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Utrecht, Netherlands

Utrecht University is a university in Utrecht, the Netherlands. It is one of the oldest universities in the Netherlands and one of the largest in Europe. Established March 26, 1636, it had an enrollment of 30,449 students in 2012, and employed 5,295 faculty and staff. In 2011, 485 PhD degrees were awarded and 7,773 scientific articles were published. The 2013 budget of the university was €765 million.The university is rated as the best university in the Netherlands by the Shanghai Ranking of World Universities 2013, and ranked as the 13th best European university and the 52nd best university of the world.The university's motto is "Sol Iustitiae Illustra Nos," which means "Sun of Justice, shine upon us." This motto was gleaned from a literal Latin Bible translation of Malachi 4:2. Utrecht University is led by the University Board, consisting of prof. dr. Bert van der Zwaan and Hans Amman. Wikipedia.

Gadella B.M.,University Utrecht
Society of Reproduction and Fertility supplement | Year: 2010

In order to achieve fertilization sperm cells, first need to successfully interact with the zona pellucida. To this end, the sperm surface is extensively remodeled during capacitation and the resulting sperm cells also possess hyperactivated motility. Together, this serves to mediate optimal recognition of the zona pellucida in the oviduct or after in vitro fertilization incubations (primary zona pellucida binding). When the sperm cell attaches to the zona pellucida, it will be triggered to undergo the acrosome reaction which allows the hyperactivated motile sperm cell to drill through the zona pellucida (secondary zona pellucida binding coinciding with sequential local zona pellucida digestion and rebinding). After successful zona penetration, some sperm cells may enter the perivitelline space. This delaying strategy of the oocyte allows only one sperm cell at a given time to bind and fuse with the oocyte (fertilization) and thus minimizes the risk of polyspermy. The fertilization fusion between the oocyte and the first sperm cell is immediately followed by a polyspermic fertilization block, in which the content of the oocyte's cortical granules is released into the perivitelline space. The cortical reaction blocks further sperm-oocyte fusion either by sticking at the oolemma or by the induction of a biochemical reaction of the zona pellucida (zona pellucida hardening). The cortical reaction thus blocks sperm-zona pellucida binding and/or sperm-zona pellucida penetration. This review summarizes the current understanding of sperm-zona pellucida interactions in relation to mammalian fertilization. The lack of knowledge about sperm-zona pellucida binding in ruminants will be critically discussed.

Karin M.,University of California at San Diego | Clevers H.,Princess Maxima Center and Hubrecht Institute | Clevers H.,University Utrecht
Nature | Year: 2016

Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies. © 2016 Macmillan Publishers Limited. All rights reserved.

Leslie N.R.,Heriot - Watt University | Den Hertog J.,University Utrecht | Den Hertog J.,Institute of Biology Leiden
Cell | Year: 2014

Tumor suppressors block the development of cancer and are often lost during tumor development. Papa et al. show that partial loss of normal PTEN tumor suppressor function can be compounded by additional disruption caused by the expression of inactive mutant PTEN protein. This has significant implications for patients with PTEN gene mutations. © 2014 Elsevier Inc.

O'Leary D.H.,Tufts University | Bots M.L.,University Utrecht
European Heart Journal | Year: 2010

Carotid ultrasound provides quantitative measurements of carotid intima-media thickness (CIMT) that can be used to assess cardiovascular disease (CVD) risk in individuals and monitor ongoing disease progression and regression in clinical trials. It is non-invasive, rapid, reproducible, and carries no risk. Numerous epidemiological studies have established that CIMT is a marker of subclinical atherosclerosis and is associated with established CVD risk factors and with both prevalent and incident CVD. The use of CIMT in outcome trials as a surrogate or predictor of CVD outcomes is widespread. Carotid ultrasound is being employed to test the efficacy of CVD treatment in order to identify potential useful drugs earlier and to possibly speed regulatory approval. Successive trials have generated lessons learned and applied, with slow but steady improvement in CIMT measurement reproducibility. © 2010 The Author.

Dekker F.J.,University of Groningen | Van Den Bosch T.,University of Groningen | Martin N.I.,University Utrecht
Drug Discovery Today | Year: 2014

Lysine acetylation is a reversible post-translational modification (PTM) of cellular proteins and represents an important regulatory switch in signal transduction. Lysine acetylation, in combination with other PTMs, directs the outcomes as well as the activation levels of important signal transduction pathways such as the nuclear factor (NF)-κB pathway. Small molecule modulators of the 'writers' (HATs) and 'erasers' (HDACs) can regulate the NF-κB pathway in a specific manner. This review focuses on the effects of frequently used HAT and HDAC inhibitors on the NF-κB signal transduction pathway and inflammatory responses, and their potential as novel therapeutics. © 2013 The Authors.

Houbraken J.,Fungal Biodiversity Center | Houbraken J.,University Utrecht | Samson R.A.,Fungal Biodiversity Center
Studies in Mycology | Year: 2011

Species of Trichocomaceae occur commonly and are important to both industry and medicine. They are associated with food spoilage and mycotoxin production and can occur in the indoor environment, causing health hazards by the formation of β-glucans, mycotoxins and surface proteins. Some species are opportunistic pathogens, while others are exploited in biotechnology for the production of enzymes, antibiotics and other products. Penicillium belongs phylogenetically to Trichocomaceae and more than 250 species are currently accepted in this genus. In this study, we investigated the relationship of Penicillium to other genera of Trichocomaceae and studied in detail the phylogeny of the genus itself. In order to study these relationships, partial RPB1, RPB2 (RNA polymerase II genes), Tsr1 (putative ribosome biogenesis protein) and Cct8 (putative chaperonin complex component TCP-1) gene sequences were obtained. The Trichocomaceae are divided in three separate families: Aspergillaceae, Thermoascaceae and Trichocomaceae. The Aspergillaceae are characterised by the formation flask-shaped or cylindrical phialides, asci produced inside cleistothecia or surrounded by Hülle cells and mainly ascospores with a furrow or slit, while the Trichocomaceae are defined by the formation of lanceolate phialides, asci borne within a tuft or layer of loose hyphae and ascospores lacking a slit. Thermoascus and Paecilomyces, both members of Thermoascaceae, also form ascospores lacking a furrow or slit, but are differentiated from Trichocomaceae by the production of asci from croziers and their thermotolerant or thermophilic nature. Phylogenetic analysis shows that Penicillium is polyphyletic. The genus is re-defined and a monophyletic genus for both anamorphs and teleomorphs is created (Penicillium sensu stricto). The genera Thysanophora, Eupenicillium, Chromocleista, Hemicarpenteles and Torulomyces belong in Penicillium s. str. and new combinations for the species belonging to these genera are proposed. Analysis of Penicillium below genus rank revealed the presence of 25 clades. A new classification system including both anamorph and teleomorph species is proposed and these 25 clades are treated here as sections. An overview of species belonging to each section is presented. © 2011 CBS-KNAW Fungal Biodiversity Centre.

Mickelbart M.V.,Purdue University | Hasegawa P.M.,Purdue University | Bailey-Serres J.,University of California at Riverside | Bailey-Serres J.,University Utrecht
Nature Reviews Genetics | Year: 2015

Crop yield reduction as a consequence of increasingly severe climatic events threatens global food security. Genetic loci that ensure productivity in challenging environments exist within the germplasm of crops, their wild relatives and species that are adapted to extreme environments. Selective breeding for the combination of beneficial loci in germplasm has improved yields in diverse environments throughout the history of agriculture. An effective new paradigm is the targeted identification of specific genetic determinants of stress adaptation that have evolved in nature and their precise introgression into elite varieties. These loci are often associated with distinct regulation or function, duplication and/or neofunctionalization of genes that maintain plant homeostasis. © 2015 Macmillan Publishers Limited.

Christgen M.,Hannover Medical School | Derksen P.W.B.,University Utrecht
Breast Cancer Research | Year: 2015

Infiltrating lobular breast cancer (ILC) is the most common special breast cancer subtype. With mutational or epigenetic inactivation of the cell adhesion molecule E-cadherin (CDH1) being confined almost exclusively to ILC, this tumor entity stands out from all other types of breast cancers. The molecular basis of ILC is linked to loss of E-cadherin, as evidenced by human CDH1 germline mutations and conditional knockout mouse models. A better understanding of ILC beyond the level of descriptive studies depends on physiologically relevant and functional tools. This review provides a detailed overview on ILC models, including well-characterized cell lines, xenograft tumors and genetically engineered mouse models. We consider advantages and limitations of these models and evaluate their representativeness for human ILC. The still incompletely defined mechanisms by which loss of E-cadherin drives malignant transformation are discussed based on recent findings in these models. Moreover, candidate genes and signaling pathways potentially involved in ILC development and progression as well as anticancer drug and endocrine resistance are highlighted. © Christgen and Derksen licensee BioMed Central.

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

Van Dillen L.F.,Leiden University | Papies E.K.,University Utrecht | Hofmann W.,University of Chicago
Journal of Personality and Social Psychology | Year: 2013

The present research shows in 4 studies that cognitive load can reduce the impact of temptations on cognition and behavior and, thus, challenges the proposition that distraction always hampers selfregulation. Participants performed different speeded categorization tasks with pictures of attractive and neutral food items (Studies 1-3) and attractive and unattractive female faces (Study 4), while we assessed their reaction times as an indicator of selective attention (Studies 1, 3, and 4) or as an indicator of hedonic thoughts about food (Study 2). Cognitive load was manipulated by a concurrent digit span task. Results show that participants displayed greater attention to tempting stimuli (Studies 1, 3, and 4) and activated hedonic thoughts in response to palatable food (Study 2), but high cognitive load completely eliminated these effects. Moreover, cognitive load during the exposure to attractive food reduced food cravings (Study 1) and increased healthy food choices (Study 3). Finally, individual differences in sensitivity to food temptations (Study 3) and interest in alternative relationship partners (Study 4) predicted selective attention to attractive stimuli, but again, only when cognitive load was low. Our findings suggest that recognizing the tempting value of attractive stimuli in our living environment requires cognitive resources. This has the important implication that, contrary to traditional views, performing a concurrent demanding task may actually diminish the captivating power of temptation and thus facilitate self-regulation. © 2012 American Psychological Association.

de Jong G.,University Utrecht
Journal of Thermal Biology | Year: 2010

The temperature-size rule, the observation that most ectotherms grow faster but reach smaller size at higher temperatures, has defied a general explanation. Here, the temperature-size rule in Drosophila aldrichi and Drosophila buzzatii is investigated, using data on development rate and adult dry weight at nine temperatures. In both species the linear regression of dry weight on temperature is negative. The data are used to infer the potential for a description of temperature dependent size by biophysical modelling. The biophysical Sharpe-Schoolfield model for biological rates and its derivative model for adult weight yield detailed patterns for the two species' development rate, growth rate, and adult weight. These detailed patterns do not confirm the existence of a simple temperature-size rule. The species differ significantly in the values of the parameters in the Sharpe-Schoolfield model, and as a consequence in different patterns of weight over temperatures. The different parameters of the Sharpe-Schoolfield model play distinct roles in the patterns of weight over temperatures. A temperature-size rule as a negative regression of weight on temperature might statistically follow from an upper temperature boundary for growth that is lower than the upper temperature boundary for development; as such a relation between the upper temperature boundaries for growth and development would lead to a decrease of weight at high temperature. © 2009 Elsevier Ltd.

Boelen P.A.,University Utrecht | Carleton R.N.,University of Regina
Journal of Nervous and Mental Disease | Year: 2012

Intolerance of uncertainty (IU) has been found to be involved in several anxiety disorders, including generalized anxiety disorder and obsessive- compulsive disorder (OCD). Few studies have examined the role of IU in health anxiety (HA)/hypochondriacal concerns (HC). We conducted two studies exploring the associations between IU and HA/HC. The first study included undergraduates (n = 114) and indicated an association between IU and several HA/HC indices. When controlling for neuroticism, worry about illness was the single index of HA/HC that remained associated with IU. In the second study among bereaved adults (n = 126), IU was associated with one index of HA/HC but not when neuroticism and anxiety sensitivity were controlled. In both studies, IU was found to be more strongly associated with OCD symptoms and worry than with HA/HC. Copyright © 2012 by Lippincott Williams & Wilkins.

Recently reported risks of colorectal cancer (CRC) in inflammatory bowel disease (IBD) have been lower than those reported before 2000. The aim of this meta-analysis was to update the CRC risk of ulcerative and Crohn's colitis, investigate time trends, and identify high-risk modifiers. The MEDLINE search engine was used to identify all published cohort studies on CRC risk in IBD. Publications were critically appraised for study population, Crohn's disease localization, censoring for colectomy, and patient inclusion methods. The following data were extracted: total and stratified person-years at risk, number of observed CRC, number of expected CRC in background population, time period of inclusion, and geographical location. Pooled standardized incidence ratios and cumulative risks for 10-year disease intervals were calculated. Results were corrected for colectomy and isolated small bowel Crohn's disease. The pooled standardized incidence ratio of CRC in all patients with IBD in population-based studies was 1.7 (95% confidence interval [CI], 1.2-2.2 ). High-risk groups were patients with extensive colitis and an IBD diagnosis before age 30 with standardized incidence ratios of 6.4 (95% confidence interval, 2.4-17.5) and 7.2 (95% confidence interval, 2.9-17.8), respectively. Cumulative risks of CRC were 1%, 2%, and 5% after 10, 20, and >20 years of disease duration, respectively. The risk of CRC is increased in patients with IBD but not as high as previously reported and not in all patients. This decline could be the result of aged cohorts. The risk of CRC is significantly higher in patients with longer disease duration, extensive disease, and IBD diagnosis at young age.

Bakker S.,University Utrecht
Energy Policy | Year: 2010

The hydrogen hype of the last decade has passed and it is now seemingly substituted by the electric vehicle hype. A technological hype can have both positive as well as negative consequences. On the one hand it attracts sponsors for technology development but on the other hand the high expectations might result in disappointment and subsequent withdrawal of the sponsors. In this paper I ask the question to what extent the car industry has created the hype and how it has done so. The industry's role is studied through their prototyping activities and accompanying statements on market entry. I conclude that the car industry has indeed inflated the hype, especially through its public statements on market release after the turn of the millennium. Furthermore, it can be concluded that the industry has shown a double repertoire of both highly optimistic and more modest statements. It is possible that statements are used deliberately to serve the industry's interests whenever needed. Without neglecting the positive influence of technological hype on public policy and private funding for R&D efforts, more modest promises could serve the development of sustainable mobility better. For policy makers the challenge is to remain open to different options instead of following hypes and disappointments as they come and go. © 2010 Elsevier Ltd.

Stefano R.D.,Harvard - Smithsonian Center for Astrophysics | Voss R.,Radboud University Nijmegen | Claeys J.S.W.,University Utrecht
Astrophysical Journal Letters | Year: 2011

In the single-degenerate scenario for Type Ia supernovae (SNe Ia), a white dwarf (WD) must gain a significant amount of matter from a companion star. Because the accreted mass carries angular momentum, the WD is likely to achieve fast spin periods, which can increase the critical mass, M crit, needed for explosion. When M crit is higher than the maximum mass achieved by the WD, the central regions of the WD must spin down before it can explode. This introduces super-Chandrasekhar single-degenerate explosions, and a delay between the completion of mass gain and the time of the explosion. Matter ejected from the binary during mass transfer therefore has a chance to become diffuse, and the explosion occurs in a medium with a density similar to that of typical regions of the interstellar medium. Also, either by the end of the WD's mass increase or else by the time of explosion, the donor may exhaust its stellar envelope and become a WD. This alters, generally diminishing, explosion signatures related to the donor star. Nevertheless, the spin-up/spin-down model is highly predictive. Prior to explosion, progenitors can be super-M Ch WDs in either wide binaries with WD companions or cataclysmic variables. These systems can be discovered and studied through wide-field surveys. Post-explosion, the spin-up/spin-down model predicts a population of fast-moving WDs, low-mass stars, and even brown dwarfs. In addition, the spin-up/spin-down model provides a paradigm which may be able to explain both the similarities and the diversity observed among SNe Ia. © 2011. The American Astronomical Society. All rights reserved.

Schuurman J.-P.,St. Antonius Hospital | Rinkes I.H.M.B.,University Utrecht | Go P.M.N.Y.H.,St. Antonius Hospital
Annals of Surgery | Year: 2012

Objective: The aim of this study was to compare the outcome of the hemorrhoidal artery ligation procedure for hemorrhoidal disease with and without use of the provided Doppler transducer. Background: Hemorrhoidal artery ligation, known as HAL (hemorrhoidal artery ligation) or THD (transanal hemorrhoidal dearterialization) procedure, is a common treatment modality for hemorrhoidal disease in which a Doppler transducer is used to locate the supplying arteries that are subsequently ligated. It has been suggested that the use of the Doppler transducer does not contribute to the beneficial effect of these ligation procedures. Methods: The authors conducted a single-blinded randomized clinical trial and assigned a total of 82 patients with grade II and III hemorrhoidal disease to undergo either a HAL/THD procedure without use of the Doppler transducer (non-Doppler group, 40 patients) or a conventional HAL/THD procedure (Doppler group, 42 patients). Primary endpoint was improvement of self-reported clinical parameters after both 6 weeks and 6 months. This study is registered at trialregister.nl and carries the ID number: NTR2139. Results: After 6 weeks and 6 months in both the non-Doppler and the Doppler group, significant improvement was observed with regard to blood loss, pain, prolapse, and problems with defecation (P < 0.05). The improvement of symptoms between both groups did not differ significantly (P > 0.05), except for prolapse, which improved more in the non-Doppler group (P = 0.047). There were more complications and unscheduled postoperative events in the Doppler group (P < 0.0005). After 6 months, 31% of the patients in the non-Doppler group and 21% in the Doppler group reported completely complaint free (P = 0.313). Conclusions: The authors' findings confirm that the hemorrhoidal artery ligation procedure significantly reduces signs and symptoms of hemorrhoidal disease. The authors' data also show that the Doppler transducer does not contribute to this beneficial effect. © 2012 by Lippincott Williams & Wilkins.

Vermeulen L.,Center for Experimental Molecular Medicine | Vermeulen L.,University of Cambridge | Snippert H.J.,University Utrecht
Nature Reviews Cancer | Year: 2014

Intestinal stem cells (ISCs) and colorectal cancer (CRC) biology are tightly linked in many aspects. It is generally thought that ISCs are the cells of origin for a large proportion of CRCs and crucial ISC-associated signalling pathways are often affected in CRCs. Moreover, CRCs are thought to retain a cellular hierarchy that is reminiscent of the intestinal epithelium. Recent studies offer quantitative insights into the dynamics of ISC behaviour that govern homeostasis and thereby provide the necessary baseline parameters to begin to apply these analyses during the various stages of tumour development. © 2014 Macmillan Publishers Limited. All rights reserved.

Erkelens C.J.,University Utrecht
Journal of Vision | Year: 2013

One of the striking features of vision is that we can experience depth in two-dimensional images. Since the Renaissance, artists have used linear perspective to create sensations of depth and slant. What is not known is how the brain measures linear perspective information from the retinal image. Here, an experimental technique and geometric computations were used to isolate slant related to linear perspective from slant induced by other cues. Grid stimuli, designed to induce strong impressions of slant, were sufficiently simple to allow accurate predictions on the basis of numeric computations. Measurement of slant about the vertical axis as functions of slant depicted on the screen and slant of the screen relative to the observer showed that linear perspective explained 95% of the slant judgments. Precision and accuracy of the judgments suggest a neural substrate that is able to make highly accurate comparisons between orientations of lines imaged at different retinal locations. The neural basis of slant from the linear perspective has not yet been clarified. Long-range connections in V1, however, and cells in V2, V4, lateral occipital cortex, and caudal intraparietal sulcus have features that suggest an involvement in slant perception. © 2013 ARVO.

Castelle B.,CNRS Laboratory of Oceanic Environments and Paleo-environments (EPOC) | Ruessink B.G.,University Utrecht
Journal of Geophysical Research: Earth Surface | Year: 2011

We use a nonlinear morphodynamic model to demonstrate that time-varying forcing, in particular the time-varying angle of wave incidence, is crucial to the development of rip channels in terms of rip channel morphology, nonlinear behavior, longshore migration, and mean rip spacing. The time-varying angle of incidence leads to different mean rip spacings than the time-integrated time-invariant forcing and to systematically less developed bar and rip morphologies at more alongshore variable scales. This supports the common field observation of irregular and random alongshore rip spacings, and contrasts with the regular spacing predicted by existing time-invariant template, and instability models. Time-varying wave incidence also generally results in the onset of splitting of shoals and an increase in merging of rip channels. In addition, a time-varying angle of incidence with zero mean can drive a significant net alongshore migration of the rip channels. Abrupt changes in wave conditions are responsible for this net longshore migration through cumulative effects of the mismatch between wave conditions and bar and rip morphology orientation. Copyright 2011 by the American Geophysical Union.

Bijlsma J.W.J.,University Utrecht
Polskie Archiwum Medycyny Wewnetrznej | Year: 2010

Three important concepts have become standard of care in treating rheumatoid arthritis (RA): 1) development of new drugs: biologic agents; 2) treatment strategies: not an individual drug, but the timely combination of different drugs, given as a specific strategy; 3) treat to target: targeting treatment to the individual patient and adapting treatment when necessary. These concepts led to the development of the European League against Rheumatism recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs. Three so called overarching principles have been formulated, followed by 15 concrete recommendations for the management of RA. These 15 recommendations are described and discussed in this review, with some personal comments. An enormous gain in the development of RA has been achieved, and it is now time to consolidate that gain and make optimal treatment available for every RA patient in Europe. The guidelines described in this article will help physicians to actually do so. Copyright by Medycyna Praktyczna, 2010.

Approximately 25% of adults regularly experience heartburn, a symptom of gastro-oesophageal reflux disease (GORD). Most patients are treated empirically (without specific diagnostic evaluation e.g. endoscopy. Among patients who have an upper endoscopy, findings range from a normal appearance, mild erythema to severe oesophagitis with stricture formation. Patients without visible damage to the oesophagus have endoscopy negative reflux disease (ENRD). The pathogenesis of ENRD, and its response to treatment may differ from GORD with oesophagitis. Summarise, quantify and compare the efficacy of short-term use of proton pump inhibitors (PPI), H2-receptor antagonists (H2RA) and prokinetics in adults with GORD, treated empirically and in those with endoscopy negative reflux disease (ENRD). We searched MEDLINE (January 1966 to November 2008), EMBASE (January 1988 to November 2008), and EBMR in November 2008. Randomised controlled trials reporting symptomatic outcome after short-term treatment for GORD using proton pump inhibitors, H2-receptor antagonists or prokinetic agents. Participants had to be either from an empirical treatment group (no endoscopy used in treatment allocation) or from an endoscopy negative reflux disease group (no signs of erosive oesophagitis). Two authors independently assessed trial quality and extracted data. Thirty-two trials (9738 participants) were included: fifteen in the empirical treatment group, thirteen in the ENRD group and four in both. In empirical treatment of GORD the relative risk (RR) for heartburn remission (the primary efficacy variable) in placebo-controlled trials for PPI was 0.37 (two trials, 95% confidence interval (CI) 0.32 to 0.44), for H2RAs 0.77 (two trials, 95% CI 0.60 to 0.99) and for prokinetics 0.86 (one trial, 95% CI 0.73 to 1.01). In a direct comparison PPIs were more effective than H2RAs (seven trials, RR 0.66, 95% CI 0.60 to 0.73) and prokinetics (two trials, RR 0.53, 95% CI 0.32 to 0.87). In treatment of ENRD, the RR for heartburn remission for PPI versus placebo was 0.73 (eight trials, 95% CI 0.67 to 0.78) and for H2RA versus placebo was 0.84 (two trials, 95% CI 0.74 to 0.95). The RR for PPI versus H2RA was 0.78 (three trials, 95% CI 0.62 to 0.97) and for PPI versus prokinetic 0.72 (one trial, 95% CI 0.56 to 0.92). PPIs are more effective than H2RAs in relieving heartburn in patients with GORD who are treated empirically and in those with ENRD, although the magnitude of benefit is greater for those treated empirically.

Rodrigues J.P.G.L.M.,Stanford University | Rodrigues J.P.G.L.M.,University Utrecht | Levitt M.,Stanford University | Chopra G.,Stanford University
Nucleic Acids Research | Year: 2012

The KoBaMIN web server provides an online interface to a simple, consistent and computationally efficient protein structure refinement protocol based on minimization of a knowledge-based potential of mean force. The server can be used to refine either a single protein structure or an ensemble of proteins starting from their unrefined coordinates in PDB format. The refinement method is particularly fast and accurate due to the underlying knowledge-based potential derived from structures deposited in the PDB; as such, the energy function implicitly includes the effects of solvent and the crystal environment. Our server allows for an optional but recommended step that optimizes stereochemistry using the MESHI software. The KoBaMIN server also allows comparison of the refined structures with a provided reference structure to assess the changes brought about by the refinement protocol. The performance of KoBaMIN has been benchmarked widely on a large set of decoys, all models generated at the seventh worldwide experiments on critical assessment of techniques for protein structure prediction (CASP7) and it was also shown to produce top-ranking predictions in the refinement category at both CASP8 and CASP9, yielding consistently good results across a broad range of model quality values. The web server is fully functional and freely available at http://csb.stanford.edu/kobamin. © 2012 The Author(s).

Donega C.D.M.,University Utrecht
Chemical Society Reviews | Year: 2011

Colloidal heteronanocrystals (HNCs) can be regarded as solution-grown inorganic-organic hybrid nanomaterials, since they consist of inorganic nanoparticles that are coated with a layer of organic ligand molecules. The hybrid nature of these nanostructures provides great flexibility in engineering their physical and chemical properties. The inorganic particles are heterostructured, i.e. they comprise two (or more) different materials joined together, what gives them remarkable and unique properties that can be controlled by the composition, size and shape of each component of the HNC. The interaction between the inorganic component and the organic ligand molecules allows the size and shape of the HNCs to be controlled and gives rise to novel properties. Moreover, the organic surfactant layer opens up the possibility of surface chemistry manipulation, making it possible to tailor a number of properties. These features have turned colloidal HNCs into promising materials for a number of applications, spurring a growing interest on the investigation of their preparation and properties. This critical review provides an overview of recent developments in this rapidly expanding field, with emphasis on semiconductor HNCs (e.g., quantum dots and quantum rods). In addition to defining the state of the art and highlighting the key issues in the field, this review addresses the fundamental physical and chemical principles needed to understand the properties and preparation of colloidal HNCs (283 references). © 2011 The Royal Society of Chemistry.

Dai L.,University Utrecht
Water International | Year: 2015

Although formal law plays an increasing role in water governance in China, the political arena has a large influence upon it. This article seeks to provide a new perspective to understand water governance and what role formal laws play during China’s transition phase through the lens of the ‘Captain of the River’, a newly developed water governance instrument in China. © 2014, © 2014 International Water Resources Association.

Holwerda S.J.,University Utrecht
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

CTCF has it all. The transcription factor binds to tens of thousands of genomic sites, some tissue-specific, others ultra-conserved. It can act as a transcriptional activator, repressor and insulator, and it can pause transcription. CTCF binds at chromatin domain boundaries, at enhancers and gene promoters, and inside gene bodies. It can attract many other transcription factors to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNA polymerase II, and it forms chromatin loops. Yet, or perhaps therefore, CTCF's exact function at a given genomic site is unpredictable. It appears to be determined by the associated transcription factors, by the location of the binding site relative to the transcriptional start site of a gene, and by the site's engagement in chromatin loops with other CTCF-binding sites, enhancers or gene promoters. Here, we will discuss genome-wide features of CTCF binding events, as well as locus-specific functions of this remarkable transcription factor.

Cornelissen S.A.,University Utrecht
Journal of vascular surgery | Year: 2012

During endovascular abdominal aortic aneurysm repair (EVAR), blood is trapped in the aneurysm sac at the moment the endograft is deployed. It is generally assumed that this blood will coagulate and evolve into an organized thrombus. It is unknown whether this process always occurs, what its time span is, and how it influences aneurysm shrinkage. With magnetic resonance imaging (MRI), quantitative analysis of the aneurysm sac is possible in terms of endoleak volume as well as unorganized thrombus volume and organized thrombus volume. We investigated the presence of unorganized thrombus in nonshrinking aneurysms years after EVAR. Fourteen patients with a nonshrinking aneurysm without endoleak on computed tomography/computed tomography angiography underwent MRI with a blood pool agent (gadofosveset trisodium). Precontrast T1-, precontrast T2-, and postcontrast T1-weighted images (3 and 30 minutes after injection) were acquired and evaluated for the presence of endoleak. The aneurysm sac was segmented into endoleak, unorganized thrombus, and organized thrombus by interactively thresholding the differently weighted images. The classification was visualized in real-time as a color overlay on the MR images. The volumes of endoleak, unorganized thrombus, and organized thrombus were calculated. Median time after EVAR was 2 years (range, 1-8.2 years). The average aneurysm sac volume of the patients was 167 ± 107 mL (mean ± standard deviation). Nine patients had an endoleak on the postcontrast T1-w images 30 minutes after injection. On average, the aneurysm sac contained 78 ± 61 mL unorganized thrombus, which corresponded to 51 ± 21 volume-percentage, irrespective of the presence of an endoleak on the blood pool agent enhanced MRI images (independent t-test, P = .8). In our study group, half of the nonshrinking aneurysm sac contents consisted of unorganized thrombus years after EVAR. Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Bijlsma J.W.J.,University Utrecht
Rheumatology (United Kingdom) | Year: 2012

DMARDs aim to improve long-term prognosis of RA, as indicated by reduced progression of radiographic damage and maintenance of function. However, it may be more appropriate to consider disease-modifying strategies rather than drugs alone. Despite the challenges (e.g. lack of standard outcome measures, poor reporting of dose levels), a systematic review of 15 studies involving more than 1400 patients showed that glucocorticoid treatment for 1-2 years slowed radiographic progression compared with control treatment. Evidence for longer term disease-modifying benefits of glucocorticoids comes from individual studies with extended follow-up. In the Utrecht study, patients with early RA originally assigned to prednisone 10 mg/day for 2 years and then tapered off the therapy showed significantly less radiographic progression at follow-up after a further 3 years than patients originally assigned placebo, with no significant difference in the use of synthetic DMARD therapy. In the combination therapy in early RA (COBRA) study, patients with newly diagnosed RA treated with glucocorticoid (starting with 60 mg/day, quickly reduced to 7.5 mg/day for weeks 7-28 and subsequently stopped), MTX up to week 40 and SSZ showed significantly decreased radiographic progression compared with those treated with SSZ alone. The benefits of short-term combination therapy on disease progression were still apparent at 5-year and 11-year follow-up. In conclusion, there is clear evidence that treatment regimens including low-dose glucocorticoids given early in RA slow radiographic progression, meeting the definition of a DMARD. Furthermore, the evidence suggests that such treatment strategies favourably alter the disease course even after glucocorticoid discontinuation. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

Van Koten G.,University Utrecht
Topics in Organometallic Chemistry | Year: 2013

During the past 40 years, the monoanionic, tridentate ligand platform that has been named Pincer has established itself as a privileged ligand in a variety of research and application areas. Exciting discoveries with NCN and PCP-pincer metal complexes in the late 1970s created a firm basis for the tremendous development of the field. Some of the basic findings are summarized with emphasis on the organometallic aspects of the ECE-pincer metal system. © 2013 Springer-Verlag Berlin Heidelberg.

