Amsterdam, Netherlands
Amsterdam, Netherlands

Time filter

Source Type

Bakker S.T.,Netherlands Cancer Institute | De Winter J.P.,VU University Amsterdam | Te Riele H.,Netherlands Cancer Institute
DMM Disease Models and Mechanisms | Year: 2013

Fanconi anaemia (FA) is a rare autosomal recessive or X-linked inherited disease characterised by an increased incidence of bone marrow failure (BMF), haematological malignancies and solid tumours. Cells from individuals with FA show a pronounced sensitivity to DNA interstrand crosslink (ICL)-inducing agents, which manifests as G2-M arrest, chromosomal aberrations and reduced cellular survival. To date, mutations in at least 15 different genes have been identified that cause FA; the products of all of these genes are thought to function together in the FA pathway, which is essential for ICL repair. Rapidly following the discovery of FA genes, mutant mice were generated to study the disease and the affected pathway. These mutant mice all show the characteristic cellular ICL-inducing agent sensitivity, but only partially recapitulate the developmental abnormalities, anaemia and cancer predisposition seen in individuals with FA. Therefore, the usefulness of modelling FA in mice has been questioned. In this Review, we argue that such scepticism is unjustified. We outline that haematopoietic defects and cancer predisposition are manifestations of FA gene defects in mice, albeit only in certain genetic backgrounds and under certain conditions. Most importantly, recent work has shown that developmental defects in FA mice also arise with concomitant inactivation of acetaldehyde metabolism, giving a strong clue about the nature of the endogenous lesion that must be repaired by the functional FA pathway. This body of work provides an excellent example of a paradox in FA research: that the dissimilarity, rather than the similarity, between mice and humans can provide insight into human disease. We expect that further study of mouse models of FA will help to uncover the mechanistic background of FA, ultimately leading to better treatment options for the disease.

Drescher J.,New York Medical College | Drescher J.,New York University | Cohen-Kettenis P.T.,VU University Amsterdam | Reed G.M.,National Autonomous University of Mexico
The Lancet Psychiatry | Year: 2016

As part of the development of the eleventh revision of the International Classification of Diseases (ICD-11), WHO appointed a Working Group on Sexual Disorders and Sexual Health to recommend changes necessary in the classification of mental and behavioural disorders in ICD-10 that are related to sexuality and gender identity. This Personal View focuses on the Working Group's proposals to include the diagnosis gender incongruence of childhood in ICD-11 and to move gender incongruence of childhood out of the mental and behavioural disorders chapter of ICD-11. We outline the history of ICD and DSM child gender diagnoses, expert consensus, knowledge gaps, and controversies related to the diagnosis and treatment of extremely gender-variant children. We argue that retaining the gender incongruence of childhood category is justified as a basis to structure clinical care and to ensure access to appropriate services for this vulnerable population, which provides opportunities for education and informed consent, the development of standards and pathways of care to help guide clinicians and family members, and a basis for future research efforts. © 2016 Elsevier Ltd.

van Wilgen C.P.,University of Groningen | Verhagen E.A.L.M.,VU University Amsterdam
Journal of Science and Medicine in Sport | Year: 2012

Objectives: Preventive approaches for overuse injuries in sports will be more successful when synchronised with athletes' and coaches' beliefs. We interviewed athletes and coaches in order to better characterize their beliefs about the definition of an overuse injury, as well as the intrinsic and extrinsic risk factors that underlie overuse injuries. Design: Qualitative study using in-depth interviews in athletes and coaches of different sports. Methods: Athletes who had experienced overuse injuries and coaches who trained athletes who had sustained overuse injuries from sports clubs were invited to participate through interview. We explored each participant's individual definition of an overuse injury and the beliefs concerning the intrinsic and extrinsic risk factors concerning overuse injuries were explored. Results: After nine athletes and nine coaches, sample size saturation was confirmed. Athletes and coaches integrate somatic as well as psychological and sociological factors into the definition of and risk factors for overuse injuries. Intrinsic factors for an overuse injury were related to physical factors, technique, psychological factors and heredity. The extrinsic factors were related to situational, social and training factors, as well as the individual coach. Conclusions: Athletes and coaches have a holistic view on the definition of overuse injuries, and the intrinsic and extrinsic risk factors for overuse injuries. If preventive approaches for overuse injuries are developed and implemented, they should incorporate physical factors, as well as incorporate psychological and social factors. Based on the input of coaches and athletes, the latter are important risk factors for overuse injuries. © 2011 Sports Medicine Australia.

Borlaug B.A.,Mayo Medical School | Paulus W.J.,VU University Amsterdam
European Heart Journal | Year: 2011

Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). Morbidity and mortality in HFpEF are similar to values observed in patients with HF and reduced EF, yet no effective treatment has been identified. While early research focused on the importance of diastolic dysfunction in the pathophysiology of HFpEF, recent studies have revealed that multiple non-diastolic abnormalities in cardiovascular function also contribute. Diagnosis of HFpEF is frequently challenging and relies upon careful clinical evaluation, echo-Doppler cardiography, and invasive haemodynamic assessment. In this review, the principal mechanisms, diagnostic approaches, and clinical trials are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future. © 2010 The Author.

Cohen C.I.,SUNY Downstate Medical Center | Meesters P.D.,VU University Amsterdam | Zhao J.,SUNY Downstate Medical Center
The Lancet Psychiatry | Year: 2015

Worldwide, in the past few decades, the demographics of older people (ie, people 55 years and over) with schizophrenia have changed completely with respect to absolute numbers of people affected, the proportion of all people with the disorder, life expectancy, and residential status. The ageing schizophrenia population has created vast health-care needs and their medical comorbidity contributes to higher mortality than in the general population. Proposals to classify schizophrenia into early-onset, late-onset, and very-late-onset subtypes now should be tempered by the recognition that comorbid medical and neurological disorders can contribute to psychotic symptoms in later life. The concept of outcome has become more nuanced with an appreciation that various outcomes can occur, largely independent of each other, that need different treatment approaches. Data show that schizophrenia in later life is not a stable end-state but one of fluctuation in symptoms and level of functioning, and show that pathways to improvement and recovery exist. Several novel non-pharmacological treatment strategies have been devised that can augment the clinical options used to address the specific needs of older adults with schizophrenia. © 2015 Elsevier Ltd.

van Elburg R.A.J.,University of Groningen | van Elburg R.A.J.,VU University Amsterdam | van Ooyen A.,VU University Amsterdam
PLoS Computational Biology | Year: 2010

Neurons display a wide range of intrinsic firing patterns. A particularly relevant pattern for neuronal signaling and synaptic plasticity is burst firing, the generation of clusters of action potentials with short interspike intervals. Besides ion-channel composition, dendritic morphology appears to be an important factor modulating firing pattern. However, the underlying mechanisms are poorly understood, and the impact of morphology on burst firing remains insufficiently known. Dendritic morphology is not fixed but can undergo significant changes in many pathological conditions. Using computational models of neocortical pyramidal cells, we here show that not only the total length of the apical dendrite but also the topological structure of its branching pattern markedly influences inter- and intraburst spike intervals and even determines whether or not a cell exhibits burst firing. We found that there is only a range of dendritic sizes that supports burst firing, and that this range is modulated by dendritic topology. Either reducing or enlarging the dendritic tree, or merely modifying its topological structure without changing total dendritic length, can transform a cell's firing pattern from bursting to tonic firing. Interestingly, the results are largely independent of whether the cells are stimulated by current injection at the soma or by synapses distributed over the dendritic tree. By means of a novel measure called mean electrotonic path length, we show that the influence of dendritic morphology on burst firing is attributable to the effect both dendritic size and dendritic topology have, not on somatic input conductance, but on the average spatial extent of the dendritic tree and the spatiotemporal dynamics of the dendritic membrane potential. Our results suggest that alterations in size or topology of pyramidal cell morphology, such as observed in Alzheimer's disease, mental retardation, epilepsy, and chronic stress, could change neuronal burst firing and thus ultimately affect information processing and cognition. © 2010 van Elburg, van Ooyen.

Verhagen E.,VU University Amsterdam | Verhagen E.,University of Ballarat
British Journal of Sports Medicine | Year: 2015

Online technology dominates our era and eHealth has become a reality for sports clinicians and researchers. Contemporary online platforms enable self-monitoring and provide tailored feedback to the different stakeholders who play a role in the health and care of athletes. Innovations such as digital monitoring, mobile applications and connected hardware provide the critical tools to solve current enigmas in sports medicine research, and to streamline and facilitate injury prevention, management and rehabilitation. eHealth is not an emerging future of sports medicine-the technology to move our field forward in terms of research and practice is already available. This Analysis is based on Evert Verhagen's keynote presentation at the IOC World Conference on Injury and Illness Prevention in Sport (Monaco, 12 April 2014). It outlines the use of eHealth in research, implementation and practice, and provides an overview of possibilities and opportunities that existing and emerging eHealth solutions provide for sports and exercise medicine and physiotherapy.

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

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

Boer D.,University of Groningen | Den Dunnen W.J.,VU University Amsterdam
Physical Review Letters | Year: 2010

The W boson can obtain a small right-handed coupling to quarks and leptons through mixing with a hypothetical W′ boson that appears in many extensions of the standard model. Measuring or even bounding this coupling to the light quarks is very challenging. Only one model independent bound on the absolute value of the complex mixing parameter has been obtained to date. Here we discuss a method sensitive to both the real and CP-violating imaginary parts of the coupling, independent of assumptions on the new physics, and demonstrate quantitatively the feasibility of its measurement at RHIC. © 2010 The American Physical Society.

Krabbendam L.,VU University Amsterdam | Hooker C.I.,Harvard University | Aleman A.,University of Groningen
Schizophrenia Bulletin | Year: 2014

Epidemiological studies have suggested that the association between city upbringing and minority status with risk for schizophrenia can be explained by social mechanisms. Neuroimaging approaches hold promise for investigating this claim. Recent studies have shown that in healthy individuals, city upbringing and minority status are associated with increased activity in brain circuits involved in emotion regulation during social evaluative processing. These findings support the hypothesis that changes in the ability to regulate social stress contribute to the mechanism of risk. This is in accordance with a body of evidence demonstrating the sensitivity of the human brain to social stress, based on observational studies investigating the neurological sequelae of interpersonal trauma and experimental studies manipulating exposure to interpersonal distress. In this report, we summarize these initial findings, discuss methodological and conceptual challenges of pursuing this line of inquiry in schizophrenia, and suggest an outline for future research. © 2014 The Author. Published by Oxford University Press.

Bagdonaite J.,VU University Amsterdam | Ubachs W.,VU University Amsterdam | Murphy M.T.,Swinburne University of Technology | Whitmore J.B.,Swinburne University of Technology
Astrophysical Journal | Year: 2014

Rovibronic molecular hydrogen (H2) transitions at redshift z abs ≃ 2.659 toward the background quasar B0642-5038 are examined for a possible cosmological variation in the proton-to-electron mass ratio μ. We utilize an archival spectrum from the Very Large Telescope/Ultraviolet and Visual Echelle Spectrograph (UVES) with a signal-to-noise ratio of 35 per 2.5 km s-1 pixel at the observed H2 wavelengths (335-410 nm). Some 111 H2 transitions in the Lyman and Werner bands have been identified in the damped Lyα system for which a kinetic gas temperature of 84 K and a molecular fraction log f = -2.18 ± 0.08 are determined. The H2 absorption lines are included in a comprehensive fitting method, which allows us to extract a constraint on a variation of the proton-electron mass ratio Δμ/μ from all transitions at once. We obtain Δμ/μ = (17.1 ± 4.5stat ± 3.7sys) × 10 -6. However, we find evidence that this measurement has been affected by wavelength miscalibration errors recently identified in UVES. A correction based on observations of objects with solar-like spectra gives a smaller Δμ/μ value and contributes to a larger systematic uncertainty: Δμ/μ = (12.7 ± 4.5stat ± 4.2sys) × 10 -6. © 2014. The American Astronomical Society. All rights reserved.

Boer D.,University of Groningen | Brodsky S.J.,SLAC | Brodsky S.J.,University of Southern Denmark | Mulders P.J.,VU University Amsterdam | Pisano C.,University of Cagliari
Physical Review Letters | Year: 2011

We show that linearly polarized gluons inside unpolarized hadrons can be directly probed in jet or heavy quark pair production in electron-hadron collisions. We discuss the simplest cos2 asymmetries and estimate their maximal value, concluding that measurements of the unknown linearly polarized gluon distribution in the proton should be feasible in future Electron-Ion Collider or Large Hadron electron Collider experiments. Analogous asymmetries in hadron-hadron collisions suffer from factorization breaking contributions and would allow us to quantify the importance of initial- and final-state interactions. © 2011 American Physical Society.

