pathogens | Year: 2010

Wild bird movements and aggregations following spells of cold weather may have resulted in the spread of highly pathogenic avian influenza virus (HPAIV) H5N1 in Europe during the winter of 2005-2006. Waterbirds are constrained in winter to areas where bodies of water remain unfrozen in order to feed. On the one hand, waterbirds may choose to winter as close as possible to their breeding grounds in order to conserve energy for subsequent reproduction, and may be displaced by cold fronts. On the other hand, waterbirds may choose to winter in regions where adverse weather conditions are rare, and may be slowed by cold fronts upon their journey back to the breeding grounds, which typically starts before the end of winter. Waterbirds will thus tend to aggregate along cold fronts close to the 0°C isotherm during winter, creating conditions that favour HPAIV H5N1 transmission and spread. We determined that the occurrence of outbreaks of HPAIV H5N1 infection in waterbirds in Europe during the winter of 2005-2006 was associated with temperatures close to 0°C. The analysis suggests a significant spatial and temporal association of outbreaks caused by HPAIV H5N1 in wild birds with maximum surface air temperatures of 0°C-2°C on the day of the outbreaks and the two preceding days. At locations where waterbird census data have been collected since 1990, maximum mallard counts occurred when average and maximum surface air temperatures were 0°C and 3°C, respectively. Overall, the abundance of mallards (Anas platyrhynchos) and common pochards (Aythya ferina) was highest when surface air temperatures were lower than the mean temperatures of the region investigated. The analysis implies that waterbird movements associated with cold weather, and congregation of waterbirds along the 0°C isotherm likely contributed to the spread and geographical distribution of outbreaks of HPAIV H5N1 infection in wild birds in Europe during the winter of 2005-2006. © 2010 Reperant et al.


Robroek S.J.W.,Erasmus Medical Center | Van Den Berg T.I.J.,Erasmus Medical Center | Plat J.F.,PreventNed | Burdorf A.,Erasmus Medical Center
Occupational and Environmental Medicine | Year: 2011

Objectives: This study aims to investigate the role of lifestyle factors in relation to the presence and degree of productivity loss at work and sick leave. Methods: A cross-sectional study recruited 10 624 workers in 49 companies in the Netherlands in 2005-2009. Productivity loss at work was measured on a 10-point scale indicating how much work was actually performed on the previous workday. Sick leave was measured by asking how many days in the past 12 months workers were off work due to health problems. Logistic regression analyses were applied to study the association between obesity and lifestyle behaviours and both outcome measures. Results: Obesity was associated with the presence of sick leave (OR 1.25) and prolonged duration (OR 1.55). Insufficient physical activity (OR 1.12) and smoking (OR 1.17) were also associated with the presence of sick leave. Smoking (OR 1.45), obesity (OR 1.29) and insufficient fruit and vegetable intake (OR 1.22) were associated with the degree of productivity loss at work. The combined population attributable fractions of lifestyle factors for sick leave and the higher levels of productivity loss at work were above 10%. Conclusions: Lifestyle-related factors, especially smoking and obesity, were associated with the presence and duration of sick leave and degree of productivity loss at work. More than 10% of sick leave and the higher levels of productivity loss at work may be attributed to lifestyle behaviours and obesity. Hence, primary interventions on lifestyle may have a noticeable contribution to maintaining a productive workforce.


Coppus A.M.W.,Center for the Intellectually Disabled | Coppus A.M.W.,Radboud University Nijmegen | Coppus A.M.W.,Erasmus Medical Center
Developmental Disabilities Research Reviews | Year: 2013

Increases in the life expectancy of people with Intellectual Disability have followed similar trends to those found in the general population. With the exception of people with severe and multiple disabilities or Down syndrome, the life expectancy of this group now closely approximates with that of the general population. Middle and old age, which until 30 years ago were not recognized in this population, are now important parts of the life course of these individuals. Older adults with Intellectual Disabilities form a small, but significant and growing proportion of older people in the community. How these persons grow older and how symptoms and complications of the underlying cause of the Intellectual Disability will influence their life expectancy is of the utmost importance. © 2013 Wiley Periodicals, Inc.


White T.,Erasmus Medical Center | White T.,University of Minnesota | Hilgetag C.C.,Jacobs University Bremen | Hilgetag C.C.,Boston University
Development and Psychopathology | Year: 2011

There is emerging evidence for a connection between the surface morphology of the brain and its underlying connectivity. The foundation for this relationship is thought to be established during brain development through the shaping influences of tension exerted by viscoelastic nerve fibers. The tension-based morphogenesis results in compact wiring that enhances efficient neural processing. Individuals with schizophrenia present with multiple symptoms that can include impaired thought, action, perception, and cognition. The global nature of these symptoms has led researchers to explore a more global disruption of neuronal connectivity as a theory to explain the vast array of clinical and cognitive symptoms in schizophrenia. If cerebral function and form are linked through the organization of neural connectivity, then a disruption in neural connectivity may also alter the surface morphology of the brain. This paper reviews developmental theories of gyrification and the potential interaction between gyrification and neuronal connectivity. Studies of gyrification abnormalities in children, adolescents, and adults with schizophrenia demonstrate a relationship between disrupted function and altered morphology in the surface patterns of the cerebral cortex. This altered form may provide helpful clues in understanding the neurobiological abnormalities associated with schizophrenia. © Copyright Cambridge University Press 2011.


Hotulainen P.,University of Helsinki | Hoogenraad C.C.,Erasmus Medical Center
Journal of Cell Biology | Year: 2010

Dendritic spines are small actin-rich protrusions from neuronal dendrites that form the postsynaptic part of most excitatory synapses and are major sites of information processing and storage in the brain. Changes in the shape and size of dendritic spines are correlated with the strength of excitatory synaptic connections and heavily depend on remodeling of its underlying actin cytoskeleton. Emerging evidence suggests that most signaling pathways linking synaptic activity to spine morphology influence local actin dynamics. Therefore, specific mechanisms of actin regulation are integral to the formation, maturation, and plasticity of dendritic spines and to learning and memory. © 2010 Hotulainen and Hoogenraad.