Speksnijder C.M.,University Utrecht
Journal of the American Podiatric Medical Association | Year: 2010

Background: The proximal insertional disorder of the plantar fascia is plantar fasciosis. Although plantar fasciosis is frequently seen by different health-care providers, indistinctness of etiology and pathogenesis is still present. A variety of interventions are seen in clinical practice. Taping constructions are frequently used for the treatment of plantar fasciosis. However, a systematic review assessing the efficacy of this therapy modality is not available. Methods: To assess the efficacy of a taping construction as an intervention or as part of an intervention in patients with plantar fasciosis on pain and disability, controlled trials were searched for in CINAHL, EMBASE, MEDLINE, Cochrane CENTRAL, and PEDro using a specific search strategy. The Physiotherapy Evidence Database scale was used to judge methodological quality. Clinical relevance was assessed with five specific questions. A best-evidence synthesis consisting of five levels of evidence was applied for qualitative analysis. Results: Five controlled trials met the inclusion criteria. Three trials with high methodological quality and of clinical relevance contributed to the best-evidence synthesis. The findings were strong evidence of pain improvement at 1-week follow-up, inconclusive results for change in level of disability in the short term, and indicative findings that the addition of taping on stretching exercises has a surplus value. Conclusions: There is limited evidence that taping can reduce pain in the short term in patients with plantar fasciosis. The effect on disability is inconclusive.

Grasseni C.,University Utrecht
Journal of Political Ecology | Year: 2014

This article presents a case study of the solidarity economy in Italy: the Italian G.A.S. - Gruppi di Acquisto Solidale, which I translate as Solidarity Purchase Groups. GAS are often conceptualized as "alternative food networks". Beyond this categorization, I highlight their novelty in relational, political, and ecological terms, with respect to their capacity to forge new partnerships between consumers and producers. Introducing an ethnographic study that I have developed in a recent monograph (Grasseni 2013), I dwell here in particular on how the solidarity economy is embedded in practice. I argue that gasistas' provisioning activism is something different to mere "ethical consumerism." Activists use the notion of "co-production" to describe their engagement as a concurrent rethinking of the social, economic, and ecological aspects of provisioning. Building also on a quantitative survey of the GAS movement in northern Italy, I pursue an ethnographic understanding of "co-production." I argue that producers and consumers in GAS networks "co-produce" both economic value and ecological knowledge, while re-embedding their provisioning practice in mutuality and relationality.

Zuiderbaan W.,University Utrecht
Journal of vision | Year: 2012

Antagonistic center-surround configurations are a central organizational principle of our visual system. In visual cortex, stimulation outside the classical receptive field can decrease neural activity and also decrease functional Magnetic Resonance Imaging (fMRI) signal amplitudes. Decreased fMRI amplitudes below baseline-0% contrast-are often referred to as "negative" responses. Using neural model-based fMRI data analyses, we can estimate the region of visual space to which each cortical location responds, i.e., the population receptive field (pRF). Current models of the pRF do not account for a center-surround organization or negative fMRI responses. Here, we extend the pRF model by adding surround suppression. Where the conventional model uses a circular symmetric Gaussian function to describe the pRF, the new model uses a circular symmetric difference-of-Gaussians (DoG) function. The DoG model allows the pRF analysis to capture fMRI signals below baseline and surround suppression. Comparing the fits of the models, an increased variance explained is found for the DoG model. This improvement was predominantly present in V1/2/3 and decreased in later visual areas. The improvement of the fits was particularly striking in the parts of the fMRI signal below baseline. Estimates for the surround size of the pRF show an increase with eccentricity and over visual areas V1/2/3. For the suppression index, which is based on the ratio between the volumes of both Gaussians, we show a decrease over visual areas V1 and V2. Using non-invasive fMRI techniques, this method gives the possibility to examine assumptions about center-surround receptive fields in human subjects.

Markus H.S.,University of Cambridge | van der Worp H.B.,University Utrecht | Rothwell P.M.,University of Oxford
The Lancet Neurology | Year: 2013

A fifth of all strokes and transient ischaemic attacks occur in the posterior circulation arterial territory. Diagnosis can be challenging, in part because of substantial overlap in symptoms and signs with ischaemia in the anterior circulation. Improved methods of non-invasive imaging of the vertebrobasilar arterial tree have been used in recent prospective follow-up studies, which have shown a high risk of early recurrent stroke, particularly when there is associated vertebrobasilar stenosis. This finding emphasises the importance of urgent secondary prevention, and the role of stenting for vertebral stenosis is being investigated. © 2013 Elsevier Ltd.

Middelburg J.J.,University Utrecht
Geophysical Research Letters | Year: 2011

Organic matter recycling releases ammonium, and under anoxic conditions, other reduced metabolites that can be used by chemoautotrophs to fix inorganic carbon. Here I present an estimate for the global rate of oceanic carbon fixation by chemoautotrophs (0.77 Pg C y -1). Near-shore and shelf sediments (0.29 Pg C y -1) and nitrifiers in the euphotic zone (0.29 Pg C y -1) and the dark ocean (0.11 Pg C y -1) are the most important contributors. This input of new organic carbon to the ocean is similar to that supplied by world-rivers and eventually buried in oceanic sediments. Chemoautotrophy driven by organic carbon recycling is globally more important than that fuelled by water-rock interactions and hydrothermal vent systems. Copyright © 2011 by the American Geophysical Union.

Jacobs J.W.G.,University Utrecht
Rheumatology (United Kingdom) | Year: 2012

Optimizing the use of key non-biologic drugs (MTX, prednisone) may prolong disease control, thereby delaying the need for costly biologic therapies. A number of lessons about the optimal use of therapy emerge from clinical studies. Clinical outcomes with non-biologic treatments, given early in the course of the disease, are as good as with biologic treatments. Combinations of treatments are usually required to achieve rapid and sustained remission. MTX remains an important anchor drug for RA therapy and should be given as soon as the diagnosis is made. As early disease control is important, the dose of MTX should be escalated rapidly to adequate levels. Tolerability of MTX is generally good relative to that of other alternative treatments. MTX (s.c.) may be considered if the response to oral MTX is inadequate or MTX is poorly tolerated. In addition to suppressing signs and symptoms of RA, glucocorticoids appear to have disease-modifying effects, at least in early RA. The disease-modifying effects of glucocorticoids probably persist after discontinuation of therapy. The risk of adverse effects of low-dose glucocorticoids is often overestimated. Administration of low-dose glucocorticoids in accordance with physiological circadian rhythms may bring efficacy and safety benefits. As a case in point, the CAMERA (Computer Assisted Management in Early Rheumatoid Arthritis) II study applied these lessons and has clearly shown the benefits of optimizing MTX and prednisone therapy. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

Oome S.,Center for Biosystems Genomics | Van Den Ackerveken G.,University Utrecht
Molecular Plant-Microbe Interactions | Year: 2014

Nep1-like proteins (NLP) are best known for their cytotoxic activity in dicot plants. NLP are taxonomically widespread among microbes with very different lifestyles. To learn more about this enigmatic protein family, we analyzed more than 500 available NLP protein sequences from fungi, oomycetes, and bacteria. Phylogenetic clustering showed that, besides the previously documented two types, an additional, more divergent, third NLP type could be distinguished. By closely examining the three NLP types, we identified a noncytotoxic subgroup of type 1 NLP (designated type 1a), which have substitutions in amino acids making up a cation-binding pocket that is required for cytotoxicity. Type 2 NLP were found to contain a putative calcium-binding motif, which was shown to be required for cytotoxicity. Members of both type 1 and type 2 NLP were found to possess additional cysteine residues that, based on their predicted proximity, make up potential disulfide bridges that could provide additional stability to these secreted proteins. Type 1 and type 2 NLP, although both cytotoxic to plant cells, differ in their ability to induce necrosis when artificially targeted to different cellular compartments in planta, suggesting they have different mechanisms of cytotoxicity. © 2014 The American Phytopathological Society.

Poot M.,University Utrecht
Molecular Syndromology | Year: 2015

Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward. © 2015 S. Karger AG, Basel.

Joels M.,University Utrecht
Psychoneuroendocrinology | Year: 2011

Exposure to stressful situations activates two hormonal systems that help the organism to adapt. On the one hand stress hormones achieve adaptation by affecting peripheral organs, on the other hand by altering brain function such that appropriate behavioral strategies are selected for optimal performance at the short term, while relevant information is stored for reference in the future. In this chapter we describe how cellular effects induced by stress hormones - in particular by glucocorticoids - may contribute to the behavioral outcome after a single stressor. In addition to situations of acute stress, chronic uncontrollable and unpredictable stress also exerts profound effects on structure and function of limbic neurons. The impact of chronic stress is not a mere cumulative effect of what is seen after acute stress exposure. Dendritic trees are expanded in some regions but reduced in others. In general, cells are exposed to a higher calcium load upon depolarization, but show attenuated responses to serotonin. Synaptic strengthening is largely impaired. In this viewpoint we speculate how cellular effects after chronic stress may be maladaptive and could contribute to the development of psychopathology in genetically vulnerable individuals. © 2010 Elsevier Ltd.

Geraerts R.,University Utrecht
Proceedings - IEEE International Conference on Robotics and Automation | Year: 2010

A central problem of applications dealing with virtual environments is planning a collision-free path for a character. Since environments and their characters are growing more realistic, a character's path needs to be visually convincing, meaning that the path is smooth, short, has some clearance to the obstacles in the environment, and avoids other characters. Up to now, it has proved difficult to meet these criteria simultaneously and in real-time. We introduce a new data structure, i.e. the Explicit Corridor Map, which allows creating the shortest path, the path that has the largest amount of clearance, or any path in between. Besides being efficient, the corresponding algorithms are surprisingly simple. By integrating the data structure and algorithms into the Indicative Route Method, we show that visually convincing short paths can be obtained in real-time. ©2010 IEEE.

Van Beijeren H.,University Utrecht
Physical Review Letters | Year: 2012

Anomalous transport in one-dimensional translation invariant Hamiltonian systems with short range interactions is shown to belong in general to the Kardar-Parisi-Zhang universality class. Exact asymptotic forms for density-density and current-current time correlation functions and their Fourier transforms are given in terms of the Prähofer-Spohn scaling functions, obtained from their exact solution for the polynuclear growth model. The exponents of corrections to scaling are found as well, but not so the coefficients. Mode coupling theories developed previously are found to be adequate for weakly nonlinear chains but in need of corrections for strongly anharmonic interparticle potentials. A simple condition is given under which Kardar-Parisi-Zhang behavior does not apply, sound attenuation is only logarithmically superdiffusive, and heat conduction is more strongly superdiffusive than under Kardar-Parisi-Zhang behavior. © 2012 American Physical Society.

Schauer R.,University of Kiel | Kamerling J.P.,University Utrecht
ChemBioChem | Year: 2011

trans-Sialidases constitute a special group of the sialidase family. They occur in some trypanosome species and, in a unique reversible reaction, transfer sialic acids from one glycosidic linkage with galactose (donor) to another galactose (acceptor), to form (α2-3)-sialyl linkages. Trypanosomes cause such devastating human diseases as Chagas disease in South America (Trypanosoma cruzi) or sleeping sickness in Africa (Trypanosoma brucei). The trans-sialidases strongly contribute to the pathogenicity of the trypanosomes by scavenging sialic acids from the host or blood meal to coat the parasite surface; this aids their survival strategy in the insect's intestine, and in the blood circulation or cells of the host, and serves to compromise the immune system of the human or animal host. American and African trypanosomes express trans-sialidases at different stages of their vector/host development. They are transmitted to humans by insect vectors (tsetse fly or other insect "bug" species). trans-Sialidase activity with varying linkage specificity has also been found in a few bacteria species and in human serum. trans-Sialidases are of increasing practical importance for the chemo-enzymatic synthesis of sialylated glycans. The search for appropriate inhibitors of trans-sialidases and vaccination strategies is intensifying, as less toxic medicaments for the treatment of these widespread and often chronic tropical diseases are required. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Van Binsbergen E.,University Utrecht
Cytogenetic and Genome Research | Year: 2011

Array-based methods have enabled the detection of many genomic gains and losses. These are stated as copy number variants (CNVs) and comprise up to 13% of the human genome. Based on their breakpoints and modes of formation CNVs are termed recurrent or nonrecurrent. Recurrent CNVs are flanked by low copy repeats and are of a fixed size. They arise as a result of misalignment during meiosis by a mechanism named nonallelic homologous recombination. Several of such recurrent CNVs have been linked to human diseases. Nonrecurrent CNVs, which are not flanked by low copy repeats, are of variable size and may arise via mechanisms like nonhomologous end joining and replication-based mechanisms described by the fork stalling and template switching and microhomology-mediated break-induced replication models. It is becoming clear that most disease-causing CNVs are nonrecurrent and generally arise via replication-based mechanisms. Furthermore, it is now appreciated that genomic features other than low copy repeats play a role in the formation of nonrecurrent CNVs. This review will discuss the different mechanisms of CNV formation and how high resolution analyses of CNV breakpoints have added to our knowledge of their precise structure. Copyright © 2011 S. Karger AG, Basel.

This article proposes a further conceptualization of ethnic and racial identity (ERI) as a fundamental topic in developmental research. Adding to important recent efforts to conceptually integrate and synthesize this field, it is argued that ERI research will be enhanced by more fully considering the implications of the social identity approach. These implications include (a) the conceptualization of social identity, (b) the importance of identity motives, (c) systematic ways for theorizing and examining the critical role of situational and societal contexts, and (d) a dynamic model of the relation between ERI and context. These implications have not been fully considered in the developmental literature but offer important possibilities for moving the field forward in new directions. © 2016 The Society for Research in Child Development, Inc.

Van Nostrum C.F.,University Utrecht
Soft Matter | Year: 2011

Polymeric micelles constitute an important class of nanomaterials that are highly attractive for pharmaceutical applications. The hydrophobic core of the micelles can be loaded with poorly water soluble drugs, while the shell of the micelles provides colloidal stability in vitro and in vivo. In recent years, covalent cross-linking of micelles is attracting increasing attention, because in vitro data show that it can prevent the self-assembled micelles from dissociation, can modulate drug release and may provide tools for triggered release. This paper reviews the methods used to cross-link either the core or the shell of the micelles, and focuses on drug delivery applications of cross-linked micelles. Whereas non-cross-linked micelles generally do not improve pharmacokinetics of encapsulated drugs when compared to common drug formulations, recent in vivo data show that cross-linking provides dramatic improvements in both pharmacokinetics and biodistribution of the micelles, and that drugs can fully benefit from that when they are covalently linked to the micelles. Although the field is still in its infancy, the latest results promise a bright future of cross-linked micelles for drug delivery and/or diagnostic applications. © The Royal Society of Chemistry 2011.

Leogrande E.,University Utrecht
Nuclear Physics A | Year: 2014

Two-particle angular correlations between unidentified charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions. The correlations are expressed as associated yield per trigger particle. Near-side and away-side per-trigger yields are studied as a function of multiplicity class. From the near-side and away-side yields, the uncorrelated seeds are calculated, which are proportional to the number of multiple parton interactions (MPIs) in Pythia. The uncorrelated seeds are also studied as a function of the number of binary collisions Ncoll from Glauber model in order to relate them to the number of hard scatterings. © 2014 CERN.

Pierik R.,University Utrecht | De Wit M.,University of Lausanne
Journal of Experimental Botany | Year: 2014

Plants compete with neighbouring vegetation for limited resources. In competition for light, plants adjust their architecture to bring the leaves higher in the vegetation where more light is available than in the lower strata. These architectural responses include accelerated elongation of the hypocotyl, internodes and petioles, upward leaf movement (hyponasty), and reduced shoot branching and are collectively referred to as the shade avoidance syndrome. This review discusses various cues that plants use to detect the presence and proximity of neighbouring competitors and respond to with the shade avoidance syndrome. These cues include light quality and quantity signals, mechanical stimulation, and plant-emitted volatile chemicals. We will outline current knowledge about each of these signals individually and discuss their possible interactions. In conclusion, we will make a case for a whole-plant, ecophysiology approach to identify the relative importance of the various neighbour detection cues and their possible interactions in determining plant performance during competition. © 2014 The Author.

De Graaf-Roelfsema E.,University Utrecht
Veterinary Journal | Year: 2014

One of the principal components of equine metabolic syndrome (EMS) is hyperinsulinaemia combined with insulin resistance. It has long been known that hyperinsulinaemia occurs after the development of insulin resistance. But it is also known that hyperinsulinaemia itself can induce insulin resistance and obesity and might play a key role in the development of metabolic syndrome. This review focuses on the physiology of glucose and insulin metabolism and the pathophysiological mechanisms in glucose homeostasis in the horse (compared with what is already known in humans) in order to gain insight into the pathophysiological principles underlying EMS. The review summarizes new insights on the oral uptake of glucose by the gut and the enteroinsular axis, the role of diet in incretin hormone and postprandial insulin responses, the handling of glucose by the liver, muscle and fat tissue, and the production and secretion of insulin by the pancreas under healthy and disrupted glucose homeostatic conditions in horses. © 2013 Elsevier Ltd.

Ketting R.F.,University Utrecht
Advances in Experimental Medicine and Biology | Year: 2010

During the last decade of the 20th century a totally novel way of gene regulation was revealed. Findings that at frst glance appeared freak features of plants or C. elegans turned out to be mechanistically related and deeply conserved throughout evolution. this important insight was primed by the landmark discovery of RNA interference, or RNAi, in 1998. This work started an entire novel feld of research, now usually referred to as RNA silencing. the common denominator of the phenomena grouped in this feld are small RNA molecules, often derived from double stranded RNA precursors, that in association with proteins of the so-called Argonaute family, are capable of directing a variety of effector complexes to cognate RNA and/or DNA molecules. one of these processes is now widely known as microRNA-mediated gene silencing and I will provide a partially historical framework of the many steps that have led to our current understanding of micro RNA biogenesis and function. this chapter is meant to provide a general overview of the various processes involved. for a comprehensive description of current models, I refer interested readers to the reviews and primary literature references provided in this chapter and to the further contents of this book. © 2010 Landes Bioscience and Springer Science+Business Media, LLC.

Leusen J.H.W.,University Utrecht
EMBO Reports | Year: 2012

The 'Immunoreceptors' meeting took place in July 2012 in beautiful Snowmass Village in Colorado, USA. At an altitude of more than two kilometres, researchers and clinicians discussed the molecular aspects of immunoreceptors, ranging from B- and T-cell receptors, to complement and Fc receptors. © 2012 European Molecular Biology Organization.

Roelofs G.-J.,University Utrecht
Atmospheric Chemistry and Physics | Year: 2013

The dominant removal mechanism of soluble aerosol is wet deposition. The atmospheric lifetime of aerosol, relevant for aerosol radiative forcing, is therefore coupled to the atmospheric cycling time of water vapor. This study investigates the coupling between water vapor and aerosol lifetimes in a well-mixed atmosphere. Based on a steady-state study by Pruppacher and Jaenicke (1995) we describe the coupling in terms of the processing efficiency of air by clouds and the efficiencies of water vapor condensation, of aerosol activation, and of the transfer from cloud water to precipitation. We extend this to expressions for the temperature responses of the water vapor and aerosol lifetimes. Previous climate model results (Held and Soden, 2006) suggest a water vapor lifetime temperature response of +5.3 ± 2.0% K-1. This can be used as a first guess for the aerosol lifetime temperature response, but temperature sensitivities of the aerosol lifetime simulated in recent aerosol-climate model studies extend beyond this range and include negative values. This indicates that other influences probably have a larger impact on the computed aerosol lifetime than its temperature response, more specifically changes in the spatial distributions of aerosol (precursor) emissions and precipitation patterns, and changes in the activation efficiency of aerosol. These are not quantitatively evaluated in this study but we present suggestions for model experiments that may help to understand and quantify the different factors that determine the aerosol atmospheric lifetime. © Author(s) 2013.

Oerlemans J.,University Utrecht
Cryosphere | Year: 2013

In this note, the total dissipative melting in temperate glaciers is studied. The analysis is based on the notion that the dissipation is determined by the loss of potential energy due to the downward motion of mass (ice, snow, meltwater and rain). A mathematical formulation of the dissipation is developed and applied to a simple glacier geometry. In the next step, meltwater production resulting from enhanced ice motion during a glacier surge is calculated. The amount of melt energy available follows directly from the lowering of the centre of gravity of the glacier. To illustrate the concept, schematic calculations are presented for a number of glaciers with different geometric characteristics. Typical dissipative melt rates, expressed as water-layer depth averaged over the glacier, range from a few centimetres per year for smaller glaciers to half a metre per year for Franz Josef Glacier, one of the most active glaciers in the world (in terms of mass turnover). The total generation of meltwater during a surge is typically half a metre. For Variegated Glacier a value of 70 cm is found, for Kongsvegen 20 cm. These values refer to water layer depth averaged over the entire glacier. The melt rate depends on the duration of the surge. It is generally an order of magnitude greater than water production by 'normal' dissipation. On the other hand, the additional basal melt rate during a surge is comparable in magnitude with the water input from meltwater and precipitation. This suggests that enhanced melting during a surge does not grossly change the total water budget of a glacier. Basal water generated by enhanced sliding is an important ingredient in many theories of glacier surges. It provides a positive feedback mechanism that actually makes the surge happen. The results found here suggest that this can only work if water generated by enhanced sliding accumulates in a part of the glacier base where surface meltwater and rain have no or very limited access. This finding seems compatible with the fact that, on many glaciers, surges are initiated in the lower accumulation zone. © 2013 Author(s).

Yarde F.,University Utrecht
Human reproduction (Oxford, England) | Year: 2013

Is there an association between acute prenatal famine exposure or birthweight and subsequent reproductive performance and age at menopause? No association was found between intrauterine famine exposure and reproductive performance, but survival analysis showed that women exposed in utero were 24% more likely to experience menopause at any age. Associations between prenatal famine and subsequent reproductive performance have been examined previously with inconsistent results. Evidence for the effects of famine exposure on age at natural menopause is limited to one study of post-natal exposure. This cohort study included men and women born around the time of the Dutch famine of 1944-1945. The study participants (n = 1070) underwent standardized interviews on reproductive parameters at a mean age of 59 years. The participants were grouped as men and women with prenatal famine exposure (n = 407), their same-sex siblings (family controls, n = 319) or other men and women born before or after the famine period (time controls, n = 344). Associations of famine exposure with reproductive performance and menopause were analysed using logistic regression and survival analysis with competing risk, after controlling for family clustering. Gestational famine exposure was not associated with nulliparity, age at birth of first child, difficulties conceiving or pregnancy outcome (all P> 0.05) in men or women. At any given age, women were more likely to experience menopause after gestational exposure to famine (hazard ratio 1.24; 95% CI 1.03, 1.51). The association was not attenuated with an additional control for a woman's birthweight. In this study, there was no association between birthweight and age at menopause after adjustment for gestational famine exposure. Age at menopause was self-reported and assessed retrospectively. The study power to examine associations with specific gestational periods of famine exposure and reproductive function was limited. Our findings support previous results that prenatal famine exposure is not related to reproductive performance in adult life. However, natural menopause occurs earlier after prenatal famine exposure, suggesting that early life events can affect organ function even at the ovarian level. This study was funded by the NHLBI/NIH (R01 HL-067914). Not applicable.

Dobrin A.,University Utrecht
Nuclear Physics A | Year: 2014

The elliptic flow coefficient, v2, is presented for π±, K±, KS0, p+p, ϕ, Λ+Λ, E-+E+, Ω-+Ω+ in Pb-Pb collisions at √sNN=2.76 TeV with the ALICE detector. Results obtained with the scalar product method are reported as a function of transverse momentum, pT, out to pT=6 GeV/c at different collision centralities. For pT<2 GeV/c, v2 exhibits a particle mass dependence. Particles tend to group into mesons and baryons for pT>3 GeV/c. Deviations from the number of constituent quark scaling at the level of ±20% are found for pT>2-3 GeV/c. The results are compared to hydrodynamic calculations coupled to a hadronic cascade model. © 2014 CERN.

Zhou Y.,Nikhef | Zhou Y.,University Utrecht
Nuclear Physics A | Year: 2014

Anisotropic azimuthal correlations are used to probe the properties and the evolution of the system created in heavy-ion collisions. Two-particle azimuthal correlations are used in the searches of pT dependent fluctuations of flow angle and magnitude, measured with the ALICE detector. The comparison of hydrodynamic calculations with measurements are also presented in this contribution. © 2014 The Authors.

Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that exert neurodevelopmental and neurobehavioral effects in vivo in humans and animals. Acute in vitro neurotoxic effects include changes in cell viability, oxidative stress, and basal intracellular calcium levels. Though these acute cellular effects could partly explain the observed in vivo effects, other mechanisms, such as effects on calcium influx and neurotransmitter receptor function, likely contribute to the disturbance in neurotransmission. This concise review combines in vitro data on cell viability, oxidative stress and basal calcium levels with recent data that clearly demonstrate that (hydroxylated) PCBs and (hydroxylated) PBDEs can exert acute effects on voltage-gated Ca2+ channels as well as on excitatory and inhibitory neurotransmitter receptors in vitro. These novel mechanisms of action are shared by NDL-PCBs, OH-PBDEs, and some other persistent organic pollutants, such as tetrabromobisphenol-A, and could have profound effects on neurodevelopment, neurotransmission, and neurobehavior in vivo. © 2013 Springer-Verlag Berlin Heidelberg.

Van Dinter M.,University Utrecht
Geologie en Mijnbouw/Netherlands Journal of Geosciences | Year: 2013

From the 40s A.D. onwards a dense military system was established in the Lower Rhine delta in the Netherlands. Long since, it is questioned why this system was established in a wetland area and even turned into the northwest frontier of the Roman Empire, the Limes. A new detailed palaeogeographical map, based on a digital elevation model (LIDAR), soil maps and excavation results, was constructed. This reconstruction provides insight and understanding of the interactions between the natural environment in this part of the delta on the one hand and the establishment of this part of the Limes along the Old Rhine between Utrecht and Katwijk on the other. This study shows that the distinctive landscape of the western Rhine-Meuse delta, with an exceptionally large number of tributaries, determined the spatial pattern of the military structures. All forts (castella) were erected on the southern natural levees of the river Rhine, directly alongside the river, regardless of height and composition of the subsoil and alongside or opposite routes that provided natural access to the river. We conclude that their aim was to guard all waterways that gave access to the river Rhine from the Germanic residential areas further north and from/to the Meuse tributary further south in the delta. In addition, a system of small military structures, mostly watchtowers, was erected between the forts to watch over the river Rhine and its river traffic. Furthermore, at least two canals were established to create shorter and safely navigable transport routes to the river Meuse. At first, this integrated system of castella and watchtowers probably aimed to protect against Germanic invasions and to create a safe corridor for transport and built up of army supplies for the British invasion in 43 A.D. Only later on, probably by the end of the first century, this corridor turned into a frontier zone.

Hol E.M.,University Utrecht | Hol E.M.,An institute of the Royal Netherlands Academy of Arts and science | Hol E.M.,University of Amsterdam | Pekny M.,Gothenburg University | And 2 more authors.
Current Opinion in Cell Biology | Year: 2015

Glial fibrillary acidic protein (GFAP) is the hallmark intermediate filament (IF; also known as nanofilament) protein in astrocytes, a main type of glial cells in the central nervous system (CNS). Astrocytes have a range of control and homeostatic functions in health and disease. Astrocytes assume a reactive phenotype in acute CNS trauma, ischemia, and in neurodegenerative diseases. This coincides with an upregulation and rearrangement of the IFs, which form a highly complex system composed of GFAP (10 isoforms), vimentin, synemin, and nestin. We begin to unravel the function of the IF system of astrocytes and in this review we discuss its role as an important crisis-command center coordinating cell responses in situations connected to cellular stress, which is a central component of many neurological diseases. © 2015 Elsevier Ltd.

Storek J.,University of Calgary | Mohty M.,University Pierre and Marie Curie | Boelens J.J.,University Utrecht
Biology of Blood and Marrow Transplantation | Year: 2015

Anti-T cell globulin (ATG) is polyclonal IgG from rabbits immunized with human thymocytes or a human T cell line. Prophylaxis using ATG infused with conditioning for adult marrow or blood stem cell transplantation reduces both acute and chronic graft-versus-host disease (GVHD). However, ATG is not or minimally efficacious in steroid refractory GVHD treatment. Regarding preemptive therapy, ATG is promising; however, further work is needed on establishing adequate biomarkers to be used as triggers for preemptive therapy before it can be used routinely. Relapse is not increased by ATG, except possibly in the setting of reduced-intensity conditioning. Infections are probably increased when using high but not low-dose ATG, except for Epstein-Barr virus-driven post-transplantation lymphoproliferative disorder, which may be increased even with low-dose ATG. Survival is not improved with ATG; however, survival free of immunosuppressive therapy is improved. Pharmacokinetics of ATG are highly variable, resulting in highly variable areas under the time-concentration curves. Optimized dosing of ATG might improve transplantation outcomes. In conclusion, ATG reduces GVHD and, thus, may improve quality of life, without compromising survival. © 2015 American Society for Blood and Marrow Transplantation.

Modgil S.,Kings College London | Prakken H.,University Utrecht
Argument and Computation | Year: 2014

This article gives a tutorial introduction to the ASPIC+ framework for structured argumentation. The philosophical and conceptual underpinnings of ASPIC+ are discussed, the main definitions are illustrated with examples and several ways are discussed to instantiate the framework and to reconstruct other approaches as special cases of the framework. The ASPIC+ framework is based on two ideas: the first is that conflicts between arguments are often resolved with explicit preferences, and the second is that arguments are built with two kinds of inference rules: strict, or deductive rules, whose premises guarantee their conclusion, and defeasible rules, whose premises only create a presumption in favour of their conclusion. Accordingly, arguments can in ASPIC+ be attacked in three ways: on their uncertain premises, or on their defeasible inferences, or on the conclusions of their defeasible inferences. ASPIC+ is not a system but a framework for specifying systems. A main objective of the study of the ASPIC+ framework is to identify conditions under which instantiations of the framework satisfy logical consistency and closure properties. © 2014 Taylor and Francis.

'T Hooft G.,University Utrecht
Foundations of Physics | Year: 2016

Hawking particles emitted by a black hole are usually found to have thermal spectra, if not exactly, then by a very good approximation. Here, we argue differently. It was discovered that spherical partial waves of in-going and out-going matter can be described by unitary evolution operators independently, which allows for studies of space-time properties that were not possible before. Unitarity dictates space-time, as seen by a distant observer, to be topologically non-trivial. Consequently, Hawking particles are only locally thermal, but globally not: we explain why Hawking particles emerging from one hemisphere of a black hole must be 100 % entangled with the Hawking particles emerging from the other hemisphere. This produces exclusively pure quantum states evolving in a unitary manner, and removes the interior region for the outside observer, while it still completely agrees locally with the laws of general relativity. Unitarity is a starting point; no other assumptions are made. Region I and the diametrically opposite region II of the Penrose diagram represent antipodal points in a PT or CPT relation, as was suggested before. On the horizon itself, antipodal points are identified. A candidate instanton is proposed to describe the formation and evaporation of virtual black holes of the type described here. © 2016 The Author(s)

Wosten H.A.B.,University Utrecht | Scholtmeijer K.,Wageningen University
Applied Microbiology and Biotechnology | Year: 2015

Hydrophobins are proteins exclusively produced by filamentous fungi. They self-assemble at hydrophilic-hydrophobic interfaces into an amphipathic film. This protein film renders hydrophobic surfaces of gas bubbles, liquids, or solid materials wettable, while hydrophilic surfaces can be turned hydrophobic. These properties, among others, make hydrophobins of interest for medical and technical applications. For instance, hydrophobins can be used to disperse hydrophobic materials; to stabilize foam in food products; and to immobilize enzymes, peptides, antibodies, cells, and anorganic molecules on surfaces. At the same time, they may be used to prevent binding of molecules. Furthermore, hydrophobins have therapeutic value as immunomodulators and can been used to produce recombinant proteins. © 2015, Springer-Verlag Berlin Heidelberg.