Nijboer T.C.W.,University Utrecht | Kollen B.J.,University of Groningen | Kwakkel G.,University Utrecht | Kwakkel G.,VU University Amsterdam
Cortex | Year: 2013

The aim of the current study was to investigate recovery of visuospatial neglect during the first year after stroke. Visuospatial neglect was measured using two frequently and widely used tests: the letter cancellation test (LCT) and the line bisection test (LBT). This was a prospective cohort study of 101 stroke patients. Of these 101 patients, 51 patients showed visuospatial neglect. All time-dependent measures were taken weekly, starting from within 14days after stroke onset. From week 10-20 biweekly measurements were obtained. Follow-up measurements were performed at weeks 26, 38, and finally 52. For the present study, number of misses in the LCT, split on contralesional versus ipsilesional side, as well as the deviation from the actual midpoint in mm in the LBT were used. The longitudinal relationship of (bi)weekly time on improvement in LBT and LCT were investigated using random coefficient analysis and joinpoint analyses. Results indicated that progress of time is an independent covariate that reflects neurological recovery of visuospatial neglect. Additionally, trend changes were obtained in between 12 and 14weeks post-stroke with respect to the neglected side. This is the first prospective cohort study in which the time course of neglect is investigated by using intensive serial measurements in the early months post-stroke. © 2012.

Vermeulen L.,Center for Experimental Molecular Medicine | Meijer G.A.,VU University Amsterdam
Nature Reviews Gastroenterology and Hepatology | Year: 2015

Colorectal cancer (CRC) is considered a heterogeneous disease, both regarding pathogenesis and clinical behaviour. Four decades ago, the adenoma-carcinoma pathway was presented as the main pathway towards CRC, a conclusion that was largely based on evidence from observational morphological studies. This concept was later substantiated at the genomic level. Over the past decade, evidence has been generated for alternative routes in which CRC might develop, in particular the serrated neoplasia pathway. Providing indisputable evidence for the neoplastic potential of serrated polyps has been difficult. Reasons include the absence of reliable longitudinal observations on individual serrated lesions that progress to cancer, a shortage of available animal models for serrated lesions and challenging culture conditions when generating organoids of serrated lesions for in vitro studies. However, a growing body of circumstantial evidence has been accumulated, which indicates that ≥ 15% of CRCs might arise through the serrated neoplasia pathway. An even larger amount of post-colonoscopy colorectal carcinomas (carcinomas occurring within the surveillance interval after a complete colonoscopy) have been suggested to originate from serrated polyps. The aim of this Review is to assess the current status of the serrated neoplasia pathway in CRC and highlight clinical implications. © 2015 Macmillan Publishers Limited.

van de Wiel M.A.,VU University Amsterdam | Picard F.,Laboratoire Biometrie et Biologie Evolutive | van Wieringen W.N.,VU University Amsterdam | Ylstra B.,VU University Amsterdam
Briefings in Bioinformatics | Year: 2011

Analysis of DNA copy number profiles requires methods tailored to the specific nature of these data. The number of available data analysis methods has grown enormously in the last 5 years. We discuss the typical characteristics of DNA copy number data, as measured by microarray technology and review the extensive literature on preprocessing methods such as segmentation and calling. Subsequently, the focus narrows to applications of DNA copy number in cancer, in particular, several downstream analyses of multi-sample data sets such as testing, clustering and classification. Finally, we look ahead: what should we prepare for and which methodology-related topics may deserve attention in the near future? © The Author 2010. Published by Oxford University Press.

Huisman W.,VU University Amsterdam
British Journal of Criminology | Year: 2013

Recently, Situational Crime Prevention Theory (SCPT) has been proposed as an alternative to offender-based theories of white-collar crime. This paper uses the results of a cross-case analysis of 23 criminal investigations of environmental crime in the Netherlands to explore the fruitfulness of SCPT as a method of scientific study of environmental crime and the development of prevention strategies. This analysis shows that most environmental crimes are crimes of omission, while SCPT is designed for predatory crimes of commission. In addition, while it is concluded that SCPT is helpful in analysing opportunities for environmental crime, it is difficult to draw innovative prevention strategies on the basis of SCPT, since most suggestions have already been covered in contemporary models for environmental regulation. © The Author 2013. Published by Oxford University Press on behalf of the Centre for Crime and Justice Studies (ISTD). All rights reserved.

Boer D.,University of Groningen | Pisano C.,VU University Amsterdam
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

In this paper we consider Higgs boson plus jet production as a process that is sensitive to the linear polarization of gluons inside the unpolarized protons of the LHC. The leading order expressions for the transverse momentum distribution of the Higgs boson plus jet pair are provided in terms of transverse momentum dependent quark and gluon distributions. This includes both angular independent and azimuthal angular dependent contributions, presented directly in the laboratory frame. Lacking experimental constraints on the linearly polarized gluon distribution, we study its effects on Higgs boson plus jet production using two different models to illustrate the generic features and maximal effects. It is found that the cos2φ distribution may be the most promising observable, as it is driven by only one initial linearly polarized gluon. The potential advantages of the Higgs boson plus jet process compared to other processes sensitive to the linear polarization of gluons are discussed. © 2015 American Physical Society.

Stroebe W.,University Utrecht | Stroebe W.,University of Groningen | Van Koningsbruggen G.M.,VU University Amsterdam | Papies E.K.,University Utrecht | Aarts H.,University Utrecht
Psychological Review | Year: 2013

Theories of eating regulation often attribute overweight to a malfunction of homeostatic regulation of body weight. With the goal conflict model of eating, we present a new perspective that attributes the difficulty of chronic dieters (i.e., restrained eaters) in regulating their food intake to a conflict between 2 incompatible goals-namely, eating enjoyment and weight control. This model explains the findings of previous research and provides novel insights into the psychological mechanism responsible for both dietary failure and success. According to this model, although chronic dieters are motivated to pursue their weight control goal, they often fail in food-rich environments because they are surrounded by palatable food cues that strongly prime the goal of eating enjoyment. Due to the incompatibility of the eating enjoyment goal and the weight control goal, such increase in the activation of the eating enjoyment goal results in (a) an inhibition of the cognitive representation of the weight control goal and (b) preferential processing of palatable food stimuli. Both these processes interfere with the effective pursuit of the weight control goal and facilitate unhealthy eating. However, there is a minority of restrained eaters for whom, most likely due to past success in exerting self-control, tasty high-calorie food has become associated with weight control thoughts. For them, exposure to palatable food increases the accessibility of the weight control goal, enabling them to control their body weight in food-rich environments. Evidence for these proposed psychological mechanisms is provided, and implications for interventions are discussed. © 2012 American Psychological Association.

Poater J.,VU University Amsterdam | Sola M.,University of Girona | Vinas C.,Institute Of Ciencies Dels Materials Of Barcelona | Teixidor F.,Institute Of Ciencies Dels Materials Of Barcelona
Angewandte Chemie - International Edition | Year: 2014

A bridge between classical organic polycyclic aromatic hydrocarbons (PAH) and closo borohydride clusters is established by showing that they share a common origin regulated by the number of valence electrons in an electronic confined space. Application of the proposed electronic confined space analogy (ECSA) method to archetypal PAHs leads to the conclusion that the 4n+2 Wade-Mingos rule for three-dimensional closo boranes is equivalent to the (4n+2)π Hückel rule for two-dimensional PAHs. More importantly, use of ECSA allows design of new interesting fused closo boranes which can be a source of inspiration for synthetic chemists. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Shen H.-W.,Medical University of South Carolina | Shen H.-W.,Peking University | Gipson C.D.,Medical University of South Carolina | Huits M.,VU University Amsterdam | Kalivas P.W.,Medical University of South Carolina
Neuropsychopharmacology | Year: 2014

Addictive drug use causes long-lasting changes in synaptic strength and dendritic spine morphology in the nucleus accumbens that might underlie the vulnerability to relapse. Although activity in mesocorticolimbic circuitry is required for reinstating cocaine seeking, its role in reinstatement-associated synaptic plasticity is not well characterized. Using rats extinguished from cocaine self-administration, we found potentiated synaptic strength (assessed as the AMPA/NMDA current amplitude ratio) and increased spine head diameter in medium spiny neurons in the accumbens core (NAcore). The basal changes in synaptic strength and morphology in cocaine-extinguished animals were further augmented during cocaine-induced reinstatement. Two NAcore afferents contributing to cocaine reinstatement are glutamatergic inputs from the prelimbic prefrontal cortex (PL) and dopamine from the ventral tegmental area (VTA). Pharmacological inhibition of either PL or VTA prevented cocaine-primed reinstatement. However, inhibiting the PL further potentiated AMPA/NMDA and spine head diameter, while inactivating the VTA or the combined systemic administration of dopamine D1 and D2 antagonists prevented the increase in AMPA/NMDA and spine diameter induced by cocaine priming. These data indicate that neuronal activity in the VTA and associated dopamine receptor stimulation is necessary for the synaptic potentiation in the NAcore during cocaine-induced reinstatement. Although activity in the PL was necessary for reinstatement, it inhibited synaptic potentiation initiated by an acute cocaine injection. Thus, although the PL and VTA differentially regulate the direction of synaptic plasticity induced by a cocaine-priming injection, coordinated synaptic potentiation by both NAcore afferents is necessary for cocaine-induced relapse. © 2014 American College of Neuropsychopharmacology.

Hoeper M.M.,Hannover Medical School | Bogaard H.J.,VU University Amsterdam | Condliffe R.,Royal Hallamshire Hospital | Frantz R.,Rochester College | And 7 more authors.
Journal of the American College of Cardiology | Year: 2013

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure ≥25 mm Hg at rest, measured during right heart catheterization. There is still insufficient evidence to add an exercise criterion to this definition. The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory pulmonary artery wedge pressure (PAWP) ≤15 mm Hg and a pulmonary vascular resistance >3 Wood units. Right heart catheterization remains essential for a diagnosis of PH or PAH. This procedure requires further standardization, including uniformity of the pressure transducer zero level at the midthoracic line, which is at the level of the left atrium. One of the most common problems in the diagnostic workup of patients with PH is the distinction between PAH and PH due to left heart failure with preserved ejection fraction (HFpEF). A normal PAWP does not rule out the presence of HFpEF. Volume or exercise challenge during right heart catheterization may be useful to unmask the presence of left heart disease, but both tools require further evaluation before their use in general practice can be recommended. Early diagnosis of PAH remains difficult, and screening programs in asymptomatic patients are feasible only in high-risk populations, particularly in patients with systemic sclerosis, for whom recent data suggest that a combination of clinical assessment and pulmonary function testing including diffusion capacity for carbon monoxide, biomarkers, and echocardiography has a higher predictive value than echocardiography alone. © 2013 by the American College of Cardiology Foundation. Published by Elsevier Inc.

Crow W.T.,Hydrology and Remote Sensing Laboratory | Cosh M.H.,VU University Amsterdam
IEEE Transactions on Geoscience and Remote Sensing | Year: 2010

A recently developed data assimilation technique offers the potential to greatly expand the geographic domain over which remotely sensed surface soil moisture retrievals can be evaluated by effectively substituting (relatively plentiful) rain-gauge observations for (less commonly available) ground-based soil moisture measurements. The technique is based on calculating the Pearson correlation coefficient Rvalue between rainfall errors and Kalman filter analysis increments realized during the assimilation of a remotely sensed soil moisture product into the antecedent precipitation index (API). Here, the existing Rvalue approach is modified by reformulating it to run on an anomaly basis where long-term seasonal trends are explicitly removed and by calculating API analysis increments using a RauchTungStriebel smoother instead of a Kalman filter. This reformulated approach is then applied to a number of Advanced Microwave Scanning Radiometer soil moisture products acquired within three heavily instrumented watershed sites in the southern U.S. Rvalue-based evaluations of soil moisture products within these sites are verified based on comparisons with available ground-based soil moisture measurements. Results demonstrate that, without access to ground-based soil moisture measurements, the Rvalue; methodology can accurately mimic anomaly correlation coefficients calculated between remotely sensed soil moisture products and soil moisture observations obtained from dense ground-based networks. Sensitivity results also indicate that the predictive skill of the Rvalue metric is enhanced by both proposed modifications to its methodology. Finally,Rvalue calculations are expanded to a quasi-global (50° S50°N) domain using rainfall measurements derived from the Tropical Rainfall Measurement Mission Precipitation Analysis. Spatial patterns in calculated Rvalue fields are compared to regions of strong landatmosphere coupling and used to refine expectations concerning the global distribution of land areas in which remotely sensed surface soil moisture retrievals will contribute to atmospheric forecasting applications. © 2006 IEEE.