Jansen N.A.,Erasmus Medical Center | Giesler G.J.,University of Minnesota
Journal of Neurophysiology | Year: 2015

We tested the possibility that the trigeminoparabrachial tract (VcPbT), a projection thought to be importantly involved in nociception, might also contribute to sensation of itch. In anesthetized rats, 47 antidromically identified VcPbT neurons with receptive fields involving the cheek were characterized for their responses to graded mechanical and thermal stimuli and intradermal injections of pruritogens (serotonin, chloroquine, and _-alanine), partial pruritogens (histamine and capsaicin), and an algogen (mustard oil). All pruriceptive VcPbT neurons were responsive to mechanical stimuli, and more than half were additionally responsive to thermal stimuli. The majority of VcPbT neurons were activated by injections of serotonin, histamine, capsaicin, and/or mustard oil. A subset of neurons were inhibited by injection of chloroquine. The large majority of VcPbT neurons projected to the ipsilateral and/or contralateral external lateral parabrachial and Kölliker-Fuse nuclei, as evidenced by antidromic mapping techniques. Analyses of mean responses and spike-timing dynamics of VcPbT neurons suggested clear differences in firing rates between responses to noxious and pruritic stimuli. Comparisons between the present data and those previously obtained from trigeminothalamic tract (VcTT) neurons demonstrated several differences in responses to some pruritogens. For example, responses of VcPbT neurons to injection of serotonin often endured for nearly an hour and showed a delayed peak in discharge rate. In contrast, responses of VcTT neurons endured for roughly 20 min and no delayed peak of firing was noted. Thus the longer duration responses to 5-HT and the delay in peak firing of VcPbT neurons better matched behavioral responses to stimulation in awake rats than did those of VcTT neurons. The results indicate that VcPbT neurons may have important roles in the signaling of itch as well as pain. © 2015 the American Physiological Society.


Taniwaki M.,University of Bern | Stefanini G.G.,University of Bern | Silber S.,Kardiologische Praxis und Praxisklinik | Richardt G.,Segeberger Kliniken GmbH | And 5 more authors.
Journal of the American College of Cardiology | Year: 2014

Objectives The aim of the study was to investigate 4-year outcomes and predictors of repeat revascularization in patients treated with the Resolute zotarolimus-eluting stent (R-ZES) (Medtronic, Minneapolis, Minnesota) and XIENCE V everolimus-eluting stent (EES) (Abbott Vascular, Abbott Park, Illinois) in the RESOLUTE (A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention) All-Comers trial. Background Data on long-term outcomes of new-generation drug-eluting stents are limited, and predictors of repeat revascularization due to restenosis and/or progression of disease are largely unknown. Methods Patients were randomly assigned to treatment with the R-ZES (n = 1,140) or the EES (n = 1,152). We assessed pre-specified safety and efficacy outcomes at 4 years including target lesion failure and stent thrombosis. Predictors of revascularization at 4 years were identified by Cox regression analysis. Results At 4 years, the rates of target lesion failure (15.2% vs. 14.6%, p = 0.68), cardiac death (5.4% vs. 4.7%, p = 0.44), and target vessel myocardial infarction (5.3% vs. 5.4%, p = 1.00), clinically-indicated target lesion revascularization (TLR) (7.0% vs. 6.5%, p = 0.62), and definite/probable stent thrombosis (2.3% vs. 1.6%, p = 0.23) were similar with the R-ZES and EES. Independent predictors of TLR were age, insulin-treated diabetes, SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score, treatment of saphenous vein grafts, ostial lesions, and in-stent restenosis. Independent predictors of any revascularization were age, diabetes, previous percutaneous coronary intervention, absence of ST-segment elevation myocardial infarction, smaller reference vessel diameter, SYNTAX score, and treatment of left anterior descending, right coronary artery, saphenous vein grafts, ostial lesions, or in-stent restenosis. Conclusions R-ZES and EES demonstrated similar safety and efficacy throughout 4 years. TLR represented less than one-half of all repeat revascularization procedures. Patient- and lesion-related factors predicting the risk of TLR and any revascularization showed considerable overlap. (A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention [RESOLUTE-AC]; NCT00617084). © 2014 by the American College of Cardiology Foundation.


Mina M.J.,Princeton University | Mina M.J.,Emory University | Metcalf C.J.E.,Princeton University | Metcalf C.J.E.,U.S. National Institutes of Health | And 4 more authors.
Science | Year: 2015

Immunosuppression after measles is known to predispose people to opportunistic infections for a period of several weeks to months. Using population-level data, we show that measles has a more prolonged effect on host resistance, extending over 2 to 3 years. We find that nonmeasles infectious disease mortality in high-income countries is tightly coupled to measles incidence at this lag, in both the pre- and post-vaccine eras. We conclude that long-term immunologic sequelae of measles drive interannual fluctuations in nonmeasles deaths. This is consistent with recent experimental work that attributes the immunosuppressive effects of measles to depletion of B and T lymphocytes. Our data provide an explanation for the long-term benefits of measles vaccination in preventing all-cause infectious disease. By preventing measles-associated immune memory loss, vaccination protects polymicrobial herd immunity. © 2015, American Association for the Advancement of Science. All rights reserved.