Sark W.G.J.H.M.V.,University Utrecht
Applied Energy | Year: 2011

Outdoor performance of photovoltaic (PV) modules suffers from elevated temperatures. Conversion efficiency losses of up to about 25% can result, depending on the type of integration of the modules in the roof. Cooling of modules would therefore enhance annual PV performance. Instead of module cooling we propose to use the thermal waste by attaching thermoelectric (TE) converters to the back of PV modules, to form a PV-TE hybrid module. Due to the temperature difference over the TE converter additional electricity can be generated. Employing present day thermoelectric materials with typical figure of merits (Z) of 0.004K-1 at 300K may lead to efficiency enhancements of up to 23% for roof integrated PV-TE modules, as is calculated by means of an idealized model. The annual energy yield would increase by 14.7-11%, for two annual irradiance and temperature profiles studied, i.e., for Malaga, Spain, and Utrecht, the Netherlands, respectively. As new TE materials are being developed, efficiency enhancements of up to 50% and annual energy yield increases of up to 24.9% may be achievable. The developed idealized model, however, is judged to overestimate the results by about 10% for practical PV-TE hybrids. © 2011 Elsevier Ltd.

Braun K.P.J.,University Utrecht | Schmidt D.,Epilepsy Research Group
Current Opinion in Neurology | Year: 2014

Purpose of review: Based on the available evidence, we aim to balance risks and benefits of antiepileptic drug (AED) withdrawal in medically and surgically treated adults and children who achieved remission. We summarize risks and predictors of seizure relapse after AED withdrawal and chances of not regaining seizure freedom. Finally, we discuss how AED discontinuation can inform us on the natural course of the epileptic disorder. Recent findings: In medically treated patients, the risk of recurrence after AED withdrawal is increased until 2 years after withdrawal, although long-term seizure outcomes seem to be unaffected by drug policies. Most relapses occur during the first year after withdrawal. Several predictors of postwithdrawal relapse have been identified. The risk of developing uncontrollable epilepsy following withdrawal is less than one in five. Whether AED withdrawal after epilepsy surgery contributes to seizure outcome has never been studied in a randomized controlled manner. Recent studies suggested that AED reduction merely unmasks incomplete surgical success. The risk of not regaining seizure freedom after postoperative relapse is around 30% and probably not affected by AED reduction. Timing of AED discontinuation does not influence eventual seizure outcomes. Summary: There is no proof that AED withdrawal itself negatively affects long-term seizure outcomes in patients who became seizure-free under AED treatment or after epilepsy surgery. AED discontinuation unveils the natural history of the epilepsy in medically treated patients, and the completeness of resection of the epileptogenic network in patients who underwent epilepsy surgery.

Vermeulen M.,University Utrecht
Methods in Enzymology | Year: 2012

Posttranslational modifications (PTMs) on core histones regulate essential processes inside the nucleus such as transcription, replication, and DNA repair. An important function of histone PTMs is the recruitment or stabilization of chromatin-modifying proteins, which are also called chromatin "readers." We have developed a generic SILAC-based peptide pull-down approach to identify such readers for histone PTMs in an unbiased manner. In this chapter, the workflow behind this method will be presented in detail. © 2012 Elsevier Inc. All rights reserved.

Burbach J.P.H.,University Utrecht
Methods in Molecular Biology | Year: 2011

We know neuropeptides now for over 40 years as chemical signals in the brain. The discovery of neuropeptides is founded on groundbreaking research in physiology, endocrinology, and biochemistry during the last century and has been built on three seminal notions: (1) peptide hormones are chemical signals in the endocrine system; (2) neurosecretion of peptides is a general principle in the nervous system; and (3) the nervous system is responsive to peptide signals. These historical lines have contributed to how neuropeptides can be defined today: "Neuropeptides are small proteinaceous substances produced and released by neurons through the regulated secretory route and acting on neural substrates." Thus, neuropeptides are the most diverse class of signaling molecules in the brain engaged in many physiological functions. According to this definition almost 70 genes can be distinguished in the mammalian genome, encoding neuropeptide precursors and a multitude of bioactive neuropeptides. In addition, among cytokines, peptide hormones, and growth factors there are several subfamilies of peptides displaying most of the hallmarks of neuropeptides, for example neural chemokines, cerebellins, neurexophilins, and granins. All classical neuropeptides as well as putative neuropeptides from the latter families are presented as a resource. © 2011 Springer Science+Business Media, LLC.

Boeters S.,CPB | Koornneef J.,University Utrecht
Energy Economics | Year: 2011

What are the excess costs of a separate 20% target for renewable energy as a part of the EU climate policy for 2020? We answer this question using a computable general equilibrium model, WorldScan, which has been extended with a bottom-up module of the electricity sector. The model set-up makes it possible to base the calibration directly on available estimates of costs and capacity potentials for renewable energy sources. In our base case simulation, the costs of EU climate policy with the renewables target are 6% higher than those of a policy without this target. The uncertainty in this estimate is considerable, however, and depends on our assumptions about the availability of low-cost renewable energy: the initial cost level, the steepness of the supply curves and share of renewable energy in the baseline. Within the range we explore, the excess costs vary from zero (when the target is not a binding constraint) to 32% (when the cost progression and the initial cost disadvantage for renewable energy are high and its initial share is low). © 2011 Elsevier B.V.

Medema R.H.,University Utrecht | Medema R.H.,Netherlands Cancer Institute | MacUrek L.,Academy of Sciences of the Czech Republic
Oncogene | Year: 2012

DNA-damaging therapies represent the most frequently used non-surgical anticancer strategies in the treatment of human tumors. These therapies can kill tumor cells, but at the same time they can be particularly damaging and mutagenic to healthy tissues. The efficacy of DNA-damaging treatments can be improved if tumor cell death is selectively enhanced, and the recent application of poly-(ADP-ribose) polymerase inhibitors in BRCA1/2-deficient tumors is a successful example of this. DNA damage is known to trigger cell-cycle arrest through activation of DNA-damage checkpoints. This arrest can be reversed once the damage has been repaired, but irreparable damage can promote apoptosis or senescence. Alternatively, cells can reenter the cell cycle before repair has been completed, giving rise to mutations. In this review we discuss the mechanisms involved in the activation and inactivation of DNA-damage checkpoints, and how the transition from arrest and cell-cycle re-entry is controlled. In addition, we discuss recent attempts to target the checkpoint in anticancer strategies. © 2012 Macmillan Publishers Limited All rights reserved.

Van De Meent M.,University Utrecht
Classical and Quantum Gravity | Year: 2011

We examine the continuum limit of the piecewise flat locally finite gravity model introduced by 't Hooft. In the linear weak field limit, we find the energy-momentum tensor and metric perturbation of an arbitrary configuration of defects. The energy-momentum turns out to be restricted to satisfy certain conditions. The metric perturbation is mostly fixed by the energy-momentum except for its lightlike modes which reproduce linear gravitational waves, despite no such waves being present at the microscopic level. © 2011 IOP Publishing Ltd.

Ten Cate O.,University Utrecht
Academic Medicine | Year: 2014

The undergraduate medical degree, leading to a license to practice, has traditionally been the defining professional milestone of the physician. Developments in health care and medical education and training, however, have changed the significance of the medical degree in the continuum of education toward clinical practice. The author discusses six questions that should lead us to rethink the current status and significance of the medical degree and, consequently, that of the physician. These questions include the quest for core knowledge and competence of the doctor, the place of the degree in the education continuum, the increasing length of training, the sharing of health care tasks with other professionals, and the nature of professional identity in a multitasking world. The author concludes by examining ways to redefine what it means to be a "medical doctor.".

Tee J.-M.,University Utrecht | Peppelenbosch M.P.,Erasmus University Rotterdam
Critical Reviews in Biochemistry and Molecular Biology | Year: 2010

The ankyrin repeat is a protein module with high affinity for other ankyrin repeats based on strong Van der Waals forces. The resulting dimerization is unusually resistant to both mechanical forces and alkanization, making this module exceedingly useful for meeting the extraordinary demands of muscle physiology. Many aspects of muscle function are controlled by the superfamily ankyrin repeat domain containing proteins, including structural fixation of the contractile apparatus to the muscle membrane by ankyrins, the archetypical member of the family. Additionally, other ankyrin repeat domain containing proteins critically control the various differentiation steps during muscle development, with Notch and developmental stage-specific expression of the members of the Ankyrin repeat and SOCS box (ASB) containing family of proteins controlling compartment size and guiding the various steps of muscle specification. Also, adaptive responses in fully formed muscle require ankyrin repeat containing proteins, with Myotrophin/V-1 ankyrin repeat containing proteins controlling the induction of hypertrophic responses following excessive mechanical load, and muscle ankyrin repeat proteins (MARPs) acting as protective mechanisms of last resort following extreme demands on muscle tissue. Knowledge on mechanisms governing the ordered expression of the various members of superfamily of ankyrin repeat domain containing proteins may prove exceedingly useful for developing novel rational therapy for cardiac disease and muscle dystrophies. © 2010 Informa UK Ltd.

Braidot E.,University Utrecht
Nuclear Physics A | Year: 2011

During the 2008 run RHIC provided high luminosity in both p + p and d + Au collisions at sNN=200 GeV. Electromagnetic calorimeter acceptance in STAR was enhanced by the new Forward Meson Spectrometer (FMS), and is now almost continuous over -1<η<4 and the full azimuth. This large acceptance provides sensitivity to the gluon density in the nucleus down to x≈10-3, as expected for 2→2 parton scattering. Measurements of the azimuthal correlation between a forward π0 and an associated particle at large rapidity are sensitive to the low- x gluon density. Data exhibit the qualitative features expected from gluon saturation. A comparison to calculations using the Color Glass Condensate (CGC) model is presented. © 2011 Elsevier B.V.

Bijlsma J.W.,University Utrecht
Rheumatology (Oxford, England) | Year: 2010

There is a range of pharmacological options available to the rheumatologist for treating arthritis. Non-selective NSAIDs or Cox-2 selective inhibitors are widely prescribed to reduce inflammation and alleviate pain; however, they must be used with caution in individuals with an increased cardiovascular, renal or gastrointestinal (GI) risk. The potential cardiovascular risks of Cox-2 selective inhibitors came to light over a decade ago. The conflicting nature of the study data reflects some context dependency, but the evidence shows a varying degree of cardiovascular risk with both Cox-2 selective inhibitors and non-selective NSAIDs. This risk appears to be dose dependent, which may have important ramifications for arthritis patients who require long-term treatment with high doses of anti-inflammatory drugs. The renal effects of non-selective NSAIDs have been well characterized. An increased risk of adverse renal events was found with rofecoxib but not celecoxib, suggesting that this is not a class effect of Cox-2 selective inhibitors. Upper GI effects of non-selective NSAID treatment, ranging from abdominal pain to ulceration and bleeding are extensively documented. Concomitant prescription of a proton pump inhibitor can help in the upper GI tract, but probably not in the lower. Evidence suggests that Cox-2 selective inhibitors are better tolerated in the entire GI tract. More evidence is required, and a composite end-point is being evaluated. Appropriate treatment strategies are needed depending on the level of upper and lower GI risk. Rheumatologists must be vigilant in assessing benefit-risk when prescribing a Cox-2 selective inhibitor or non-selective NSAID and should choose appropriate agents for each individual patient.

De Mol N.J.,University Utrecht
Methods in Molecular Biology | Year: 2012

Surface plasmon resonance (SPR) is a well-established label-free technique to detect mass changes near an SPR surface. For 20 years the benefits of SPR have been proven in biomolecular interaction analysis, including measurements of affinity and kinetics. The emergence of proteomics and a need for high throughput analysis drives the development of SPR systems capable of analyzing microarrays. The use of SPR imaging (also known as SPR microscopy) makes it possible to use multiplexed arrays to follow binding reactions. As SPR only analyzes the binding process, but not the identity of captured molecules on the SPR surface, technologies have been developed to integrate SPR with mass spectrometric (MS) analysis. Such approaches involve the recovery of analytes from the SPR surface and subsequent MALDI-TOF MS analysis, or LC-MS/MS after tryptic digestion of recovered proteins. An approach compatible with SPR arrays is on-chip MALDI-TOF MS, from arrayed spots on an SPR surface. This review describes some exciting developments in the application of SPR to proteomics, using instruments which are on the market already, or are expected to be available in the years to come. © 2012 Springer Science+Business Media, LLC.

The effect of temperature and irradiance during growth on photosynthetic traits of two accessions of Arabidopsis thaliana was investigated. Plants were grown at 10 and 22 °C, and at 50 and 300 μmol photons m-2 s-1 in a factorial design. As known from other cold-tolerant herbaceous species, growth of Arabidopsis at low temperature resulted in increases in photosynthetic capacity per unit leaf area and chlorophyll. Growth at high irradiance had a similar effect. However, the growth temperature and irradiance showed interacting effects for several capacity-related variables. Temperature effects on the ratio between electron transport capacity and carboxylation capacity were also different in low compared to high irradiance grown Arabidopsis. The carboxylation capacity per unit Rubisco, a measure for the in vivo Rubisco activity, was low in low irradiance grown plants but there was no clear growth temperature effect. The limitation of photosynthesis by the utilization of triose-phosphate in high temperature grown plants was less when grown at low compared to high irradiance. Several of these traits contribute to reduced efficiency of the utilization of resources for photosynthesis of Arabidopsis at low irradiance. The two accessions from contrasting climates showed remarkably similar capabilities of developmental acclimation to the two environmental factors. Hence, no evidence was found for photosynthetic adaptation of the photosynthetic apparatus to specific climatic conditions. © 2012 The Author(s).

Lozano R.,University Utrecht | Lozano R.,Organisational Sustainability Ltd.
Journal of Cleaner Production | Year: 2013

Recently, there has been a rapid growth in company sustainability reporting, as well as an improvement in quality of reports. A number of guidelines have been instrumental in this process; however, they still do not consider the importance of the inter-linkages and synergies among the different indicators and dimensions. This paper focuses on assessing sustainability inter-linkages in corporate sustainability reporting. For this study, the reports from fifty-three European companies, covering thirteen industries at A+ Global Reporting Initiative level and third party certified, were selected. These reports were analysed following a two prong, quasi-quantitative approach - firstly by checking which of the reports covered any of the inter-linking issues, and secondly by checking how well these were covered (i.e. the performance). The results showed that, although not explicitly demanded by the guidelines, the coverage of the interlinking issues ranged from medium to high, whilst performance ranged from low to high. Given the holistic nature of business and of sustainability, and the lack of inclusion of this in the current reporting guidelines, this paper calls for an update of the theory, and of the guidelines, to ensure that a more systemic approach is adopted in business praxis. It also makes an appeal to SR managers and champions, and those compiling the reports, to actively look for the inter-linking issues and dimensions, in order to gain new insights with a view to reducing, or even avoiding, conflicts between/among issues. © 2013 Elsevier Ltd. All rights reserved.

Lambooy T.,Nyenrode Business University | Lambooy T.,University Utrecht
Journal of Cleaner Production | Year: 2011

Freshwater scarcity is no longer limited to sub-Saharan developing countries; also in Western society, access to unlimited amounts of freshwater is not assured at all times. It has been argued - and laid down in many national legal systems - that access to freshwater is a basic human right. What if corporate freshwater use threatens to interfere with this human right? The main focus of the article is to explore the role of todays companies in relation to freshwater. A number of tools have been developed to attend to the necessity to reduce corporate use of freshwater. The article discusses specialised water reporting instruments such as the 2007 Global Water Tool and the water footprint calculation method. In addition, attention is paid to a CERES report (2010) revealing that the majority of the 100 worlds leading companies in water-intensive industries still has weak management and disclosures of water-related risks and opportunities. To obtain concrete information about corporate water strategies and practices, an explorative analysis was conducted on 20 Dutch multinational companies. The article highlights various innovative practices. In sum, it is demonstrated that companies are expected to bear responsibility for their impact on water resources, in particular when it influences public access to water in areas with freshwater scarcity and/or weak government. Notwithstanding the critical conclusions of the CERES report, it is interesting to see an evolution in corporate research concerning sustainable water use and the development of greener products and greener ways of production. © 2010 Elsevier Ltd. All rights reserved.

Donahue M.J.,Vanderbilt University | Strother M.K.,Vanderbilt University | Hendrikse J.,University Utrecht
Stroke | Year: 2012

Changes in cerebral hemodynamics underlie a broad spectrum of ischemic cerebrovascular disorders. An ability to accurately and quantitatively measure hemodynamic (cerebral blood flow and cerebral blood volume) and related metabolic (cerebral metabolic rate of oxygen) parameters is important for understanding healthy brain function and comparative dysfunction in ischemia. Although positron emission tomography, single-photon emission tomography, and gadolinium-MRI approaches are common, more recently MRI approaches that do not require exogenous contrast have been introduced with variable sensitivity for hemodynamic parameters. The ability to obtain hemodynamic measurements with these new approaches is particularly appealing in clinical and research scenarios in which follow-up and longitudinal studies are necessary. The purpose of this review is to outline current state-of-the-art MRI methods for measuring cerebral blood flow, cerebral blood volume, and cerebral metabolic rate of oxygen and provide practical tips to avoid imaging pitfalls. MRI studies of cerebrovascular disease performed without exogenous contrast are synopsized in the context of clinical relevance and methodological strengths and limitations. © 2012 American Heart Association, Inc.

Dunaif A.,Northwestern University | Fauser B.C.J.M.,University Utrecht
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: It has become evident over the past 30 years that polycystic ovary syndrome (PCOS) is more than a reproductive disorder. It has metabolic sequelae that can affect women across the lifespan. Diagnostic criteria based on the endocrine features of the syndrome, hyperandrogenism and chronic anovulation, such as the National Institutes of Health (NIH) criteria, identifywomenat high metabolic risk. The additional phenotypes defined by the Rotterdam diagnostic criteria identify women with primarily reproductive rather than metabolic dysfunction. Objective: The aim is to discuss the rationale for a separatenamefor the syndrome that is associated with high metabolic risk while maintaining the current name for the phenotypes with primarily reproductive morbidity. Intervention: The NIH Office for Disease Prevention-Sponsored Evidence-Based Methodology Workshop on Polycystic Ovary Syndrome recommended that a new name is needed for PCOS. Positions: The authors propose that PCOS be retained for the reproductive phenotypes and that a new name be created for the phenotypes at high metabolic risk. Conclusions: There should be two names for the PCOS phenotypes: those with primarily reproductive consequences should continue to be called PCOS, and those with important metabolic consequences should have a new name. Copyright © 2013 by The Endocrine Society.

Leget C.,University Utrecht
Medicine, Health Care and Philosophy | Year: 2013

The concept of dignity is notoriously vague. In this paper it is argued that the reason for this is that there are three versions of dignity that are often confused. First we will take a short look at the history of the concept of dignity in order to demonstrate how already from Roman Antiquity two versions of dignity can be distinguished. Subsequently, the third version will be introduced and it will be argued that although the three versions of dignity hang together, they should also be clearly distinguished in order to avoid confusion. The reason for distinguishing the three versions is because all three of them are only partially effective. This will be demonstrated by taking the discussion about voluntary 'dying with dignity' as an example. Inspired by both Paul Ricoeur's concept of ethics and the ethics of care a proposition will be done as to how the three versions of dignity may sustain each other and help achieve what neither one of the versions can do on its own. © 2012 Springer Science+Business Media B.V.

Kasteleijn-Nolst Trenite D.G.A.,University Utrecht
Epilepsia | Year: 2012

Summary Most patients with epilepsy report that seizures are sometimes, or exclusively, provoked by general internal precipitants (such as stress, fatigue, fever, sleep, and menstrual cycle) and by external precipitants (such as excess alcohol, heat, bathing, eating, reading, and flashing lights). Some patients describe very exotic and precise triggers, like tooth brushing or listening to a particular melody. Nevertheless, the most commonly noticed seizure increasers by far are stress, lack of sleep, and fatigue. Recognized reflex seizure triggers are usually sensory and visual, such as television, discotheques, and video games. Visually evoked seizures comprise 5% of the total of 6% reflex seizures. The distinction between provocative and reflex factors and seizures seems artificial, and in many patients, maybe all, there is a combination of these. It seems plausible that all of the above-mentioned factors can misbalance the actual brain network; at times, accumulation of factors leads then to primary generalized, partial, or secondarily generalized seizures. If the provoking factors are too exotic, patients may be sent to the psychiatrist. Conversely, if the seizure-provoking fluctuating mechanisms include common habits and environmental factors, these may hardly be considered as provocative factors. Awareness of precipitating factors and its possible interactions might help us to unravel the pathophysiology of epilepsy and to change the notion that seizure occurrence is unpredictable. This article provides an overview of the epidemiology, classification, diagnosis, treatment, and especially similarities in the variety of provocative and reflex factors with resulting general hypotheses. © 2012 International League Against Epilepsy.

Gonzalez S.F.,Harvard University | Degn S.E.,University of Aarhus | Pitcher L.A.,Harvard University | Woodruff M.,Harvard University | And 2 more authors.
Annual Review of Immunology | Year: 2011

The clonal selection theory first proposed by Macfarlane Burnet is a cornerstone of immunology (1). At the time, it revolutionized the thinking of immunologists because it provided a simple explanation for lymphocyte specificity, immunological memory, and elimination of self-reactive clones (2). The experimental demonstration by Nossal & Lederberg (3) that B lymphocytes bear receptors for a single antigen raised the central question of where B lymphocytes encounter antigen. This question has remained mostly unanswered until recently. Advances in techniques such as multiphoton intravital microscopy (4, 5) have provided new insights into the trafficking of B cells and their antigen. In this review, we summarize these advances in the context of our current view of B cell circulation and activation. © 2011 by Annual Reviews. All rights reserved.

Svircevic V.,University Utrecht
The Cochrane database of systematic reviews | Year: 2013

A combination of general anaesthesia (GA) with thoracic epidural analgesia (TEA) may have a beneficial effect on clinical outcomes by reducing the risk of perioperative complications after cardiac surgery. The objective of this review was to determine the impact of perioperative epidural analgesia in cardiac surgery on perioperative mortality and cardiac, pulmonary or neurological morbidity. We performed a meta-analysis to compare the risk of adverse events and mortality in patients undergoing cardiac surgery under general anaesthesia with and without epidural analgesia. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12) in The Cochrane Library; MEDLINE (PubMed) (1966 to November 2012); EMBASE (1989 to November 2012); CINHAL (1982 to November 2012) and the Science Citation Index (1988 to November 2012). We included randomized controlled trials comparing outcomes in adult patients undergoing cardiac surgery with either GA alone or GA in combination with TEA. All publications found during the search were manually and independently reviewed by the two authors. We identified 5035 titles, of which 4990 studies did not satisfy the selection criteria or were duplicate publications, that were retrieved from the five different databases. We performed a full review on 45 studies, of which 31 publications met all inclusion criteria. These 31 publications reported on a total of 3047 patients, 1578 patients with GA and 1469 patients with GA plus TEA. Through our search (November 2012) we have identified 5035 titles, of which 31 publications met our inclusion criteria and reported on a total of 3047 patients. Compared with GA alone, the pooled risk ratio (RR) for patients receiving GA with TEA showed an odds ratio (OR) of 0.84 (95% CI 0.33 to 2.13, 31 studies) for mortality; 0.76 (95% CI 0.49 to 1.19, 17 studies) for myocardial infarction; and 0.50 (95% CI 0.21 to 1.18, 10 studies) for stroke. The relative risks (RR) for respiratory complications and supraventricular arrhythmias were 0.68 (95% CI 0.54 to 0.86, 14 studies) and 0.65 (95% CI 0.50 to 0.86, 15 studies) respectively. This meta-analysis of studies, identified to 2010, showed that the use of TEA in patients undergoing coronary artery bypass graft surgery may reduce the risk of postoperative supraventricular arrhythmias and respiratory complications. There were no effects of TEA with GA on the risk of mortality, myocardial infarction or neurological complications compared with GA alone.

De Groot P.G.,University Utrecht
Thrombosis Research | Year: 2011

The antiphospholipid syndrome is an autoimmune disease characterised by the clinical features of recurrent thrombosis in the venous or arterial circulation and foetal losses in combination with circulating anti-phospholipid antibodies in the blood of the afflicted patients. Over the last 25 years numerous studies have established the correlation between the presence of antibodies against anionic phospholipids and thrombo-embolic manifestations but how these antibodies cause thrombosis is still unclear. Most scientists now accept the fact that only a subset of the antiphospholipid antibodies has clinical relevance. Not antibodies to anionic phospholipids but rather antibodies to β2-glycoprotein I are thought to be the major cause for the pathological manifestations. β2-Glycoprotein I is a plasma protein without a known function and persons lacking β2-Glycoprotein I are completely healthy. Our challenge is to understand why auto-antibodies against such a dispensable protein are so common and how antibodies directed against a protein without obvious function can induce the severe clinical manifestations observed in this syndrome. © 2010 Elsevier B.V. All rights reserved.

Hoogenraad T.U.,University Utrecht
International Journal of Alzheimer's Disease | Year: 2011

Breakthrough in treatment of Alzheimer's disease with a shift from irrational dangerous chelation therapy to rational safe evidence based oral zinc therapy. Evidence based medicine: After synthesizing the best available clinical evidence I conclude that oral zinc therapy is a conscientious choice for treatment of free copper toxicosis in individual patients with Alzheimer's disease. Hypothesis 1: Age related free copper toxicosis is a causal factor in pathogenesis of Alzheimer's disease. There are 2 neurodegenerative diseases with abnormalities in copper metabolism: (a) the juvenile form with degeneration in the basal ganglia (Wilson's disease) and (b) the age related form with cortical neurodegeneration (Alzheimer's disease). Initially the hypothesis has been that neurodegeneration was caused by accumulation of copper in the brain but later experiences with treatment of Wilson's disease led to the conviction that free plasma copper is the toxic form of copper: it catalyzes amyloid formation thereby generating oxidative stress, free radicals and degeneration of cortical neurons. Hypothesis 2: Oral zinc therapy is an effective and safe treatment of free copper toxicosis in Alzheimer's disease. Proposed dosage: 50mg elementary zinc/day. Warning: Chelation therapy is irrational and dangerous in treatment of copper toxicosis in Alzheimer's disease. © 2011 Tjaard U. Hoogenraad.

Princen S.,University Utrecht
Marine Policy | Year: 2010

Over the past two decades profound changes have taken place in the European Union's (EU) fisheries policy. Partly these changes have occurred within the EU's Common Fisheries Policy itself, but partly policy change has been effected by the application of environmental legislation and policy instruments to fisheries issues. This article argues that the process of policy change in EU fisheries policy can best be understood in terms of the interaction of policy images and policy venues that is at the core of the punctuated equilibrium theory of policy-making. As a result of the rise of a biodiversity perspective on fisheries issues, environmental policy-makers have become active in fisheries issues, which has led to profound changes in both the content of fisheries policies and the institutional organisation around this issue area. © 2009 Elsevier Ltd. All rights reserved.

Chubar N.,University Utrecht
Journal of Colloid and Interface Science | Year: 2011

New inorganic ion exchangers based on double Mg-Al hydrous oxides were generated via the new non-traditional sol-gel synthesis method which avoids using metal alkoxides as raw materials. Surface chemical and adsorptive properties of the final products were controlled by several ways of hydrogels and xerogels treatments which produced the materials of the layered structure, mixed hydrous oxides or amorphous adsorbents. The final adsorptive materials obtained via thermal treatment of xerogels were the layered mesoporous materials with carbonate in the interlayer space, surface abundance with hydroxylic groups and maximum adsorptive capacity to arsenate. Higher affinity of Mg-Al hydrous oxides towards H2AsO4- is confirmed by steep adsorption isotherms having plateau (removal capacity) at 220. mg[As]. gdw-1 for the best sample at pH = 7, fast adsorption kinetics and little pH effect. Adsorption of arsenite, fluoride, bromate, bromide, selenate, borate by Mg-Al hydrous oxides was few times high either competitive (depending on the anion) as compare with the conventional inorganic ion exchange adsorbents. © 2011 Elsevier Inc.

Waldinger M.D.,University Utrecht
Current Opinion in Psychiatry | Year: 2014

Purpose of review: As there are various drugs and different treatment strategies to delay ejaculation, a review of the current drug treatments for premature ejaculation is relevant for daily clinical practice. Recent findings: There are four premature ejaculation subtypes: lifelong premature ejaculation, acquired premature ejaculation, variable premature ejaculation and subjective premature ejaculation. These premature ejaculation subtypes vary in the duration of the intravaginal ejaculation latency time, their course in life and frequency of early ejaculations. Drug treatment is mainly required for lifelong and acquired premature ejaculation. On the other hand, counseling, psychoeducation and local anesthetics are particularly indicated for variable premature ejaculation and subjective premature ejaculation. Apart from the efficacy of various drugs, drugs against premature ejaculation can be taken on-demand or on a daily basis. However, apart from the on-demand use of dapoxetine, all other premature ejaculation treatments are off-label. Summary: Drug treatment is the first choice of treatment for lifelong premature ejaculation and may also be indicated for acquired premature ejaculation. Together with the patient, the clinician can choose which drug and which treatment strategy is most suitable for the patient and his partner. © 2014 Wolters Kluwer Health | Lippincott Williams and Wilkins.

Snellings R.,University Utrecht
Journal of Physics G: Nuclear and Particle Physics | Year: 2011

The ALICE detector at the Large Hadron Collider (LHC) recorded first Pb-Pb collisions at √SNN = 2.76 TeV in November and December of 2010. We report on the measurements of anisotropic flow for charged and identified particles. From the comparison with measurements at lower energies and with model predictions, we find that the system created at these collision energies is described well by hydrodynamical model calculations and behaves like analmost perfect fluid. © CERN 2011. Published under licence by IOP Publishing Ltd.

Weicht B.,University Utrecht
Journal of Aging Studies | Year: 2013

The provision and arrangement of care for elderly people is one of the main challenges for the future of European welfare states. In both political and public discourses elderly people feature as the subjects who are associated with particular needs, wishes and desires and for whom care needs to be guaranteed and organised. Underlying the cultural construction of the care regime and culture is an ideal type model of the elderly person. This paper analyses the discursive construction of elderly people in the discourses on care in Austria. An understanding of how elderly people as subjects, their wishes and needs and their position within society are constructed enables us to analyse, question and challenge the current dominant care arrangements and its cultural embeddings. The paper demonstrates the processes of silencing, categorisation and passivation of elderly people and it is argued that the socio-discursive processes lead to a particular image of the elderly person which consequently serves as the basis on which the care regime is built. © 2013 Elsevier Inc.

de Vries S.J.,University Utrecht
Nature protocols | Year: 2010

Computational docking is the prediction or modeling of the three-dimensional structure of a biomolecular complex, starting from the structures of the individual molecules in their free, unbound form. HADDOCK is a popular docking program that takes a data-driven approach to docking, with support for a wide range of experimental data. Here we present the HADDOCK web server protocol, facilitating the modeling of biomolecular complexes for a wide community. The main web interface is user-friendly, requiring only the structures of the individual components and a list of interacting residues as input. Additional web interfaces allow the more advanced user to exploit the full range of experimental data supported by HADDOCK and to customize the docking process. The HADDOCK server has access to the resources of a dedicated cluster and of the e-NMR GRID infrastructure. Therefore, a typical docking run takes only a few minutes to prepare and a few hours to complete.

Chojnacki M.,University Utrecht
Journal of Physics G: Nuclear and Particle Physics | Year: 2011

Results of the measurement of the π, K, p transverse momentum (p t) spectra at mid-rapidity in proton-proton collisions at √s = 7 TeV are presented. Particle identification was performed using the energy loss signal in the inner tracking system and the time projection chamber, while information from the time-of-flight detector was used to identify particles at higher transverse momentum. From the spectra at √s = 7 TeV, the mean transverse momentum (〈pt〉) and particle ratios were extracted and compared to results obtained for collisions at √s = 0.9 TeV and lower energies. © CERN 2011. Published under licence by IOP Publishing Ltd.