Azijli K.,University of Groningen | Azijli K.,VU University Amsterdam | Weyhenmeyer B.,University of Groningen | Peters G.J.,VU University Amsterdam | And 2 more authors.
Cell Death and Differentiation | Year: 2013

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based therapy is currently evaluated in clinical studies as a tumor cell selective pro-apoptotic approach. However, besides activating canonical caspase-dependent apoptosis by binding to TRAIL-specific death receptors, the TRAIL ligand can activate non-canonical cell survival or proliferation pathways in resistant tumor cells through the same death receptors, which is counterproductive for therapy. Even more, recent studies indicate metastases-promoting activity of TRAIL. In this review, the remarkable dichotomy in TRAIL signaling is highlighted. An overview of the currently known mechanisms involved in non-canonical TRAIL signaling and the subsequent activation of various kinases is provided. These kinases include RIP1, IκB/ NF-κB, MAPK p38, JNK, ERK1/2, MAP3K TAK1, PKC, PI3K/Akt and Src. The functional consequences of their activation, often being stimulation of tumor cell survival and in some cases enhancement of their invasive behavior, are discussed. Interestingly, the non-canonical responses triggered by TRAIL in resistant tumor cells resemble that of TRAIL-induced signals in non-transformed cells. Better knowledge of the mechanism underlying the dichotomy in TRAIL receptor signaling may provide markers for selecting patients who will likely benefit from TRAIL-based therapy and could provide a rationalized basis for combination therapies with TRAIL death receptor-targeting drugs. © 2013 Macmillan Publishers Limited.

Drop B.,VU University Amsterdam | Yadav K.n. S.,University of Groningen | Boekema E.J.,University of Groningen | Croce R.,VU University Amsterdam
Plant Journal | Year: 2014

State transitions represent a photoacclimation process that regulates the light-driven photosynthetic reactions in response to changes in light quality/quantity. It balances the excitation between photosystem I (PSI) and II (PSII) by shuttling LHCII, the main light-harvesting complex of green algae and plants, between them. This process is particularly important in Chlamydomonas reinhardtii in which it is suggested to induce a large reorganization in the thylakoid membrane. Phosphorylation has been shown to be necessary for state transitions and the LHCII kinase has been identified. However, the consequences of state transitions on the structural organization and the functionality of the photosystems have not yet been elucidated. This situation is mainly because the purification of the supercomplexes has proved to be particularly difficult, thus preventing structural and functional studies. Here, we have purified and analysed PSI and PSII supercomplexes of C. reinhardtii in states 1 and 2, and have studied them using biochemical, spectroscopic and structural methods. It is shown that PSI in state 2 is able to bind two LHCII trimers that contain all four LHCII types, and one monomer, most likely CP29, in addition to its nine Lhcas. This structure is the largest PSI complex ever observed, having an antenna size of 340 Chls/P700. Moreover, all PSI-bound Lhcs are efficient in transferring energy to PSI. A projection map at 20 Å resolution reveals the structural organization of the complex. Surprisingly, only LHCII type I, II and IV are phosphorylated when associated with PSI, while LHCII type III and CP29 are not, but CP29 is phosphorylated when associated with PSII in state2. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

Bonjer H.J.,VU University Amsterdam | Deijen C.L.,VU University Amsterdam | Abis G.A.,VU University Amsterdam | Cuesta M.A.,VU University Amsterdam | And 9 more authors.
New England Journal of Medicine | Year: 2015

Background: Laparoscopic resection of colorectal cancer is widely used. However, robust evidence to conclude that laparoscopic surgery and open surgery have similar outcomes in rectal cancer is lacking. A trial was designed to compare 3-year rates of cancer recurrence in the pelvic or perineal area (locoregional recurrence) and survival after laparoscopic and open resection of rectal cancer. Methods: In this international trial conducted in 30 hospitals, we randomly assigned patients with a solitary adenocarcinoma of the rectum within 15 cm of the anal verge, not invading adjacent tissues, and without distant metastases to undergo either laparoscopic or open surgery in a 2:1 ratio. The primary end point was locoregional recurrence 3 years after the index surgery. Secondary end points included disease-free and overall survival. Results: A total of 1044 patients were included (699 in the laparoscopic-surgery group and 345 in the open-surgery group). At 3 years, the locoregional recurrence rate was 5.0% in the two groups (difference, 0 percentage points; 90% confidence interval [CI], -2.6 to 2.6). Disease-free survival rates were 74.8% in the laparoscopic-surgery group and 70.8% in the open-surgery group (difference, 4.0 percentage points; 95% CI, -1.9 to 9.9). Overall survival rates were 86.7% in the laparoscopic-surgery group and 83.6% in the open-surgery group (difference, 3.1 percentage points; 95% CI, -1.6 to 7.8). Conclusions: Laparoscopic surgery in patients with rectal cancer was associated with rates of locoregional recurrence and disease-free and overall survival similar to those for open surgery. Copyright © 2015 Massachusetts Medical Society. All rights reserved.

Henriksen K.,Nordic Bioscience A S | Bollerslev J.,University of Oslo | Everts V.,VU University Amsterdam | Karsdal M.A.,Nordic Bioscience A S
Endocrine Reviews | Year: 2011

Osteoclasts have traditionally been associated exclusively with catabolic functions that are a prerequisite for bone resorption. However, emerging data suggest that osteoclasts also carry out functions that are important for optimal bone formation and bone quality. Moreover, recent findings indicate that osteoclasts have different subtypes depending on their location, genotype, and possibly in response to drug intervention. The aim of the current review is to describe the subtypes of osteoclasts in four different settings: 1) physiological, in relation to turnover of different bone types; 2) pathological, as exemplified by monogenomic disorders; 3) pathological, as identified by different disorders; and 4) in drug-induced situations. The profiles of these subtypes strongly suggest that these osteoclasts belong to a heterogeneous cell population, namely, a diverse macrophage-associated cell type with bone catabolic and anabolic functions that are dependent on both local and systemic parameters. Further insight into these osteoclast subtypes may be important for understanding cell-cell communication in the bone microenvironment, treatment effects, and ultimately bone quality. Copyright © 2011 by The Endocrine Society.

Lamers F.,National Health Research Institute | Vogelzangs N.,VU University Amsterdam | Merikangas K.R.,National Health Research Institute | De Jonge P.,University of Groningen | And 4 more authors.
Molecular Psychiatry | Year: 2013

The hypothalamic-pituitary-adrenal (HPA) axis and the inflammatory response system have been suggested as pathophysiological mechanisms implicated in the etiology of major depressive disorder (MDD). Although meta-analyses do confirm associations between depression and these biological systems, effect sizes vary greatly among individual studies. A potentially important factor explaining variability is heterogeneity of MDD. Aim of this study was to evaluate the association between depressive subtypes (based on latent class analysis) and biological measures. Data from 776 persons from the Netherlands Study of Depression and Anxiety, including 111 chronic depressed persons with melancholic depression, 122 with atypical depression and 543 controls were analyzed. Inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-α), metabolic syndrome components, body mass index (BMI), saliva cortisol awakening curves (area under the curve with respect to the ground (AUCg) and with respect to the increase (AUCi)), and diurnal cortisol slope were compared among groups. Persons with melancholic depression had a higher AUCg and higher diurnal slope compared with persons with atypical depression and with controls. Persons with atypical depression had significantly higher levels of inflammatory markers, BMI, waist circumference and triglycerides, and lower high-density lipid cholesterol than persons with melancholic depression and controls. This study confirms that chronic forms of the two major subtypes of depression are associated with different biological correlates with inflammatory and metabolic dysregulation in atypical depression and HPA-axis hyperactivity in melancholic depression. The data provide further evidence that chronic forms of depressive subtypes differ not only in their symptom presentation, but also in their biological correlates. These findings have important implications for future research on pathophysiological pathways of depression and treatment. © 2013 Macmillan Publishers Limited. All rights reserved 1359-4184/13.

Slotman B.J.,VU University Amsterdam | Van Tinteren H.,Netherlands Cancer Institute | Praag J.O.,Erasmus University Rotterdam | Knegjens J.L.,Netherlands Cancer Institute | And 4 more authors.
The Lancet | Year: 2015

Background Most patients with extensive stage small-cell lung cancer (ES-SCLC) who undergo chemotherapy, and prophylactic cranial irradiation, have persistent intrathoracic disease. We assessed thoracic radiotherapy for treatment of this patient group. Methods We did this phase 3 randomised controlled trial at 42 hospitals: 16 in Netherlands, 22 in the UK, three in Norway, and one in Belgium. We enrolled patients with WHO performance score 0-2 and confirmed ES-SCLC who responded to chemotherapy. They were randomly assigned (1:1) to receive either thoracic radiotherapy (30 Gy in ten fractions) or no thoracic radiotherapy. All underwent prophylactic cranial irradiation. The primary endpoint was overall survival at 1 year in the intention-to-treat population. Secondary endpoints included progression-free survival. This study is registered with the Nederlands Trial Register, number NTR1527. Findings We randomly assigned 498 patients between Feb 18, 2009, and Dec 21, 2012. Three withdrew informed consent, leaving 247 patients in the thoracic radiotherapy group and 248 in the control group. Mean interval between diagnosis and randomisation was 17 weeks. Median follow-up was 24 months. Overall survival at 1 year was not significantly different between groups: 33% (95% CI 27-39) for the thoracic radiotherapy group versus 28% (95% CI 22-34) for the control group (hazard ratio [HR] 0·84, 95% CI 0·69-1·01; p=0·066). However, in a secondary analysis, 2-year overall survival was 13% (95% CI 9-19) versus 3% (95% CI 2-8; p=0·004). Progression was less likely in the thoracic radiotherapy group than in the control group (HR 0·73, 95% CI 0·61-0·87; p=0·001). At 6 months, progression-free survival was 24% (95% CI 19-30) versus 7% (95% CI 4-11; p=0·001). We recorded no severe toxic effects. The most common grade 3 or higher toxic effects were fatigue (11 vs 9) and dyspnoea (three vs four). Interpretation Thoracic radiotherapy in addition to prophylactic cranial irradiation should be considered for all patients with ES-SCLC who respond to chemotherapy. Funding Dutch Cancer Society (CKTO), Dutch Lung Cancer Research Group, Cancer Research UK, Manchester Academic Health Science Centre Trials Coordination Unit, and the UK National Cancer Research Network. © 2015 Elsevier Ltd.

Van Der Veldt A.A.M.,VU University Amsterdam | Lammertsma A.A.,VU University Amsterdam
Clinical Cancer Research | Year: 2014

Although numerous anticancer drugs are widely used in the clinic, many questions remain about pharmacokinetics, biodistribution, toxicities, and efficacy. Positron emission tomography (PET) using radiolabeled drugs is a promising method to further understand the clinical behavior of anticancer agents. In addition, it may contribute to better guided treatment planning in individual patients with cancer. Among the available anticancer drugs, considerable experience has been gained with radiolabeling taxanes. At present, two radiolabeled taxanes, paclitaxel and docetaxel, are available as PET tracers. In the present review, data available for the labeled taxanes [18F]paclitaxel and [11C]docetaxel are discussed and linked to clinical observations following paclitaxel and docetaxel therapy, respectively. In addition, the review discusses the applications and the future of PET using radiolabeled drugs. Experience gained with [18F]paclitaxel and [11C]docetaxel may be extrapolated to other taxanes and may provide a framework for the development and clinical implementation of other radiolabeled anticancer drugs, even outside the taxane era. © 2014 American Association for Cancer Research.

Tops M.,VU University Amsterdam | Koole S.L.,VU University Amsterdam | Ijzerman H.,University of Tilburg | Buisman-Pijlman F.T.A.,University of Adelaide
Pharmacology Biochemistry and Behavior | Year: 2014

The present article advances a neurobiological model of the reciprocal associations between social attachment and drug abuse, and social attachment and chronic stress, as overlapping systems are involved in stress coping and social attachment. In terms of coping, responding to a novel stressor or challenge involves initial novelty processing and activation of learning mechanisms that allow habituation to the stressor through familiarization. Similarly, social attachments are initially formed by being attracted by rewarding properties of an as-yet novel individual, and subsequently developing feelings of attachment towards the familiarized individual. Attachment and familiarization increase the availability of "internal working models" for the control of behavior and emotion, which may explain why secure attachments are associated with increased resilience in the face of stress, accompanied by less reactive reward responding (i.e., increased resilience against drug addiction). The present article seeks to illuminate the role of the neuropeptide oxytocin, which may be involved in the overlapping mechanisms of stable attachment formation and stress coping by shifting processing from novelty and reward seeking to appreciation of familiarity. Oxytocin may accomplish this by facilitating a ventral-to-dorsal shift in activation in corticostriatal loops, which produces a shift from a reactive reward drive (wanting) to stable appreciation of familiar social aspects ("liking" or "loving"). The authors suggest that through dopaminergic, serotonergic and endogenous opioid mechanisms, oxytocin is involved in shifting the balance between wanting and liking in corticostriatal loops by facilitating consolidation of social information from ventral reactive reward systems to dorsal internal working models that aid in prospectively selecting optimal actions in the future, increasing resilience in the face of stress and addiction. © 2013 Elsevier Inc. All rights reserved.