Van Soest R.J.,Erasmus Medical Center | De Morree E.S.,Erasmus Medical Center | Shen L.,Sanofi S.A. | Tannock I.F.,Princess Margaret Hospital | And 2 more authors.
European Urology | Year: 2014

Background Since 2004, docetaxel has been the standard first-line systemic therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). With abiraterone recently becoming available in the predocetaxel setting, it is warranted to identify subgroups of patients who may obtain the greatest benefit from docetaxel and particularly qualify for receiving docetaxel as first-line treatment for mCRPC. Objective We aimed to identify factors that could characterize subgroups of patients who obtain the greatest benefit from the use of docetaxel. Design, setting, and participants TAX327 was multinational, randomized, phase 3 study that was conducted from 2000 to 2002 in 1006 men with mCRPC. Intervention Patients were randomized to receive docetaxel every 3 wk (D3), weekly docetaxel (D1), or mitoxantrone every 3 wk (M3), each with prednisone. Outcome measurements and statistical analysis We investigated whether patients with poorly differentiated tumors (Gleason score ≥7) at diagnosis had greater benefit from D3 compared with M3 than patients with better differentiated tumors (Gleason score ≤6). Using a Cox model, we compared overall survival (OS) between the treatment groups within each subgroup of Gleason score. Results and limitations The TAX 327 data showed that the OS benefit of D3 versus M3 was greater in patients with high-grade tumors (median OS: 18.9 vs 14.5 mo; p = 0.009) than in patients with low-grade tumors (median OS: 21.6 vs 20.7 mo; p = 0.674). Limitations of a retrospective analysis apply. Conclusions The survival benefit obtained with docetaxel is most pronounced in patients with high-Gleason-score tumors (Gleason ≥7). In a time of shifting paradigms in mCRPC, with abiraterone becoming available prior to docetaxel chemotherapy, Gleason score may help in selecting patients who obtain the greatest benefit from docetaxel as first-line treatment for mCRPC. Prospective validation of these findings is warranted. © 2013 European Association of Urology.


Fitzpatrick J.M.,University College Dublin | De Wit R.,Erasmus Medical Center
European Urology | Year: 2014

Context In the past few years, there has been a rapid increase in the number of therapies available to treat metastatic castration-resistant prostate cancer (mCRPC). Currently, approved treatments consist of the taxane class of cytotoxic drugs and androgen-targeted therapies. The challenge for clinicians is to decide the best sequence in which to give these therapies to provide the greatest benefit to their patients. Objective To review recent research into the mechanism of action of taxanes in prostate cancer (PCa) cells and the clinical evidence for an interaction between taxanes and androgen-targeted therapies. The implications of these findings for clinical practice are discussed. Evidence acquisition A nonsystematic review of the relevant medical literature between 2004 and the present, in combination with clinical trial data reported at oncology meetings during 2012, was undertaken. Our perspective, focussing on the potential implications for sequencing of therapies for mCRPC, is provided. Evidence synthesis Taxanes are shown to interact with androgen signalling in PCa cells at both the cytoplasmic level (via microtubules) and the nuclear level, affecting transcriptional regulators of androgen-responsive gene expression. Data from clinical trials suggest that androgen deprivation can potentially decrease the efficacy of taxanes in treating PCa. Conclusions These findings have important implications for clinical practice, and there is an urgent need for strong clinical data to support a recommendation for an optimal sequence of therapies. © 2013 European Association of Urology.


Amin S.B.,University of Nantes | Amin S.B.,Erasmus Medical Center | Amin S.B.,Dana-Farber Cancer Institute
Leukemia | Year: 2014

With advent of several treatment options in multiple myeloma (MM), a selection of effective regimen has become an important issue. Use of gene expression profile (GEP) is considered an important tool in predicting outcome; however, it is unclear whether such genomic analysis alone can adequately predict therapeutic response. We evaluated the ability of GEP to predict complete response (CR) in MM. GEP from pretreatment MM cells from 136 uniformly treated MM patients with response data on an IFM, France led study were analyzed. To evaluate variability in predictive power due to microarray platform or treatment types, additional data sets from three different studies (n=511) were analyzed using same methods. We used several machine learning methods to derive a prediction model using training and test subsets of the original four data sets. Among all methods employed for GEP-based CR predictive capability, we got accuracy range of 56-78% in test data sets and no significant difference with regard to GEP platforms, treatment regimens or in newly diagnosed or relapsed patients. Importantly, permuted P-value showed no statistically significant CR predictive information in GEP data. This analysis suggests that GEP-based signature has limited power to predict CR in MM, highlighting the need to develop comprehensive predictive model using integrated genomics approach.


Svishcheva G.R.,RAS Institute of Cytology and Genetics | Axenovich T.I.,RAS Institute of Cytology and Genetics | Belonogova N.M.,RAS Institute of Cytology and Genetics | Van Duijn C.M.,Erasmus Medical Center | Aulchenko Y.S.,RAS Institute of Cytology and Genetics
Nature Genetics | Year: 2012

The variance component tests used in genome-wide association studies (GWAS) including large sample sizes become computationally exhaustive when the number of genetic markers is over a few hundred thousand. We present an extremely fast variance components-based two-step method, GRAMMAR-Gamma, developed as an analytical approximation within a framework of the score test approach. Using simulated and real human GWAS data sets, we show that this method provides unbiased estimates of the SNP effect and has a power close to that of the likelihood ratio test-based method. The computational complexity of our method is close to its theoretical minimum, that is, to the complexity of the analysis that ignores genetic structure. The running time of our method linearly depends on sample size, whereas this dependency is quadratic for other existing methods. Simulations suggest that GRAMMAR-Gamma may be used for association testing in whole-genome resequencing studies of large human cohorts. © 2012 Nature America, Inc. All rights reserved.