Gehring U.,University Utrecht
Environmental health : a global access science source | Year: 2013

Environmental exposures during pregnancy and early life may have adverse health effects. Single birth cohort studies often lack statistical power to tease out such effects reliably. To improve the use of existing data and to facilitate collaboration among these studies, an inventory of the environmental exposure and health data in these studies was made as part of the ENRIECO (Environmental Health Risks in European Birth Cohorts) project. The focus with regard to exposure was on outdoor air pollution, water contamination, allergens and biological organisms, metals, pesticides, smoking and second hand tobacco smoke (SHS), persistent organic pollutants (POPs), noise, radiation, and occupational exposures. The review lists methods and data on environmental exposures in 37 European birth cohort studies. Most data is currently available for smoking and SHS (N=37 cohorts), occupational exposures (N=33), outdoor air pollution, and allergens and microbial agents (N=27). Exposure modeling is increasingly used for long-term air pollution exposure assessment; biomonitoring is used for assessment of exposure to metals, POPs and other chemicals; and environmental monitoring for house dust mite exposure assessment. Collaborative analyses with data from several birth cohorts have already been performed successfully for outdoor air pollution, water contamination, allergens, biological contaminants, molds, POPs and SHS. Key success factors for collaborative analyses are common definitions of main exposure and health variables. Our review emphasizes that such common definitions need ideally be arrived at in the study design phase. However, careful comparison of methods used in existing studies also offers excellent opportunities for collaborative analyses. Investigators can use this review to evaluate the potential for future collaborative analyses with respect to data availability and methods used in the different cohorts and to identify potential partners for a specific research question.

Benschop J.J.,University Utrecht
Molecular cell | Year: 2010

Analyses of biological processes would benefit from accurate definitions of protein complexes. High-throughput mass spectrometry data offer the possibility of systematically defining protein complexes; however, the predicted compositions vary substantially depending on the algorithm applied. We determine consensus compositions for 409 core protein complexes from Saccharomyces cerevisiae by merging previous predictions with a new approach. Various analyses indicate that the consensus is comprehensive and of high quality. For 85 out of 259 complexes not recorded in GO, literature search revealed strong support in the form of coprecipitation. New complexes were verified by an independent interaction assay and by gene expression profiling of strains with deleted subunits, often revealing which cellular processes are affected. The consensus complexes are available in various formats, including a merge with GO, resulting in 518 protein complex compositions. The utility is further demonstrated by comparison with binary interaction data to reveal interactions between core complexes. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Gho J.M.,University Utrecht
Journal of cardiac failure | Year: 2013

Dilated cardiomyopathy (DCM) is the most common form of nonischemic cardiomyopathy worldwide and can lead to sudden cardiac death and heart failure. Despite ongoing advances made in the treatment of DCM, improvement of outcome remains problematic. Stem cell therapy has been extensively studied in preclinical and clinical models of ischemic heart disease, showing potential benefit. DCM is associated with a major health burden, and few studies have been performed on cell therapy for DCM. In this systematic review we aimed to provide an overview of preclinical and clinical studies performed on cell therapy for DCM. A systematic search, critical appraisal, and summarized outcomes are presented. In total, 29 preclinical and 15 clinical studies were included. Methodologic quality of reported studies in general was low based on the Centre for Evidence Based Medicine, Oxford University, criteria. A large heterogeneity in inclusion criteria, procedural characteristics, and outcome measures was noted. The majority of studies showed a significant increase in left ventricular ejection fraction after cell therapy during follow-up. Stem cell therapy has shown moderate but significant effects in clinical trials for ischemic heart disease, but it remains to be determined if we can extrapolate these results to DCM patients. There is a need for methodologically sound studies to elucidate underlying mechanisms and translate those into improved therapy for clinical practice. To validate safety and efficacy of cell therapy for DCM, adequate randomized (placebo) controlled trials using different strategies are mandatory. Copyright © 2013 Elsevier Inc. All rights reserved.

ten Cate O.T.J.,University Utrecht
Advances in Health Sciences Education | Year: 2013

Providing feedback to trainees in clinical settings is considered important for development and acquisition of skill. Despite recommendations how to provide feedback that have appeared in the literature, research shows that its effectiveness is often disappointing. To understand why receiving feedback is more difficult than it appears, this paper views the feedback process through the lens of Self-Determination Theory (SDT). SDT claims that the development and maintenance of intrinsic motivation, associated with effective learning, requires feelings of competence, autonomy and relatedness. These three psychological needs are not likely to be satisfied in most feedback procedures. It explains why feedback is often less effective than one would expect. Suggestions to convey feedback in ways that may preserve the trainee's autonomy are provided. © 2012 Springer Science+Business Media B.V.

Metal and metal oxide chelating-based phosphopeptide enrichment technologies provide powerful tools for the in-depth profiling of phosphoproteomes. One weakness inherent to current enrichment strategies is poor binding of phosphopeptides containing multiple basic residues. The problem is exacerbated when strong cation exchange (SCX) is used for pre-fractionation, as under low pH SCX conditions phosphorylated peptides with multiple basic residues elute with the bulk of the tryptic digest and therefore require more stringent enrichment. Here, we report a systematic evaluation of the characteristics of a novel phosphopeptide enrichment approach based on a combination of low pH SCX and Ti(4+)-immobilized metal ion affinity chromatography (IMAC) comparing it one-to-one with the well established low pH SCX-TiO(2) enrichment method. We also examined the effect of 1,1,1,3,3,3-hexafluoroisopropanol (HFP), trifluoroacetic acid (TFA), or 2,5-dihydroxybenzoic acid (DHB) in the loading buffer, as it has been hypothesized that high levels of TFA and the perfluorinated solvent HFP improve the enrichment of phosphopeptides containing multiple basic residues. We found that Ti(4+)-IMAC in combination with TFA in the loading buffer, outperformed all other methods tested, enabling the identification of around 5000 unique phosphopeptides containing multiple basic residues from 400 μg of a HeLa cell lysate digest. In comparison, ∼ 2000 unique phosphopeptides could be identified by Ti(4+)-IMAC with HFP and close to 3000 by TiO(2). We confirmed, by motif analysis, the basic phosphopeptides enrich the number of putative basophilic kinases substrates. In addition, we performed an experiment using the SCX/Ti(4+)-IMAC methodology alongside the use of collision-induced dissociation (CID), higher energy collision induced dissociation (HCD) and electron transfer dissociation with supplementary activation (ETD) on considerably more complex sample, consisting of a total of 400 μg of triple dimethyl labeled MCF-7 digest. This analysis led to the identification of over 9,000 unique phosphorylation sites. The use of three peptide activation methods confirmed that ETD is best capable of sequencing multiply charged peptides. Collectively, our data show that the combination of SCX and Ti(4+)-IMAC is particularly advantageous for phosphopeptides with multiple basic residues.

Venekamp R.P.,University Utrecht
Cochrane database of systematic reviews (Online) | Year: 2013

Acute otitis media (AOM) is one of the most common diseases in early infancy and childhood. Antibiotic use for AOM varies from 56% in the Netherlands to 95% in the USA, Canada and Australia. To assess the effects of antibiotics for children with AOM. We searched CENTRAL (2012, Issue 10), MEDLINE (1966 to October week 4, 2012), OLDMEDLINE (1958 to 1965), EMBASE (January 1990 to November 2012), Current Contents (1966 to November 2012), CINAHL (2008 to November 2012) and LILACS (2008 to November 2012). Randomised controlled trials (RCTs) comparing 1) antimicrobial drugs with placebo and 2) immediate antibiotic treatment with expectant observation (including delayed antibiotic prescribing) in children with AOM. Two review authors independently assessed trial quality and extracted data. For the review of antibiotics against placebo, 12 RCTs (3317 children and 3854 AOM episodes) from high-income countries were eligible. However, one trial did not report patient-relevant outcomes, leaving 11 trials with generally low risk of bias. Pain was not reduced by antibiotics at 24 hours (risk ratio (RR) 0.89; 95% confidence interval (CI) 0.78 to 1.01) but almost a third fewer had residual pain at two to three days (RR 0.70; 95% CI 0.57 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) 20) and fewer had pain at four to seven days (RR 0.79; 95% CI 0.66 to 0.95; NNTB 20). When compared with placebo, antibiotics did not alter the number of abnormal tympanometry findings at either four to six weeks (RR 0.92; 95% CI 0.83 to 1.01) or at three months (RR 0.97; 95% CI 0.76 to 1.24), or the number of AOM recurrences (RR 0.93; 95% CI 0.78 to 1.10). However, antibiotic treatment did lead to a statistically significant reduction of tympanic membrane perforations (RR 0.37; 95% CI 0.18 to 0.76; NNTB 33) and halved contralateral AOM episodes (RR 0.49; 95% CI 0.25 to 0.95; NNTB 11) as compared with placebo. Severe complications were rare and did not differ between children treated with antibiotics and those treated with placebo. Adverse events (such as vomiting, diarrhoea or rash) occurred more often in children taking antibiotics (RR 1.34; 95% CI 1.16 to 1.55; number needed to treat for an additional harmful outcome (NNTH) 14). Funnel plots do not suggest publication bias. Individual patient data meta-analysis of a subset of included trials found antibiotics to be most beneficial in children aged less than two with bilateral AOM, or with both AOM and otorrhoea.For the review of immediate antibiotics against expectant observation, five trials (1149 children) were eligible. Four trials (1007 children) reported outcome data that could be used for this review. From these trials, data from 959 children could be extracted for the meta-analysis on pain at days three to seven. No difference in pain was detectable at three to seven days (RR 0.75; 95% CI 0.50 to 1.12). No serious complications occurred in either the antibiotic group or the expectant observation group. Additionally, no difference in tympanic membrane perforations and AOM recurrence was observed. Immediate antibiotic prescribing was associated with a substantial increased risk of vomiting, diarrhoea or rash as compared with expectant observation (RR 1.71; 95% CI 1.24 to 2.36). Antibiotic treatment led to a statistically significant reduction of children with AOM experiencing pain at two to seven days compared with placebo but since most children (82%) settle spontaneously, about 20 children must be treated to prevent one suffering from ear pain at two to seven days. Additionally, antibiotic treatment led to a statistically significant reduction of tympanic membrane perforations (NNTB 33) and contralateral AOM episodes (NNTB 11). These benefits must be weighed against the possible harms: for every 14 children treated with antibiotics, one child experienced an adverse event (such as vomiting, diarrhoea or rash) that would not have occurred if antibiotics had been withheld. Antibiotics appear to be most useful in children under two years of age with bilateral AOM, or with both AOM and otorrhoea. For most other children with mild disease, an expectant observational approach seems justified. We have no trials in populations with higher risks of complications.

Walder F.,Institute for Sustainability science | Van Der Heijden M.G.A.,Institute for Sustainability science | Van Der Heijden M.G.A.,University of Zurich | Van Der Heijden M.G.A.,University Utrecht
Nature Plants | Year: 2015

Arbuscular mycorrhizal (AM) fungi are one of the most important groups of plant symbionts. These fungi provide mineral nutrients to plants in exchange for carbon. Although substantial amounts of resources are exchanged, the factors that regulate trade in the AM symbiosis are poorly understood. Recent evidence for the reciprocally regulated exchange of resources by AM fungi and plants has led to the suggestion that these symbioses operate according to biological market dynamics, in which interactions are viewed from an economic perspective, and the most beneficial partners are favoured. Here we present five arguments that challenge the importance of reciprocally regulated exchange, and thereby market dynamics, for resource exchange in the AM symbiosis, and suggest that such reciprocity is only found in a subset of symbionts, under specific conditions. We instead propose that resource exchange in the AM symbiosis is determined by competition for surplus resources, functional diversity and sink strength. © 2015 Macmillan Publishers Limited. All rights reserved.

McQuarrie N.,University of Pittsburgh | Van Hinsbergen D.J.,University of Oslo | Van Hinsbergen D.J.,University Utrecht
Geology | Year: 2013

The Arabia-Eurasia collision has been linked to global cooling, the slowing of Africa, Mediterranean extension, the rifting of the Red Sea, an increase in exhumation and sedimentation on the Eurasian plate, and the slowing and deformation of the Arabian plate. Collision age estimates range from the Late Cretaceous to Pliocene, with most estimates between 35 and 20 Ma. We assess the consequences of these collision ages on the magnitude and location of continental consumption by compiling all documented shortening within the region, and integrating this with plate kinematic reconstructions. Shortening estimates across the orogen allow for ~350 km of Neogene upper crustal contraction, necessitating collision by 20 Ma. A 35 Ma collision requires additional subduction of ~400-600 km of Arabian continental crust. Using the Oman ophiolite as an analogue, ophiolitic fragments preserved along the Zagros suture zone permit ~180 km of subduction of the Arabian continental margin plus overlying ophiolites. Wholesale subduction of this more dense continental margin plus ophiolites would reconstruct ~400-500 km of postcollisional Arabia-Eurasia convergence, consistent with a ca. 27 Ma initial collision age. This younger Arabia-Eurasia collision suggests a noncollisional mechanism for the slowing of Africa, and associated extension. © 2013 Geological Society of America.

De Vos M.,Center for Reproductive Medicine | Devroey P.,Center for Reproductive Medicine | Fauser B.C.,University Utrecht
The Lancet | Year: 2010

Primary ovarian insufficiency is a subclass of ovarian dysfunction in which the cause is within the ovary. In most cases, an unknown mechanism leads to premature exhaustion of the resting pool of primordial follicles. Primary ovarian insufficiency might also result from genetic defects, chemotherapy, radiotherapy, or surgery. The main symptom is absence of regular menstrual cycles, and the diagnosis is confirmed by detection of raised follicle-stimulating hormone and declined oestradiol concentrations in the serum, suggesting a primary ovarian defect. The disorder usually leads to sterility, and has a large effect on reproductive health when it arises at a young age. Fertility-preservation options can be offered to some patients with cancer and those at risk of early menopause, such as those with familial cases of primary ovarian insufficiency. Long-term deprivation of oestrogen has serious implications for female health in general; and for bone density, cardiovascular and neurological systems, wellbeing, and sexual health in particular. © 2010 Elsevier Ltd.

C-type distal radial fractures remain challenging fractures. Currently locking plates are very popular because of their length preserving, stability. A considerable drawback is the high cost. Since 2003 we have been using mini AO plates (2.7 mm) as an alternative. We analysed our results and performed a cost analysis. Retrospective analysis was performed of all patients operated upon between 2003 and 2008 for C type distal radius fractures. Reduction was achieved with mini AO plates, applied in a buttress fashion, with ligamentotaxis. Rehabilitation consisted of immediate mobilisation. Pre- and postoperative X-rays, operative results and patient charts were reviewed. Furthermore, we prospectively evaluated the functional results using VAS, DASH and Mayo wrist scores. Lastly, we assessed the implant costs and compared them to locking plates. Thirty-four patients were treated with a mean age of 49 years. Mean radial shortening improved 2 mm; dorsal and radial angulation improved 23 and 4°, respectively. At consolidation (eight weeks) the average radial shortening was 0.75 mm, a volar angulation of 3°, and 21° of radial angulation. Functional results were excellent, demonstrated by a mean VAS score less than 1, a DASH score of 12 and a Mayo wrist score of 87. Compared to locking plates, there was an overall reduction in material costs of 15,300 Euro. Our technique has excellent biomechanical stability, enabling immediate functional rehabilitation, good anatomical and functional outcome with significantly lower costs.

Scheerlinck L.M.,University Utrecht
The International journal of oral & maxillofacial implants | Year: 2013

To compare the donor site complication rate and length of hospital stay following the harvest of bone from the iliac crest, calvarium, or mandibular ramus. Ninety-nine consecutively treated patients were included in this retrospective observational single-center study. Iliac crest bone was harvested in 55 patients, calvarial bone in 26 patients, and mandibular ramus bone in 18 patients. Harvesting of mandibular ramus bone was associated with the lowest percentages of major complications (5.6%), minor complications (22.2%), and total complications (27.8%). Harvesting of iliac crest bone was related to the highest percentages of minor complications (56.4%) and total complications (63.6%), whereas harvesting of calvarial bone induced the highest percentage of major complications (19.2%). The length of the hospital stay was significantly influenced by the choice of donor site (P = .003) and age (P = .009); young patients with the mandibular ramus as the donor site had the shortest hospital stay. Harvesting of mandibular ramus bone was associated with the lowest percentage of complications and the shortest hospital stay. When the amount of bone to be obtained is deemed sufficient, mandibular ramus bone should be the first choice for the reconstruction of maxillofacial defects.

Clevers H.C.,University Utrecht | Bevins C.L.,University of California at Davis
Annual Review of Physiology | Year: 2013

Paneth cells are highly specialized epithelial cells of the small intestine, where they coordinate many physiological functions. First identified more than a century ago on the basis of their readily discernible secretory granules by routine histology, these cells are located at the base of the crypts of Lieberkühn, tiny invaginations that line the mucosal surface all along the small intestine. Investigations over the past several decades determined that these cells synthesize and secrete substantial quantities of antimicrobial peptides and proteins. More recent studies have determined that these antimicrobial molecules are key mediators of host-microbe interactions, including homeostatic balance with colonizing microbiota and innate immune protection from enteric pathogens. Perhaps more intriguing, Paneth cells secrete factors that help sustain and modulate the epithelial stem and progenitor cells that cohabitate in the crypts and rejuvenate the small intestinal epithelium. Dysfunction of Paneth cell biology contributes to the pathogenesis of chronic inflammatory bowel disease. Copyright © 2013 by Annual Reviews. All rights reserved.

Subarachnoid hemorrhage (SAH) represents a considerable health problem with an incidence of 6-7 per 100.000 individuals per year in Western society. We investigated the long-term consequences of SAH on behavior, neuroinflammation and gray- and white-matter damage using an endovascular puncture model in Wistar rats. Rats were divided into a mild or severe SAH group based on their acute neurological score at 24 h post-SAH. The degree of hemorrhage determined in post-mortem brains at 48 h strongly correlated with the acute neurological score. Severe SAH induced increased TNF-α, IL-1β, IL-10, MCP-1, MIP2, CINC-1 mRNA expression and cortical neutrophil influx at 48 h post-insult. Neuroinflammation after SAH was very long-lasting and still present at day 21 as determined by Iba-1 staining (microglia/macrophages) and GFAP (astrocytes). Long-term neuroinflammation was strongly associated with the degree of severity of SAH. Cerebral damage to gray- and white-matter was visualized by immunohistochemistry for MAP2 and MBP at 21 days after SAH. Severe SAH induced significant gray- and white-matter damage. MAP2 loss at day 21 correlated significantly with the acute neurological score determined at 24 h post-SAH. Sensorimotor behavior, determined by the adhesive removal task and von Frey test, was affected after severe SAH at day 21. In conclusion, we are the first to show that SAH induces ongoing cortical inflammation. Moreover, SAH induces mainly cortical long-term brain damage, which is associated with long-term sensorimotor damage.

Cramer J.,University Utrecht
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2013

Material efficiency is one of the major challenges facing our society in the twenty-first century. Research can help to understand how we can make the transition towards a material-efficient society. This study focuses on the role of the government in such transition processes. Use is made of literature in the field of public administration and innovation literature, particularly transition management. On the basis of three Dutch examples (plastics, e-waste and bio-energy), the complex system change towards a material-efficient society will be reflected upon. These case studies underline the need for a tailor-made governance approach instead of a top-down government approach to enhance material efficiency in practice. The role of the government is not restricted to formulating policies and then leaving it up to other actors to implement these policies. Instead, it is a continuous interplay between the different actors during the whole implementation process. As such, the government's role is to steer the development in the desired direction and orchestrate the process from beginning to end. In order to govern with a better compass, scientifically underpinned guiding principles and indicators are needed. This is a challenge for researchers both in public administration and in transition management. © 2013 The Author(s) Published by the Royal Society. All rights reserved.

Bender S.A.,University of California at Los Angeles | Duine R.A.,University Utrecht | Tserkovnyak Y.,University of California at Los Angeles
Physical Review Letters | Year: 2012

We theoretically investigate spin transfer between a system of quasiequilibrated Bose-Einstein-condensed magnons in an insulator in direct contact with a conductor. While charge transfer is prohibited across the interface, spin transport arises from the exchange coupling between insulator and conductor spins. In a normal insulator phase, spin transport is governed solely by the presence of thermal and spin-diffusive gradients; the presence of Bose-Einstein condensation (BEC), meanwhile, gives rise to a temperature-independent condensate spin current. Depending on the thermodynamic bias of the system, spin may flow in either direction across the interface, engendering the possibility of a dynamical phase transition of magnons. We discuss the experimental feasibility of observing a BEC steady state (fomented by a spin Seebeck effect), which is contrasted to the more familiar spin-transfer-induced classical instabilities. © 2012 American Physical Society.

Herfs P.G.,University Utrecht
Human resources for health | Year: 2014

BACKGROUND: In most countries of the European Economic Area (EEA), there is no large-scale migration of medical graduates with diplomas obtained outside the EEA, which are international medical graduates (IMGs). In the United Kingdom however, health care is in part dependent on the influx of IMGs. In 2005, of all the doctors practising in the UK, 31% were educated outside the country. In most EEA-countries, health care is not dependent on the influx of IMGs.The aim of this study is to present data relating to the changes in IMG migration in the UK since the extension of the European Union in May 2004. In addition, data are presented on IMG migration in the Netherlands. These migration flows show that migration patterns differ strongly within these two EU-countries.METHOD: This study makes use of registration data on migrating doctors from the General Medical Council (GMC) in the UK and from the Dutch Department of Health. Moreover, data on the ratio of medical doctors in relation to a country's population were extracted from the World Health Organization (WHO).RESULTS: The influx of IMGs in the UK has changed in recent years due to the extension of the European Union in 2004, the expansion of UK medical schools and changes in the policy towards non-EEA doctors.The influx of IMGs in the Netherlands is described in detail. In the Netherlands, many IMGs come from Afghanistan, Iraq and Surinam.DISCUSSION AND CONCLUSIONS: There are clear differences between IMG immigration in the UK and in the Netherlands. In the UK, the National Health Service continues to be very reliant on immigration to fill shortage posts, whereas the number of immigrant doctors working in the Netherlands is much smaller. Both the UK and the Netherlands' regulatory bodies have shared great concerns about the linguistic and communication skills of both EEA and non-EEA doctors seeking to work in these countries. IMG migration is a global and intricate problem. The source countries, not only those where English is the first or second language, experience massive IMG migration flows.

De Haan M.C.,University Utrecht | Pickhardt P.J.,University of Wisconsin - Madison
Gut | Year: 2015

Colorectal cancer (CRC) is the second most common cancer and second most common cause of cancerrelated deaths in Europe. The introduction of CRC screening programmes using stool tests and flexible sigmoidoscopy, have been shown to reduce CRC-related mortality substantially. In several European countries, population-based CRC screening programmes are ongoing or being rolled out. Stool tests like faecal occult blood testing are non-invasive and simple to perform, but are primarily designed to detect early invasive cancer. More invasive tests like colonoscopy and CT colonography (CTC) aim at accurately detecting both CRC and cancer precursors, thus providing for cancer prevention. This review focuses on the accuracy, acceptance and safety of CTC as a CRC screening technique and on the current position of CTC in organised population screening. Based on the detection characteristics and acceptability of CTC screening, it might be a viable screening test. The potential disadvantage of radiation exposure is probably overemphasised, especially with newer technology. At this time-point, it is not entirely clear whether the detection of extracolonic findings at CTC is of net benefit and is cost effective, but with responsible handling, this may be the case. Future efforts will seek to further improve the technique, refine appropriate diagnostic algorithms and study cost-effectiveness.

Bots M.L.,University Utrecht | Sutton-Tyrrell K.,University of Pittsburgh
Journal of the American College of Cardiology | Year: 2012

Carotid intima-media thickness (CIMT) measurements have been used in cardiovascular research for more than 2 decades. There is a wealth of evidence showing that CIMT can be assessed in a reproducible manner and that increased CIMT relates to unfavorable risk factor levels and atherosclerosis elsewhere in the arterial system and to the risk of vascular events. Change in CIMT over time can be readily assessed, and trials showed that the rate of change is modifiable by treatment. Several issues important for the cardiovascular research community and its application in clinical practice are still outstanding. Promising future areas for CIMT measurements are: 1) application in studies among children and adolescents; 2) use of CIMT trials positioned decisively before the start of a morbidity and mortality trial; and 3) the use of CIMT measurement in risk stratification in those with an intermediate 10-year risk estimate. © 2012 American College of Cardiology Foundation.

Knol M.J.,University Utrecht | VanderWeele T.J.,Harvard University
International Journal of Epidemiology | Year: 2012

Authors often do not give sufficient information to draw conclusions about the size and statistical significance of interaction on the additive and multiplicative scales. To improve this, we provide four steps, template tables and examples. We distinguish two cases: when the causal effect of intervening on one exposure, across strata of another factor, is of interest ('effect modification'); and when the causal effect of intervening on two exposures is of interest ('interaction'). Assume we study whether X modifies the effect of A on D, where A, X and D are dichotomous. We propose presenting: (i) relative risks (RRs), odds ratios (ORs) or risk differences (RDs) for each (A, X) stratum with a single reference category taken as the stratum with the lowest risk of D; (ii) RRs, ORs or RDs for A within strata of X; (iii) interaction measures on additive and multiplicative scales; (iv) the A-D confounders adjusted for. Assume we study the interaction between A and B on D, where A, B and D are dichotomous. Steps (i) and (iii) are similar to presenting effect modification. (ii) Present RRs, ORs or RDs for A within strata of B and for B within strata of A. (iv) List the A-D and B-D confounders adjusted for. These four pieces of information will provide a reader the information needed to assess effect modification or interaction. The presentation can be further enriched when exposures have multiple categories. Our proposal hopefully encourages researchers to present effect modification and interaction analyses in as informative a manner as possible. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved.

Bolhuis J.J.,University Utrecht | Okanoya K.,RIKEN | Okanoya K.,University of Tokyo | Scharff C.,Free University of Berlin
Nature Reviews Neuroscience | Year: 2010

Vocal imitation in human infants and in some orders of birds relies on auditory-guided motor learning during a sensitive period of development. It proceeds from 'babbling' (in humans) and 'subsong' (in birds) through distinct phases towards the full-fledged communication system. Language development and birdsong learning have parallels at the behavioural, neural and genetic levels. Different orders of birds have evolved networks of brain regions for song learning and production that have a surprisingly similar gross anatomy, with analogies to human cortical regions and basal ganglia. Comparisons between different songbird species and humans point towards both general and species-specific principles of vocal learning and have identified common neural and molecular substrates, including the forkhead box P2 (FOXP2) gene. © 2010 Macmillan Publishers Limited. All rights reserved.

Melanoma is the most lethal form of skin cancer and successful treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence of resistance, whereas immunotherapy is mainly effective in selected subsets of patients. Thus, there is a need to identify new targets to improve treatment of metastatic melanoma. To this extent, we searched for markers that are elevated in melanoma and are under regulation of potentially druggable enzymes. Here, we show that the pro-proliferative transcription factor FOXM1 is elevated and activated in malignant melanoma. FOXM1 activity correlated with expression of the enzyme Pin1, which we found to be indicative of a poor prognosis. In functional experiments, Pin1 proved to be a main regulator of FOXM1 activity through MEK-dependent physical regulation during the cell cycle. The Pin1-FOXM1 interaction was enhanced by BRAFV600E, the driver oncogene in the majority of melanomas, and in extrapolation of the correlation data, interference with\ Pin1 in BRAFV600E-driven metastatic melanoma cells impaired both FOXM1 activity and cell survival. Importantly, cell-permeable Pin1-FOXM1-blocking peptides repressed the proliferation of melanoma cells in freshly isolated human metastatic melanoma ex vivo and in three-dimensional-cultured patient-derived melanoids. When combined with the BRAFV600E-inhibitor PLX4032 a robust repression in melanoid viability was obtained, establishing preclinical value of patient-derived melanoids for prognostic use of drug sensitivity and further underscoring the beneficial effect of Pin1-FOXM1 inhibitory peptides as anti-melanoma drugs. These proof-of-concept results provide a starting point for development of therapeutic Pin1-FOXM1 inhibitors to target metastatic melanoma.Oncogene advance online publication, 17 August 2015; doi:10.1038/onc.2015.282. © 2015 Macmillan Publishers Limited

Pieters R.J.,University Utrecht
Advances in Experimental Medicine and Biology | Year: 2011

In the process of adhesion, bacteria often carry proteins on their surface, adhesins, that bind to specific components of tissue cells or the extracellular matrix. In many cases these components are carbohydrate structures. The carbohydrate binding specificities of many bacteria have been uncovered over the years. The design and synthesis of inhibitors of bacterial adhesion has the potential to create new therapeutics for the prevention and possibly treatment of bacterial infections. Unfortunately, the carbohydrate structures often bind only weakly to the adhesion proteins, although drug design approaches can improve the situation. Furthermore, in some cases linking carbohydrates covalently together, to create so-called multivalent systems, can also significantly enhance the inhibitory potency. Besides adhesion inhibition as a potential therapeutic strategy, the adhesion proteins can also be used for detection. Novel methods to do this are being developed. These include the use of microarrays and glyconanoparticles. New developments in these areas are discussed. © 2011 Springer Science+Business Media B.V.

Vanderschuren L.J.,University Utrecht
Cold Spring Harbor perspectives in medicine | Year: 2013

It is increasingly recognized that studying drug taking in laboratory animals does not equate to studying genuine addiction, characterized by loss of control over drug use. This has inspired recent work aimed at capturing genuine addiction-like behavior in animals. In this work, we summarize empirical evidence for the occurrence of several DSM-IV-like symptoms of addiction in animals after extended drug use. These symptoms include escalation of drug use, neurocognitive deficits, resistance to extinction, increased motivation for drugs, preference for drugs over nondrug rewards, and resistance to punishment. The fact that addiction-like behavior can occur and be studied in animals gives us the exciting opportunity to investigate the neural and genetic background of drug addiction, which we hope will ultimately lead to the development of more effective treatments for this devastating disorder.

Prakken B.,University Utrecht | Albani S.,Sanford Burnham Institute for Medical Research | Martini A.,University of Genoa
The Lancet | Year: 2011

Juvenile idiopathic arthritis is a heterogeneous group of diseases characterised by arthritis of unknown origin with onset before age of 16 years. Pivotal studies in the past 5 years have led to substantial progress in various areas, ranging from disease classification to new treatments. Gene expression profiling studies have identified different immune mechanisms in distinct subtypes of the disease, and can help to redefine disease classification criteria. Moreover, immunological studies have shown that systemic juvenile idiopathic arthritis is an acquired autoinflammatory disease, and have led to successful studies of both interleukin-1 and interleukin-6 blockade. In other forms of the disease, synovial inflammation is the consequence of a disturbed balance between proinflammatory effector cells (such as T-helper-17 cells), and anti-inflammatory regulatory cells (such as FOXP3-positive regulatory T cells). Moreover, specific soluble biomarkers (S100 proteins) can guide individual treatment. Altogether these new developments in genetics, immunology, and imaging are instrumental to better define, classify, and treat patients with juvenile idiopathic arthritis. © 2011 Elsevier Ltd.

Middelburg J.J.,University Utrecht
Biogeosciences | Year: 2014

Stable isotopes have been used extensively to study food-web functioning, that is, the flow of energy and matter among organisms. Traditional food-web studies are based on the natural variability of isotopes and are limited to larger organisms that can be physically separated from their environment. Recent developments allow isotope ratio measurements of microbes and this in turn allows the measurement of entire food webs, in other words, from small producers at the bottom to large consumers at the top. Here, I provide a concise review on the use and potential of stable isotopes to reconstruct end-to-end food webs. I will first discuss food web reconstruction based on natural abundances isotope data and will then show that the use of stable isotopes as deliberately added tracers provides complementary information. Finally, challenges and opportunities for end-to-end food web reconstructions in a changing world are discussed. © Author(s) 2014.