Westerhof B.E.,BMEYE Inc | Westerhof B.E.,Heart Failure Research Center | Westerhof N.,VU University Amsterdam
Journal of Hypertension | Year: 2012

Background: Increased large artery stiffness is a major determinant of systolic pressure and indicator of cardiovascular events. The reflected wave, its arrival time (return time) and magnitude, contributes to systolic pressure, and is a supposed indicator of aortic stiffness. With aortic stiffening, the return time is assumed to decrease inversely with PWV as 2L/PWV, where L is the aortic length. However, several studies reported that the inflection point of aortic pressure, a surrogate of return time, varies little with aortic stiffness. Methods: We studied the effects of aortic stiffness on wave reflection in an anatomically accurate arterial model. Return time is time difference of forward, Pf, and backward, Pb, pressure. Return time, inflection and shoulder points, augmentation index, and reflection magnitude (Pb/Pf) were calculated by standard rules. Results: Peripheral resistance does not affect reflection directly, but only through pressure (stiffness) changes. Magnitude of reflected waves depend about equally on aortic geometry (taper, branches) and distal aortic reflection. Therefore, relations of augmentation index and reflection magnitude with stiffness are nonlinear and complex; augmentation index is most sensitive to stiffness. Between PWV 6 and 12 m/s, representing ages of 20-80 years, return time and inflection and shoulder points change differently with stiffness and PWV cannot be derived from them. Pulse pressure is strongly dependent on aortic stiffness. Taper changes return time by a factor 2, but has little effect on reflection magnitude, augmentation index, and inflection point. Conclusion: Accurate quantitative information on arterial stiffness cannot be obtained from reflection parameters. The augmentation index is most sensitive to stiffness changes. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Heijboer A.C.,VU University Amsterdam | Blankenstein M.A.,VU University Amsterdam | Kema I.P.,University of Groningen | Buijs M.M.,Medial Diagnostic Centers
Clinical Chemistry | Year: 2012

BACKGROUND: Recent recognition of its broad pathophysiological importance has triggered an increased interest in 25-hydroxyvitamin D [25(OH)D]. By consequence, throughput in 25(OH)D testing has become an issue for clinical laboratories, and several automated assays for measurement of 25(OH)D are now available. The aim of this study was to test the accuracy and robustness of these assays by comparing their results to those of an isotope dilution/online solid-phase extraction liquid chromatography/tandem mass spectrometry (ID-XLC-MS/MS) method. We put specific focus on the influence of vitamin D-binding protein (DBP) by using samples with various concentrations of DBP. METHODS: We used 5 automated assays (Architect, Centaur, iSYS, Liaison, and Elecsys), 1 RIA (Diasorin) preceded by extraction, and an ID-XLC-MS/MS method to measure 25(OH)D concentrations in plasma samples of 51 healthy individuals, 52 pregnant women, 50 hemodialysis patients, and 50 intensive care patients. Using ELISA, we also measured DBP concentrations in these samples. RESULTS: Most of the examined 25(OH)D assays showed significant deviations in 25(OH)D concentrations from those of the ID-XLC-MS/MS method. As expected, DBP concentrations were higher in samples of pregnant women and lower in samples of IC patients compared to healthy controls. In 4 of the 5 fully automated 25(OH)D assays, we observed an inverse relationship between DBP concentrations and deviations from the ID-XLC-MS/MS results. CONCLUSIONS: 25(OH)D measurements performed with most immunoassays suffer from inaccuracies that are DBP concentration dependent. Therefore, when interpreting results of 25(OH)D measurements, careful consideration of the measurement method is necessary. © 2011 American Association for Clinical Chemistry.

Kouril R.,University of Groningen | Dekker J.P.,VU University Amsterdam | Boekema E.J.,University of Groningen
Biochimica et Biophysica Acta - Bioenergetics | Year: 2012

Green plant photosystem II (PSII) is involved in the light reactions of photosynthesis, which take place in the thylakoid membrane of the chloroplast. PSII is organized into large supercomplexes with variable amounts of membrane-bound peripheral antenna complexes. These supercomplexes are dimeric and contain usually 2-4 copies of trimeric LHCII complexes and have a further tendency to associate into megacomplexes or into crystalline domains, of which several types have been characterized. This review focuses on the overall composition and structure of the PSII supercomplex of green plants and its organization and interactions within the photosynthetic membrane. Further, we present the current knowledge how the thylakoid membrane is three-dimensionally organized within the chloroplast. We also discuss how the supramolecular organization in the thylakoid membrane and the PSII flexibility may play roles in various short-term regulatory mechanisms of green plant photosynthesis. This article is part of a Special Issue entitled: Photosystem II. © 2011 Elsevier B.V. All rights reserved.

Mol B.W.J.,University of Adelaide | Roberts C.T.,University of Adelaide | Thangaratinam S.,Queen Mary, University of London | Magee L.A.,BC Womens Hospital | And 2 more authors.
The Lancet | Year: 2016

Pre-eclampsia affects 3-5% of pregnancies and is traditionally diagnosed by the combined presentation of high blood pressure and proteinuria. New definitions also include maternal organ dysfunction, such as renal insufficiency, liver involvement, neurological or haematological complications, uteroplacental dysfunction, or fetal growth restriction. When left untreated, pre-eclampsia can be lethal, and in low-resource settings, this disorder is one of the main causes of maternal and child mortality. In the absence of curative treatment, the management of pre-eclampsia involves stabilisation of the mother and fetus, followed by delivery at an optimal time. Although algorithms to predict pre-eclampsia are promising, they have yet to become validated. Simple preventive measures, such as low-dose aspirin, calcium, and diet and lifestyle interventions, show potential but small benefit. Because pre-eclampsia predisposes mothers to cardiovascular disease later in life, pregnancy is also a window for future health. A collaborative approach to discovery and assessment of the available treatments will hasten our understanding of pre-eclampsia and is an effort much needed by the women and babies affected by its complications. © 2016 Elsevier Ltd.

Boomsma J.K.,VU University Amsterdam | Boer D.,University of Groningen
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2010

Both in heavy-ion collisions and in magnetars very strong magnetic fields are produced, which has an influence on the phases of matter involved. In this paper we investigate the effect of strong magnetic fields (B∼5mπ2/e=1. 7×1019G) on the chiral symmetry restoring phase transition using the Nambu-Jona-Lasinio model. It is observed that the pattern of phase transitions depends on the relative magnitude of the magnetic field and the instanton interaction strength. We study two specific regimes in the phase diagram, high chemical potential and zero temperature and vice versa, which are of relevance for neutron stars and heavy-ion collisions, respectively. In order to shed light on the behavior of the phase transitions, we study the dependence of the minima of the effective potential on the occupation of Landau levels. We observe a near degeneracy of multiple minima with differing occupation numbers, of which some become the global minimum upon changing the magnetic field or the chemical potential. These minima differ considerably in the amount of chiral symmetry breaking and, in some cases, also of isospin breaking. © 2010 The American Physical Society.

Wernand M.R.,Netherlands Institute for Sea Research | van der Woerd H.J.,VU University Amsterdam | Gieskes W.W.C.,University of Groningen
PLoS ONE | Year: 2013

Marine primary productivity is an important agent in the global cycling of carbon dioxide, a major 'greenhouse gas', and variations in the concentration of the ocean's phytoplankton biomass can therefore explain trends in the global carbon budget. Since the launch of satellite-mounted sensors globe-wide monitoring of chlorophyll, a phytoplankton biomass proxy, became feasible. Just as satellites, the Forel-Ule (FU) scale record (a hardly explored database of ocean colour) has covered all seas and oceans - but already since 1889. We provide evidence that changes of ocean surface chlorophyll can be reconstructed with confidence from this record. The EcoLight radiative transfer numerical model indicates that the FU index is closely related to chlorophyll concentrations in open ocean regions. The most complete FU record is that of the North Atlantic in terms of coverage over space and in time; this dataset has been used to test the validity of colour changes that can be translated to chlorophyll. The FU and FU-derived chlorophyll data were analysed for monotonously increasing or decreasing trends with the non-parametric Mann-Kendall test, a method to establish the presence of a consistent trend. Our analysis has not revealed a globe-wide trend of increase or decrease in chlorophyll concentration during the past century; ocean regions have apparently responded differentially to changes in meteorological, hydrological and biological conditions at the surface, including potential long-term trends related to global warming. Since 1889, chlorophyll concentrations have decreased in the Indian Ocean and in the Pacific; increased in the Atlantic Ocean, the Mediterranean, the Chinese Sea, and in the seas west and north-west of Japan. This suggests that explanations of chlorophyll changes over long periods should focus on hydrographical and biological characteristics typical of single ocean regions, not on those of 'the' ocean. © 2013 Wernand et al.

De Borst M.H.,University of Groningen | Vervloet M.G.,VU University Amsterdam | Ter Wee P.M.,VU University Amsterdam | Navis G.,University of Groningen
Journal of the American Society of Nephrology | Year: 2011

There is increasingly evidence that the interactions between vitamin D, fibroblast growth factor 23 (FGF-23), and klotho form an endocrine axis for calcium and phosphate metabolism, and derangement of this axis contributes to the progression of renal disease. Several recent studies also demonstrate negative regulation of the renin gene by vitamin D. In chronic kidney disease (CKD), low levels of calcitriol, due to the loss of 1-alpha hydroxylase, increase renal renin production. Activation of the renin-angiotensin-aldosterone system (RAAS), in turn, reduces renal expression of klotho, a crucial factor for proper FGF-23 signaling. The resulting high FGF-23 levels suppress 1-alpha hydroxylase, further lowering calcitriol. This feedback loop results in vitamin D deficiency, RAAS activation, high FGF-23 levels, and renal klotho deficiency, all of which associate with progression of renal damage. Here we examine current evidence for an interaction between the RAAS and the vitamin D-FGF-23-klotho axis as well as its possible implications for progression of CKD. Copyright © 2011 by the American Society of Nephrology.

Boer D.,University of Groningen | Den Dunnen W.J.,VU University Amsterdam | Pisano C.,University of Cagliari | Schlegel M.,University of Tübingen | Vogelsang W.,University of Tübingen
Physical Review Letters | Year: 2012

We study how gluons carrying linear polarization inside an unpolarized hadron contribute to the transverse momentum distribution of Higgs bosons produced in hadronic collisions. They modify the distribution produced by unpolarized gluons in a characteristic way that could be used to determine whether the Higgs boson is a scalar or a pseudoscalar particle. © 2012 American Physical Society.

Scheper W.,VU University Amsterdam | Hoozemans J.J.M.,VU University Amsterdam
Acta Neuropathologica | Year: 2015

The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER) to a disturbance in protein folding. The so-called ER stress sensors PERK, IRE1 and ATF6 play a central role in the initiation and regulation of the UPR. The accumulation of misfolded and aggregated proteins is a common characteristic of neurodegenerative diseases. With the discovery of the basic machinery of the UPR, the idea was born that the UPR or part of its machinery could be involved in neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prion disease. Over the last decade, the UPR has been addressed in an increasing number of studies on neurodegeneration. The involvement of the UPR has been investigated in human neuropathology across different neurological diseases, as well as in cell and mouse models for neurodegeneration. Studies using different disease models display discrepancies on the role and function of the UPR during neurodegeneration, which can often be attributed to differences in methodology. In this review, we will address the importance of investigation of human brain material for the interpretation of the role of the UPR in neurological diseases. We will discuss evidence for UPR activation in neurodegenerative diseases, and the methodology to study UPR activation and its connection to brain pathology will be addressed. More recently, the UPR is recognized as a target for drug therapy for treatment and prevention of neurodegeneration, by inhibiting the function of specific mediators of the UPR. Several preclinical studies have shown a proof-of-concept for this approach targeting the machinery of UPR, in particular the PERK pathway, in different models for neurodegeneration and have yielded paradoxical results. The promises held by these observations will need further support by clarification of the observed differences between disease models, as well as increased insight obtained from human neuropathology. © 2015, The Author(s).