El Barzouhi A.,Leiden University | Vleggeert-Lankamp C.L.A.M.,Leiden University | Lycklama A Nijeholt G.J.,Medical Center Haaglanden | Van Der Kallen B.F.,Medical Center Haaglanden | And 5 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Magnetic resonance imaging (MRI) is frequently performed during follow-up in patients with known lumbar-disk herniation and persistent symptoms of sciatica. The association between findings on MRI and clinical outcome is controversial. METHODS: We studied 283 patients in a randomized trial comparing surgery and prolonged conservative care for sciatica and lumbar-disk herniation. Patients underwent MRI at baseline and after 1 year. We used a 4-point scale to assess disk herniation on MRI, ranging from 1 for "definitely present" to 4 for "definitely absent." A favorable clinical outcome was defined as complete or nearly complete disappearance of symptoms at 1 year. We compared proportions of patients with a favorable outcome among those with a definite absence of disk herniation and those with a definite, probable, or possible presence of disk herniation at 1 year. The area under the receiver-operating-characteristic (ROC) curve was used to assess the prognostic accuracy of the 4-point scores regarding a favorable or unfavorable outcome, with 1 indicating perfect discriminatory value and 0.5 or less indicating no discriminatory value. RESULTS: At 1 year, 84% of the patients reported having a favorable outcome. Disk herniation was visible in 35% with a favorable outcome and in 33% with an unfavorable outcome (P = 0.70). A favorable outcome was reported in 85% of patients with disk herniation and 83% without disk herniation (P = 0.70). MRI assessment of disk herniation did not distinguish between patients with a favorable outcome and those with an unfavorable outcome (area under ROC curve, 0.48). CONCLUSIONS: MRI performed at 1-year follow-up in patients who had been treated for sciatica and lumbar-disk herniation did not distinguish between those with a favorable outcome and those with an unfavorable outcome. (Funded by the Netherlands Organization for Health Research and Development and the Hoelen Foundation; Controlled Clinical Trials number, ISRCTN26872154.) Copyright © 2013 Massachusetts Medical Society.


Wong V.W.-S.,Chinese University of Hong Kong | Janssen H.L.A.,University of Western Ontario | Janssen H.L.A.,Erasmus Medical Center
Journal of Hepatology | Year: 2015

Summary Chronic hepatitis B is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. Accurate prediction of HCC risk is important for decisions on antiviral therapy and HCC surveillance. In the last few years, a number of Asian groups have derived and validated several HCC risk scores based on well-known risk factors such as cirrhosis, age, male sex and high viral load. Overall, these scores have high negative predictive values of over 95% in excluding HCC development in 3 to 10 years. The REACH-B score was derived from a community cohort of non-cirrhotic patients and is better applied in the primary care setting. In contrast, the GAG-HCC and CU-HCC scores were derived from hospital cohorts and include cirrhosis as a major integral component. While the latter scores may be more applicable to patients at specialist clinics, the diagnosis of cirrhosis based on routine imaging and clinical parameters can be inaccurate. To this end, recent developments in non-invasive tests of liver fibrosis may further refine the risk prediction. The application of HCC risk scores in patients on antiviral therapy and in other ethnic groups should be evaluated in future studies. © 2015 European Association for the Study of the Liver.


Soonawala D.,Leiden University | Rimmelzwaan G.F.,Erasmus Medical Center | Gelinck L.B.S.,MC Haaglanden | Visser L.G.,Leiden University | Kroon F.P.,Leiden University
PLoS ONE | Year: 2011

Background: The immunogenicity of 2009 pandemic influenza A(H1N1) (pH1N1) vaccines and the effect of previous influenza vaccination is a matter of current interest and debate. We measured the immune response to pH1N1 vaccine in HIV-infected patients and in healthy controls. In addition we tested whether recent vaccination with seasonal trivalent inactivated vaccine (TIV) induced cross-reactive antibodies to pH1N1. (clinicaltrials.gov Identifier:NCT01066169) Methods and Findings: In this single-center prospective cohort study MF59-adjuvanted pH1N1 vaccine (Focetria®, Novartis) was administered twice to 58 adult HIV-infected patients and 44 healthy controls in November 2009 (day 0 and day 21). Antibody responses were measured at baseline, day 21 and day 56 with hemagglutination-inhibition (HI) assay. The seroprotection rate (defined as HI titers ≥1:40) for HIV-infected patients was 88% after the first and 91% after the second vaccination. These rates were comparable to those in healthy controls. Post-vaccination GMT, a sensitive marker of the immune competence of a group, was lower in HIV-infected patients. We found a high seroprotection rate at baseline (31%). Seroprotective titers at baseline were much more common in those who had received 2009-2010 seasonal TIV three weeks prior to the first dose of pH1N1 vaccine. Using stored serum samples of 51 HIV-infected participants we measured the pH1N1 specific response to 2009-2010 seasonal TIV. The seroprotection rate to pH1N1 increased from 22% to 49% after vaccination with 2009-2010 seasonal TIV. Seasonal TIV induced higher levels of antibodies to pH1N1 in older than in younger subjects. Conclusion: In HIV-infected patients on combination antiretroviral therapy, with a median CD4+ T-lymphocyte count above 500 cells/mm3, one dose of MF59-adjuvanted pH1N1 vaccine induced a high seroprotection rate comparable to that in healthy controls. A second dose had a modest additional effect. Furthermore, seasonal TIV induced cross-reactive antibodies to pH1N1 and this effect was more pronounced in older subjects. © 2011 Soonawala et al.


Vickers A.J.,Sloan Kettering Cancer Center | Roobol M.J.,Erasmus Medical Center | Lilja H.,Sloan Kettering Cancer Center | Lilja H.,Lund University | Lilja H.,University of Tampere
Annual Review of Medicine | Year: 2012

A sophisticated reading of the randomized trial evidence suggests that, although screening for prostate cancer with prostate-specific antigen (PSA) can reduce cancer-specific mortality, it does so at considerable cost in terms of the number of men who need to be screened, biopsied, and treated to prevent one death. The challenge is to design screening programs that maximize benefits (reducing prostate cancer mortality) and minimize costs (overtreatment). Recent research has suggested that this can be achieved by risk-stratifying screening and biopsy; increasing reliance on active surveillance for low-risk cancer; restricting radical prostatectomy to high-volume surgeons; and using appropriately high-dose radiotherapy. In current U.S. practice, however, many men who are screened are unlikely to benefit, most men found to have low-risk cancers are referred for unnecessary curative treatment, and much treatment is given at low-volume centers. © 2012 by Annual Reviews. All rights reserved.