Rothwell P.M.,University of Oxford | Algra A.,University Utrecht | Amarenco P.,University Paris Diderot
The Lancet | Year: 2011

Stroke is a major cause of death and disability worldwide. Without improvements in prevention, the burden will increase during the next 20 years because of the ageing population, especially in developing countries. Major advances have occurred in secondary prevention during the past three decades, which demonstrate the broader potential to prevent stroke. We review the main medical treatments that should be considered for most patients with transient ischaemic attack or ischaemic stroke in the acute phase and the long term, and draw attention to recent developments. © 2011 Elsevier Ltd.

Van Der Schee W.,University Utrecht | Romatschke P.,University of Colorado at Boulder | Pratt S.,Michigan State University
Physical Review Letters | Year: 2013

We present a fully dynamical simulation of central nuclear collisions around midrapidity at LHC energies. Unlike previous treatments, we simulate all phases of the collision, including the equilibration of the system. For the simulation, we use numerical relativity solutions to anti-de Sitter space/conformal field theory for the preequilibrium stage, viscous hydrodynamics for the plasma equilibrium stage, and kinetic theory for the low-density hadronic stage. Our preequilibrium stage provides initial conditions for hydrodynamics, resulting in sizable radial flow. The resulting light particle spectra reproduce the measurements from the ALICE experiment at all transverse momenta. © 2013 American Physical Society.

Hakanen J.J.,Finnish Institute of Occupational Health | Schaufeli W.B.,University Utrecht
Journal of Affective Disorders | Year: 2012

Background: Burnout and work engagement have been viewed as opposite, yet distinct states of employee well-being. We investigated whether work-related indicators of well-being (i.e. burnout and work engagement) spill-over and generalize to context-free well-being (i.e. depressive symptoms and life satisfaction). More specifically, we examined the causal direction: does burnout/work engagement lead to depressive symptoms/life satisfaction, or the other way around? Methods: Three surveys were conducted. In 2003, 71% of all Finnish dentists were surveyed (n = 3255), and the response rate of the 3-year follow-up was 84% (n = 2555). The second follow-up was conducted four years later with a response rate of 86% (n = 1964). Structural equation modeling was used to investigate the cross-lagged associations between the study variables across time. Results: Burnout predicted depressive symptoms and life dissatisfaction from T1 to T2 and from T2 to T3. Conversely, work engagement had a negative effect on depressive symptoms and a positive effect on life satisfaction, both from T1 to T2 and from T2 to T3, even after adjusting for the impact of burnout at every occasion. Limitations: The study was conducted among one occupational group, which limits its generalizability. Conclusions: Work-related well-being predicts general wellbeing in the long-term. For example, burnout predicts depressive symptoms and not vice versa. In addition, burnout and work engagement are not direct opposites. Instead, both have unique, incremental impacts on life satisfaction and depressive symptoms. © 2012 Elsevier B.V.

Loss of cellular adhesion leads to the progression of breast cancer through acquisition of anchorage independence, also known as resistance to anoikis. Although inactivation of E-cadherin is essential for acquisition of anoikis resistance, it has remained unclear how metastatic breast cancer cells counterbalance the induction of apoptosis without E-cadherin-dependent cellular adhesion. We report here that E-cadherin inactivation in breast cancer cells induces PI3K/AKT-dependent FOXO3 inhibition and identify FOXO3 as a novel and direct transcriptional activator of the pro-apoptotic protein BMF. As a result, E-cadherin-negative breast fail to upregulate BMF upon transfer to anchorage independence, leading to anoikis resistance. Conversely, expression of BMF in E-cadherin-negative metastatic breast cancer cells is sufficient to inhibit tumour growth and dissemination in mice. In conclusion, we have identified repression of BMF as a major cue that underpins anoikis resistance and tumour dissemination in E-cadherin-deficient metastatic breast cancer.Cell Death and Differentiation advance online publication, 1 April 2016; doi:10.1038/cdd.2016.33. © 2016 Macmillan Publishers Limited

Jakobsson L.,Karolinska Institutet | van Meeteren L.A.,University Utrecht
Experimental Cell Research | Year: 2013

Blood vessels are composed of endothelial cells, mural cells (smooth muscle cells and pericytes) and their shared basement membrane. During embryonic development a multitude of signaling components orchestrate the formation of new vessels. The process is highly dependent on correct dosage, spacing and timing of these signaling molecules. As vessels mature some cascades remain active, albeit at very low levels, and may be reactivated upon demand. Members of the Transforming growth factor Β (TGF-Β) protein family are strongly engaged in developmental angiogenesis but are also regulators of vascular integrity in the adult. In humans various genetic alterations within this protein family cause vascular disorders, involving disintegration of vascular integrity. Here we summarize and discuss recent data gathered from conditional and endothelial cell specific genetic loss-of-function of members of the TGF-Β family in the mouse. © 2013 Elsevier Inc.

Bosch J.L.H.R.,University Utrecht | Weiss J.P.,SUNY Downstate Medical School
Journal of Urology | Year: 2013

Purpose: Nocturia is a troubling condition with implications for daytime functioning. However, it often goes unreported. Many prevalence studies exist but differences in populations and definitions of nocturia render assimilation of the data difficult. This review provides an overview of the nocturia prevalence literature. Materials and Methods: A PubMed® search was performed to identify articles published in English from 1990 to February 2009 reporting nocturia prevalence in community based populations. Rates reported as overall data, and by age and by gender, were plotted for comparison. Results: A total of 43 relevant articles were identified. Prevalence rates in younger men (20 to 40 years) were 1 or more voids in 11% to 35.2% and 2 or more voids in 2% to 16.6%. Prevalence rates in younger women were 1 or more voids in 20.4% to 43.9% and 2 or more voids in 4.4% to 18%. In older men (older than 70 years) rates were 1 or more void in 68.9% to 93% and 2 or more voids in 29% to 59.3%. In older women rates were 1 or more void in 74.1% to 77.1% and 2 or more voids in 28.3% to 61.5%. Therefore, in practice up to 1 in 5 or 6 younger people consistently wake to void at least twice each night. In some studies younger women appeared more likely to be affected than men. Up to 60% of older people void 2 or more times nightly. Conclusions: Nocturia is common across populations. It is most prevalent in older people but it also affects a significant proportion of younger individuals. Clinicians should be alert to the possibility that nocturia may impact the sleep, quality of life and overall health of their patients. Since the condition is highly multifactorial, frequency-volume charts are invaluable tools for the diagnosis of underlying factors and for treatment selection. © 2013 American Urological Association Education and Research, Inc.

Boelen P.,University Utrecht
Anxiety, Stress and Coping | Year: 2010

Research has shown that intolerance of uncertainty (IU) - the tendency to react negatively to situations that are uncertain - is involved in worry and generalized anxiety disorder, as well as in other anxiety symptoms and disorders. To our knowledge, no studies have yet examined the association between IU and emotional distress connected with the death of a loved one. Yet, it seems plausible that those who have more difficulties to tolerate the uncertainties that oftentimes occur following such a loss experience more intense distress. The current study examined this assumption, using self-reported data from 134 bereaved individuals. Findings showed that IU was positively and significantly correlated with symptom levels of complicated grief and posttraumatic stress disorder (PTSD), even when controlling for time since loss (the single demographic/loss-related variable associated with symptom levels), and for neuroticism and worry, which are both correlates of IU. Furthermore, IU was specifically related with worry and symptom levels of PTSD, but not complicated grief, when controlling the shared variance between worry, complicated grief severity, and PTSD-severity. The present findings complement prior research that has shown that IU is a cognitive vulnerability factor for worry, and indicate that it may also be involved in emotional distress following loss. © 2010 Taylor & Francis.

Dittrich B.,Albert Einstein Institute | Hohn P.A.,University Utrecht
Classical and Quantum Gravity | Year: 2012

A general canonical formalism for discrete systems is developed, which can handle varying phase space dimensions and constraints. The central ingredient is Hamilton's principal function that generates canonical time evolution and ensures that the canonical formalism reproduces the dynamics of the covariant formulation following directly from the action. We apply this formalism to simplicial gravity and (Euclidean) Regge calculus, in particular. A discrete forward/backward evolution is realized by gluing/removing single simplices step by step to/from a bulk triangulation and amounts to Pachner moves in the triangulated hypersurfaces. As a result, the hypersurfaces evolve in a discrete multi-fingered time through the full Regge solution. Pachner moves are an elementary and ergodic class of homeomorphisms and generically change the number of variables, but can be implemented as canonical transformations on naturally extended phase spaces. Some moves introduce a priori free data that, however, may become fixed a posteriori by constraints arising in subsequent moves. The end result is a general and fully consistent formulation of canonical Regge calculus, thereby removing a longstanding obstacle in connecting covariant simplicial gravity models to canonical frameworks. The presented scheme is, therefore, interesting in view of many approaches to quantum gravity, but may also prove useful for numerical implementations. © 2012 IOP Publishing Ltd.

Sandler H.,German Cancer Research Center | Kreth J.,German Cancer Research Center | Timmers H.T.M.,University Utrecht | Stoecklin G.,German Cancer Research Center
Nucleic Acids Research | Year: 2011

The carbon catabolite repressor protein 4 (Ccr4)-Negative on TATA (Not) complex controls gene expression at two levels. In the nucleus, it regulates the basal transcription machinery, nuclear receptor-mediated transcription and histone modifications. In the cytoplasm, the complex is required for messenger RNA (mRNA) turnover through its two associated deadenylases, Ccr4 and Caf1. Not1 is the largest protein of the Ccr4-Not complex and serves as a scaffold for other subunits of the complex. Here, we provide evidence that human Not1 in the cytoplasm associates with the C-terminal domain of tristetraprolin (TTP), an RNA binding protein that mediates rapid degradation of mRNAs containing AU-rich elements (AREs). Not1 shows extensive interaction through its central region with TTP, whereas binding of Caf1 is restricted to a smaller central domain within Not1. Importantly, Not1 is required for the rapid decay of ARE-mRNAs, and TTP can recruit the Caf1 deadenylase only in presence of Not1. Thus, cytoplasmic Not1 provides a platform that allows a specific RNA binding protein to recruit the Caf1 deadenylase and thereby trigger decay of its target mRNAs. © 2011 The Author(s).

Zoller S.,ETH Zurich | Zoller S.,Swiss Institute of Bioinformatics | Schneider A.,University Utrecht
Molecular Biology and Evolution | Year: 2013

Amino acid substitution matrices describe the rates by which amino acids are replaced during evolution. In contrast to nucleotide or codon models, amino acid substitution matrices are in general parameterless and empirically estimated, probably because there is no obvious parametrization for amino acid substitutions. Principal component analysis has previously been used to improve codon substitution models by empirically finding the most relevant parameters. Here, we apply the same method to amino acid substitution matrices, leading to a semiempirical substitution model that can adjust the transition rates to the protein sequences under investigation. Our new model almost invariably achieves the best likelihood values in large-scale comparisons with established amino acid substitution models OTT, WAG, and LC). In particular for longer alignments, these likelihood gains are considerably larger than what could be expected from simply having more parameters. The application of our model differs from that of mixture models (such as UL2 or UL3), as we optimize one rate matrix per alignment, whereas mixture models apply the variation per alignments site. This makes our model computationally more efficient, while the performance is comparable to that of UL3. Applied to the phylogenetic problem of the origin of placental mammals, our new model and the UL3 mixed model are the only ones of the tested models that cluster Afrotheria and Xenarthra into a clade called Atlantogenata, which would be in correspondence with recent findings using more sophisticated phylogenetic methods. © The Author 2012.

Devuyst O.,Catholic University of Louvain | Devuyst O.,University of Zurich | Knoers N.V.A.M.,University Utrecht | Remuzzi G.,Centro Anna Maria Astori | Schaefer F.,University of Heidelberg
The Lancet | Year: 2014

At least 10% of adults and nearly all children who receive renal-replacement therapy have an inherited kidney disease. These patients rarely die when their disease progresses and can remain alive for many years because of advances in organ-replacement therapy. However, these disorders substantially decrease their quality of life and have a large effect on health-care systems. Since the kidneys regulate essential homoeostatic processes, inherited kidney disorders have multisystem complications, which add to the usual challenges for rare disorders. In this review, we discuss the nature of rare inherited kidney diseases, the challenges they pose, and opportunities from technological advances, which are well suited to target the kidney. Mechanistic insights from rare disorders are relevant for common disorders such as hypertension, kidney stones, cardiovascular disease, and progression of chronic kidney disease.

Snippert H.J.,University Utrecht
Cell | Year: 2016

The notion that the colon's deep crypt pockets provide a protected location that shields stem cells from potentially toxic substances is widely accepted. In this issue of Cell, Kaiko et al. reveal how a metabolite abundantly produced by the gut microbiota can inhibit stem cell proliferation but is blocked from doing so by crypt architecture. © 2016 Elsevier Inc.

Moss A.C.,Center for Inflammatory Bowel Disease | Brinks V.,University Utrecht | Carpenter J.F.,Aurora Pharmaceutical
Alimentary Pharmacology and Therapeutics | Year: 2013

Background Anti-drug antibodies (ADAs) to biologic therapies contribute to the loss of response and infusion reactions to anti-TNF drugs in patients with inflammatory bowel disease (IBD). The reasons behind this immunogenicity are complex, and have not been the focus of a dedicated review for prescribers. Aim To provide an overview of the patient, product and prescriber factors, which have been associated with the immunogenicity of anti-TNF therapy, and draw conclusions for clinical practice. Methods Review of representative observational studies and clinical trials from the IBD and other literature, which report associations with ADA development, with a focus on infliximab and adalimumab. Results ADAs develop in 10-20% of patients receiving anti-TNF maintenance therapy, and these patients are three times more likely to lose response as ADA-negative patients. Patient genotype plays a role in ADA risk in a minority of patients, but age or disease type is not a major factor. Drug mishandling, such as agitation or freeze-thaw cycles, can induce protein aggregates, which are known to be immunogenic. Prescription of maintenance therapy with concomitant immunomodulators, and achieving suitable trough drug levels, reduces the risk of ADAs in patients with IBD. Conclusions Patients and prescribers can take several steps to reduce the risk of development of anti-drug antibodies to anti-TNF antibodies. Further research is required to determine if immunogenic factors identified in other situations apply to use of anti-TNFs in IBD. © 2013 John Wiley & Sons Ltd.

Nierkens S.,Radboud University Nijmegen | Nierkens S.,University Utrecht | Tel J.,Radboud University Nijmegen | Janssen E.,University of Cincinnati | Adema G.J.,Radboud University Nijmegen
Trends in Immunology | Year: 2013

Antigen cross-presentation describes the process through which dendritic cells (DCs) acquire exogenous antigens for presentation on MHC class I molecules. The ability to cross-present has been thought of as a feature of specialized DC subsets. Emerging data, however, suggest that the cross-presenting ability of each DC subset is tuned by and dependent on several factors, such as DC location and activation status, and the type of antigen and inflammatory signals. Thus, we argue that capacity of cross-presentation is not an exclusive trait of one or several distinct DC subtypes, but rather a common feature of the DC family in both mice and humans. Understanding DC subset activation and antigen-presentation pathways might yield improved tools and targets to exploit the unique cross-presenting capacity of DCs in immunotherapy. © 2013 Elsevier Ltd.

Den Hartog S.A.M.,Pennsylvania State University | Spiers C.J.,University Utrecht
Journal of Geophysical Research: Solid Earth | Year: 2014

A microphysical model is developed for the steady state frictional behavior of illite-quartz fault gouge and applied to subduction megathrust P-T conditions. The model assumes a foliated, phyllosilicate-supported microstructure which shears by rate-independent frictional slip on the aligned phyllosilicates plus thermally activated deformation of the intervening quartz clasts. At low slip rates or high temperatures, the deformation of the clasts is easy, accommodating slip on the foliation without dilatation. With increasing velocity or decreasing temperature, the shear of the clasts becomes more difficult, increasing bulk shear strength, until slip is activated on inclined portions of the phyllosilicate foliation, where it anastomoses around the clasts. Slip at these sites leads to dilation involving clast/matrix debonding, balanced, at steady state, by compaction through thermally activated clast deformation. Model predictions, taking pressure solution as the thermally activated mechanism, show three regimes of velocity-dependent frictional behavior at temperatures in the range of 200-500°C, with velocity weakening occurring at 300-400°C, in broad agreement with previous experiments on illite-quartz gouge. Effects of slip rate, normal stress, and quartz fraction predicted by the model also resemble those seen experimentally. Extrapolation of themodel to earthquake nucleation slip rates successfully predicts the onset of velocity-weakening behavior at the updip seismogenic limit on subduction megathrusts. The model further implies that the onset of seismogenesis is controlled by the thermally activated initiation of fault rock compaction through pressure solution of quartz, which counteracts dilatation due to slip on the fault rock foliation. ©2014. American Geophysical Union.

Meye F.J.,Institute du Fer a Moulin | Meye F.J.,French Institute of Health and Medical Research | Meye F.J.,University Pierre and Marie Curie | Adan R.A.H.,University Utrecht
Trends in Pharmacological Sciences | Year: 2014

Overconsumption of high caloric food plays an important role in the etiology of obesity. Several factors drive such hedonic feeding. High caloric food is often palatable. In addition, when an individual is sated, stress and food-related cues can serve as potent feeding triggers. A better understanding of the neurobiological underpinnings of food palatability and environmentally triggered overconsumption would aid the development of new treatment strategies. In the current review we address the pivotal role of the mesolimbic dopamine reward system in the drive towards high caloric palatable food and its relation to stress- and cue-induced feeding. We also discuss how this system may be affected by both established and potential anti-obesity drug targets. © 2013 Elsevier Ltd. All rights reserved.

Matsumoto T.,University Utrecht | Yoshida K.,Kyoto University
Journal of High Energy Physics | Year: 2014

We consider γ-deformations of the AdS5×S5 superstring as Yang-Baxter sigma models with classical r-matrices satisfying the classical Yang-Baxter equation (CYBE). An essential point is that the classical r-matrices are composed of Cartan generators only and then generate abelian twists. We present examples of the r-matrices that lead to real γ-deformations of the AdS5×S5 superstring. Finally we discuss a possible classification of integrable deformations and the corresponding gravity solution in terms of solutions of CYBE. This classification may be called the gravity/CYBE correspondence. © 2014 The Author(s).

Clevers H.,University Utrecht
Cell | Year: 2016

Recent advances in 3D culture technology allow embryonic and adult mammalian stem cells to exhibit their remarkable self-organizing properties, and the resulting organoids reflect key structural and functional properties of organs such as kidney, lung, gut, brain and retina. Organoid technology can therefore be used to model human organ development and various human pathologies 'in a dish." Additionally, patient-derived organoids hold promise to predict drug response in a personalized fashion. Organoids open up new avenues for regenerative medicine and, in combination with editing technology, for gene therapy. The many potential applications of this technology are only beginning to be explored. © 2016 Elsevier Inc.

Cats are strict carnivores and in the wild rely on a diet solely based on animal tissues to meet their specific and unique nutritional requirements. Although the feeding ecology of cats in the wild has been well documented in the literature, there is no information on the precise nutrient profile to which the cat's metabolism has adapted. The present study aimed to derive the dietary nutrient profile of free-living cats. Studies reporting the feeding habits of cats in the wild were reviewed and data on the nutrient composition of the consumed prey items obtained from the literature. Fifty-five studies reported feeding strategy data of cats in the wild. After specific exclusion criteria, twenty-seven studies were used to derive thirty individual dietary nutrient profiles. The results show that feral cats are obligatory carnivores, with their daily energy intake from crude protein being 52 %, from crude fat 46 % and from N-free extract only 2 %. Minerals and trace elements are consumed in relatively high concentrations compared with recommended allowances determined using empirical methods. The calculated nutrient profile may be considered the nutrient intake to which the cat's metabolic system has adapted. The present study provides insight into the nutritive, as well as possible non-nutritive aspects of a natural diet of whole prey for cats and provides novel ways to further improve feline diets to increase health and longevity.

VanderWeele T.J.,Harvard University | Knol M.J.,University Utrecht
Annals of Internal Medicine | Year: 2011

In randomized trials with subgroup analyses, the primary treatment or intervention of interest is randomized, but the secondary factors defining subgroups are not. This article clarifies when confounding is an issue in subgroup analyses. If investigators are interested simply in targeting subpopulations for intervention, control for confounding is not needed. If investigators are interested in intervening on the secondary factors that define the subgroups to increase the treatment effect or in attributing the subgroup differences to the secondary factors themselves, then confounding is relevant and must be controlled for. The authors demonstrate this point by using examples from published randomized trials. © 2011 American College of Physicians.

Lovelock C.E.,University of Oxford | Rinkel G.J.E.,University Utrecht | Rothwell P.M.,University of Oxford
Neurology | Year: 2010

BACKGROUND: Treatment of aneurysmal subarachnoid hemorrhage (SAH) has changed substantially over the last 25 years but there is a lack of reliable population-based data on whether case-fatality or functional outcomes have improved. METHODS: We determined changes in the standardized incidence and outcome of SAH in the same population between 1981 and 1986 (Oxford Community Stroke Project) and 2002 and 2008 (Oxford Vascular Study). In a meta-analysis with other population-based studies, we used linear regression to determine time trends in outcome. RESULTS: There were no reductions in incidence of SAH (RR = 0.79, 95% confidence interval [CI] 0.48-1.29, p = 0.34) and in 30-day case-fatality (RR = 0.67, 95% CI 0.39-1.13, p = 0.14) in the Oxford Vascular Study vs Oxford Community Stroke Project, but there was a decrease in overall mortality (RR = 0.47, 0.23-0.97, p = 0.04). Following adjustment for age and baseline SAH severity, patients surviving to hospital had reduced risk of death or dependency (modified Rankin score > 3) at 12 months in the Oxford Vascular Study (RR = 0.51, 0.29-0.88, p = 0.01). Among 32 studies covering 39 study periods from 1980 to 2005, 7 studied time trends within single populations. Unadjusted case-fatality fell by 0.9% per annum (0.3-1.5, p = 0.007) in a meta-analysis of data from all studies, and by 0.9% per annum (0.2-1.6%, p = 0.01) within the 7 population studies. CONCLUSION: Mortality due to subarachnoid hemorrhage fell by about 50% in our study population over the last 2 decades, due mainly to improved outcomes in cases surviving to reach hospital. This improvement is consistent with a significant decrease in case-fatality over the last 25 years in our pooled analysis of other similar population-based studies. Copyright © 2010 by AAN Enterprises, Inc.

The immune system plays a major role in protecting the host against viral infection. Rapid initial protection is conveyed by innate immune cells, while adaptive immunity (including T lymphocytes) requires several days to develop, yet provides high specificity and long-lasting memory. Invariant natural killer T (iNKT) cells are an unusual subset of T lymphocytes, expressing a semi-invariant T cell receptor together with markers of the innate NK cell lineage. Activated iNKT cells can exert direct cytolysis and can rapidly release a variety of immune-polarizing cytokines, thereby regulating the ensuing adaptive immune response. iNKT cells recognize lipids in the context of the antigen-presenting molecule CD1d. Intriguingly, CD1d-restricted iNKT cells appear to play a critical role in anti-viral defense: increased susceptibility to disseminated viral infections is observed both in patients with iNKT cell deficiency as well as in CD1d- and iNKT cell-deficient mice. Moreover, viruses have recently been found to use sophisticated strategies to withstand iNKT cell-mediated elimination. This review focuses on CD1d-restricted lipid presentation and the strategies viruses deploy to subvert this pathway.

Ben-Elia E.,University Utrecht | Shiftan Y.,Technion - Israel Institute of Technology
Transportation Research Part A: Policy and Practice | Year: 2010

This paper presents a learning-based model of route-choice behavior when information is provided in real time. In a laboratory controlled experiment, participants made a long series of binary route-choice trials relying on real-time information and learning from their personal experience reinforced through feedback. A discrete choice model with a Mixed Logit specification, accounting for panel effects, was estimated based on the experiment's data. It was found that information and experience have a combined effect on drivers' route-choice behavior. Informed participants had faster learning rates and tended to base their decisions on memorization relating to previous outcomes whereas non-informed participants were slower in learning, required more exploration and tended to rely mostly on recent outcomes. Informed participants were more prone to risk-seeking and had greater sensitivity to travel time variability. In comparison, non-informed participants appeared to be more risk-averse and less sensitive to variability. These results have important policy implications on the design and implementation of ATIS initiatives. The advantage of incorporating insights from Prospect Theory and reinforced learning to improve the realism of travel behavior models is also discussed. © 2010 Elsevier Ltd. All rights reserved.

Chen G.-Q.,Tsinghua University | Patel M.K.,University Utrecht
Chemical Reviews | Year: 2012

A technical and environmental review dealt with the derivation of plastics from biological sources in the past and to be done so in the future. Bio-based sustainable plastics needed to be developed to avoid problems caused by the petrochemical plastics. Materials derived from biological sources including starch, cellulose, fatty acids, sugars, proteins, and other sources were consumed by microorganisms that converted these raw materials into various monomers. These monomers were suitable for polymer production including, hydroxyalkanoic acids, D- and L-lactic acid, succinic acid, bio-1,4-butanediol, (R)-3-hydroxypropionic acid, bio-ethylene, and 1,3-propanediol. These monomers were used to produce various bio-based plastics including polyhydroxyalkanoates (PHA), polylactic acid (PLA), and poly(butylene succinate) (PBS).

Roussel-Jazede V.,University Utrecht
Molecular membrane biology | Year: 2011

Autotransporters produced by Gram-negative bacteria consist of an N-terminal signal sequence, a C-terminal translocator domain (TD), and a passenger domain in between. The TD facilitates the secretion of the passenger across the outer membrane. It generally consists of a channel-forming β-barrel that can be plugged by an α-helix that is formed by a polypeptide fragment immediately N-terminal to the barrel domain in the sequence. In this work, we characterized the TD of the hemoglobin protease Hbp of Escherichia coli by comparing its properties with the TDs of NalP of Neisseria meningitidis and IgA protease of Neisseria gonorrhoeae. All TDs were produced in inclusion bodies and folded in vitro. In the case of the TD of Hbp, this procedure resulted in autocatalytic intramolecular processing, which mimicked the in vivo processing. Liposome-swelling assays and planar lipid bilayer experiments revealed that the pore of the Hbp TD was largely obstructed. In contrast, an Hbp TD variant that lacked only one amino-acid residue from the N terminus showed the opening and closing of a channel comparable to what was reported for the TD of NalP. Additionally, the naturally processed helix contributed to the stability of the TD, as shown by chemical denaturation monitored by tryptophan fluorescence. Overall these results show that Hbp is processed by an autocatalytic intramolecular mechanism resulting in the stable docking of the α-helix in the barrel. In addition, we could show that the α-helix contributes to the stability of TDs.

Hogeweg L.,University Utrecht
Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention | Year: 2010

Automatic detection of tuberculosis (TB) on chest radiographs is a difficult problem because of the diverse presentation of the disease. A combination of detection systems for abnormalities and normal anatomy is used to improve detection performance. A textural abnormality detection system operating at the pixel level is combined with a clavicle detection system to suppress false positive responses. The output of a shape abnormality detection system operating at the image level is combined in a next step to further improve performance by reducing false negatives. Strategies for combining systems based on serial and parallel configurations were evaluated using the minimum, maximum, product, and mean probability combination rules. The performance of TB detection increased, as measured using the area under the ROC curve, from 0.67 for the textural abnormality detection system alone to 0.86 when the three systems were combined. The best result was achieved using the sum and product rule in a parallel combination of outputs.

In recent years, many mouse models have been developed to mark and trace the fate of adult cell populations using fluorescent proteins. High-resolution visualization of such fluorescent markers in their physiological setting is thus an important aspect of adult stem cell research. Here we describe a protocol to produce sections (150-200 μm) of near-native tissue with optimal tissue and cellular morphology by avoiding artifacts inherent in standard freezing or embedding procedures. The activity of genetically expressed fluorescent proteins is maintained, thereby enabling high-resolution three-dimensional (3D) reconstructions of fluorescent structures in virtually all types of tissues. The procedure allows immunofluorescence labeling of proteins to depths up to 50 μm, as well as a chemical 'Click-iT' reaction to detect DNA-intercalating analogs such as ethynyl deoxyuridine (EdU). Generation of near-native sections ready for imaging analysis takes approximately 2-3 h. Postsectioning processes, such as antibody labeling or EdU detection, take up to 10 h.

Persengiev S.P.,University Utrecht
Discovery medicine | Year: 2012

The study of microRNA (miRNA) regulation in the pathogenesis of autoimmune diseases and hematopoietic malignancies provides new understanding of the mechanisms of disease and is currently the focus of many researchers in the field. Autoimmune disorders and cancers of immune system comprise a wide range of genetically complex diseases that share certain aspects of dysregulated genetic networks, most notably deactivation of apoptosis. miRNA mechanisms control gene expression at the post-transcriptional level, linking mRNA processing and gene function. Considerable amount of data have been accumulated that indicate that the alteration of miRNA expression closely mirrors the development of immune system diseases and is likely to play a role in their pathogenesis. However, a knowledge gap remains in our understanding of how miRNA dysregulation and the specific effects of miRNAs on target gene expression underlay the disease phenotype. Here we review a number of studies describing miRNA alterations in autoimmune diseases and hematopoietic cancers and discuss potential miRNA-regulated mechanisms that differentially influence the development of autoimmunity as compared to cancer progression.

Gene expression-based classification systems have identified an aggressive colon cancer subtype with mesenchymal features, possibly reflecting epithelial-to-mesenchymal transition (EMT) of tumor cells. However, stromal fibroblasts contribute extensively to the mesenchymal phenotype of aggressive colon tumors, challenging the notion of tumor EMT. To separately study the neoplastic and stromal compartments of colon tumors, we have generated a stroma gene filter (SGF). Comparative analysis of stromahigh and stromalow tumors shows that the neoplastic cells in stromahigh tumors express specific EMT drivers (ZEB2, TWIST1, TWIST2) and that 98% of differentially expressed genes are strongly correlated with them. Analysis of differential gene expression between mesenchymal and epithelial cancer cell lines revealed that hepatocyte nuclear factor 4α (HNF4α), a transcriptional activator of intestinal (epithelial) differentiation, and its target genes are highly expressed in epithelial cancer cell lines. However, mesenchymal-type cancer cell lines expressed only part of the mesenchymal genes expressed by tumor-derived neoplastic cells, suggesting that external cues were lacking. We found that collagen-I dominates the extracellular matrix in aggressive colon cancer. Mimicking the tumor microenvironment by replacing laminin-rich Matrigel with collagen-I was sufficient to induce tumor-specific mesenchymal gene expression, suppression of HNF4α and its target genes, and collective tumor cell invasion of patient-derived colon tumor organoids. The data connect collagen-rich stroma to mesenchymal gene expression in neoplastic cells and to collective tumor cell invasion. Targeting the tumor-collagen interface may therefore be explored as a novel strategy in the treatment of aggressive colon cancer.Oncogene advance online publication, 21 March 2016; doi:10.1038/onc.2016.60. © 2016 Macmillan Publishers Limited

Since the concentration of free iron in the human host is low, efficient iron-acquisition mechanisms constitute important virulence factors for pathogenic bacteria. In Gram-negative bacteria, TonB-dependent outer membrane receptors are implicated in iron acquisition. It is far less clear how other metals that are also scarce in the human host are transported across the bacterial outer membrane. With the aim of identifying novel vaccine candidates, we characterized in this study a hitherto unknown receptor in Neisseria meningitidis. We demonstrate that this receptor, designated ZnuD, is produced under zinc limitation and that it is involved in the uptake of zinc. Upon immunization of mice, it was capable of inducing bactericidal antibodies and we could detect ZnuD-specific antibodies in human convalescent patient sera. ZnuD is highly conserved among N. meningitidis isolates and homologues of the protein are found in many other Gram-negative pathogens, particularly in those residing in the respiratory tract. We conclude that ZnuD constitutes a promising candidate for the development of a vaccine against meningococcal disease for which no effective universal vaccine is available. Furthermore, the results suggest that receptor-mediated zinc uptake represents a novel virulence mechanism that is particularly important for bacterial survival in the respiratory tract.