Snijders D.,Medical Center Alkmaar | Daniels J.M.A.,VU University Amsterdam | De Graaff C.S.,Medical Center Alkmaar | Van Der Werf T.S.,University of Groningen | Boersma W.G.,Medical Center Alkmaar
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Some studies have shown a beneficial effect of corticosteroids in patients with community-acquired pneumonia (CAP), possibly by diminishing local and systemic antiinflammatory host response. Objectives: To assess the efficacy of adjunctive prednisolone treatment in patients hospitalized with CAP. Methods: Hospitalized patients, clinically and radiologically diagnosed with CAP using standard clinical and radiological criteria, were randomized to receive 40 mg prednisolone for 7 days or placebo, along with antibiotics. Primary outcome was clinical cure at Day 7. Secondary outcomes were clinical cure at Day 30, length of stay, time to clinical stability, defervescence, and C-reactive protein. Disease severity was scored using CURB-65 (a severity index for community-acquired pneumonia evaluating Confusion, blood Urea nitrogen, Respiratory rate, Blood pressure, and age 65 or older) and Pneumonia Severity Index. Measurements and Main Results: We enrolled 213 patients. Fifty-four (25.4%) patients had a CURB-65 score greater than 2, and 93 (43.7%) patients were in Pneumonia Severity Index class IV-V. Clinical cure at Days 7 and 30 was 84/104 (80.8%) and 69/104 (66.3%) in the prednisolone group and 93/109 (85.3%) and 84/109 (77.1%) in the placebo group (P = 0.38 and P = 0.08). Patients on prednisolone had faster defervescence and faster decline in serum C-reactive protein levels compared with placebo. Subanalysis of patients with severe pneumonia did not show differences in clinical outcome. Late failure (>72 h after admittance) was more common in the prednisolone group (20 patients, 19.2%) than in the placebo group (10 patients, 6.4%; P = 0.04). Adverse events were few and not different between the two groups. Conclusions: Prednisolone (at 40 mg) once daily for a week does not improve outcome in hospitalized patients with CAP. A benefit in more severely ill patients cannot be excluded. Because of its association with increased late failure and lack of efficacy prednisolone should not be recommended as routine adjunctive treatment in CAP. Clinical trial registered with (NCT 00170196).

Agency: GTR | Branch: ESRC | Program: | Phase: Research Grant | Award Amount: 24.84K | Year: 2012

The World Health Organization (WHO) model of age-friendly cities emphasizes the theme of supportive urban environments for older citizens. These defined as encouraging active ageing by optimizing opportunities for health, participation and security in order to enhance quality of life as people age (WHO, Global Age-friendly Cities, 2007). The goal of establishing age-friendly cities should be seen in the context of pressures arising from population ageing and urbanisation. By 2030, two-thirds of the worlds population will reside in cities, with - for urban areas in high-income countries - at least one-quarter of their populations aged 60 and over. This development raises important issues for older people: To what extent will cities develop as age-friendly communities? Will so-called global cities integrate or segregate their ageing populations? What kind of variations might occur across different types of urban areas? How are different groups of older people affected by urban change? The age-friendly city perspective has been influential in raising awareness about the impact of population ageing. Against this, the value of this approach has yet to be assessed in the context of modern cities influenced by pressures associated with global social and economic change. The IPNS has four main objectives: first, to build a collaborative research-based network focused on understanding population ageing in the context of urban environments; second to develop a research proposal for a cross-national study examining different approaches to building age-friendly cities; third to provide a systematic review of data sets and other resources of relevance to developing a research proposal on age-friendly cities; fourth, to develop training for early career resarchers working on ageing and urban issues. The network represents the first attempt to facilitate comparative research on the issue of age-friendly cities. It builds upon two meetings held at the Universities of Keele and Manchester in 2011 that sought to establish the basis for cross-national work around the age-friendly theme. The IPNS represents brings together world class research groups in Europe, Hong Kong and North America, professionals concerned with urban design and architecture, and leading NGOs working in the field of ageing. A range of activities have been identified over the two-year funding period: (1) Preparation of research proposals for a cross-national study of approaches to developing age-friendly urban environments. (2) Two workshops to specify theoretical and methodological issues raised by demographic change and urbanisation. (3) A Summer School exploring links between data resources of potential relevance to the ageing and urbanisation theme and which might underpin research proposals. (4) Master classes for network members from key researchers in the field of urbanisation and ageing. (5) A workshop with a user-based theme developing older peoples participation in research on building age-friendly communities. (6) Themed workshops (face-to-face and via video-link) to identify research and policy gaps drawing on inter-disciplinary perspectives The IPNS will be sustained in a variety of ways at the end of the funding period. A collaborative research proposal as well as one to maintain the network will be major outputs from the project and work with potential funding bodies will continue after 2014. Dissemination activities will continue through professional networks, symposia at major international conferences, and involvement in expert meetings. The project will continue to be advertised through the maintenance of a website maintained by the host UK HEI. The project will continue to make a contribution to policy development around the theme of age-friendly cities, notably with the main NGOs working in the field.

Cacioppo J.T.,University of Chicago | Cacioppo S.,University of Chicago | Cole S.W.,University of California at Los Angeles | Capitanio J.P.,University of California at Davis | And 2 more authors.
Perspectives on Psychological Science | Year: 2015

Loneliness typically refers to the feelings of distress and dysphoria resulting from a discrepancy between a person’s desired and achieved levels of social relations, and there is now considerable evidence that loneliness is a risk factor for poor psychological and physical health. Loneliness has traditionally been conceptualized as a uniquely human phenomenon. However, over millions of years of evolution, efficient and manifold neural, hormonal, and molecular mechanisms have evolved for promoting companionship and mutual protection/assistance and for organizing adaptive responses when there is a significant discrepancy between the preferred and realized levels of social connection. We review evidence suggesting that loneliness is not a uniquely human phenomenon, but, instead, as a scientific construct, it represents a generally adaptive predisposition that can be found across phylogeny. Central to this argument is the premise that the brain is the key organ of social connections and processes. Comparative studies and animal models, particularly when integrated with human studies, have much to contribute to the understanding of loneliness and its underlying principles, mechanisms, consequences, and potential treatments. © The Author(s) 2015

Agency: Cordis | Branch: FP7 | Program: | Phase: | Award Amount: 3.42M | Year: 2007

DRIVER is a multi-phase effort whose vision and primary objective is to establish a cohesive, pan-European infrastructure of Digital Repositories, offering sophisticated functionality services to both researchers and the general public. The present proposal (DRIVER Phase-II) aims to introduce key innovations compared to the original DRIVER project, while building on its results. The main novelties envisioned are: Establishment of a European Confederation of Digital Repositories as a strategic arm of DRIVER; Inclusion of Digital Repositories with non-textual or non-publication content, e.g., images, presentations, and possibly primary data; Construction of enhanced publications, which combine interrelated information objects into a logical whole, e.g., publications coupled with relevant presentations and associated datasets; Provision of advanced functionality to address the requirements raised by the above innovations or to serve varied modes of scientists research explorations. Additionally, DRIVER Phase-II moves from a test-bed to a production-quality infrastructure, expands the geographical coverage of Digital Repositories included in it, intensifies state-of-the-art and future-direction studies, and escalates dissemination, training, and community building activities. DRIVER Phase-II significantly broadens the horizons of the whole DRIVER endeavour regarding infrastructure operation, functionality innovation, and community relevance, and constitutes a major step on the way to the envisioned Knowledge Society.

News Article | February 15, 2017

-- Largest imaging study of ADHD to date identifies differences in five regions of the brain, with greatest differences seen in children rather than adults. Attention-deficit hyperactivity disorder (ADHD) is associated with the delayed development of five brain regions and should be considered a brain disorder, according to a study published in The Lancet Psychiatry. The study is the largest to look at the brain volumes of people with ADHD, involving more than 3200 people. The authors say the findings could help improve understanding of the disorder, and might be important in challenging beliefs that ADHD is a label for difficult children or the result of poor parenting. ADHD symptoms include inattention and/or hyperactivity and acting impulsively. The disorder affects more than one in 20 (5.3%) under-18 year olds, and two-thirds of those diagnosed continue to experience symptoms as adults. Previous studies have linked differences in brain volume with the disorder, but small sample sizes mean results have been inconclusive. Areas thought to be involved in ADHD are located in the basal ganglia - a part of the brain that controls emotion, voluntary movement and cognition - and research has previously found that the caudate and putamen regions within the ganglia are smaller in people with ADHD. The new international study measured differences in the brain structure of 1713 people with a diagnosis of ADHD and 1529 people without, all aged between four and 63 years old. All 3242 people had an MRI scan to measure their overall brain volume, and the size of seven regions of the brain that were thought to be linked to ADHD - the pallidum, thalamus, caudate nucleus, putamen, nucleus accumbens, amygdala and hippocampus. The researchers also noted whether those with ADHD had ever taken psychostimulant medication, for example Ritalin. The study found that overall brain volume and five of the regional volumes were smaller in people with ADHD - the caudate nucleus, putamen, nucleus accumbens, amygdala and hippocampus. "These differences are very small - in the range of a few percent - so the unprecedented size of our study was crucial to help identify these. Similar differences in brain volume are also seen in other psychiatric disorders, especially major depressive disorder." said lead author Dr Martine Hoogman, Radboud University Medical Center, Nijmegen, The Netherlands. [1] The differences observed were most prominent in the brains of children with ADHD, but less obvious in adults with the disorder. Based on this, the researchers propose that ADHD is a disorder of the brain, and suggest that delays in the development of several brain regions are characteristic of ADHD. Besides the caudate nucleus and putamen, for which previous studies have already shown links to ADHD, researchers were able to conclusively link the amygdala, nucleus accumbens and hippocampus to ADHD. The researchers hypothesise that the amygdala is associated with ADHD through its role in regulating emotion, and the nucleus accumbens may be associated with the motivation and emotional problems in ADHD via its role in reward processing. The hippocampus' role in the disorder might act through its involvement in motivation and emotion. At the time of their MRI scan, 455 people with ADHD were receiving psychostimulant medication, and looking back further, 637 had had the medication in their lifetime. The different volumes of the five brain regions involved in ADHD were present whether or not people had taken medication, suggesting the differences in brain volumes are not a result of psychostimulants. "The results from our study confirm that people with ADHD have differences in their brain structure and therefore suggest that ADHD is a disorder of the brain," added Dr Hoogman. "We hope that this will help to reduce stigma that ADHD is 'just a label' for difficult children or caused by poor parenting. This is definitely not the case, and we hope that this work will contribute to a better understanding of the disorder." [1] While the study included large numbers of people of all ages, its design means that it cannot determine how ADHD develops throughout life. Therefore, longitudinal studies tracking people with ADHD from childhood to adulthood to see how the brain differences change over time will be an important next step in the research. Writing in a linked Comment Dr Jonathan Posner, Columbia University, USA, said: "[This] is the largest study of its kind and well powered to detect small effect sizes. Large sample sizes are particularly important in the study of ADHD because of the heterogeneity of the disorder both in the biological cause and clinical manifestation... This study represents an important contribution to the field by providing robust evidence to support the notion of ADHD as a brain disorder with substantial effects on the volumes of subcortical nuclei. Future meta-analyses and mega-analyses will need to investigate medication effects as well as the developmental course of volumetric differences in this disorder." The study was funded by the National Institutes of Health. The study is part of the ENIGMA Consortium, where researchers are also studying the structure of the brain in other psychiatric disorders, allowing researchers to define differences and similarities between the disorders. It was conducted by scientists from Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, University of Southern California, University of Groningen, QIMR Berghofer Medical Research Institute, University Medical Center Utrecht, National Human Genome Research Institute, Asociación para la Innovación en Análisis, Gestión y Procesamiento de Datos Científicos y Tecnológicos, University Hospital Aachen, JARA Translational Brain Medicine, Research Center Juelich, Harvard Medical School, The Broad Institute, University of Bergen, Cincinnati Children's Hospital Medical Center, University of California, UC San Diego, University of Tübingen, University of Würzburg, University of Dublin, NYU Langone Medical Center, King's College London, Heidelberg University, Federal University of Rio de Janeiro, University of Zurich, Child Mind Institute, Nathan Kline Institute for Psychiatric Research, Otto-von-Guericke-University, Maastricht University, University Hospital Frankfurt, Haukeland University Hospital, Child and Adolescent Mental Health Center, Beth Israel Deaconess Medical Center, Karakter Child and Adolescent Psychiatry, VU University Amsterdam, Universitat Autònoma de Barcelona, Fundació IMIM, Hospital Universitari Vall d'Hebron, SUNY Upstate Medical University, National Institute of Mental Health. [1] Quote direct from author and cannot be found in the text of the Article. IF YOU WISH TO PROVIDE A LINK FOR YOUR READERS, PLEASE USE THE FOLLOWING, WHICH WILL GO LIVE AT THE TIME THE EMBARGO LIFTS:

Nurmohamed M.T.,VU University Amsterdam | Heslinga M.,Amsterdam Rheumatology and Immunology Center | Kitas G.D.,Russells Hall Hospital
Nature Reviews Rheumatology | Year: 2015

Patients with rheumatoid arthritis (RA) and other inflammatory joint diseases (IJDs) have an increased risk of premature death compared with the general population, mainly because of the risk of cardiovascular disease, which is similar in patients with RA and in those with diabetes mellitus. Pathogenic mechanisms and clinical expression of cardiovascular comorbidities vary greatly between different rheumatic diseases, but atherosclerosis seems to be associated with all IJDs. Traditional risk factors such as age, gender, dyslipidaemia, hypertension, smoking, obesity and diabetes mellitus, together with inflammation, are the main contributors to the increased cardiovascular risk in patients with IJDs. Although cardiovascular risk assessment should be part of routine care in such patients, no disease-specific models are currently available for this purpose. The main pillars of cardiovascular risk reduction are pharmacological and nonpharmacological management of cardiovascular risk factors, as well as tight control of disease activity. © 2015 Macmillan Publishers Limited.