Preiser J.-C.,Free University of Brussels | Ichai C.,University of Nice Sophia Antipolis | Orban J.-C.,University of Nice Sophia Antipolis | Groeneveld A.B.,Erasmus Medical Center
British journal of anaesthesia | Year: 2014

The metabolic response to stress is part of the adaptive response to survive critical illness. Several mechanisms are well preserved during evolution, including the stimulation of the sympathetic nervous system, the release of pituitary hormones, a peripheral resistance to the effects of these and other anabolic factors, triggered to increase the provision of energy substrates to the vital tissues. The pathways of energy production are altered and alternative substrates are used as a result of the loss of control of energy substrate utilization by their availability. The clinical consequences of the metabolic response to stress include sequential changes in energy expenditure, stress hyperglycaemia, changes in body composition, and psychological and behavioural problems. The loss of muscle proteins and function is a major long-term consequence of stress metabolism. Specific therapeutic interventions, including hormone supplementation, enhanced protein intake, and early mobilization, are investigated. This review aims to summarize the pathophysiological mechanisms, the clinical consequences, and therapeutic implications of the metabolic response to stress. © The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.


Thongjuea S.,University of Bergen | Stadhouders R.,Erasmus Medical Center | Grosveld F.G.,Erasmus Medical Center | Soler E.,Erasmus Medical Center | And 4 more authors.
Nucleic Acids Research | Year: 2013

The coupling of chromosome conformation capture (3C) with next-generation sequencing technologies enables the high-throughput detection of long-range genomic interactions, via the generation of ligation products between DNA sequences, which are closely juxtaposed in vivo. These interactions involve promoter regions, enhancers and other regulatory and structural elements of chromosomes and can reveal key details of the regulation of gene expression. 3C-seq is a variant of the method for the detection of interactions between one chosen genomic element (viewpoint) and the rest of the genome. We present r3Cseq, an R/Bioconductor package designed to perform 3C-seq data analysis in a number of different experimental designs. The package reads a common aligned read input format, provides data normalization, allows the visualization of candidate interaction regions and detects statistically significant chromatin interactions, thus greatly facilitating hypothesis generation and the interpretation of experimental results. We further demonstrate its use on a series of real-world applications. © 2013 The Author(s) 2013. Published by Oxford University Press.


Lansdorp-Vogelaar I.,Erasmus Medical Center | Knudsen A.B.,Massachusetts General Hospital | Brenner H.,German Cancer Research Center
Epidemiologic Reviews | Year: 2011

Colorectal cancer is an important public health problem. Several screening methods have been shown to be effective in reducing colorectal cancer mortality. The objective of this review was to assess the cost-effectiveness of the different colorectal cancer screening methods and to determine the preferred method from a cost-effectiveness point of view. Five databases (MEDLINE, EMBASE, the Cost-Effectiveness Analysis Registry, the British National Health Service Economic Evaluation Database, and the lists of technology assessments of the Centers for Medicare and Medicaid Services) were searched for cost-effectiveness analyses published in English between January 1993 and December 2009. Fifty-five publications relating to 32 unique cost-effectiveness models were identified. All studies found that colorectal cancer screening was cost-effective or even cost-saving compared with no screening. However, the studies disagreed as to which screening method was most effective or had the best incremental cost-effectiveness ratio for a given willingness to pay per life-year gained. There was agreement among studies that the newly developed screening tests of stool DNA testing, computed tomographic colonography, and capsule endoscopy were not yet cost-effective compared with the established screening options. © 2011 The Author.


Vedder M.M.,Erasmus Medical Center | de Bekker-Grob E.W.,Erasmus Medical Center | Lilja H.G.,Sloan Kettering Cancer Center | Lilja H.G.,University of Tampere | And 4 more authors.
European Urology | Year: 2014

Background: Prostate-specific antigen (PSA) testing has limited accuracy for the early detection of prostate cancer (PCa). Objective: To assess the value added by percentage of free to total PSA (%fPSA), prostate cancer antigen 3 (PCA3), and a kallikrein panel (4k-panel) to the European Randomised Study of Screening for Prostate Cancer (ERSPC) multivariable prediction models: risk calculator (RC) 4, including transrectal ultrasound, and RC 4 plus digital rectal examination (4+DRE) for prescreened men. Design, setting, and participants: Participants were invited for rescreening between October 2007 and February 2009 within the Dutch part of the ERSPC study. Biopsies were taken in men with a PSA level ≥3.0 ng/ml or a PCA3 score ≥10. Additional analyses of the 4k-panel were done on serum samples. Outcome measurements and statistical analysis: Outcome was defined as PCa detectable by sextant biopsy. Receiver operating characteristic curve and decision curve analyses were performed to compare the predictive capabilities of %fPSA, PCA3, 4k-panel, the ERSPC RCs, and their combinations in logistic regression models. Results and limitations: PCa was detected in 119 of 708 men. The %fPSA did not perform better univariately or added to the RCs compared with the RCs alone. In 202 men with an elevated PSA, the 4k-panel discriminated better than PCA3 when modelled univariately (area under the curve [AUC]: 0.78 vs 0.62; p = 0.01). The multivariable models with PCA3 or the 4k-panel were equivalent (AUC: 0.80 for RC 4+DRE). In the total population, PCA3 discriminated better than the 4k-panel (univariate AUC: 0.63 vs 0.56; p = 0.05). There was no statistically significant difference between the multivariable model with PCA3 (AUC: 0.73) versus the model with the 4k-panel (AUC: 0.71; p = 0.18). The multivariable model with PCA3 performed better than the reference model (0.73 vs 0.70; p = 0.02). Decision curves confirmed these patterns, although numbers were small. Conclusions: Both PCA3 and, to a lesser extent, a 4k-panel have added value to the DRE-based ERSPC RC in detecting PCa in prescreened men. Patient summary: We studied the added value of novel biomarkers to previously developed risk prediction models for prostate cancer. We found that inclusion of these biomarkers resulted in an increase in predictive ability. © 2014.