Visser G.H.A.,University Utrecht
Journal of Obstetrics and Gynaecology Canada | Year: 2012

This review assesses the rise and fall of the unique Dutch system of obstetric care. Why did home deliveries continue in the Netherlands when they almost completely disappeared in the rest of the Western world? Why is the Dutch system currently under so much pressure? Did the participants continue for too long with too conservative an approach? Which of the good things of the past have been lost? © 2012 Society of Obstetricians and Gynaecologists of Canada.

Zufferey S.,University Utrecht
Journal of Pragmatics | Year: 2014

I argue that the communication of given information is part of the procedural instructions conveyed by some connectives like the French puisque. I submit in addition that the encoding of givenness has cognitive implications that are visible during online processing. I assess this hypothesis empirically by comparing the way the clauses introduced by two French causal connectives, puisque and parce que, are processed during online reading when the following segment is 'given' or 'new'. I complement these results by an acceptability judgement task using the same sentences. These experiments confirm that introducing a clause conveying given information is a core feature characterizing puisque, as the segment following it is read faster when it contains given rather than new information, and puisque is rated as more acceptable than parce que in such contexts. I discuss the implications of these results for future research on the description of the meaning of connectives. © 2013 Elsevier B.V.

Schrickx J.A.,University Utrecht
Veterinary Journal | Year: 2014

Inhibition of the drug transporter P-glycoprotein (P-gp) by the oral flea preventative spinosad has been suggested as the underlying cause of the drug-drug interaction with ivermectin. In this study, an in vitro model consisting of canine cells was validated to describe the inhibitory effect of drugs on canine P-gp. In this model, ivermectin, cyclosporin, verapamil, loperamide and ketoconazole inhibited P-gp function with IC50 values ranging from 0.1 to 3.7μmol/L. Spinosad was a potent inhibitor of canine P-gp with an IC50 value of 0.27μmol/L or 0.2μg/mL. The risk of spinosad causing P-gp related drug-drug interactions in the dog could be predicted by the IC50 value, the oral dosage and plasma concentrations. © 2014 Elsevier Ltd.

Koster E.S.,University Utrecht
Journal of managed care pharmacy : JMCP | Year: 2014

The number of patients using methotrexate (MTX) has increased during the last decade. Because of the narrow therapeutic range and potential risks of incorrect use, vigilance is required when dispensing MTX. In 2009, the Royal Dutch Pharmacists Society, in accordance with the Dutch Health Care Inspectorate, published safe MTX dispensing recommendations for community pharmacies. To examine adherence to recommendations aimed at safe {line separator}MTX dispensing. This study was conducted within a convenience sample of 78 community pharmacies belonging to the Utrecht Pharmacy Practice Network for Education and Research (UPPER). Data were collected in May 2011. 95 pharmacists and 337 pharmacy technicians were interviewed to assess self-reported adherence with dispensing recommendations. In addition, medication records for patients using MTX were extracted in 52 pharmacies in order to objectively assess adoption of recommendations. More than 75% of the pharmacists and pharmacy technicians reported to be adherent to 6 of the 11 recommendations. There are variations in reported adherence between team members working in 1 pharmacy; higher adherence rates ( greater than 75%) for the pharmacy team as a whole were only shown for 2 recommendations (recording of day of intake on the label and moment of authorization by the pharmacist). The medication records showed that adherence with working procedures significantly increased: The number of dispensed records with notification of the day of intake on the medication label increased from 9.9% of the records per pharmacy in 2008 to 77.1% in 2010 (P less than 0.001). Dutch community pharmacies seem to be adherent to most safe dispensing recommendations. However, inconsistencies exist between team members that emphasize the importance of addressing this issue and discussing recommendations within the team, as there is still room for improvement to ensure safe dispensing.

Siersema P.D.,University Utrecht
Endoscopy | Year: 2015

Publication of scientific manuscripts remains our core method of sharing knowledge and advanced scientific inquiry. Pressures to publish for reasons other than pure discovery have the potential to corrupt this process. The core principles of scientific ethics outlined above provide guidance on how to maintain the integrity of our scientific process. We, as journal editors, are committed to the advancement of scientific knowledge and the ethical process of publication. We do the best we can to make sure that the articles we publish fulfill all the criteria of a well-conducted study. © Georg Thieme Verlag KGStuttgart New York.

Van der Stigchel S.,University Utrecht
Vision Research | Year: 2010

In recent years, the number of studies that have used deviations of saccade trajectories as a measure has rapidly increased. This review discusses these recent studies and summarizes advances in this field. A division can be made into studies that have used saccade deviations to measure the amount of attention allocated in space and studies that have measured the strength of the activity of a distractor. Saccade deviations have also been used to measure target selection in special populations. Most importantly, recent studies have revealed novel knowledge concerning the spatial tuning and temporal dynamics of target selection in the oculomotor system. Deviations in saccade trajectories have shown to constitute a valuable measure of various processes that control and influence our behavior which can be applied to multiple domains. © 2010 Elsevier Ltd.

Clevers H.,University Utrecht
Nature Medicine | Year: 2011

Over the last decade, the notion that tumors are maintained by their own stem cells, the so-called cancer stem cells, has created great excitement in the research community. This review attempts to summarize the underlying concepts of this notion, to distinguish hard facts from beliefs and to define the future challenges of the field. © 2011 Nature America, Inc. All rights reserved.

Van Smeden M.,University Utrecht
American Journal of Epidemiology | Year: 2014

Latent class models (LCMs) combine the results of multiple diagnostic tests through a statistical model to obtain estimates of disease prevalence and diagnostic test accuracy in situations where there is no single, accurate reference standard. We performed a systematic review of the methodology and reporting of LCMs in diagnostic accuracy studies. This review shows that the use of LCMs in such studies increased sharply in the past decade, notably in the domain of infectious diseases (overall contribution: 59%). The 64 reviewed studies used a range of differently specified parametric latent variable models, applying Bayesian and frequentist methods. The critical assumption underlying the majority of LCM applications (61%) is that the test observations must be independent within 2 classes. Because violations of this assumption can lead to biased estimates of accuracy and prevalence, performing and reporting checks of whether assumptions are met is essential. Unfortunately, our review shows that 28% of the included studies failed to report any information that enables verification of model assumptions or performance. Because of the lack of information on model fit and adequate evidence "external" to the LCMs, it is often difficult for readers to judge the validity of LCM-based inferences and conclusions reached. © The Author 2013.

Akhmanova A.,University Utrecht | Dogterom M.,FOM Institute for Atomic and Molecular Physics
Cell | Year: 2011

The ability of growing microtubules to undergo catastrophes-abrupt switches from growth to shortening-is one of the key aspects of microtubule dynamics important for shaping cellular microtubule arrays. Gardner et al. show that catastrophes occur at a microtubule age-dependent rate and that depolymerizing kinesins can affect this process in fundamentally different ways. © 2011 Elsevier Inc.

van Nuland R.,University Utrecht
PloS one | Year: 2013

The process of eukaryotic transcription initiation involves the assembly of basal transcription factor complexes on the gene promoter. The recruitment of TFIID is an early and important step in this process. Gene promoters contain distinct DNA sequence elements and are marked by the presence of post-translationally modified nucleosomes. The contributions of these individual features for TFIID recruitment remain to be elucidated. Here, we use immobilized reconstituted promoter nucleosomes, conventional biochemistry and quantitative mass spectrometry to investigate the influence of distinct histone modifications and functional DNA-elements on the binding of TFIID. Our data reveal synergistic effects of H3K4me3, H3K14ac and a TATA box sequence on TFIID binding in vitro. Stoichiometry analyses of affinity purified human TFIID identified the presence of a stable dimeric core. Several peripheral TAFs, including those interacting with distinct promoter features, are substoichiometric yet present in substantial amounts. Finally, we find that the TAF3 subunit of TFIID binds to poised promoters in an H3K4me3-dependent manner. Moreover, the PHD-finger of TAF3 is important for rapid induction of target genes. Thus, fine-tuning of TFIID engagement on promoters is driven by synergistic contacts with both DNA-elements and histone modifications, eventually resulting in a high affinity interaction and activation of transcription.

Grieve A.G.,University Utrecht
Cold Spring Harbor perspectives in biology | Year: 2011

Classical secretion consists of the delivery of transmembrane and soluble proteins to the plasma membrane and the extracellular medium, respectively, and is mediated by the organelles of the secretory pathway, the Endoplasmic Reticulum (ER), the ER exit sites, and the Golgi, as described by the Nobel Prize winner George Palade (Palade 1975). At the center of this transport route, the Golgi stack has a major role in modifying, processing, sorting, and dispatching newly synthesized proteins to their final destinations. More recently, however, it has become clear that an increasing number of transmembrane proteins reach the plasma membrane unconventionally, either by exiting the ER in non-COPII vesicles or by bypassing the Golgi. Here, we discuss the evidence for Golgi bypass and the possible physiological benefits of it. Intriguingly, at least during Drosophila development, Golgi bypass seems to be mediated by a Golgi protein, dGRASP, which is found ectopically localized to the plasma membrane.

Kawaguchi I.,Kyoto University | Matsumoto T.,University Utrecht | Yoshida K.,Kyoto University
Journal of High Energy Physics | Year: 2014

We consider Jordanian deformations of the AdS5×S 5 superstring action. These deformations correspond to non-standard q-deformations. In particular, it is possible to perform a partial deformation, for example, of the AdS5 part only, or of the S5 part only. Then the classical action and the Lax pair are constructed with a linear, twisted and extended R operator. It is shown that the action preserves the symmetry. © The Authors.

Lozano R.,University Utrecht
Corporate Social Responsibility and Environmental Management | Year: 2015

Since company boards are increasingly discussing 'sustainability', it becomes necessary to examine the nature of sustainability drivers. Most approaches to corporate sustainability drivers have focused either on internal or external drivers. This paper is aimed at providing a more holistic perspective on the different corporate sustainability drivers in order to better catalyse change from the unsustainable status quo to a more sustainable-oriented state. Empirical data was collected from experts and company leaders. The findings show that, internally, leadership and the business case are the most important drivers, whilst the most important external drivers are reputation, customer demands and expectations, and regulation and legislation. The paper proposes a corporate sustainability driver model, which considers both internal and external drivers, and complements these with drivers that connect them. This offers a holistic perspective on how companies can be more proactive in their journey to becoming more sustainability orientated. © 2013 John Wiley & Sons, Ltd and ERP Environment.

Avalos A.M.,Whitehead Institute For Biomedical Research | Meyer-Wentrup F.,University Utrecht | Ploegh H.L.,Whitehead Institute For Biomedical Research
Advances in Immunology | Year: 2014

The B-cell receptor (BCR) for antigen is a key sensor required for B-cell development, survival, and activation. Rigorous selection checkpoints ensure that the mature B-cell compartment in the periphery is largely purged of self-reactive B cells. However, autoreactive B cells escape selection and persist in the periphery as anergic or clonally ignorant B cells. Under the influence of genetic or environmental factors, which are not completely understood, autoreactive B cells may be activated. Similar activation can also occur at different stages of B-cell maturation in the bone marrow or in peripheral lymphoid organs and give rise to malignant B cells. The pathology that typifies neoplastic lymphocytes and autoreactive B cells differs: malignant B cells proliferate and occupy niches otherwise taken up by healthy leukocytes or erythrocytes, while autoreactive B cells produce pathogenic antibodies or present self-antigen to T cells. However, both malignant and autoreactive B cells share the commonality of deregulated BCR pathways as principal contributors to pathogenicity. We first summarize current views of BCR activation. We then explore how anomalous BCR pathways correlate with malignancies and autoimmunity. We also elaborate on the activation of TLR pathways in abnormal B cells and how they contribute to maintenance of pathology. Finally, we outline the benefits and emergence of mouse models generated by somatic cell nuclear transfer to study B-cell function in manners for which current transgenic models may be less well suited. © 2014 Elsevier Inc.

Spek A.L.,University Utrecht
Acta Crystallographica Section C: Structural Chemistry | Year: 2015

The completion of a crystal structure determination is often hampered by the presence of embedded solvent molecules or ions that are seriously disordered. Their contribution to the calculated structure factors in the least-squares refinement of a crystal structure has to be included in some way. Traditionally, an atomistic solvent disorder model is attempted. Such an approach is generally to be preferred, but it does not always lead to a satisfactory result and may even be impossible in cases where channels in the structure are filled with continuous electron density. This paper documents the SQUEEZE method as an alternative means of addressing the solvent disorder issue. It conveniently interfaces with the 2014 version of the least-squares refinement program SHELXL [Sheldrick (2015). Acta Cryst. C71. In the press] and other refinement programs that accept externally provided fixed contributions to the calculated structure factors. The PLATON SQUEEZE tool calculates the solvent contribution to the structure factors by back-Fourier transformation of the electron density found in the solvent-accessible region of a phase-optimized difference electron-density map. The actual least-squares structure refinement is delegated to, for example, SHELXL. The current versions of PLATON SQUEEZE and SHELXL now address several of the unnecessary complications with the earlier implementation of the SQUEEZE procedure that were a necessity because least-squares refinement with the now superseded SHELXL97 program did not allow for the input of fixed externally provided contributions to the structure-factor calculation. It is no longer necessary to subtract the solvent contribution temporarily from the observed intensities to be able to use SHELXL for the least-squares refinement, since that program now accepts the solvent contribution from an external file (.fab file) if the ABIN instruction is used. In addition, many twinned structures containing disordered solvents are now also treatable by SQUEEZE. The details of a SQUEEZE calculation are now automatically included in the CIF archive file, along with the unmerged reflection data. The current implementation of the SQUEEZE procedure is described, and discussed and illustrated with three examples. Two of them are based on the reflection data of published structures and one on synthetic reflection data generated for a published structure. © 2015 International Union of Crystallography.

van Kampen H.S.,University Utrecht
Behavioural Processes | Year: 2015

To be able to reproduce, animals need to survive and interact with an ever changing environment. Therefore, they create a cognitive representation of that environment, from which they derive expectancies regarding current and future events. These expected events are compared continuously with information gathered through exploration, to guide behaviour and update the existing representation. When a moderate discrepancy between perceived and expected events is detected, exploration is employed to update the internal representation so as to alter the expectancy and make it match the perceived event. When the discrepancy is relatively large, exploration is inhibited, and animals will try to alter the perceived event utilizing aggression or fear. The largest discrepancies are associated with a tendency to flee. When an exploratory, fear, or aggressive behaviour pattern proofs to be the optimal solution for a particular discrepancy, the response will become conditioned to events that previously preceded the occurrence of that discrepancy. When primary needs are relatively low, animals will actively look for or create moderately violated expectancies in order to learn about objects, behaviour patterns, and the environment. In those situations, exploratory tendencies will summate with ongoing behaviour and, when all primary needs are satiated, may even be performed exclusively. This results in behavioural variability, play, and active information-seeking.This article is part of a Special Issue entitled: In Honor of Jerry Hogan. © 2014 Elsevier B.V.

Diederen K.M.,University Utrecht
Psychological medicine | Year: 2013

Although auditory verbal hallucinations (AVH) are a core symptom of schizophrenia, they also occur in non-psychotic individuals, in the absence of other psychotic, affective, cognitive and negative symptoms. AVH have been hypothesized to result from deviant integration of inferior frontal, parahippocampal and superior temporal brain areas. However, a direct link between dysfunctional connectivity and AVH has not yet been established. To determine whether hallucinations are indeed related to aberrant connectivity, AVH should be studied in isolation, for example in non-psychotic individuals with AVH. Resting-state connectivity was investigated in 25 non-psychotic subjects with AVH and 25 matched control subjects using seed regression analysis with the (1) left and (2) right inferior frontal, (3) left and (4) right superior temporal and (5) left parahippocampal areas as the seed regions. To correct for cardiorespiratory (CR) pulsatility rhythms in the functional magnetic resonance imaging (fMRI) data, heartbeat and respiration were monitored during scanning and the fMRI data were corrected for these rhythms using the image-based method for retrospective correction of physiological motion effects RETROICOR. In comparison with the control group, non-psychotic individuals with AVH showed increased connectivity between the left and the right superior temporal regions and also between the left parahippocampal region and the left inferior frontal gyrus. Moreover, this group did not show a negative correlation between the left superior temporal region and the right inferior frontal region, as was observed in the healthy control group. Aberrant connectivity of frontal, parahippocampal and superior temporal brain areas can be specifically related to the predisposition to hallucinate in the auditory domain.

What is the impact of initiating GnRH antagonist co-treatment for in vitro fertilization (IVF) on cycle day (CD) 2 compared with CD 6 on live birth rate (LBR) per started cycle and on the cumulative live birth rate (CLBR)? Early initiation of GnRH antagonist does not appear to improve clinical outcomes of IVF compared with midfollicular initiation. During ovarian stimulation for IVF, GnRH antagonist co-treatment is usually administered from the midfollicular phase onwards. Earlier initiation may improve the follicular phase hormonal milieu and therefore overall clinical outcomes. This open-label, multicentre randomized controlled trial was conducted between September 2009 and July 2011. A web-based program was used for randomization and 617 IVF-intracytoplasmic sperm injection (ICSI) patients were included. Recombinant FSH (150-225 IU) was administered daily from CD 2 onwards in both groups. The study group (CD2; n = 308) started GnRH antagonist co-treatment on CD 2, whereas the control group (CD6; n = 309) started on CD 6. There were no significant differences in clinical outcomes between the two groups. A non-significant trend towards a higher LBR per started cycle and CLBR was observed in the CD6 group compared with the CD2 group (LBR: 24.0 versus 21.5%, P = 0.5; CLBR: 29.9 versus 26.7%, P = 0.6). The study was terminated prematurely because no significant difference was observed in clinical outcomes after 617 inclusions. A much larger study population would be needed to detect a small significant difference in favour of either study arm, which raises the question of whether this would be relevant for clinical practice. The present study shows that the additional treatment burden and costs of starting GnRH antagonist on CD 2 instead of on CD 6 are not justified, as early initiation of GnRH antagonist does not improve LBRs. This study was partially supported by a grant from Merck Serono. O.H., M.J.C.E, A.V., P.A.D., R.E.B., G.J.E.O., C.A.G.H., G.C.D.M., H.J.V., P.F.M.H. and A.B. have nothing to declare. F.J.B. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gedeon Richter, Merck Serono, MSD and Roche. B.J.C. has received fees and grant support from the following companies (in alphabetic order): Ferring, Merck Serono and MSD. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, Ferring, Merck Serono and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, MSD, Merck Serono, Organon, Schering Plough and Serono. N.S.M. has received fees and grant support from the following companies (in alphabetic order): Anecova, Ferring, Merck Serono, MSD, Organon and Serono. www.clinicaltrials.gov, no. NCT00866034.

Kenemans J.L.,University Utrecht
Neuroscience and Biobehavioral Reviews | Year: 2015

Inhibition concerns the capacity to suppress on-going response tendencies. Patient data and results from neuro-imaging and magnetic-stimulation studies point to a proactive mechanism involving top-down control signals that potentiate inhibitory sensory-motor connections, depending on whether possibly necessary inhibition is anticipated or not. The proactive mechanism is manifest in stronger sensory-cortex responses to stop signals yielding successful inhibition, observed as a modulation of short-latency human evoked potentials (N1) which may overlap with generic mechanisms for infrequent-event detection. A second, reactive, mechanism would be much more independent of the specific inhibition context, and generalize to situations in which behavioral interrupt is not dictated by task demands but invoked by the salience of task-irrelevant but potentially distracting events. The reactive mechanism is visible in a longer-latency human event-related potential termed frontal P3 (fP3) which is elicited by (successful) stop stimuli and most likely originates from dorsal-medial prefrontal cortex (preSMA), and is dissociated from the proactive mechanism pharmacologically and by individual differences. Implications may arise for more personalized treatments of disorders such as ADHD. © 2015 Elsevier Ltd.

Beckers G.J.L.,University Utrecht | Rattenborg N.C.,Max Planck Institute for Ornithology (Seewiesen)
Neuroscience and Biobehavioral Reviews | Year: 2015

Brain rhythms occurring during sleep are implicated in processing information acquired during wakefulness, but this phenomenon has almost exclusively been studied in mammals. In this review we discuss the potential value of utilizing birds to elucidate the functions and underlying mechanisms of such brain rhythms. Birds are of particular interest from a comparative perspective because even though neurons in the avian brain homologous to mammalian neocortical neurons are arranged in a nuclear, rather than a laminar manner, the avian brain generates mammalian-like sleep-states and associated brain rhythms. Nonetheless, until recently, this nuclear organization also posed technical challenges, as the standard surface EEG recording methods used to study the neocortex provide only a superficial view of the sleeping avian brain. The recent development of high-density multielectrode recording methods now provides access to sleep-related brain activity occurring deep in the avian brain. Finally, we discuss how intracerebral electrical imaging based on this technique can be used to elucidate the systems-level processing of hippocampal-dependent and imprinting memories in birds. © 2014 Elsevier Ltd.

Olivier B.,University Utrecht | Olivier B.,Yale University
European Journal of Pharmacology | Year: 2015

The neurotransmitter serotonin is an evolutionary ancient molecule that has remarkable modulatory effects in almost all central nervous system integrative functions, such as mood, anxiety, stress, aggression, feeding, cognition and sexual behavior. After giving a short outline of the serotonergic system (anatomy, receptors, transporter) the authors contributions over the last 40 years in the role of serotonin in depression, aggression, anxiety, stress and sexual behavior is outlined. Each area delineates the work performed on animal model development, drug discovery and development. Most of the research work described has started from an industrial perspective, aimed at developing animals models for psychiatric diseases and leading to putative new innovative psychotropic drugs, like in the cases of the SSRI fluvoxamine, the serenic eltoprazine and the anxiolytic flesinoxan. Later this research work mainly focused on developing translational animal models for psychiatric diseases and implicating them in the search for mechanisms involved in normal and diseased brains and finding new concepts for appropriate drugs. © 2014 Elsevier B.V. All rights reserved.

Dantzer R.,University of Houston | Heijnen C.J.,University of Houston | Heijnen C.J.,University Utrecht | Kavelaars A.,University of Houston | And 2 more authors.
Trends in Neurosciences | Year: 2014

The exact nature and pathophysiology of fatigue remain largely elusive despite its high prevalence in physically ill patients. Studies on the relationship between the immune system and the central nervous system provide a new perspective on the mechanisms of fatigue. Inflammatory mediators that are released by activated innate immune cells at the periphery and in the central nervous system alter the metabolism and activity of neurotransmitters, generate neurotoxic compounds, decrease neurotrophic factors, and profoundly disturb the neuronal environment. The resulting alterations in fronto-striatal networks together with the activation of insula by inflammatory interoceptive stimuli underlie the many dimensions of fatigue including reduced incentive motivation, decreased behavioral flexibility, uncertainty about usefulness of actions, and awareness of fatigue. © 2013.

To assess the consequences of applying different mortality timeframes on standardised mortality ratios of individual hospitals and, secondarily, to evaluate the association between in-hospital standardised mortality ratios and early post-discharge mortality rate, length of hospital stay, and transfer rate. Retrospective analysis of routinely collected hospital data to compare observed deaths in 50 diagnostic categories with deaths predicted by a case mix adjustment method. 60 Dutch hospitals. 1 228 815 patients discharged in the period 2008 to 2010. In-hospital standardised mortality ratio, 30 days post-admission standardised mortality ratio, and 30 days post-discharge standardised mortality ratio. Compared with the in-hospital standardised mortality ratio, 33% of the hospitals were categorised differently with the 30 days post-admission standardised mortality ratio and 22% were categorised differently with the 30 days post-discharge standardised mortality ratio. A positive association was found between in-hospital standardised mortality ratio and length of hospital stay (Pearson correlation coefficient 0.33; P=0.01), and an inverse association was found between in-hospital standardised mortality ratio and early post-discharge mortality (Pearson correlation coefficient -0.37; P=0.004). Applying different mortality timeframes resulted in differences in standardised mortality ratios and differences in judgment regarding the performance of individual hospitals. Furthermore, associations between in-hospital standardised mortality rates, length of stay, and early post-discharge mortality rates were found. Combining these findings suggests that standardised mortality ratios based on in-hospital mortality are subject to so-called "discharge bias." Hence, early post-discharge mortality should be included in the calculation of standardised mortality ratios.

Tauzin B.,University Utrecht | Debayle E.,Ecole Normale Superieure de Lyon | Wittlinger G.,French National Center for Scientific Research
Nature Geoscience | Year: 2010

Within the upper mantle, the seismic discontinuity at 410-km depth marks the top of the transition zone and is attributed to pressure-induced transformation of olivine into wadsleyite mineral assemblage. Just above the 410-km discontinuity, a layer characterized by low seismic wave velocities has been identified regionally. This low velocity layer shows poor lateral continuity and is thought to represent partial melting induced by local effects, such as the dehydration of subducted crust or the dehydration of water-bearing silicates beneath continental platforms in association with mantle plumes. However, some models predict that the low-velocity layer should extend globally, because the weaker water storage capacity of upper mantle minerals should induce partial melting of water-bearing silicates throughout this region. Here we report seismic observations from 89 stations worldwide that indicate a thick, intermittent low-velocity layer is located near 350 km depth in the mantle. The low velocity layer is not limited to regions associated with subduction or mantle plumes, and shows no affinity to a particular tectonic environment. We suggest that our data image the thickest parts of a more continuous global structure that shows steep lateral variations in thickness. The presence of a global layer of partial melt above the 410-km discontinuity would modify material circulation in the Earth mantle and may help to reconcile geophysical and geochemical observations. © 2010 Macmillan Publishers Limited. All rights reserved.

Smallenburg F.,University of Rome La Sapienza | Filion L.,University Utrecht | Sciortino F.,University of Rome La Sapienza
Nature Physics | Year: 2014

One of the most controversial hypotheses for explaining the origin of the thermodynamic anomalies characterizing liquid water postulates the presence of a metastable second-order liquid-liquid critical point located in the 'no-man's land'. In this scenario, two liquids with distinct local structure emerge near the critical temperature. Unfortunately, as spontaneous crystallization is rapid in this region, experimental support for this hypothesis relies on significant extrapolations, either from the metastable liquid or from amorphous solid water. Although the liquid-liquid transition is expected to feature in many tetrahedrally coordinated liquids, including silicon, carbon and silica, even numerical studies of atomic and molecular models have been unable to conclusively prove the existence of this transition. Here we provide such evidence for a model in which it is possible to continuously tune the softness of the interparticle interaction and the flexibility of the bonds, the key ingredients controlling the existence of the critical point. We show that conditions exist where the full coexistence is thermodynamically stable with respect to crystallization. Our work offers a basis for designing colloidal analogues of water exhibiting liquid-liquid transitions in equilibrium, opening the way for experimental confirmation of the original hypothesis.

Feelders A.,University Utrecht
Proceedings - IEEE International Conference on Data Mining, ICDM | Year: 2010

In many applications of data mining we know beforehand that the response variable should be increasing (or decreasing) in the attributes. Such relations between response and attributes are called monotone. In this paper we present a new algorithm to compute an optimal monotone classification of a data set for convex loss functions. Moreover, we show how the algorithm can be extended to compute all optimal monotone classifications with little additional effort. Monotone relabeling is useful for at least two reasons. Firstly, models trained on relabeled data sets often have better predictive performance than models trained on the original data. Secondly, relabeling is an important building block for the construction of monotone classifiers. We apply the new algorithm to investigate the effect on the prediction error of relabeling the training sample for k nearest neighbour classification and classification trees. In contrast to previous work in this area, we consider all optimal monotone relabelings. The results show that, for small training samples, relabeling the training data results in significantly better predictive performance. © 2010 IEEE.

Adan R.A.H.,University Utrecht
Trends in Neurosciences | Year: 2013

Regulation of body weight is organized by distributed brain circuits that use a variety of neuropeptides and transmitters, and that are responsive to endocrine and metabolic signals. Targeting of these circuits with novel pharmaceutical drugs would be helpful additions to lifestyle interventions for the treatment of obesity. The recent FDA approval of two anti-obesity drugs holds promise in a field in which previous drugs were removed from clinical use because of unacceptable psychiatric and cardiovascular side effects. Here, the modes of action of anti-obesity drugs are reviewed. © 2012 Elsevier Ltd.

Biessels G.J.,University Utrecht | Reagan L.P.,University of South Carolina | Reagan L.P.,Wm Jennings Bryan Dorn Veterans Affairs Medical Center
Nature Reviews Neuroscience | Year: 2015

Clinical studies suggest a link between type 2 diabetes mellitus (T2DM) and insulin resistance (IR) and cognitive dysfunction, but there are significant gaps in our knowledge of the mechanisms underlying this relationship. Animal models of IR help to bridge these gaps and point to hippocampal IR as a potential mediator of cognitive dysfunction in T2DM, as well as in Alzheimer disease (AD). This Review highlights these observations and discusses intervention studies which suggest that the restoration of insulin activity in the hippocampus may be an effective strategy to alleviate the cognitive decline associated with T2DM and AD. © 2015 Macmillan Publishers Limited.

Iseger T.A.,Kings College London | Bossong M.G.,Kings College London | Bossong M.G.,University Utrecht
Schizophrenia Research | Year: 2015

Despite extensive study over the past decades, available treatments for schizophrenia are only modestly effective and cause serious metabolic and neurological side effects. Therefore, there is an urgent need for novel therapeutic targets for the treatment of schizophrenia. A highly promising new pharmacological target in the context of schizophrenia is the endocannabinoid system. Modulation of this system by the main psychoactive component in cannabis, δ9-tetrahydrocannabinol (THC), induces acute psychotic effects and cognitive impairment. However, the non-psychotropic, plant-derived cannabinoid agent cannabidiol (CBD) may have antipsychotic properties, and thus may be a promising new agent in the treatment of schizophrenia. Here we review studies that investigated the antipsychotic properties of CBD in human subjects. Results show the ability of CBD to counteract psychotic symptoms and cognitive impairment associated with cannabis use as well as with acute THC administration. In addition, CBD may lower the risk for developing psychosis that is related to cannabis use. These effects are possibly mediated by opposite effects of CBD and THC on brain activity patterns in key regions implicated in the pathophysiology of schizophrenia, such as the striatum, hippocampus and prefrontal cortex. The first small-scale clinical studies with CBD treatment of patients with psychotic symptoms further confirm the potential of CBD as an effective, safe and well-tolerated antipsychotic compound, although large randomised clinical trials will be needed before this novel therapy can be introduced into clinical practice. © 2015 Elsevier B.V.