Butz M.,Jülich Research Center | Steenbuck I.D.,Albert Ludwigs University of Freiburg | Van Ooyen A.,VU University Amsterdam
Frontiers in Synaptic Neuroscience | Year: 2014

In networks with small-world topology, which are characterized by a high clustering coefficient and a short characteristic path length, information can be transmitted efficiently and at relatively low costs. The brain is composed of small-world networks, and evolution may have optimized brain connectivity for efficient information processing. Despite many studies on the impact of topology on information processing in neuronal networks, little is known about the development of network topology and the emergence of efficient small-world networks. We investigated how a simple growth process that favors short-range connections over long-range connections in combination with a synapse formation rule that generates homeostasis in post-synaptic firing rates shapes neuronal network topology. Interestingly, we found that small-world networks benefited from homeostasis by an increase in efficiency, defined as the averaged inverse of the shortest paths through the network. Efficiency particularly increased as small-world networks approached the desired level of electrical activity. Ultimately, homeostatic small-world networks became almost as efficient as random networks. The increase in efficiency was caused by the emergent property of the homeostatic growth process that neurons started forming more long-range connections, albeit at a low rate, when their electrical activity was close to the homeostatic set-point. Although global network topology continued to change when neuronal activities were around the homeostatic equilibrium, the small-world property of the network was maintained over the entire course of development. Our results may help understand how complex systems such as the brain could set up an efficient network topology in a self-organizing manner. Insights from our work may also lead to novel techniques for constructing large-scale neuronal networks by self-organization. © 2014 Butz, Steenbuck and van Ooyen.

Prather A.A.,University of California at San Francisco | Vogelzangs N.,VU University Amsterdam | Penninx B.W.J.H.,VU University Amsterdam
Journal of Psychiatric Research | Year: 2015

Systemic inflammation has emerged as a potential pathway linking depressive and anxiety disorders with disease risk. Short and long sleep duration, as well as insomnia, are common among psychiatric populations and have previously been related to increased inflammation. The aim of the present study was to investigate associations between sleep duration and insomnia with biomarkers of inflammation and to explore whether these associations varied by psychiatric diagnostic status. To this end, self-reported measures of sleep duration, insomnia symptoms, and markers of inflammation, including C-reactive protein (CRP), interleukin-(IL)-6, and tumor necrosis factor (TNF)-α, were obtained in 2553 adults (aged 18-65 years) diagnosed with current/recent or remitted depressive and/or anxiety disorders and healthy controls enrolled in the Netherlands Study of Depression and Anxiety (NESDA). Regression analyses revealed associations between sleep duration and levels of CRP and IL-6 with higher levels observed in long sleepers. These associations remained statistically significant after controlling for age, gender, education, body mass index, smoking, alcohol consumption, medical comorbidities, medication use, psychotropic medication use, and psychiatric diagnostic status. There were no clear associations between insomnia symptoms and levels of inflammation. Relationships between sleep duration and inflammation did not vary as a function of psychiatric diagnostic status. These findings suggest that elevated levels of systemic inflammation may represent a mechanism linking long sleep duration and disease risk among those with and without depressive and anxiety disorders. © 2014 Elsevier Ltd.

Fernandez I.,Complutense University of Madrid | Bickelhaupt F.M.,VU University Amsterdam | Bickelhaupt F.M.,Radboud University Nijmegen
Chemical Society Reviews | Year: 2014

In this Tutorial Review, we make the point that a true understanding of trends in reactivity (as opposed to measuring or simply computing them) requires a causal reactivity model. To this end, we present and discuss the Activation Strain Model (ASM). The ASM establishes the desired causal relationship between reaction barriers, on one hand, and the properties of reactants and characteristics of reaction mechanisms, on the other hand. In the ASM, the potential energy surface ΔE(ζ) along the reaction coordinate ζ is decomposed into the strain ΔEstrain(ζ) of the reactants that become increasingly deformed as the reaction proceeds, plus the interaction ΔEint(ζ) between these deformed reactants, i.e., ΔE(ζ) = ΔEstrain(ζ) + ΔE int(ζ). The ASM can be used in conjunction with any quantum chemical program. An analysis of the method and its application to problems in organic and organometallic chemistry illustrate the power of the ASM as a unifying concept and a tool for rational design of reactants and catalysts. This journal is © the Partner Organisations 2014.

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

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

Butz M.,Jülich Research Center | van Ooyen A.,VU University Amsterdam
PLoS Computational Biology | Year: 2013

Lasting alterations in sensory input trigger massive structural and functional adaptations in cortical networks. The principles governing these experience-dependent changes are, however, poorly understood. Here, we examine whether a simple rule based on the neurons' need for homeostasis in electrical activity may serve as driving force for cortical reorganization. According to this rule, a neuron creates new spines and boutons when its level of electrical activity is below a homeostatic set-point and decreases the number of spines and boutons when its activity exceeds this set-point. In addition, neurons need a minimum level of activity to form spines and boutons. Spine and bouton formation depends solely on the neuron's own activity level, and synapses are formed by merging spines and boutons independently of activity. Using a novel computational model, we show that this simple growth rule produces neuron and network changes as observed in the visual cortex after focal retinal lesions. In the model, as in the cortex, the turnover of dendritic spines was increased strongest in the center of the lesion projection zone, while axonal boutons displayed a marked overshoot followed by pruning. Moreover, the decrease in external input was compensated for by the formation of new horizontal connections, which caused a retinotopic remapping. Homeostatic regulation may provide a unifying framework for understanding cortical reorganization, including network repair in degenerative diseases or following focal stroke. © 2013 Butz, van Ooyen.

Wesseling P.,VU University Amsterdam | Wesseling P.,Radboud University Nijmegen | van den Bent M.,Erasmus Cancer Center | Perry A.,University of California at San Francisco
Acta Neuropathologica | Year: 2015

For nearly a century, the diagnosis and grading of oligodendrogliomas and oligoastrocytomas has been based on histopathology alone. Roughly 20 years ago, the first glioma-associated molecular signature was found with complete chromosome 1p and 19q codeletion being particularly common in histologically classic oligodendrogliomas. Subsequently, this codeletion appeared to not only carry diagnostic, but also prognostic and predictive information, the latter aspect only recently resolved after carefully constructed clinical trials with very long follow-up times. More recently described biomarkers, including the non-balanced translocation leading to 1p/19q codeletion, promoter hypermethylation of the MGMT gene, mutations of the IDH1 or IDH2 gene, and mutations of FUBP1 (on 1p) or CIC (on 19q), have greatly enhanced our understanding of oligodendroglioma biology, although their diagnostic, prognostic, and predictive roles are less clear. It has therefore been suggested that complete 1p/19q codeletion be required for the diagnosis of ‘canonical oligodendroglioma’. This transition to an integrated morphological and molecular diagnosis may result in the disappearance of oligoastrocytoma as an entity, but brings new challenges as well. For instance it needs to be sorted out how (histopathological) criteria for grading of ‘canonical oligodendrogliomas’ should be adapted, how pediatric oligodendrogliomas (known to lack codeletions) should be defined, which platforms and cut-off levels should ideally be used for demonstration of particular molecular aberrations, and how the diagnosis of oligodendroglioma should be made in centers/countries where molecular diagnostics is not available. Meanwhile, smart integration of morphological and molecular information will lead to recognition of biologically much more uniform groups within the spectrum of diffuse gliomas and thereby facilitate tailored treatments for individual patients. © 2015, The Author(s).

Radua J.,King's College London | Van Den Heuvel O.A.,VU University Amsterdam | Surguladze S.,King's College London | Mataix-Cols D.,King's College London
Archives of General Psychiatry | Year: 2010

Context: Whether obsessive-compulsive disorder (OCD) is adequately classified as an anxiety disorder is a matter of considerable debate. Objectives: To quantitatively compare structural brain changes in OCD and other anxiety disorders using novel voxel-based meta-analytical methods and to generate an online database to facilitate replication and further analyses by other researchers. Data Sources: The PubMed, ScienceDirect, and Scopus databases were searched between 2001 (the date of the first voxel-based morphometry study in any anxiety disorder) and 2009. All voxel-based morphometry studies comparing patients with any anxiety disorder and healthy controls were retrieved. Manual searches were also conducted. Authors were contacted soliciting additional data. Study Selection: Thirty-seven data sets were identified, of which 26 (including 639 patients with anxiety disorders and 737 healthy controls) met inclusion criteria. Data Extraction: Coordinates were extracted from clusters of significant gray matter difference between patients patients and controls. Demographic, clinical, and methodological variables were extracted from each study or obtained from the authors. Data Synthesis: Patients with anxiety disorders (including OCD) showed decreased bilateral gray matter volumes in the dorsomedial frontal/anterior cingulate gyri. Individuals with OCD had increased bilateral gray matter volumes (vs healthy controls and vs individuals with other anxiety disorders) in the lenticular/caudate nuclei, while patients with other anxiety disorders (mainly panic and posttraumatic stress disorders) had decreased gray matter volumes in the left lenticular nucleus. The findings remained largely unchanged in quartile and jackknife sensitivity analyses. Controlling for potential confounders such as age or antidepressant medication had little impact on the results. Conclusions: The meta-analysis consistently revealed common as well as distinct neural substrates in OCD and other anxiety disorders. These results have implications for the current debate surrounding the classification of OCD in the DSM-V. ©2010 American Medical Association. All rights reserved.

De Man F.S.,VU University Amsterdam | Handoko M.L.,VU University Amsterdam | Guignabert C.,French Institute of Health and Medical Research | Guignabert C.,University Paris - Sud | And 2 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Despite its descriptionsome 25 years ago, neurohormonal activation has long been neglected as an important factor in the pathophysiology of pulmonary arterial hypertension (PAH). Neurohormonal activation was interpreted as a necessary compensatory response to maintain cardiac contractility and systemic blood pressure. Therefore, inhibitors of neurohormonal activity (like β-blockers or angiotensin-converting enzyme inhibitors) are considered contraindicated in current PAHmanagement guidelines. However, recent data revealed that sympathetic overstimulation is strongly related tomortality, andblockade of neurohormonal activity in experimental PAH improved survival and cardiac function. These novel insights shed newlight on the role of neurohormonal activity in PAH. Copyright © 2013 by the American Thoracic Society.

Fett A.-K.J.,Maastricht University | Fett A.-K.J.,VU University Amsterdam | Fett A.-K.J.,King's College London | Maat A.,University Utrecht
Schizophrenia Bulletin | Year: 2013

Social cognitive deficits are associated with psychotic symptoms, but the nature of this association remains unknown. This study uses a genetically sensitive cross-trait cross-sibling design to investigate the nature of the overlap between both phenotypes. A sample of 1032 patients, 1017 of their healthy siblings, and 579 control subjects were recruited within the Dutch Genetic Risk and Outcome in Psychosis (GROUP) study. Participants completed a battery of cognitive tests, including 2 social cognitive tests on theory of mind (ToM) and emotion recognition. Within siblings, symptoms were assessed with the Structured Interview for Schizotypy-Revised. The Positive and Negative Syndrome Scale was used to assess patients' symptoms. Within patients, social cognitive performance was consistently and significantly associated with disorganized and, to a lesser degree, with negative symptoms. Associations with positive symptoms were significant, but smaller. Suggestive of a shared etiology, both social cognitive factors showed significant familial clustering. The associations between patients' ToM and subclinical symptoms in siblings were nonsignificant, suggesting that their overlap within patients is due to individual rather than shared familial factors. Indicative of a shared etiology, familial covariation was present between patients' emotion recognition ability and disorganized and, albeit to a lesser degree, positive but not negative subclinical symptoms in siblings. © 2011 The Author.

Van De Meerakker S.Y.T.,Radboud University Nijmegen | Bethlem H.L.,VU University Amsterdam | Vanhaecke N.,University Paris - Sud | Meijer G.,Fritz Haber Institute
Chemical Reviews | Year: 2012

A study was conducted to demonstrate the manipulation of molecular beams with electric and magnetic fields. Seeded pulsed supersonic expansions were employed to conduct the investigations. The conservative forces exerted further downstream by the electric and magnetic fields enabled the researchers to manipulate and control the shape and the position of the distribution in the six-dimensional phase-space. All of the original experimental geometries were devised to create strong magnetic or electric field gradients to efficiently deflect particles from the beam axis. It was demonstrated that a detailed understanding of the influence of the external field on the energy level structure of the molecules was required for the manipulation of molecules with electric or magnetic fields.