Stone G.W.,Columbia University Medical Center | Kedhi E.,Maasstad Ziekenhuis | Kereiakes D.J.,Christ Hospital Heart and Vascular Center | Parise H.,Columbia University Medical Center | And 3 more authors.
Circulation | Year: 2011

Background-: Some (but not all) prior trials have reported differential outcomes after percutaneous coronary intervention with paclitaxel-eluting stents versus stents eluting rapamycin analogs according to the presence of diabetes mellitus. These studies lacked sufficient power to examine individual safety and efficacy end points. Methods and results-: To determine whether an interaction exists between the presence of diabetes mellitus and treatment with everolimus-eluting stents compared with paclitaxel-eluting stents, we pooled the databases from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions (SPIRIT) II, SPIRIT III, SPIRIT IV, and A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice (COMPARE) trials in which percutaneous coronary intervention was performed in 6780 patients, 1869 (27.6%) of whom had diabetes mellitus. Patients without diabetes mellitus treated with everolimus-eluting stents compared with paclitaxel-eluting stents had significantly reduced 2-year rates of mortality (1.9% versus 3.1%; P=0.01), myocardial infarction (2.5% versus 5.8%; P<0.0001), stent thrombosis (0.3% versus 2.4%; P<0.0001), and ischemia-driven target lesion revascularization (3.6% versus 6.9%; P<0.0001). In contrast, among patients with diabetes mellitus, there were no significant differences between the 2 stent types in any measured safety or efficacy parameter. Significant interactions were present between diabetic status and stent type for the 2-year end points of myocardial infarction (P=0.01), stent thrombosis (P=0.0006), and target lesion revascularization (P=0.02). Conclusions-: We have identified a substantial interaction between diabetes mellitus and stent type on clinical outcomes after percutaneous coronary intervention. In patients without diabetes mellitus, everolimus-eluting stents compared with paclitaxel-eluting stents resulted in substantial 2-year reductions in death, myocardial infarction, stent thrombosis, and target lesion revascularization, whereas no significant differences in safety or efficacy outcomes were present in diabetic patients. © 2011 American Heart Association, Inc.


Lansdorp-Vogelaar I.,Erasmus Medical Center | Knudsen A.B.,Massachusetts General Hospital | Brenner H.,German Cancer Research Center
Best Practice and Research: Clinical Gastroenterology | Year: 2010

There are several modalities available for a colorectal cancer (CRC) screening program. When determining which CRC screening program to implement, the costs of such programs should be considered in comparison to the health benefits they are expected to provide. Cost-effectiveness analysis provides a tool to do this. In this paper we review the evidence on the cost-effectiveness of CRC screening. Published studies universally indicate that when compared with no CRC screening, all screening modalities provide additional years of life at a cost that is deemed acceptable by most industrialized nations. Many recent studies even find CRC screening to be cost-saving. However, when the alternative CRC screening strategies are compared against each other in an incremental cost-effectiveness analysis, no single optimal strategy emerges across the studies. There is consensus that the new technologies of stool DNA testing, computed tomographic colonography and capsule endoscopy are not yet cost-effective compared with the established CRC screening tests. © 2010 Elsevier Ltd. All rights reserved.


Moreno J.C.,University Institute of La Paz | Visser T.J.,Erasmus Medical Center
Molecular and Cellular Endocrinology | Year: 2010

Iodotyrosine deiodinase is a thyroidal enzyme that deiodinates mono- and di-iodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to hypothyroidism, goiter and mental retardation, a clinical phenotype yet described in the 1950s, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine.DEHAL1, the gene responsible for this activity, was recently isolated and the molecular basis for the iodotyrosine deiodinase deficiency (ITDD) unraveled. The current clinical picture of mutations in DEHAL1 mostly recapitulates the " classical" phenotype of ITDD, including the psychomotor deficits. This is probably due to the lack of expression of the disease at the beginning of life, which causes ITDD being undetected in current screening programs for congenital hypothyroidism. This worrying feature calls for efforts to improve the preclinical detection of iodotyrosine deiodinase deficiency in the neonatal time. © 2010 Elsevier Ireland Ltd.


Ezendam N.P.M.,Erasmus Medical Center | Ezendam N.P.M.,Comprehensive Cancer Center South | Ezendam N.P.M.,University of Tilburg | Brug J.,VU University Amsterdam | Oenema A.,Erasmus Medical Center
Archives of Pediatrics and Adolescent Medicine | Year: 2012