Sattari S.Z.,Wageningen University | Bouwman A.F.,PBL Environmental Assessment Agency | Bouwman A.F.,University Utrecht | Giller K.E.,Wageningen University | Van Ittersum M.K.,Wageningen University
Proceedings of the National Academy of Sciences of the United States of America | Year: 2012

Phosphorus (P) is a finite and dwindling resource. Debate focuses on current production and use of phosphate rock rather than on the amounts of P required in the future to feed the world. We applied a two-pool soil P model to reproduce historical continental crop P uptake as a function of P inputs from fertilizer and manure and to estimate P requirements for crop production in 2050. The key feature is the consideration of the role of residual soil P in crop production. Model simulations closely fit historical P uptake for all continents. Cumulative inputs of P fertilizer and manure for the period 1965-2007 in Europe (1,115 kg·ha -1 of cropland) grossly exceeded the cumulative P uptake by crops (360 kg·ha -1). Since the 1980s in much of Europe, P application rates have been reduced, and uptake continues to increase due to the supply of plant-available P from residual soil P pool. We estimate that between 2008 and 2050 a global cumulative P application of 700-790 kg·ha -1 of cropland (in total 1,070-1,200 teragrams P) is required to achieve crop production according to the various Millennium Ecosystem Assessment scenarios [Alcamo J, Van Vuuren D, Cramer W (2006) Ecosystems and Human Well-Being: Scenarios, Vol 2, pp 279-354]. We estimate that average global P fertilizer use must change from the current 17.8 to 16.8-20.8 teragrams per year in 2050, which is up to 50% less than other estimates in the literature that ignore the role of residual soil P.

Magan J.M.,University Utrecht
Physical Review Letters | Year: 2016

Having analytical instances of the eigenstate thermalization hypothesis (ETH) is of obvious interest, both for fundamental and applied reasons. This is generally a hard task, due to the belief that nonlinear interactions are basic ingredients of the thermalization mechanism. In this article we prove that random Gaussian-free fermions satisfy ETH in the multiparticle sector, by analytically computing the correlations and entanglement entropies of the theory. With the explicit construction at hand, we finally comment on the differences between fully random Hamiltonians and random Gaussian systems, providing a physically motivated notion of randomness of the microscopic quantum state. © 2016 American Physical Society.

Gursoy U.,University Utrecht
Journal of High Energy Physics | Year: 2011

We investigate continuous Hawking-Page transitions in Einstein's gravity coupled to a scalar field with an arbitrary potential in the weak gravity limit. We show that this is only possible in a singular limit where the black-hole horizon marginally traps a curvature singularity. Depending on the subleading terms in the potential, a rich variety of continuous phase transitions arise. Our examples include second and higher order, including the Berezinskii- Kosterlitz-Thouless type. In the case when the scalar is dilaton, the condition for continuous phase transitions lead to (asymptotically) linear-dilaton background. We obtain the scaling laws of thermodynamic functions, as well as the viscosity coefficients near the transition. In the limit of weak gravitational interactions, the bulk viscosity asymptotes to a universal constant, independent of the details of the scalar potential. As a byproduct of our analysis we obtain a one-parameter family of kink solutions in arbitrary dimension d that interpolate between AdS near the boundary and linear-dilaton background in the deep interior. The continuous Hawking-Page transitions found here serve as holographic models for normal-to superfluid transitions.

Prokopec T.,University Utrecht
Journal of Cosmology and Astroparticle Physics | Year: 2015

We consider stochastic inflation in an interacting scalar field in spatially homogeneous accelerating space-times with a constant principal slow roll parameter. We show that, if the scalar potential is scale invariant (which is the case when scalar contains quartic self-interaction and couples non-minimally to gravity), the late-time solution on accelerating FLRW spaces can be described by a probability distribution function (PDF) ρ which is a function of H only, where () is the scalar field and H=H(t) denotes the Hubble parameter. We give explicit late-time solutions for ρarrow ρ (H), and thereby find the order corrections to the Starobinsky-Yokoyama result. This PDF can then be used to calculate e.g. various n-point functions of the (self-interacting) scalar field, which are valid at late times in arbitrary accelerating space-times with constant. © 2015 IOP Publishing Ltd and Sissa Medialab srl.

Biazin B.,Hawassa University | Sterk G.,University Utrecht
Agriculture, Ecosystems and Environment | Year: 2013

The Ethiopian Rift Valley is a dry land zone where for a long time pastoral communities have made their living from acacia-based woodlands. But many pastoralists have changed from a pastoral way of life to mixed farming over time. The aim of this study was to evaluate land-use and land cover (LULC) changes in the Central Rift Valley dry lands of Ethiopia, and determine the role of drought vulnerability as a driver. A combination of GIS/remote sensing techniques, drought vulnerability analyses, field observation and surveying were employed. Because drought vulnerability is linked more closely to the types of land-uses and social contexts rather than only climatological events, it was examined based on locally perceived criteria of drought. Accordingly, the pastoral way of life was vulnerable to severe drought during 25% of the last 28. years while the mixed farming (livestock and maize farming combined) system was vulnerable to severe drought only during 4% of the years. Over the last 5 decades, cultivated lands increased to threefold while the dense acacia coverage declined from 42% in 1965 to 9% in 2010. The observed LULC changes were driven by the interplay of recurrent drought, socioeconomic and institutional dynamics, access to markets and improved technologies such as early-maturing maize cultivars and better land management. Proper policy and technological interventions are required to develop appropriate drought adaptation strategies and avert the increasing degradation of woodlands in the Rift Valley dry lands where a pastoral way of life is still present. © 2012 Elsevier B.V.

De Rooij D.G.,University Utrecht | Griswold M.D.,Washington State University
Journal of Andrology | Year: 2012

This review focuses on 3 important advances in our understanding of rodent spermatogonial stem cells (SSC) that have emerged since 2000: the identity of SSC, the existence of a SSC niche, and gene expression in spermatogonia. It is now apparent that the original scheme, in which the Asingle (As) spermatogonia are the only stem cells, may be too simple. Rather, separation of pairs of Apaired (Apr) spermatogonia into singles might also play a role in the steady state situation. However, evidence that in the normal epithelium fragmentation of chains of Aaligned (Aal) spermatogonia into smaller clones also plays a role is not yet conclusive. New evidence presented during the last decade indicates that the As, Apr, and Aal (As,pr,al) spermatogonia are not localized at random over the tubule basal lamina, as originally assumed, but are restricted to those areas that border on interstitial tissue and, in particular, to areas containing venules and arterioles, suggesting a specific relationship of this localization with a possible SSC niche. Finally, gene expression studies are showing how both extrinsic factors produced by Sertoli cells and intrinsic factors that are products of the germ cells act either to maintain progenitor cells or to promote differentiation and the commitment to meiosis. Taken together, this new knowledge adds to our understanding of the balance between 2 opposing forces: one promoting the undifferentiated state and the other promoting the commitment to meiosis and differentiation that is essential for spermatogenesis to proceed. © American Society of Andrology.

Reggiori F.,University Utrecht | Klionsky D.J.,University of Michigan
Genetics | Year: 2013

Autophagy refers to a group of processes that involve degradation of cytoplasmic components including cytosol, macromolecular complexes, and organelles, within the vacuole or the lysosome of higher eukaryotes. The various types of autophagy have attracted increasing attention for at least two reasons. First, autophagy provides a compelling example of dynamic rearrangements of subcellular membranes involving issues of protein trafficking and organelle identity, and thus it is fascinating for researchers interested in questions pertinent to basic cell biology. Second, autophagy plays a central role in normal development and cell homeostasis, and, as a result, autophagic dysfunctions are associated with a range of illnesses including cancer, diabetes, myopathies, some types of neurodegeneration, and liver and heart diseases. That said, this review focuses on autophagy in yeast. Many aspects of autophagy are conserved from yeast to human; in particular, this applies to the gene products mediating these pathways as well as some of the signaling cascades regulating it, so that the information we relate is relevant to higher eukaryotes. Indeed, as with many cellular pathways, the initial molecular insights were made possible due to genetic studies in Saccharomyces cerevisiae and other fungi. © 2013 by the Genetics Society of America.

Dieleman J.M.,University Utrecht
Cochrane database of systematic reviews (Online) | Year: 2011

High-dose prophylactic corticosteroids are often administered during cardiac surgery. Their use, however, remains controversial, as no trials are available that have been sufficiently powered to draw conclusions on their effect on major clinical outcomes. The objective of this meta-analysis was to estimate the effect of prophylactic corticosteroids in cardiac surgery on mortality, cardiac and pulmonary complications. Major medical databases (CENTRAL, MEDLINE, EMBASE, CINAHL and Web of Science) were systematically searched for randomised studies assessing the effect of corticosteroids in adult cardiac surgery. Database were searched for the full period covered, up to December 2009. No language restrictions were applied. Randomised controlled trials comparing corticosteroid treatment to either placebo treatment or no treatment in adult cardiac surgery were selected. There were no restrictions with respect to length of the follow-up period. All selected studies qualified for pooling of results for one or more end-points. The processes of searching and selection for inclusion eligibility were performed independently by two authors. Also, quality assessment and data-extraction of selected studies were independently performed by two authors. The primary endpoints were mortality, cardiac and pulmonary complications. The main effect measure was the Peto odds ratio comparing corticosteroids to no treatment/placebo. Fifty-four randomised studies, mostly of limited quality, were included. Altogether, 3615 patients were included in these studies. The pooled odds ratio for mortality was 1.12 (95% CI 0.65 to 1.92), showing no mortality reduction in patients treated with corticosteroids. The odds ratios for myocardial and pulmonary complications were 0.95, (95% CI 0.57 to 1.60) and 0.83 (95% CI 0.49 to 1.40), respectively. The use of a random effects model did not substantially influence study results. Analyses of secondary endpoints showed a reduction of atrial fibrillation and an increase in gastrointestinal bleeding in the corticosteroids group. This meta-analysis showed no beneficial effect of corticosteroid use on mortality, cardiac and pulmonary complications in cardiac surgery patients.

Schutter D.J.L.G.,University Utrecht
Medical Hypotheses | Year: 2012

Depressive disorder can be viewed as an adaptive defense mechanism in response to excessive stress that has gone awry. The hypothalamic-pituitary-adrenal (HPA) axis is an important node in the brain's stress circuit and suggested to play a role in several subtypes of depression. While the hippocampus, amygdala and prefrontal cortex are considered important regions implicated in stress regulation and depressive disorder, the existence of reciprocal monosynaptic cerebello-hypothalamic connections and the presence of dense glucocorticoid binding sites point towards the view that the cerebellum plays a functional role in the regulation of HPA-axis as well. The present hypothesis may further contribute to contemporary neurobiological views on stress regulation and depressive disorder, and may offer a potential biological basis for developing novel neurosomatic treatment protocols. © 2012 Elsevier Ltd.

Lammers T.,University Utrecht | Lammers T.,German Cancer Research Center | Lammers T.,RWTH Aachen
Advanced Drug Delivery Reviews | Year: 2010

Copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer agents. HPMA copolymers circulate for prolonged periods of time, and by means of the Enhanced Permeability and Retention (EPR) effect, they localize to tumors both effectively and selectively. Because of their beneficial biodistribution, and because of the fact that they are able to improve the balance between the efficacy and the toxicity of chemotherapy, it is reasonable to assume that HPMA copolymers combine well with other treatment modalities. In the present review, efforts in this regard are summarized, and HPMA copolymers are shown to be able to beneficially interact with surgery, with radiotherapy, with hyperthermia, with photodynamic therapy, with chemotherapy and with each other. Together, the insights provided and the evidence obtained strongly suggest that HPMA copolymer-based nanomedicine formulations hold significant potential for improving the efficacy of combined modality anticancer therapy. © 2009 Elsevier B.V. All rights reserved.

Arts H.H.,Radboud University Nijmegen | Knoers N.V.A.M.,University Utrecht
Pediatric Nephrology | Year: 2013

Ciliopathies are a group of clinically and genetically overlapping disorders whose etiologies lie in defective cilia. These are antenna-like organelles on the apical surface of numerous cell types in a variety of tissues and organs, the kidney included. Cilia play essential roles during development and tissue homeostasis, and their dysfunction in the kidney has been associated with renal cyst formation and renal failure. Recently, the term "renal ciliopathies" was coined for those human genetic disorders that are characterized by nephronophthisis, cystic kidneys or renal cystic dysplasia. This review focuses on renal ciliopathies from a human genetics perspective. We survey the newest insights with respect to gene identification and genotype-phenotype correlations, and we reflect on candidate ciliopathies. The opportunities and challenges of next-generation sequencing (NGS) for genetic renal research and clinical DNA diagnostics are also reviewed, and we discuss the contribution of NGS to the development of personalized therapy for patients with renal ciliopathies. © 2012 The Author(s).

Voesenek L.A.C.J.,University Utrecht | Bailey-Serres J.,University of California at Riverside
Current Opinion in Plant Biology | Year: 2013

The investigation of flooding survival strategies in model, crop and wild plant species has yielded insights into molecular, physiological and developmental mechanisms of soil flooding (waterlogging) and submergence survival. The antithetical flooding escape and quiescence strategies of deepwater and submergence tolerant rice (Oryza sativa), respectively, are regulated by members of a clade of ethylene responsive factor transcriptional activators. This knowledge paved the way for the discovery that these proteins are targets of a highly conserved O2-sensing protein turnover mechanism in Arabidopsis thaliana. Further examples of genes that regulate transcription, root and shoot metabolism or development during floods have emerged. With the rapid advancement of genomic technologies, the mining of natural genetic variation in flooding tolerant wild species may ultimately benefit crop production. © 2013 Elsevier Ltd.

Meijer P.T.,University Utrecht
Marine Geology | Year: 2012

Theory for the dynamics of flow in sea straits holds promise to provide, in addition to geological evidence, insight into the configuration of the connection between the Mediterranean Sea and the Atlantic Ocean at the onset of the Messinian Salinity Crisis. This paper, for the first time, systematically explores the application of hydraulic control theory to the question of how, about 6. Ma ago, Mediterranean salinity could have risen to values associated with gypsum saturation. The theory is based on the notion that it is the greatest constriction of the flow between basin and ocean that acts to limit the exchange. The response of basin salinity to strait depth, strait width, and relative thickness of the outflow layer proves to be highly nonlinear. For strait width on the order of kilometres, an asymptotic rise in basin salinity occurs when the strait depth is on the order of a few tens of metres. Completely blocked outflow takes place when the depth is reduced to metres. The nonlinear nature of the system implies that even a slow gradual reduction in the sill depth leads to an event-like rise in basin salinity. For values of basin salinity approaching gypsum saturation the response of the basin to changes in the strait depth is significantly delayed. © 2012 Elsevier B.V.

Kalinina Ayuso V.,University Utrecht
Investigative ophthalmology & visual science | Year: 2013

To investigate the presence of biomarkers in aqueous humor (AH) from patients with uveitis associated with juvenile idiopathic arthritis (JIA). AH (N = 73) AND SERUM (N = 105) SAMPLES FROM 116 CHILDREN WERE ANALYZED USING SURFACE ENHANCED LASER DESORPTION/IONIZATION TIME OF FLIGHT MASS SPECTROMETRY (SELDI-TOF MS). JIA, silent chronic anterior uveitis (AU), other uveitis entities, and noninflammatory controls. Statistical biomarker identification was performed using the SELDI-ToF Biomarker Analysis Cluster Wizard followed by multivariate statistical analysis. Biochemical identification of biomarkers was performed by polyacrylamide gel protein separation, followed by liquid chromatography tandem mass spectrometry. ELISA was performed in a number of AH samples representing all four study groups. In the JIA group, one AH protein peak at mass/charge (m/z) 13,762 had qualitative and quantitative differences in expression compared with the other uveitis entities and the controls, but not to the group of silent chronic AU. Its quantitative expression in AH of patients with JIA and other silent chronic AU was positively associated with uveitis activity. The protein at m/z 13,762 in AH was identified as transthyretin (TTR). The TTR concentration in AH differed significantly between the study groups (P = 0.006) with considerably higher TTR concentrations in JIA and silent chronic AU samples positive for m/z 13,762 than those of the other uveitis and control groups. TTR is a potential intraocular biomarker of JIA- associated uveitis. Its role in the pathogenesis of silent chronic AU with and without arthritis needs further investigation.

Matsumoto T.,University Utrecht | Yoshida K.,Kyoto University
Journal of High Energy Physics | Year: 2014

We derive the gravity duals of noncommutative gauge theories from the Yang-Baxter sigma model description of the AdS5 × S5 superstring with classical r-matrices. The corresponding classical r-matrices are 1) solutions of the classical Yang-Baxter equation (CYBE), 2) skew-symmetric, 3) nilpotent and 4) abelian. Hence these should be called abelian Jordanian deformations. As a result, the gravity duals are shown to be integrable deformations of AdS5 × S5. Then, abelian twists of AdS5 are also investigated. These results provide a support for the gravity/CYBE correspondence proposed in arXiv:1404.1838. © 2014 The Author(s).

Van De Laar L.,Erasmus Medical Center | Coffer P.J.,University Utrecht | Coffer P.J.,Center for Cellular and Molecular Intervention | Woltman A.M.,Erasmus Medical Center
Blood | Year: 2012

Dendritic cells (DCs) represent a small and heterogeneous fraction of the hematopoietic system, specialized in antigen capture, processing, and presentation. The different DC subsets act as sentinels throughout the body and perform a key role in the induction of immunogenic as well as tolerogenic immune responses. Because of their limited lifespan, continuous replenishment of DC is required. Whereas the importance of GM-CSF in regulating DC homeostasis has long been underestimated, this cytokine is currently considered a critical factor for DC development under both steady-state and inflammatory conditions. Regulation of cellular actions by GM-CSF depends on the activation of intracellular signaling modules, including JAK/STAT, MAPK, PI3K, and canonical NF-κB. By directing the activity of transcription factors and other cellular effector proteins, these pathways influence differentiation, survival and/or proliferation of uncommitted hematopoietic progenitors, and DC subset-specific precursors, thereby contributing to specific aspects of DC subset development. The specific intracellular events resulting from GM-CSF-induced signaling provide a molecular explanation for GM-CSF-dependent subset distribution as well as clues to the specific characteristics and functions of GM-CSF-differentiated DCs compared with DCs generated by fms-related tyrosine kinase 3 ligand. This knowledge can be used to identify therapeutic targets to improve GM-CSF-dependent DC-based strategies to regulate immunity. © 2012 by The American Society of Hematology.

Overbeek S.A.,University Utrecht
Respiratory research | Year: 2011

Cigarette smoking induces peripheral inflammatory responses in all smokers and is the major risk factor for neutrophilic lung disease such as chronic obstructive pulmonary disease. The aim of this study was to investigate the effect of cigarette smoke on neutrophil migration and on β2-integrin activation and function in neutrophilic transmigration through endothelium. Utilizing freshly isolated human PMNs, the effect of cigarette smoke on migration and β2-integrin activation and function in neutrophilic transmigration was studied. In this report, we demonstrated that cigarette smoke extract (CSE) dose dependently induced migration of neutrophils in vitro. Moreover, CSE promoted neutrophil adherence to fibrinogen. Using functional blocking antibodies against CD11b and CD18, it was demonstrated that Mac-1 (CD11b/CD18) is responsible for the cigarette smoke-induced firm adhesion of neutrophils to fibrinogen. Furthermore, neutrophils transmigrated through endothelium by cigarette smoke due to the activation of β2-integrins, since pre-incubation of neutrophils with functional blocking antibodies against CD11b and CD18 attenuated this transmigration. This is the first study to describe that cigarette smoke extract induces a direct migratory effect on neutrophils and that CSE is an activator of β2-integrins on the cell surface. Blocking this activation of β2-integrins might be an important target in cigarette smoke induced neutrophilic diseases.

In the 1970s and 1980s Dutch farmers replaced their dual-purpose Friesian cows with Holsteins, a highly specialized American dairy breed. The changeover was related to a major turnabout in breeding practices that involved the adoption of quantitative genetics. Dutch commercial breeders had long resisted the quantitative approach to breeding that scientists had been recommending since World War II. After about 1970, however, they gave up their resistance: the art of breeding, it was said, finally became a science. In historical overviews this turnabout is seen as part of what is called the "modernization project" in Dutch agriculture that the government instigated after the war. Economic developments are assumed to have necessitated this project, and specialization of production is seen as a natural consequence. This essay argues that the idea that the art of breeding was turned into a science is to a certain extent misleading. Furthermore, it aims to show that economic pressures and government policies cannot adequately explain the turn toward Holsteins. A better understanding can be obtained by framing the Holsteinization process as the result of a changeover in breeding culture-that is, in the ensemble of shared convictions, beliefs, conventions, methods, practices, and the like that characterized practical cattle breeding and that involved scientific, technical, economic, aesthetic, normative, and commercial considerations. © 2012 by The History of Science Society.

Paffen C.L.E.,University Utrecht | Alais D.,University of Sydney
Frontiers in Human Neuroscience | Year: 2011

Ever since Wheatstone initiated the scientific study of binocular rivalry, it has been debated whether the phenomenon is under attentional control. In recent years, the issue of attentional modulation of binocular rivalry has seen a revival. Here we review the classical studies as well as recent advances in the study of attentional modulation of binocular rivalry. We show that (1) voluntary control over binocular rivalry is possible, yet limited, (2) both endogenous and exogenous attention influence perceptual dominance during rivalry, (3) diverting attention from rival displays does not arrest perceptual alternations, and that (4) rival targets by themselves can also attract attention. From a theoretical perspective, we suggest that attention affects binocular rivalry by modulating the effective contrast of the images in com-petition. This contrast enhancing effect of top-down attention is counteracted by a response attenuating effect of neural adaptation at early levels of visual processing, which weakens the response to the dominant image. Moreover, we conclude that although frontal and parietal brain areas involved in both binocular rivalry and visual attention overlap, an adapting reciprocal inhibition arrangement at early visual cortex is sufficient to trigger switches in perceptual dominance independently of a higher-level "selection" mechanisms. Both of these processes are reciprocal and therefore self-balancing, with the consequence that complete attentional control over binocular rivalry can never be realized. © 2011 Paffen and Alais.

Vroege G.J.,University Utrecht
Liquid Crystals | Year: 2014

A review is given of liquid crystals formed in colloidal dispersions, in particular those consisting of mineral particles. Starting with the historical development and early theory, the characteristic properties related to the colloidal nature of this type of liquid crystals are discussed. The possibility to find biaxial nematic and smectic phases is described for mixtures of rods and plates and recent examples are given of biaxial liquid crystal phases of mineral particles with inherent biaxial shape. © 2013 © 2013 Taylor & Francis.

Boomsma C.M.,University Utrecht
Cochrane database of systematic reviews (Online) | Year: 2012

In order to improve embryo implantation for in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles the use of glucocorticoids has been advocated. It has been proposed that glucocorticoids may improve the intrauterine environment by acting as immunomodulators to reduce the uterine natural killer (NK) cell count and normalise the cytokine expression profile in the endometrium and by suppression of endometrial inflammation. To investigate whether the administration of glucocorticoids around the time of implantation improved clinical outcomes in subfertile women undergoing IVF or ICSI when compared to no glucocorticoid administration. The Cochrane Menstrual Disorders and Subfertility Group Trials Register (September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (September 2011), MEDLINE (1966 to September 2011), EMBASE (1976 to September 2011), CINAHL (1982 to September 2011) and Science Direct (1966 to September 2011) were searched. Reference lists of relevant articles and relevant conference proceedings were handsearched. All randomised controlled trials (RCTs) addressing the research question were included. Two review authors independently assessed eligibility and quality of trials and extracted relevant data. Fourteen studies (involving 1879 couples) were included. Three studies reported live birth rate and these did not identify a significant difference after pooling the (preliminary) results (OR 1.21, 95% CI 0.67 to 2.19). With regard to pregnancy rates, there was also no evidence that glucocorticoids improved clinical outcome (13 RCTs; OR 1.16, 95% CI 0.94 to 1.44). However, a subgroup analysis of 650 women undergoing IVF (6 RCTs) revealed a significantly higher pregnancy rate for women using glucocorticoids (OR 1.50, 95% CI 1.05 to 2.13). There were no significant differences in adverse events, but these were poorly and inconsistently reported. Overall, there was no clear evidence that administration of peri-implantation glucocorticoids in ART cycles significantly improved the clinical outcome. The use of glucocorticoids in a subgroup of women undergoing IVF (rather than ICSI) was associated with an improvement in pregnancy rates of borderline statistical significance and should be interpreted with care. These findings were limited to the routine use of glucocorticoids and cannot be extrapolated to women with autoantibodies, unexplained infertility or recurrent implantation failure. Further well designed randomised studies are required to elucidate the possible role of this therapy in well defined patient groups.

Veltman-Verhulst S.M.,University Utrecht
Cochrane database of systematic reviews (Online) | Year: 2012

Intra-uterine insemination (IUI) is a widely used fertility treatment for couples with unexplained subfertility. Although IUI is less invasive and less expensive than in vitro fertilisation (IVF), the safety of IUI in combination with ovarian hyperstimulation (OH) is debated. The main concern about IUI treatment with OH is the increase in multiple pregnancy rate. To determine whether, for couples with unexplained subfertility, IUI improves the live birth rate compared with timed intercourse (TI), both with and without ovarian hyperstimulation (OH). We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched July 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 7), MEDLINE (1966 to July 2011), EMBASE (1980 to July 2011), PsycINFO (1806 to July 2011), SCIsearch and reference lists of articles. Authors of identified studies were contacted for missing or unpublished data. Truly randomised controlled trials (RCTs) with at least one of the following comparisons were included: IUI versus TI, both in a natural cycle; IUI versus TI, both in a stimulated cycle; IUI in a natural cycle versus IUI in a stimulated cycle; IUI with OH versus TI in a natural cycle; IUI in a natural cycle versus TI with OH. Only couples with unexplained subfertility were included. Quality assessment and data extraction were performed independently by two review authors. Outcomes were extracted and the data were pooled. Subgroup and sensitivity analyses were done where possible. One trial compared IUI in a natural cycle with expectant management and showed no evidence of increased live births (334 women: odds ratio (OR) 1.60, 95% confidence interval (CI) 0.92 to 2.8). In the six trials where IUI was compared with TI, both in stimulated cycles, there was evidence of an increased chance of pregnancy after IUI (six RCTs, 517 women: OR 1.68, 95% CI 1.13 to 2.50). A significant increase in live birth rate was found for women where IUI with OH was compared with IUI in a natural cycle (four RCTs, 396 women: OR 2.07, 95% CI 1.22 to 3.50). However the trials provided insufficient data to investigate the impact of IUI with or without OH on several important outcomes including live births, multiple pregnancies, miscarriage and risk of ovarian hyperstimulation. There was no evidence of a difference in pregnancy rate for IUI with OH compared with TI in a natural cycle (two RCTs, total 304 women: data not pooled). The final comparison of IUI in natural cycle to TI with OH showed a marginal, significant increase in live births for IUI (one RCT, 342 women: OR 1.95, 95% CI 1.10 to 3.44). There is evidence that IUI with OH increases the live birth rate compared to IUI alone. The likelihood of pregnancy was also increased for treatment with IUI compared to TI in stimulated cycles. One adequately powered multicentre trial showed no evidence of effect of IUI in natural cycles compared with expectant management. There is insufficient data on multiple pregnancies and other adverse events for treatment with OH. Therefore couples should be fully informed about the risks of IUI and OH as well as alternative treatment options.

Hulzebos E.H.,University Utrecht
Cochrane database of systematic reviews (Online) | Year: 2012

After cardiac surgery, physical therapy is a routine procedure delivered with the aim of preventing postoperative pulmonary complications. To determine if preoperative physical therapy with an exercise component can prevent postoperative pulmonary complications in cardiac surgery patients, and to evaluate which type of patient benefits and which type of physical therapy is most effective. Searches were run on the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library (2011, Issue 12 ); MEDLINE (1966 to 12 December 2011); EMBASE (1980 to week 49, 2011); the Physical Therapy Evidence Database (PEDro) (to 12 December 2011) and CINAHL (1982 to 12 December 2011). Randomised controlled trials or quasi-randomised trials comparing preoperative physical therapy with no preoperative physical therapy or sham therapy in adult patients undergoing elective cardiac surgery. Data were collected on the type of study, participants, treatments used, primary outcomes (postoperative pulmonary complications grade 2 to 4: atelectasis, pneumonia, pneumothorax, mechanical ventilation > 48 hours, all-cause death, adverse events) and secondary outcomes (length of hospital stay, physical function measures, health-related quality of life, respiratory death, costs). Data were extracted by one review author and checked by a second review author. Review Manager 5.1 software was used for the analysis. Eight randomised controlled trials with 856 patients were included. Three studies used a mixed intervention (including either aerobic exercises or breathing exercises); five studies used inspiratory muscle training. Only one study used sham training in the controls. Patients that received preoperative physical therapy had a reduced risk of postoperative atelectasis (four studies including 379 participants, relative risk (RR) 0.52; 95% CI 0.32 to 0.87; P = 0.01) and pneumonia (five studies including 448 participants, RR 0.45; 95% CI 0.24 to 0.83; P = 0.01) but not of pneumothorax (one study with 45 participants, RR 0.12; 95% CI 0.01 to 2.11; P = 0.15) or mechanical ventilation for > 48 hours after surgery (two studies with 306 participants, RR 0.55; 95% CI 0.03 to 9.20; P = 0.68). Postoperative death from all causes did not differ between groups (three studies with 552 participants, RR 0.66; 95% CI 0.02 to 18.48; P = 0.81). Adverse events were not detected in the three studies that reported on them. The length of postoperative hospital stay was significantly shorter in experimental patients versus controls (three studies with 347 participants, mean difference -3.21 days; 95% CI -5.73 to -0.69; P = 0.01). One study reported a reduced physical function measure on the six-minute walking test in experimental patients compared to controls. One other study reported a better health-related quality of life in experimental patients compared to controls. Postoperative death from respiratory causes did not differ between groups (one study with 276 participants, RR 0.14; 95% CI 0.01 to 2.70; P = 0.19). Cost data were not reported on. Evidence derived from small trials suggests that preoperative physical therapy reduces postoperative pulmonary complications (atelectasis and pneumonia) and length of hospital stay in patients undergoing elective cardiac surgery. There is a lack of evidence that preoperative physical therapy reduces postoperative pneumothorax, prolonged mechanical ventilation or all-cause deaths.

Heimeriks G.,University Utrecht
Science and Public Policy | Year: 2013

In this paper we study developments in biotechnology, genomics and nanotechnology in the period 1998-2008. The fields show changing interdisciplinary characteristics in relation to distinct co-evolutionary dynamics in research, science and society. Biotechnology emerged as a discipline in publication patterns at the same time as the number of biotechnology departments increased, whereas genomics emerged as a stable discipline, while the number of genomics departments declined. Nanotechnology maintains an interdisciplinary journal citation pattern while the number of nanotechnology departments increased. In all three fields the importance of industry-university collaborations increased, albeit to different degrees. Patterns of interdisciplinarity can thus be distinguished, as different ways in which the three dynamics co-evolve. From a governance perspective, this conceptualization provides distinct rationales for policy interventions in relation to interdisciplinarity in research, science and society. © The Author 2012. Published by Oxford University Press. All rights reserved.

van der Bilt A.,University Utrecht
Journal of Oral Rehabilitation | Year: 2011

During chewing, food is reduced in size, while saliva moistens the food and binds the masticated food into a bolus that can be easily swallowed. Characteristics of the oral system, like number of teeth, bite force and salivary flow, will influence the masticatory process. Masticatory function of healthy persons has been studied extensively the last decades. These results were used as a comparison for outcomes of various patient groups. In this review, findings from literature on masticatory function for both healthy persons and patient groups are presented. Masticatory function of patients with compromised dentition appeared to be significantly reduced when compared with the function of healthy controls. The influence of oral rehabilitation, e.g. dental restorations, implant treatment and temporomandibular disorder treatment, on masticatory function will be discussed. For instance, implant treatment was shown to have a significant positive effect on both bite force and masticatory performance. Also, patient satisfaction with an implant-retained prosthesis was high in comparison with the situation before implant treatment. The article also reviews the neuromuscular control of chewing. The jaw muscle activity needed to break solid food is largely reflexly induced. Immediate muscle response is necessary to maintain a constant chewing rhythm under varying food resistance conditions. Finally, the influence of food characteristics on the masticatory process is discussed. Dry and hard products require more chewing cycles before swallowing than moist and soft foods. More time is needed to break the food and to add enough saliva to form a cohesive bolus suitable for swallowing. © 2011 Blackwell Publishing Ltd.