Vassen W.,VU University Amsterdam | Cohen-Tannoudji C.,Kastler-Brossel Laboratory | Leduc M.,Kastler-Brossel Laboratory | Boiron D.,ParisTech Optics Institute | And 6 more authors.
Reviews of Modern Physics | Year: 2012

Experimental work on cold, trapped metastable noble gases is reviewed. The aspects which distinguish work with these atoms from the large body of work on cold, trapped atoms in general is emphasized. These aspects include detection techniques and collision processes unique to metastable atoms. Several experiments exploiting these unique features in fields including atom optics and statistical physics are described. Precision measurements on these atoms including fine structure splittings, isotope shifts, and atomic lifetimes are also discussed. © 2012 American Physical Society.

Verhoeven J.E.,VU University Amsterdam | Revesz D.,VU University Amsterdam | Wolkowitz O.M.,University of California at San Francisco | Penninx B.W.J.H.,VU University Amsterdam
BioEssays | Year: 2014

Depression might be associated with accelerated cellular aging. However, does this result in an irreversible state or is the body able to slow down or recover from such a process? Telomeres are DNA-protein complexes that protect the ends of chromosomes and generally shorten with age; and therefore index cellular aging. The majority of studies indicate that persons with depression have shorter leukocyte telomeres than similarly aged non-depressed persons, which may contribute to the observed unfavorable somatic health outcomes in the depressed population. Some small-scale preliminary studies raise the possibility that behavioral or pharmacological interventions may either slow down or else reverse this accelerated telomere shortening, possibly through increasing the activity of the telomere-lengthening enzyme telomerase. This paper covers the current state of evidence in the relationship between depression and the telomere-telomerase system and debates whether depression-related cellular aging should be considered a reversible process or permanent damage. © 2014 WILEY Periodicals, Inc.

Baker D.,Queen Mary, University of London | Lidster K.,Queen Mary, University of London | Sottomayor A.,Queen Mary, University of London | Sottomayor A.,University of Minho | And 2 more authors.
PLoS Biology | Year: 2014

There is growing concern that poor experimental design and lack of transparent reporting contribute to the frequent failure of pre-clinical animal studies to translate into treatments for human disease. In 2010, the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were introduced to help improve reporting standards. They were published in PLOS Biology and endorsed by funding agencies and publishers and their journals, including PLOS, Nature research journals, and other top-tier journals. Yet our analysis of papers published in PLOS and Nature journals indicates that there has been very little improvement in reporting standards since then. This suggests that authors, referees, and editors generally are ignoring guidelines, and the editorial endorsement is yet to be effectively implemented. © 2014 Baker et al.

Fernandez I.,Complutense University of Madrid | Sola M.,University of Girona | Bickelhaupt F.M.,VU University Amsterdam | Bickelhaupt F.M.,Radboud University Nijmegen
Chemistry - A European Journal | Year: 2013

The origin of the experimentally known preference for [6,6] over [5,6] bonds in cycloaddition reactions involving C60 has been computationally explored. To this end, the Diels-Alder reaction between cyclopentadiene and C60 has been analysed by means of the recently introduced activation strain model of reactivity in combination with the energy decomposition analysis method. Other issues, such as the aromaticity of the corresponding transition states, have also been considered. These results indicate that the major factor controlling the observed regioselectivity is the more stabilising interaction between the deformed reactants in the [6,6] reaction pathway along the entire reaction coordinate. Why [6,6]? The preference for [6,6] over [5,6] bonds in cycloaddition reactions involving C60 is experimentally well-established (see figure). However, the reasons (i.e., physical factors) behind this preference are so far completely unknown. By means of the recently introduced activation strain model of reactivity in combination with the energy decomposition analysis method, a definite answer to the question in the title is provided. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Echevarria M.G.,VU University Amsterdam | Idilbi A.,Pennsylvania State University | Scimemi I.,Complutense University of Madrid
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2014

By considering semi-inclusive deep-inelastic scattering and the (complementary) qT-spectrum for Drell-Yan lepton pair production we derive the QCD evolution for all the leading-twist transverse momentum dependent distribution and fragmentation functions. We argue that all of those functions evolve with Q2 following a single evolution kernel. This kernel is independent of the underlying kinematics and it is also spin independent. Those features hold, in impact parameter space, to all values of bT. The evolution kernel presented has all of its large logarithms resummed up to next-to-next-to leading logarithmic accuracy, which is the highest possible accuracy given the existing perturbative calculations. As a study case we apply this kernel to investigate the evolution of the Collins function, one of the ingredients that have recently attracted much attention within the phenomenological studies of spin asymmetries. Our analysis can be readily implemented to revisit previously obtained fits that involve data at different scales for other spin-dependent functions. Such improved fits are important to get better predictions - with the correct evolution kernel - for certain upcoming experiments aiming to measure the Sivers function, Collins function, transversity, and other spin-dependent functions as well. © 2014 American Physical Society.

Den Dunnen W.J.,University of Tübingen | Lansberg J.-P.,University Paris - Sud | Pisano C.,VU University Amsterdam | Schlegel M.,University of Tübingen
Physical Review Letters | Year: 2014

We argue that the study of heavy quarkonia, in particular that of Υ, produced back to back with an isolated photon in pp collisions at the LHC is the best - and currently unique - way to access the distribution of both the transverse momentum and the polarization of the gluon in an unpolarized proton. These encode fundamental information on the dynamics of QCD. We derive analytical expressions for various transverse-momentum distributions that can be measured at the LHC and which allow for a direct extraction of the aforementioned quantities. To assess the feasibility of such measurements, we evaluate the expected yields and the relevant transverse-momentum distributions for different models of the gluon dynamics inside a proton. © 2014 American Physical Society.

Schubert S.,TU Darmstadt | Gupta J.,VU University Amsterdam
Ecology and Society | Year: 2013

Increasingly, coordination mechanisms are being created at the United Nations (UN) level to enhance systemwide synergies; however, there is relatively little scientific research on these bodies. Against this background, we compare the mandates, structures, and outputs of three UN coordination mechanisms, the UN Environment Management Group, UN-Energy, and UN-Water, to understand what features enhance their ability to coordinate. We conclude that there are three key design elements that possibly enhance the ability of such mechanisms to coordinate. However, although coordination mechanisms are the easiest to set up, because they create the least political upheaval and are relatively cheap, these very characteristics hinder their ability to actually steer the bodies in their sector in such a way that synergy is optimized, duplications and contradictions are reduced, and a common strategy is adopted. Such coordination bodies can contribute to agenda setting, knowledge sharing, providing a discussion forum, and bringing together stakeholders and experts. © 2013 by the author(s).

Borissov G.,Lancaster University | Fleischer R.,NIKHEF | Fleischer R.,VU University Amsterdam | Schune M.-H.,University Paris - Sud
Annual Review of Nuclear and Particle Science | Year: 2013

CP-violating phenomena and rare decays of Bs mesons offer interesting probes to test the quark-flavor sector of the Standard Model. In view of the many new results reported, in particular from the Large Hadron Collider, this topic received a great deal of attention in 2012. We provide an overview of the most recent experimental results and new theoretical developments, and we discuss the prospects for future exploration of the Bs meson system. © Copyright ©2013 by Annual Reviews. All rights reserved.

Petzold A.,VU University Amsterdam | Petzold A.,University College London | Plant G.T.,Moorfields Eye Hospital
Journal of Neurology | Year: 2014

Chronic relapsing inflammatory optic neuropathy (CRION) is an entity that was described in 2003. Early recognition of patients suffering from CRION is relevant because of the associated risk for blindness if treated inappropriately. It seems timely to have a clinical review on this recently defined entity. A systematic literature review, irrespective of language, retrieved 22 case series and single reports describing 122 patients with CRION between 2003 and 2013. We review the epidemiology, diagnostic workup, differential diagnosis, and treatment (acute, intermediate, and long term) in view of the collective data. These data suggest that CRION is a distinct nosological entity, which is seronegative for anti-aquaporin four auto-antibodies and recognized by and managed through its dependency on immuno-suppression. Revised diagnostic criteria are proposed in light of the data compromising a critical discussion of relevant limitations. © 2013 Springer-Verlag Berlin Heidelberg.

Abma T.A.,VU University Amsterdam | Stake R.E.,University of Illinois at Urbana - Champaign
Qualitative Health Research | Year: 2014

Case studies can provide us with in-depth understanding of a single demarcated entity. Cases can be corporations and clinics, but are usually people. There are several approaches to case study. Naturalistic case study constitutes the science of the particular. The aim of naturalistic case study is to understand with minimum intervention the particularity of a case in its ordinary situation from multiple perspectives. Naturalistic case study relies on a humanistic commitment to study the world from the human perspective. The purpose here is to illuminate how five key features of naturalistic case study can be used in health research. Case studies are of use in various disciplines. In this article we show that the naturalistic case study can have extraordinary value in health research, and is useful from a variety of perspectives. We do so by presenting a case report of a 92-year-old resident moving to a care center. © The Author(s) 2014.

Pievani M.,Irccs Centro San Giovanni Of Dio | de Haan W.,VU University Amsterdam | Wu T.,Capital Medical University | Seeley W.W.,University of California at San Francisco | Frisoni G.B.,Irccs Centro San Giovanni Of Dio
The Lancet Neurology | Year: 2011

Despite advances towards understanding the molecular pathophysiology of the neurodegenerative dementias, the mechanisms linking molecular changes to neuropathology and neuropathological changes to clinical symptoms remain largely obscure. Connectivity is a distinctive feature of the brain and the integrity of functional network dynamics is crucial for normal functioning. A better understanding of network disruption in the neurodegenerative dementias might help bridge the gap between molecular changes, pathological changes, and symptoms. Recent findings on functional network disruption as assessed with resting-state or intrinsic connectivity functional MRI and electroencephalography and magnetoencephalography have shown distinct patterns of network disruption across the major neurodegenerative diseases. These network abnormalities are somewhat specific to the clinical syndromes and, in Alzheimer's disease and frontotemporal dementia, network disruption tracks the pattern of pathological changes. These findings might have practical implications for diagnostic accuracy, allowing earlier detection of neurodegenerative diseases even at the presymptomatic stage, and tracking of disease progression. © 2011 Elsevier Ltd.

Verhoeven J.E.,VU University Amsterdam | Revesz D.,VU University Amsterdam | Epel E.S.,University of California at San Francisco | Lin J.,University of California at San Francisco | And 2 more authors.
Molecular Psychiatry | Year: 2014

Patients with major depressive disorder (MDD) have an increased onset risk of aging-related somatic diseases such as heart disease, diabetes, obesity and cancer. This suggests mechanisms of accelerated biological aging among the depressed, which can be indicated by a shorter length of telomeres. We examine whether MDD is associated with accelerated biological aging, and whether depression characteristics such as severity, duration, and psychoactive medication do further impact on biological aging. Data are from the Netherlands Study of Depression and Anxiety, including 1095 current MDD patients, 802 remitted MDD patients and 510 control subjects. Telomere length (TL) was assessed as the telomere sequence copy number (T) compared to a single-copy gene copy number (S) using quantitative polymerase chain reaction. This resulted in a T/S ratio and was converted to base pairs (bp). MDD diagnosis and MDD characteristics were determined by self-report questionnaires and structured psychiatric interviews. Compared with control subjects (mean bp=5541), sociodemographic-adjusted TL was shorter among remitted MDD patients (mean bp=5459; P=0.014) and current MDD patients (mean bp=5461; P=0.012). Adjustment for health and lifestyle variables did not reduce the associations. Within the current MDD patients, separate analyses showed that both higher depression severity (P<0.01) and longer symptom duration in the past 4 years (P=0.01) were associated with shorter TL. Our results demonstrate that depressed patients show accelerated cellular aging according to a 'dose-response' gradient: those with the most severe and chronic MDD showed the shortest TL. We also confirmed the imprint of past exposure to depression, as those with remitted MDD had shorter TL than controls. © 2014 Macmillan Publishers Limited.