Objective: To evaluate the short- and long-term results of FATaintPHAT, a Web-based computer-tailored intervention aiming to increase physical activity, decrease sedentary behavior, and promote healthy eating to contribute to the prevention of excessive weight gain among adolescents. Design: Cluster randomized trial with an intervention group and a no-intervention control group. Setting: Twenty schools in the Netherlands. Participants: A total of 883 students (aged 12-13 years). Intervention: The FATaintPHAT (VETisnietVET in Dutch) Web-based computer-tailored intervention. Outcome Measures: Self-reported behaviors (diet, physical activity, sedentary behavior) and pedometer counts were measured at baseline and at 4-month and 2-year follow-up; body mass index (BMI), waist circumference, and fitness were measured at baseline and at 2-year follow-up. Descriptive and multilevel regression analyses were conducted among the total study population and among students not meeting behavioral recommendations at baseline (students at risk). Results: The complete case analyses showed that FATaintPHAT had no effect on BMI and waist circumference. However, the intervention was associated with lower odds (0.54) of drinking more than 400 mL of sugar sweetened beverages per day and with lower snack intake (β=-0.81 snacks/d) and higher vegetable intake (β=19.3 g/d) but also with a lower step count (β=-10 856 steps/wk) at 4-month follow-up. In addition, among students at risk, FATaintPHAT had a positive effect on fruit consumption (β=0.39 g/d) at 4-month follow-up and on step count (β=14 228 steps/wk) at 2-year follow-up but an inverse effect on the odds of sports participation (odds ratio, 0.45) at 4-month follow-up. No effects were found for sedentary behavior. Conclusion: The FATaintPHAT intervention was associated with positive short-term effects on diet but with no effects or unfavorable effects on physical activity and sedentary behavior. Trial Registration: Netherlands Trial Registry: ISRCTN15743786. ©2012 American Medical Association. All rights reserved.


Zini A.,McGill University | Zini A.,St Marys Hospital | Dohle G.,Erasmus Medical Center
Fertility and Sterility | Year: 2011

Objective: To perform a literature search on the association between varicocele and sperm DNA fragmentation. Design: Systematic review. Patient(s): Men with a varicocele and infertility. Intervention(s): Varicocele repair. Main Outcome Measure(s): Does the presence of a varicocele increase seminal oxidative stress and sperm DNA fragmentation? Result(s): In men with a varicocele increased levels of reactive oxygen species and sperm DNA damage can be found. This is probably related to defective spermatogenesis in these patients. Seminal oxidative stress is believed to be the source of sperm DNA damage. Patients with a varicocele and oligospermia may also have a diminished seminal antioxidant capacity. After varicocele repair sperm DNA fragmentation decreases. Conclusion(s): Varicocele is associated with sperm DNA damage, and this sperm pathology may be secondary to varicocele-mediated oxidative stress. The beneficial effect of varicocelectomy on sperm DNA damage further supports the premise that varicocele may impair sperm DNA integrity. Copyright © 2011 American Society for Reproductive Medicine.


Wolbers M.,University of Oxford | Blanche P.,University of Bordeaux Segalen | Koller M.T.,University of Basel | Witteman J.C.M.,Erasmus Medical Center | Gerds T.A.,Copenhagen University
Biostatistics | Year: 2014

The concordance probability is a widely used measure to assess discrimination of prognostic models with binary and survival endpoints. We formally define the concordance probability for a prognostic model of the absolute risk of an event of interest in the presence of competing risks and relate it to recently proposed time-dependent area under the receiver operating characteristic curve measures. For right-censored data, we investigate inverse probability of censoring weighted (IPCW) estimates of a truncated concordance index based on a working model for the censoring distribution. We demonstrate consistency and asymptotic normality of the IPCW estimate if the working model is correctly specified and derive an explicit formula for the asymptotic variance under independent censoring. The small sample properties of the estimator are assessed in a simulation study also against misspecification of the working model. We further illustrate the methods by computing the concordance probability for a prognostic model of coronary heart disease (CHD) events in the presence of the competing risk of non-CHD death. © 2014 The Author.


Gielen S.,Martin Luther University of Halle Wittenberg | Laughlin M.H.,University of Missouri | O'Conner C.,Duke University | Duncker D.J.,Erasmus Medical Center
Progress in Cardiovascular Diseases | Year: 2015

Over the last decades exercise training has evolved into an established evidence-based therapeutic strategy with prognostic benefits in many cardiovascular diseases (CVDs): In stable coronary artery disease (CAD) exercise training attenuates disease progression by beneficially influencing CVD risk factors (i.e., hyperlipidemia, hypertension) and coronary endothelial function. In heart failure (HF) with reduced ejection fraction (HFrEF) training prevents the progressive loss of exercise capacity by antagonizing peripheral skeletal muscle wasting and by promoting left ventricular reverse remodeling with reduction in cardiomegaly and improvement of ejection fraction. Novel areas for exercise training interventions include HF with preserved ejection fraction (HFpEF), pulmonary hypertension, and valvular heart disease. In HFpEF, randomized studies indicate a lusitropic effect of training on left ventricular diastolic function associated with symptomatic improvement of exercise capacity. In pulmonary hypertension, reductions in pulmonary artery pressure were observed following endurance exercise training.Recently, innovative training methods such as high-intensity interval training, resistance training and others have been introduced. Although their prognostic value still needs to be determined, these approaches may achieve superior improvements in aerobic exercise capacity and gain in muscle mass, respectively.In this review, we give an overview of the prognostic and symptomatic benefits of exercise training in the most common cardiac disease entities. Additionally, key guideline recommendations for the initiation of training programs are summarized. © 2014 Elsevier Inc.


Hankinson J.L.,Hankinson Consulting Inc. | Eschenbacher B.,Cincinnati Medical Center | Townsend M.,MC Townsend Inc. | Stocks J.,University College London | Quanjer P.H.,Erasmus Medical Center
European Respiratory Journal | Year: 2015

The 2005 American Thoracic Society (ATS)/European Respiratory Society (ERS) spirometry guidelines define valid tests as having three acceptable blows and a repeatable forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). The aim of this study was to determine how reviewer and computer-determined ATS/ERS quality could affect population reference values for FVC and FEV1. Spirometry results from 7777 normal subjects aged 8-80 years (NHANES (National Health and Nutrition Examination Survey) III) were assigned quality grades A to F for FVC and FEV1 by a computer and one reviewer (reviewer 1). Results from a subgroup of 1466 Caucasian adults (aged 19-80 years) were reviewed by two additional reviewers. Mean deviations from NHANES III predicted for FVC and FEV1 were examined by quality grade (A to F). Reviewer 1 rejected (D and F grade) 5.2% of the 7777 test sessions and the computer rejected ∼16%, primarily due to end-of-test (EOT) failures. Within the subgroup, the computer rejected 11.5% of the results and the three reviewers rejected 3.7-5.9%. Average FEV1 and FVC were minimally influenced by grades A to C allocated by reviewer 1. Quality assessment of individual blows including EOT assessments should primarily be used as an aid to good quality during testing rather than for subsequently disregarding data. Reconsideration of EOT criteria and its application, and improved grading standards and training in over-reading are required. Present EOT criteria results in the exclusion of too many subjects while having minimal impact on predicted values. Copyright © ERS 2015.