Weese J.S.,University of Guelph | van Duijkeren E.,University Utrecht
Veterinary Microbiology | Year: 2010

Staphylococci are important opportunistic pathogens in most animal species. Among the most relevant species are the coagulase positive species Staphylococcus aureus and Staphylococcus pseudintermedius. Methicillin resistance has emerged as an important problem in both of these organisms, with significant concerns about animal and public health. The relative importance of these staphylococci on different animal species varies, as do the concerns about zoonotic transmission, yet it is clear that both present a challenge to veterinary medicine. © 2009 Elsevier B.V. All rights reserved.

The large number and distribution of rollback systems in Mediterranean orogens infer the possibility of interacting extensional back-arc deformation driven by different slabs. The formation of the Pannonian back-arc basin is generally related to the rapid Miocene rollback of a slab attached to the European continent. A key area of the entire system that is neglected by kinematic studies is the connection between the South Carpathians and Dinarides. In order to derive an evolutionary model, we interpreted regional seismic lines traversing the entire Serbian part of the Pannonian Basin. The observed deformation is dominantly expressed by the formation of Miocene extensional detachments and (half) grabens. The extensional geometries and associated synkinematic sedimentation that migrated in time and space allow the definition of a continuous and essentially asymmetric early to late Miocene extensional evolution. This evolution was followed by the formation of few uplifted areas during the subsequent latest Miocene-Quaternary inversion. The present-day extensional geometry changing the strike across the basin is an effect of the clockwise rotation of the South Carpathians and Apuseni Mountains in respect to the Dinarides. Our study infers that the Carpathian rollback is not the only mechanism responsible for the formation of the Pannonian Basin; an additional middle Miocene rollback of a Dinaridic slab is required to explain the observed structures. Furthermore, the study provides constraints for the pre-Neogene orogenic evolution of this junction zone, including the affinity of major crustal blocks, obducted ophiolitic sequences and the Sava suture zone.© 2012. American Geophysical Union. All Rights Reserved.

Veldhoen M.,University Utrecht
Nuclear Physics A | Year: 2013

Particle ratios are important observables used to constrain models of particle production in heavy-ion collisions. In this work we report on a measurement of the p/π ratio in the transverse momentum range 2.0 < p T,a s s o c < 4.0 GeV/c, associated with a charged trigger particle of 5.0 < p T,t r i g < 10.0 GeV/c, in 0-10% central Pb-Pb collisions at sNN=2.76TeV. The ratio is measured in the jet peak and in a region at large δη separation from the peak (bulk region). The presented results are based on 14M minimum-bias Pb-Pb collisions, recorded by the ALICE detector. It is observed that the p/π ratio in the bulk region is compatible with the p/π ratio of an inclusive measurement, and is much larger than the p/π ratio in the jet peak. The p/π ratio in the jet peak is compatible with a PYTHIA reference, in which fragmentation in the vacuum is the dominant mechanism of particle production. © 2013 CERN.

Boer J.,Deventer Hospital | Nazary M.,University Utrecht
British Journal of Dermatology | Year: 2011

Background Hidradenitis suppurativa (HS) is a distressing chronic inflammatory skin disorder which affects predominantly the groins and axillae. In analogy to acne, oral isotretinoin has been considered in the treatment of HS, although there are strong indications that this drug has only a very limited therapeutic effect. During the past 25 years scattered case reports have described promising results of treatment with acitretin. Objectives To evaluate the long-term efficacy of acitretin monotherapy. Methods A retrospective study in 12 patients with severe, recalcitrant HS who were treated with acitretin for 9-12 months at one Dermatology Centre in the Netherlands between 2005 and 2007 and were followed up to 4 years. The patients were men and infertile women. The efficacy of the treatment was rated by the patients on global maximum pain of nodules and abscesses on a visual analogue scale (VAS) as well as by physician global assessment. Results All 12 patients achieved remission and experienced a significant decrease in pain as assessed by VAS. In nine patients long-lasting improvement was observed, with no recurrence of lesions after 6 months (n = 1), 1 year (n = 3), > 2 years (n = 2), > 3 years (n = 2) and > 4 years (n = 1). Conclusions Acitretin appears to be an effective treatment for refractory HS, leading to reduction of pain from painful nodules and reducing the extent of the disease for a prolonged period.

We report a measurement of transverse momentum spectra of jets detected with the ALICE detector in Pb-Pb collisions at sNN=2.76 TeV. Jets are reconstructed from charged particles using the anti-k T jet algorithm. The transverse momentum of tracks is measured down to 150 MeV/c which gives access to the low p T fragments of the jet. The background from soft particle production is determined for each event and subtracted. The remaining influence of underlying event fluctuations is quantified by embedding different probes into heavy-ion data. The reconstructed transverse momentum spectrum is corrected for background fluctuations by unfolding. We observe a strong suppression in central events of inclusive jets reconstructed with radii of 0.2 and 0.3. The fragmentation bias on jets introduced by requiring a high p T leading particle which rejects jets with a soft fragmentation pattern is equivalent for central and peripheral events. © 2013 CERN.

The measurement of D meson production provides key tests for parton energy-loss models, which predict that charm quarks should experience less in-medium energy loss than light quarks and gluons. The ALICE experiment has measured the production of prompt D0, D + and D * + mesons in pp and Pb-Pb collisions at the LHC at s=7 and 2.67 TeV and at sNN=2.76 TeV, respectively, via the exclusive reconstruction of their hadronic decay. The p T-differential production yields in the range 2 < p T < 16 GeV/c at central rapidity, |y| < 0.5, were used to calculate the nuclear modification factor. A suppression of a factor 3 to 4 for transverse momenta larger than 5 GeV/c in the 20% most central collisions was observed. Preliminary results in an extended p T-range, using the data sample collected during the 2011 Pb-Pb run, together with the first measurement of Ds+ nuclear modification factor will be shown. © 2013 CERN.

Wadman R.I.,University Utrecht
Cochrane database of systematic reviews (Online) | Year: 2012

Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells of the spinal cord, which leads to progressive muscle weakness. Children with SMA type I will never be able to sit without support and usually die by the age of two years. There are no known efficacious drug treatments that influence the course of the disease. This is an update of a review first published in 2009. To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA type I, and to assess if such therapy can be given safely. Drug treatment for SMA types II and III is the topic of a separate updated Cochrane review. We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to 8 March 2011). We searched the Clinical Trials Registry of the U.S. National Institute of Health (www.ClinicalTrials.gov) (8 March 2011) to identify additional trials that had not yet been published. We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA type I. Participants had to fulfil the clinical criteria and have a deletion or mutation of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis.The primary outcome measure was time from birth until death or full time ventilation. Secondary outcome measures were development of rolling, sitting or standing within one year after the onset of treatment, and adverse events attributable to treatment during the trial period. Two authors (RW and AV) independently reviewed and extracted data from all potentially relevant trials. For included studies, pooled relative risks and standardised mean differences were to be calculated to assess treatment efficacy. One small randomised controlled study comparing riluzole treatment to placebo for 10 SMA type 1 children was identified and included in the original review. No further trials were identified for the update in 2011. Regarding the primary outcome measure, three of seven children treated with riluzole were still alive at the ages of 30, 48 and 64 months, whereas all three children in the placebo group died; but the difference was not statistically significant. Regarding the secondary outcome measures, none of the children in the riluzole or placebo group developed the ability to roll, sit or stand, and no adverse effects were observed. For several reasons the overall quality of the study was low, mainly because the study was too small to detect an effect and because of baseline differences. Follow-up of the 10 included children was complete. No drug treatment for SMA type I has been proven to have significant efficacy.

Wadman R.I.,University Utrecht
Cochrane database of systematic reviews (Online) | Year: 2012

Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. There are no known efficacious drug treatments that influence the disease course of SMA. This is an update of a review first published in 2009. To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA types II and III and to assess if such therapy can be given safely. Drug treatment for SMA type I is the topic of a separate updated Cochrane review. We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to March 8 2011). We also searched clinicaltrials.gov to identify as yet unpublished trials (8 March 2011). We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a deletion or mutation of the survival motor neuron 1 (SMN1) gene (5q11.2-13.2) that was confirmed by genetic analysis.The primary outcome measure was to be change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were to be change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full time ventilation and adverse events attributable to treatment during the trial period. Two authors independently reviewed and extracted data from all potentially relevant trials. Pooled relative risks and pooled standardised mean differences were to be calculated to assess treatment efficacy. Risk of bias was systematically analysed. Six randomised placebo-controlled trials on treatment for SMA types II and III were found and included in the review: the four in the original review and two trials added in this update. The treatments were creatine (55 participants), phenylbutyrate (107 participants), gabapentin (84 participants), thyrotropin releasing hormone (9 participants), hydroxyurea (57 participants), and combination therapy with valproate and acetyl-L-carnitine (61 participants). None of these studies were completely free of bias. All studies had adequate blinding, sequence generation and reports of primary outcomes.None of the included trials showed any statistically significant effects on the outcome measures in participants with SMA types II and III. One participant died due to suffocation in the hydroxyurea trial and one participant died in the creatine trial. No participants in any of the other four trials died or reached the state of full time ventilation. Serious side effects were infrequent. There is no proven efficacious drug treatment for SMA types II and III.

Caeyenberghs K.,Ghent University | Leemans A.,University Utrecht
Human Brain Mapping | Year: 2014

The study on structural brain asymmetries in healthy individuals plays an important role in our understanding of the factors that modulate cognitive specialization in the brain. Here, we used fiber tractography to reconstruct the left and right hemispheric networks of a large cohort of 346 healthy participants (20-86 years) and performed a graph theoretical analysis to investigate this brain laterality from a network perspective. Findings revealed that the left hemisphere is significantly more "efficient" than the right hemisphere, whereas the right hemisphere showed higher values of "betweenness centrality" and "small-worldness." In particular, left-hemispheric networks displayed increased nodal efficiency in brain regions related to language and motor actions, whereas the right hemisphere showed an increase in nodal efficiency in brain regions involved in memory and visuospatial attention. In addition, we found that hemispheric networks decrease in efficiency with age. Finally, we observed significant gender differences in measures of global connectivity. By analyzing the structural hemispheric brain networks, we have provided new insights into understanding the neuroanatomical basis of lateralized brain functions. © 2014 Wiley Periodicals, Inc.

Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime. Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT. The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. NTR2657.

Glyn-Jones S.,University of Oxford | Palmer A.J.R.,University of Oxford | Agricola R.,Erasmus Medical Center | Price A.J.,University of Oxford | And 3 more authors.
The Lancet | Year: 2015

Osteoarthritis is a major source of pain, disability, and socioeconomic cost worldwide. The epidemiology of the disorder is complex and multifactorial, with genetic, biological, and biomechanical components. Aetiological factors are also joint specific. Joint replacement is an effective treatment for symptomatic end-stage disease, although functional outcomes can be poor and the lifespan of prostheses is limited. Consequently, the focus is shifting to disease prevention and the treatment of early osteoarthritis. This task is challenging since conventional imaging techniques can detect only quite advanced disease and the relation between pain and structural degeneration is not close. Nevertheless, advances in both imaging and biochemical markers offer potential for diagnosis and as outcome measures for new treatments. Joint-preserving interventions under development include lifestyle modification and pharmaceutical and surgical modalities. Some show potential, but at present few have proven ability to arrest or delay disease progression. © 2015 Elsevier Ltd.

Huettig F.,Max Planck Institute for Psycholinguistics | Brouwer S.,University Utrecht
Dyslexia | Year: 2015

It is now well established that anticipation of upcoming input is a key characteristic of spoken language comprehension. It has also frequently been observed that literacy influences spoken language processing. Here, we investigated whether anticipatory spoken language processing is related to individuals' word reading abilities. Dutch adults with dyslexia and a control group participated in two eye-tracking experiments. Experiment 1 was conducted to assess whether adults with dyslexia show the typical language-mediated eye gaze patterns. Eye movements of both adults with and without dyslexia closely replicated earlier research: spoken language is used to direct attention to relevant objects in the environment in a closely time-locked manner. In Experiment 2, participants received instructions (e.g., 'Kijk naar deCOM afgebeelde pianoCOM', look at the displayed piano) while viewing four objects. Articles (Dutch 'het' or 'de') were gender marked such that the article agreed in gender only with the target, and thus, participants could use gender information from the article to predict the target object. The adults with dyslexia anticipated the target objects but much later than the controls. Moreover, participants' word reading scores correlated positively with their anticipatory eye movements. We conclude by discussing the mechanisms by which reading abilities may influence predictive language processing. Copyright © 2015 John Wiley & Sons, Ltd.

We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.

van Zon A.,University Utrecht
Cochrane database of systematic reviews (Online) | Year: 2012

Otitis media with effusion (OME) is characterised by an accumulation of fluid in the middle ear behind an intact tympanic membrane, without the symptoms or signs of acute infection. In approximately one in three children with OME, however, a bacterial pathogen is identified in the middle ear fluid. In most cases, OME causes mild hearing impairment of short duration. When experienced in early life and when episodes of (bilateral) OME persist or recur, the associated hearing loss may be significant and have a negative impact on speech development and behaviour. Since most cases of OME will resolve spontaneously, only children with persistent middle ear effusion and associated hearing loss potentially require treatment. Previous Cochrane reviews have focused on the effectiveness of ventilation tube insertion, adenoidectomy, autoinflation, antihistamines, decongestants, and oral and topical intranasal steroids in OME. This review focuses on the effectiveness of antibiotics in children with OME. To assess the effects of antibiotics in children up to 18 years with OME. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 22 February 2012. Randomised controlled trials comparing oral antibiotics with placebo, no treatment or therapy of unproven effectiveness. Our primary outcome was complete resolution of OME at two to three months. Secondary outcomes included resolution of OME at other time points, hearing, language and speech, ventilation tube insertion and adverse effects. Two authors independently extracted data using standardised data extraction forms and assessed the quality of the included studies using the Cochrane 'Risk of bias' tool. We presented dichotomous results as risk differences as well as risk ratios, with their 95% confidence intervals. If heterogeneity was greater than 75% we did not pool data. We included 23 studies (3027 children) covering a range of antibiotics, participants, outcome measures and time points of evaluation. Overall, we assessed the studies as generally being at low risk of bias.Our primary outcome was complete resolution of OME at two to three months. The differences (improvement) in the proportion of children having such resolution (risk difference (RD)) in the five individual included studies ranged from 1% (RD 0.01, 95% CI -0.11 to 0.12; not significant) to 45% (RD 0.45, 95% CI 0.25 to 0.65). Results from these studies could not be pooled due to clinical and statistical heterogeneity.Pooled analysis of data for complete resolution at more than six months was possible, with an increase in resolution of 13% (RD 0.13, 95% CI 0.06 to 0.19).Pooled analysis was also possible for complete resolution at the end of treatment, with the following increases in resolution rates: 17% (RD 0.17, 95% CI 0.09 to 0.24) for treatment for 10 days to two weeks, 34% (RD 0.34, 95% CI 0.19 to 0.50) for treatment for four weeks, 32% (RD 0.32, 95% CI 0.17 to 0.47) for treatment for three months, and 14% (RD 0.14, 95% CI 0.03 to 0.24) for treatment continuously for at least six months.We were unable to find evidence of a substantial improvement in hearing as a result of the use of antibiotics for otitis media with effusion; nor did we find an effect on the rate of ventilation tube insertion. We did not identify any trials that looked at speech, language and cognitive development or quality of life. Data on the adverse effects of antibiotic treatment reported in six studies could not be pooled due to high heterogeneity. Increases in the occurrence of adverse events varied from 3% (RD 0.03, 95% CI -0.01 to 0.07; not significant) to 33% (RD 0.33, 95% CI 0.22 to 0.44) in the individual studies. The results of our review do not support the routine use of antibiotics for children up to 18 years with otitis media with effusion. The largest effects of antibiotics were seen in children treated continuously for four weeks and three months. Even when clear and relevant benefits of antibiotics have been demonstrated, these must be balanced against the potential adverse effects when making treatment decisions. Immediate adverse effects of antibiotics are common and the emergence of bacterial resistance has been causally linked to the widespread use of antibiotics for common conditions such as otitis media.

Klumperman J.,University Utrecht | Raposo G.,University Pierre and Marie Curie | Raposo G.,French National Center for Scientific Research
Cold Spring Harbor Perspectives in Biology | Year: 2014

Live-cell imaging reveals the endolysosomal system as a complex and highly dynamic network of interacting compartments. Distinct types of endosomes are discerned by kinetic, molecular, and morphological criteria. Although none of these criteria, or combinations thereof, can capture the full complexity of the endolysosomal system, they are extremely useful for experimental purposes. Some membrane domain specializations and specific morphological characteristics can only be seen by ultrastructural analysis after preparation for electron microscopy (EM). Immuno-EM allows a further discrimination of seemingly identical compartments by their molecular makeup. In this review we provide an overview of the ultrastructural characteristics and membrane organization of endosomal compartments, along with their organizing machineries. ©2014 Cold Spring Harbor Laboratory Press; all rights reserved.

The recognition of colonization pressure as an important risk factor for acquisition of antibiotic-resistant bacteria in the ICU, including Acinetobacter species, has major consequences for our understanding of risk factor analyses. Moreover, the importance of colonization pressure underpins the role of cross-transmission in the dynamics of antibiotic-resistant bacteria in the ICU, which has major consequences for the evaluation of the effectiveness of infection control measures. © 2012 BioMed Central Ltd.

Jennings J.H.,University of North Carolina at Chapel Hill | Rizzi G.,University of North Carolina at Chapel Hill | Rizzi G.,University Utrecht | Stamatakis A.M.,University of North Carolina at Chapel Hill | And 2 more authors.
Science | Year: 2013

The growing prevalence of overeating disorders is a key contributor to the worldwide obesity epidemic. Dysfunction of particular neural circuits may trigger deviations from adaptive feeding behaviors. The lateral hypothalamus (LH) is a crucial neural substrate for motivated behavior, including feeding, but the precise functional neurocircuitry that controls LH neuronal activity to engage feeding has not been defined. We observed that inhibitory synaptic inputs from the extended amygdala preferentially innervate and suppress the activity of LH glutamatergic neurons to control food intake. These findings help explain how dysregulated activity at a number of unique nodes can result in a cascading failure within a defined brain network to produce maladaptive feeding.

De Goeij J.M.,University of Amsterdam | Van Oevelen D.,Netherlands Institute for Sea Research | Vermeij M.J.A.,University of Amsterdam | Osinga R.,Wageningen University | And 3 more authors.
Science | Year: 2013

Ever since Darwin's early descriptions of coral reefs, scientists have debated how one of the world's most productive and diverse ecosystems can thrive in the marine equivalent of a desert. It is an enigma how the flux of dissolved organic matter (DOM), the largest resource produced on reefs, is transferred to higher trophic levels. Here we show that sponges make DOM available to fauna by rapidly expelling filter cells as detritus that is subsequently consumed by reef fauna. This "sponge loop" was confirmed in aquarium and in situ food web experiments, using 13C- and 15N-enriched DOM. The DOM-sponge-fauna pathway explains why biological hot spots such as coral reefs persist in oligotrophic seas - the reef's paradox - and has implications for reef ecosystem functioning and conservation strategies.

Vennin V.,University of Portsmouth | Starobinsky A.A.,University Utrecht
European Physical Journal C | Year: 2015

Combining the stochastic and $$\delta N$$δN formalisms, we derive non-perturbative analytical expressions for all correlation functions of scalar perturbations in single-field, slow-roll inflation. The standard, classical formulas are recovered as saddle-point limits of the full results. This yields a classicality criterion that shows that stochastic effects are small only if the potential is sub-Planckian and not too flat. The saddle-point approximation also provides an expansion scheme for calculating stochastic corrections to observable quantities perturbatively in this regime. In the opposite regime, we show that a strong suppression in the power spectrum is generically obtained, and we comment on the physical implications of this effect. © 2015, The Author(s).

Braakman I.,University Utrecht | Hebert D.N.,University of Massachusetts Amherst
Cold Spring Harbor Perspectives in Biology | Year: 2013

In this article, we will cover the folding of proteins in the lumen of the endoplasmic reticulum (ER), including the role of three types of covalent modifications: signal peptide removal, Nlinked glycosylation, and disulfide bond formation, aswell as the function and importance of resident ER folding factors. These folding factors consist of classical chaperones and their cochaperones, the carbohydrate-binding chaperones, and the folding catalysts of the PDI and proline cis-trans isomerase families. We will conclude with the perspective of the folding protein: a comparison of characteristics and folding and exit rates for proteins that travel through the ER as clients of the ER machinery. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

Verheul R.J.,University Utrecht
Journal of controlled release : official journal of the Controlled Release Society | Year: 2011

The physical stability of polyelectrolyte nanocomplexes composed of trimethyl chitosan (TMC) and hyaluronic acid (HA) is limited in physiological conditions. This may minimize the favorable adjuvant effects associated with particulate systems for nasal and intradermal immunization. Therefore, covalently stabilized nanoparticles loaded with ovalbumin (OVA) were prepared with thiolated TMC and thiolated HA via ionic gelation followed by spontaneous disulfide formation after incubation at pH 7.4 and 37°C. Also, maleimide PEG was coupled to the remaining thiol-moieties on the particles to shield their surface charge. OVA-loaded TMC/HA nanoparticles had a size of around 250-350nm, a positive zeta potential and OVA loading efficiencies up to 60%. Reacting the thiolated particles with maleimide PEG resulted in a slight reduction of zeta potential (from +7 to +4mV) and a minor increase in particle size. Stabilized TMC-S-S-HA particles (PEGylated or not) showed superior stability in saline solutions compared to non-stabilized particles (composed of nonthiolated polymers) but readily disintegrated upon incubation in a saline buffer containing 10mM dithiothreitol. In both the nasal and intradermal immunization study, OVA loaded stabilized TMC-S-S-HA particles demonstrated superior immunogenicity compared to non-stabilized particles (indicated by higher IgG titers). Intranasal, PEGylation completely abolished the beneficial effects of stabilization and it induced no enhanced immune responses against OVA after intradermal administration. In conclusion, stabilization of the TMC/HA particulate system greatly enhances the immunogenicity of OVA in nasal and intradermal vaccination. Copyright © 2011. Published by Elsevier B.V.

Recent genomic research into autism spectrum disorders (ASD) has revealed a remarkably complex genetic architecture. Large numbers of common variants, copy number variations and single nucleotide variants have been identified, yet each of them individually afforded only a small phenotypic impact. A polygenic model in which multiple genes interact either in an additive or a synergistic way appears the most plausible for the majority of ASD patients. Based on recently identified ASD candidate genes, transgenic mouse models for neuroligins/ neurorexins and genes such as Cntnap2,Cntn5, Tsc1, Tsc2, Akt3, Cyfip1, Scn1a, En2, Slc6a4, and Bckdk have been generated and studied with respect to behavioral and neuroanatomical phenotypes and sensitivity to drug treatments. From these models, a few clues for potential pharmacologic intervention emerged. The Fmr1,Shank2 and Cntn5 knockout mice exhibited alterations of glutamate receptors, which may become a target for pharmacologic modulation. Some of the phenotypes of Mecp2 knockout mice can be ameliorated by administering IGF1. In the near future, comprehensive genotyping of individual patients and siblings combined with the novel insights generated from the transgenic animal studies may provide us with personalized treatment options. Eventually, autism may indeed turn out to be a phenotypically heterogeneous group of disorders ('autisms') caused by combinations of changes in multiple possible candidate genes, being different in each patient and requiring for each combination of mutations a distinct, individually tailored treatment. Copyright © 2013 S. Karger AG, Basel.

Toelch U.,University Utrecht
Proceedings. Biological sciences / The Royal Society | Year: 2014

Copying others appears to be a cost-effective way of obtaining adaptive information, particularly when flexibly employed. However, adult humans differ considerably in their propensity to use information from others, even when this 'social information' is beneficial, raising the possibility that stable individual differences constrain flexibility in social information use. We used two dissimilar decision-making computer games to investigate whether individuals flexibly adjusted their use of social information to current conditions or whether they valued social information similarly in both games. Participants also completed established personality questionnaires. We found that participants demonstrated considerable flexibility, adjusting social information use to current conditions. In particular, individuals employed a 'copy-when-uncertain' social learning strategy, supporting a core, but untested, assumption of influential theoretical models of cultural transmission. Moreover, participants adjusted the amount invested in their decision based on the perceived reliability of personally gathered information combined with the available social information. However, despite this strategic flexibility, participants also exhibited consistent individual differences in their propensities to use and value social information. Moreover, individuals who favoured social information self-reported as more collectivist than others. We discuss the implications of our results for social information use and cultural transmission.

Vissers L.E.,University Utrecht
Journal of the American Heart Association | Year: 2013

Dietary vitamin K intake is thought to decrease the risk of cardiovascular disease (CVD) by reducing vascular calcification, although vitamin K is also involved in coagulation. Studies investigating the association between phylloquinone intake and risk of stroke are scarce, and the relation with menaquinones has not been investigated to date. We investigated the association between intake of phylloquinone and menaquinones and stroke in a prospective cohort of 35,476 healthy subjects. Information on occurrence of stroke was obtained by linkage to national registries, and stroke was further specified into ischemic and hemorrhagic stroke. Vitamin K intake was estimated using a validated food-frequency questionnaire. Multivariate Cox proportional hazards models adjusted for cardiovascular risk factors, lifestyle, and other dietary factors were used to estimate the associations. During a follow-up of 12.1 ± 2.1 years, 580 incident cases of stroke were identified, 163 of which were hemorrhagic and 324 were ischemic. Phylloquinone intake was not associated with risk of stroke with a hazard ratio (HR) of 1.09 (95% CI: 0.85 to 1.40, P(trend) 0.41) for the highest versus lowest quartile. For intake of menaquinones similar results were found, with an HR(Q4 versus Q1) of 0.99 (95% CI: 0.75 to 1.29, P(trend) 0.82). When specifying hemorrhagic and ischemic stroke or menaquinone subtypes, no significant associations were detected. In our study, neither dietary phylloquinone nor dietary menaquinones intake were associated with stroke risk.

Lorimer J.,University of Oxford | Driessen C.,University Utrecht
Transactions of the Institute of British Geographers | Year: 2014

This paper draws together recent literatures on the geography of experiments and the potential of experimental modes of conducting science and politics. It examines their implications for environmentalism in the Anthropocene. We differentiate between two different conceptions of an experiment, contrasting the singular, modern scientific understanding of an experiment with recent appeals for deliberative public experiments. Developing the concept of wild experiments we identify three axes for critical enquiry. These relate to the status of the nonhuman world as found or made, the importance afforded order and surprise in the conduct of any experiment and the degree and means by which publics are included in decisionmaking. We then illustrate the potential of this framework through a case study investigation of nature conservation, critically examining efforts to rewild and de-domesticate a polder landscape and its nonhuman inhabitants at the Oostvaardersplassen in the Netherlands. This is a flagship example of the wider enthusiasm for rewilding in nature conservation. In conclusion we reflect on wider significance and potential of these wild experiments for rethinking environmentalism in the Anthropocene. © 2013 Royal Geographical Society (with the Institute of British Geographers).

Gouda E.J.,University Utrecht
Phytotaxa | Year: 2012

Two new species belonging to the subfamily Tillandsioideae from Machu Picchu, Cusco, Peru are described and illustrated here. The new species Tillandsia machupicchuensis is close to T. tovarensis and the other new species Guzmania inkaterrae is close to G. morreniana and G. tenuifolia. Both species are abundant in the area. © 2012 Magnolia Press.

Istamto T.,University Utrecht
Environmental health : a global access science source | Year: 2014

The health impacts from traffic-related pollutants bring costs to society, which are often not reflected in market prices for transportation. We set out to simultaneously assess the willingness-to-pay (WTP) for traffic-related air pollution and noise effect on health, using a single measurement instrument and approach. We investigated the proportion and determinants of "protest vote/PV responses (people who were against valuing their health in terms of money)" and "don't know"/DK answers, and explored the effect of DK on the WTP distributions. Within the framework of the EU-funded project INTARESE, we asked over 5,200 respondents in five European countries to state their WTP to avoid health effects from road traffic-related air pollution and noise in an open-ended web-based questionnaire. Determinants of PV and DK were studied by logistic regression using variables concerning socio-demographics, income, health and environmental concern, and risk perception. About 10% of the respondents indicated a PV response and between 47-56% of respondents gave DK responses. About one-third of PV respondents thought that costs should be included in transportation prices, i.e. the polluter should pay. Logistic regression analyses showed associations of PV and DK with several factors. In addition to social-demographic, economic and health factors known to affect WTP, environmental concern, awareness of health effects, respondent's ability to relax in polluted places, and their view on the government's role to reduce pollution and on policy to improve wellbeing, also affected the PV and DK response. An exploratory weighting and imputation exercise did not show substantial effects of DK on the WTP distribution. With a proportion of about 50%, DK answers may be a more relevant issue affecting WTP than PV's. The likelihood to give PV and DK response were influenced by socio-demographic, economic and health factors, as well as environmental concerns and appreciation of environmental conditions and policies. In contested policy issues where actual policy may be based on WTP studies, PV and DK answers may indeed affect the outcome of the WTP study. PV and DK answers and their determinants therefore deserve further study in CV studies on environmental health effects.

Koo B.-K.,University of Cambridge | Clevers H.,Hubrecht Institute KNAW | Clevers H.,University Utrecht
Gastroenterology | Year: 2014

Since the discovery of LGR5 as a marker of intestinal stem cells, the field has developed explosively and led to many new avenues of research. The inner workings of the intestinal crypt stem cell niche are now well understood. The study of stem cell-enriched genes has uncovered some previously unknown aspects of the Wnt signaling pathway, the major driver of crypt dynamics. LGR5 + stem cells can now be cultured over long periods in vitro as epithelial organoids or "mini-guts." This technology opens new possibilities of using cultured adult stem cells for drug development, disease modeling, gene therapy, and regenerative medicine. This review describes the rediscovery of crypt base columnar cells as LGR5+ adult stem cells and summarizes subsequent progress, promises, unresolved issues, and challenges of the field. © 2014 by the AGA Institute.

Bakker W.J.,University Utrecht
Transcription | Year: 2013

Recently, we showed that E2F7 and E2F8 (E2F7/8) are critical regulators of angiogenesis through transcriptional control of VEGFA in cooperation with HIF. (1) Here we investigate the existence of other novel putative angiogenic E2F7/8-HIF targets, and discuss the role of the RB-E2F pathway in regulating angiogenesis during embryonic and tumor development.

DeLuca K.F.,Colorado State University | Lens S.M.A.,University Utrecht | DeLuca J.G.,Colorado State University
Journal of Cell Science | Year: 2011

Precise control of the attachment strength between kinetochores and spindle microtubules is essential to preserve genomic stability. Aurora B kinase has been implicated in regulating the stability of kinetochore - microtubule attachments but its relevant kinetochore targets in cells remain unclear. Here, we identify multiple serine residues within the N-terminus of the kinetochore protein Hec1 that are phosphorylated in an Aurora-B-kinase-dependent manner during mitosis. On all identified target sites, Hec1 phosphorylation at kinetochores is high in early mitosis and decreases significantly as chromosomes bi-orient. Furthermore, once dephosphorylated, Hec1 is not highly rephosphorylated in response to loss of kinetochore - microtubule attachment or tension. We find that a subpopulation of Aurora B kinase remains localized at the outer kinetochore even upon Hec1 dephosphorylation, suggesting that Hec1 phosphorylation by Aurora B might not be regulated wholly by spatial positioning of the kinase. Our results define a role for Hec1 phosphorylation in kinetochore - microtubule destabilization and error correction in early mitosis and for Hec1 dephosphorylation in maintaining stable attachments in late mitosis.

Boya P.,CSIC - Biological Research Cen