de Ronde W.,Kennemer Gasthuis | de Jong F.H.,Erasmus Medical Center
Reproductive Biology and Endocrinology | Year: 2011

Aromatase inhibitors effectively delay epiphysial maturation in boys and improve testosterone levels in adult men Therefore, aromatase inhibitors may be used to increase adult height in boys with gonadotropin-independent precocious puberty, idiopathic short stature and constitutional delay of puberty. Long-term efficacy and safety of the use of aromatase inhibitors has not yet been established in males, however, and their routine use is therefore not yet recommended. © 2011 de Ronde and de Jong; licensee BioMed Central Ltd.


Quanjer P.H.,Erasmus Medical Center | Brazzale D.J.,Austin Hospital | Boros P.W.,National Tuberculosis and Lung Diseases Research Institute | Pretto J.J.,John Hunter Hospital
European Respiratory Journal | Year: 2013

The aim of this study was to determine the diagnostic and interpretative consequences of adopting the Global Lungs Initiative (GLI) 2012 spirometric prediction equations. We assessed spirometric records from 17 572 subjects (49.5% females), aged 18-85 years, from hospitals in Australia and Poland. We calculated predicted forced expiratory volume in 1 s (FEV1), forced expiratory volume (FVC), FEV1/ FVC and lower limits of normal (LLN) using European Community for Steel and Coal (ECSC), National Health and Nutrition Examination Survey (NHANES) III and GLI 2012 equations. Obstruction was defined as FEV1/FVCLLN and FVC20% underdiagnosis of airway obstruction up to the age of 55 years and to 16-23% overdiagnosis in older subjects. GLI 2012 equations increase the prevalence of a "restrictive spirometric pattern" compared to ECSC but decrease it compared to NHANES. Copyright ©ERS 2013.


Kloosterhof N.K.,Daniel den Hoed Cancer Center | Kloosterhof N.K.,Erasmus MC Sophia Childrens Hospital | Bralten L.B.C.,Daniel den Hoed Cancer Center | Dubbink H.J.,Erasmus Medical Center | And 2 more authors.
The Lancet Oncology | Year: 2011

The discovery of somatic mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) in glioblastomas was remarkable because the enzyme was not previously identified with any known oncogenic pathway. IDH1 is mutated in up to 75% of grade II and grade III diffuse gliomas. Apart from acute myeloid leukaemia, other tumour types do not carry IDH1 mutations. Mutations in a homologous gene, IDH2, have also been identified, although they are much rarer. Although TP53 mutations and 1p/19q codeletions are mutually exclusive in gliomas, in both of these genotypes IDH1 mutations are common. IDH1 and IDH2 mutations are early events in the development of gliomas. Moreover, IDH1 and IDH2 mutations are a major prognostic marker for overall and progression-free survival in grade II-IV gliomas. Mutated IDH1 has an altered catalytic activity that results in the accumulation of 2-hydroxyglutarate. Molecularly, IDH1 and IDH2 mutations are heterozygous, affect only a single codon, and rarely occur together. Because IDH1 does not belong to a traditional oncogenic pathway and is specifically and commonly mutated in gliomas, the altered enzymatic activity of IDH1 may provide a fundamentally new understanding of diffuse glioma. © 2011 Elsevier Ltd.


Sharlin D.S.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Visser T.J.,Erasmus Medical Center | Forrest D.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases
Endocrinology | Year: 2011

Thyroid hormone is essential for the development of the cochlea and auditory function. Cochlear response tissues, which express thyroid hormone receptor β (encoded by Thrb), include the greater epithelial ridge and sensory epithelium residing inside the bony labyrinth. However, these response tissues lack direct blood flow, implying that mechanisms exist to shuttle hormone from the circulation to target tissues. Therefore, we investigated expression of candidate thyroid hormone transporters L-type amino acid transporter 1 (Lat1), monocarboxylate transporter (Mct)8, Mct10, and organic anion transporting polypeptide 1c1 (Oatp1c1) in mouse cochlear development by in situ hybridization and immunofluorescence analysis. L-type amino acid transporter 1 localized to cochlear blood vessels and transiently to sensory hair cells. Mct8 localized to the greater epithelial ridge, tympanic border cells underlying the sensory epithelium, spiral ligament fibrocytes, and spiral ganglion neurons, partly overlapping with the Thrb expression pattern. Mct10 was detected in a highly restricted pattern in the outer sulcus epithelium and weakly in tympanic border cells and hair cells. Organic anion transporting polypeptide 1c1 localized primarily to fibrocytes in vascularized tissues of the spiral limbus and spiral ligament and to tympanic border cells. Investigation of hypothyroid Tshr -/- mice showed that transporter expression was delayed consistent with retardation of cochlear tissue maturation but not with compensatory responses to hypothyroidism. The results demonstrate specific expression of thyroid hormone transporters in the cochlea and suggest that a network of thyroid hormone transport underlies cochlear development. Copyright © 2011 by The Endocrine Society.


Bolignano D.,CNR Institute of Clinical Physiology | Mattace-Raso F.,Erasmus Medical Center | Sijbrands E.J.G.,Erasmus Medical Center | Zoccali C.,CNR Institute of Clinical Physiology
Ageing Research Reviews | Year: 2014