Fernandez I.,Complutense University of Madrid | Bickelhaupt F.M.,VU University Amsterdam | Cossio F.P.,University of the Basque Country
Chemistry - A European Journal | Year: 2012

To understand the factors that control the activation barrier of type-I 1,2-dyotropic reactions (X-EH 2-CH 2-X*→X*- EH 2-CH 2-X, with E=C and Si, X=H, CH 3, SiH 3, F to I) and trends therein as a function of the migrating groups X, we have explored ten archetypal model reactions of this class using relativistic density functional theory (DFT) at ZORA-OLYP/TZ2P. The main trends in reactivity are rationalized using the activation strain model of chemical reactivity, which had to be extended from bimolecular to unimolecular reactions. Thus, the above type-I dyotropic reactions can be conceived as a relative rotation of the CH 2CH 2 and [X···X] fragments in X-CH 2-CH 2-X. The picture that emerges from these analyses is that reduced C-X bonding in the transition state is the origin of the reaction barrier. Also the trends in reactivity on variation of X can be understood in terms of how sensitive the C-X interaction is towards adopting the transition-state geometry. A valence bond analysis complements the analyses and confirms the picture emerging from the activation strain model. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

News Article | October 23, 2015

UPDATE: Emissions from Indonesian fires have continued to rise since this article was published and now are estimated to be roughly equal to Japan’s annual carbon dioxide emissions. See here. See also our coverage of Indonesian President Joko Widodo’s visit to the U.S. as his country’s climate crisis rages. Experts say that along with dramatic global coral bleaching, thousands of fires across Indonesia represents the next sign of an intensifying global El Niño event. And the consequences, in this case, could affect the entire globe’s atmosphere. That’s because a large number of Indonesia’s currently raging fires are consuming ancient stores of carbon-rich peat, which is found in wetlands featuring organic layers full of dead and partially decomposed plant life. This year, the very smoky peat burning has been simply massive — the fires are estimated to have caused $ 14 billion in damage so far, and are causing hazardous air conditions in much of the area, including nearby Singapore. Millions of people have been affected, and 120,000 have sought medical treatment for respiratory illnesses, according to Weather Underground’s Jeff Masters. Indeed, the 2015 Indonesian fire season has so far featured a stunning 94,192 fires. That’s more Indonesian fires than at the same time in 2006, a banner year both for fires and also for their carbon emissions to the atmosphere. Those emissions are more than large enough to have global consequences. Indeed, according to recent calculations by Guido van der Werf, a researcher at VU University Amsterdam in the Netherlands who keeps a database that tracks the global emissions from wildfires, this year’s Indonesian fires had given off an estimated 995 million metric tons of carbon dioxide equivalent emissions as of Oct. 14. That’s just shy of a billion metric tons, or a gigaton. The number is an estimate, of course, and subject to “substantial uncertainties” — but it’s also based on a well-developed methodology for estimating wildfire emissions to the atmosphere based upon satellite images of the fires themselves and the vegetation they consume. “Fire emissions are already higher than Germany’s total CO2 emissions, and the fire season is not over yet,” says van der Werf. He provided this figure, which allows you to compare how much carbon dioxide and other emissions Indonesian fires have put into the atmosphere each year since 1997 with the annual fossil fuel emissions profiles of various countries (including Indonesia itself): As you can see, 2015 is already a very notable year — and it could get considerably worse. Van der Werf says he thinks that for total Indonesian fire emissions, 2015 may ultimately nestle somewhere between 2006 and the truly catastrophic year of 1997. During that year, according to scientists who studied its aftermath, fire emissions from Indonesia alone were “equivalent to 13–40% of the mean annual global carbon emissions from fossil fuels.” And while the emissions from wildfires in many parts of the world are at least partially offset as trees and vegetation subsequently grow back and pull carbon back out of the air again, that’s not so much the case in Indonesia. “In Indonesia, what’s burning is for the large part, peat layers that have been deposited over thousands of years. So this is really a net source of emissions just like fossil fuels are,” says van der Werf. Thus, peat emissions are, in a sense, similar to Arctic permafrost emissions — built up over vast stretches of time, the carbon contained in thawing permafrost is also a new addition to the atmosphere if emitted. What the severe Indonesian fire years of 1997, 2006, and 2015 all have in common is that they were El Niño years. El Niño is a critical factor in exacerbating Indonesian fires, because it tends to deprive the islands of needed rains and drive drought conditions. Indeed, the Indonesian fires are “one of the first severe impacts of the strong El Niño that has been developing over the last year,” according to Columbia University’s International Research Institute for Climate and Society. And that also means the trouble probably isn’t over yet. A current forecast suggests “a strong likelihood of drier-than-normal conditions over broad areas of northern South America, the Caribbean, Indonesia and the Philippines” through December. But it’s really the combination of El Niño and certain agricultural practices — characterized as “slash and burn” by NASA — that is at play here. According to Susan Minnemeyer, who is the mapping and data manager for Global Forest Watch Fires, a project of the World Resources Institute, the blazes are the result of using fire itself to clear land for agriculture, as well as the draining of peat bogs and swamps – which makes them able to light up once they are dried out. “The forests in Indonesia are generally not flammable, so these fires are virtually all caused by people, or land clearing,” says Minnemeyer. She adds that there is “little enforcement and little capacity to actually put them out once they’ve started.” The total Indonesian fire emissions, says van der Werf, will show up in atmospheric measurements of carbon dioxide this year — and may even draw attention at the climate meetings that begin next month in Paris. After all, according to the U.N.’s Intergovernmental Panel on Climate Change, as of 2011 the world only had about 1,000 more gigatons of carbon dioxide to emit to the atmosphere if we want a two-third chance of keeping warming below 2 degrees Celsius from pre-industrial levels.

Berking M.,University of Marburg | Ebert D.,University of Marburg | Cuijpers P.,VU University Amsterdam | Hofmann S.G.,Boston University
Psychotherapy and Psychosomatics | Year: 2013

Background: Deficits in emotion regulation skills are possible factors maintaining major depressive disorder (MDD). Therefore, the aim of the study was to test whether integrating a systematic emotion regulation training (ERT) enhances the efficacy of routine inpatient cognitive behavioral therapy (CBT) for MDD. Methods: In a prospective randomized controlled trial, 432 inpatients meeting criteria for MDD were assigned to receive either routine CBT or CBT enriched with an intense emotion regulation skills training (CBT-ERT). Results: Participants in the CBT-ERT condition demonstrated a significantly greater reduction in depression (response rates-CBT: 75.5%, CBT-ERT: 84.9%; remission rates-CBT: 51.1%, CBT-ERT: 65.1%). Moreover, CBT-ERT participants demonstrated a significantly greater reduction of negative affect, as well as a greater increase of well-being and emotion regulation skills particularly relevant for mental health. Conclusions: Integrating strategies that target emotion regulation skills improves the efficacy of CBT for MDD. © 2013 S. Karger AG, Basel.

Weijerman M.E.,VU University Amsterdam | De Winter J.P.,Spaarne Hospital
European Journal of Pediatrics | Year: 2010

Down syndrome (DS) is one of the most common chromosomal abnormalities. Because of medical advances and improvements in overall medical care, the median survival of individuals with DS has increased considerably. This longer life expectancy requires giving the necessary care to the individual with DS over their total longer lifespan. DS medical guidelines are designed for the optimal care of the child in whom a diagnosis of DS has been confirmed. We present an overview of the most important issues related to children with DS based on the most relevant literature currently available. © 2010 The Author(s).

Staufenbiel S.M.,Erasmus University Rotterdam | Penninx B.W.J.H.,VU University Amsterdam | Spijker A.T.,PsyQ The Hague | Elzinga B.M.,Leiden University | van Rossum E.F.C.,Erasmus University Rotterdam
Psychoneuroendocrinology | Year: 2013

The deleterious effects of chronic stress on health and its contribution to the development of mental illness attract broad attention worldwide. An important development in the last few years has been the employment of hair cortisol analysis with its unique possibility to assess the long-term systematic levels of cortisol retrospectively. This review makes a first attempt to systematically synthesize the body of published research on hair cortisol, chronic stress, and mental health. The results of hair cortisol studies are contrasted and integrated with literature on acutely circulating cortisol as measured in bodily fluids, thereby combining cortisol baseline concentration and cortisol reactivity in an attempt to understand the cortisol dynamics in the development and/or maintenance of mental illnesses. The studies on hair cortisol and chronic stress show increased hair cortisol levels in a wide range of contexts/situations (e.g. endurance athletes, shift work, unemployment, chronic pain, stress in neonates, major life events). With respect to mental illnesses, the results differed between diagnoses. In major depression, the hair cortisol concentrations appear to be increased, whereas for bipolar disorder, cortisol concentrations were only increased in patients with a late age-of-onset. In patients with anxiety (generalized anxiety disorder, panic disorder), hair cortisol levels were reported to be decreased. The same holds true for patients with posttraumatic stress disorder, in whom - after an initial increase in cortisol release - the cortisol output decreases below baseline. The effect sizes are calculated when descriptive statistics are provided, to enable preliminary comparisons across the different laboratories. For exposure to chronic stressors, the effect sizes on hair cortisol levels were medium to large, whereas for psychopathology, the effect sizes were small to medium. This is a first implication that the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in the development and/or maintenance of psychopathology may be more subtle than it is in healthy but chronically stressed populations. Future research possibilities regarding the application of hair cortisol research in mental health and the need for multidisciplinary approaches are discussed. © 2012 Elsevier Ltd.

Drescher J.,New York Medical College | Cohen-Kettenis P.,VU University Amsterdam | Winter S.,University of Hong Kong
International Review of Psychiatry | Year: 2012

The World Health Organization (WHO) is in the process of revising the International Statistical Classification of Diseases and Related Health Problems (ICD) and ICD-11 has an anticipated publication date of 2015. The Working Group on the Classification of Sexual Disorders and Sexual Health (WGSDSH) is charged with evaluating clinical and research data to inform the revision of diagnostic categories related to sexuality and gender identity that are currently included in the mental and behavioural disorders chapter of ICD-10, and making initial recommendations regarding whether and how these categories should be represented in the ICD-11. The diagnostic classification of disorders related to (trans)gender identity is an area long characterized by lack of knowledge, misconceptions and controversy. The placement of these categories has shifted over time within both the ICD and the American Psychiatric Association's Diagnostic and Statistical Manual (DSM), reflecting developing views about what to call these diagnoses, what they mean and where to place them. This article reviews several controversies generated by gender identity diagnoses in recent years. In both the ICD-11 and DSM-5 development processes, one challenge has been to find a balance between concerns related to the stigmatization of mental disorders and the need for diagnostic categories that facilitate access to healthcare. In this connection, this article discusses several human rights issues related to gender identity diagnoses, and explores the question of whether affected populations are best served by placement of these categories within the mental disorders section of the classification. The combined stigmatization of being transgender and of having a mental disorder diagnosis creates a doubly burdensome situation for this group, which may contribute adversely to health status and to the attainment and enjoyment of human rights. The ICD-11 Working Group on the Classification of Sexual Disorders and Sexual Health believes it is now appropriate to abandon a psychopathological model of transgender people based on 1940s conceptualizations of sexual deviance and to move towards a model that is (1) more reflective of current scientific evidence and best practices; (2) more responsive to the needs, experience, and human rights of this vulnerable population; and (3) more supportive of the provision of accessible and high-quality healthcare services. © 2012 Institute of Psychiatry.

Broedersz C.P.,VU University Amsterdam | Broedersz C.P.,Princeton University | Mao X.,University of Pennsylvania | Lubensky T.C.,University of Pennsylvania | Mackintosh F.C.,VU University Amsterdam
Nature Physics | Year: 2011

Disordered fibre networks are the basis of many man-made and natural materials, including structural components of living cells and tissue. The mechanical stability of such networks relies on the bending resistance of the fibres, in contrast to rubbers, which are governed by entropic stretching of polymer segments. Although it is known that fibre networks exhibit collective bending deformations, a fundamental understanding of such deformations and their effects on network mechanics has remained elusive. Here we introduce a lattice-based model of fibrous networks with variable connectivity to elucidate the roles of single-fibre elasticity and network structure. These networks exhibit both a low-connectivity rigidity threshold governed by fibre-bending elasticity and a high-connectivity threshold governed by fibre-stretching elasticity. Whereas the former determines the true onset of network rigidity, we show that the latter exhibits rich zero-temperature critical behaviour, including a crossover between various mechanical regimes along with diverging strain fluctuations and a concomitant diverging correlation length. © 2011 Macmillan Publishers Limited. All rights reserved.

Kiewisch K.,VU University Amsterdam | Jacob C.R.,Karlsruhe Institute of Technology | Visscher L.,VU University Amsterdam
Journal of Chemical Theory and Computation | Year: 2013

The ability to calculate accurate electron densities of full proteins or of selected sites in proteins is a prerequisite for a fully quantum-mechanical calculation of protein-protein and protein-ligand interaction energies. Quantum-chemical subsystem methods capable of treating proteins and other biomolecular systems provide a route to calculate the electron densities of proteins efficiently and further make it possible to focus on specific parts. Here, we evaluate and extend the 3-partition frozen-density embedding (3-FDE) scheme [Jacob, C. R.; Visscher, L. J. Chem. Phys.2008, 128, 155102] for this purpose. In particular, we have extended this scheme to allow for the treatment of disulfide bridges and charged amino acid residues and have introduced the possibility to employ more general partitioning schemes. These extensions are tested both for the prediction of full protein electron densities and for focusing on the electron densities of a selected protein site. Our results demonstrate that 3-FDE is a promising tool for the fully quantum-chemical treatment of proteins. © 2013 American Chemical Society.

Aerts J.C.J.H.,VU University Amsterdam | Botzen W.J.W.,VU University Amsterdam | Emanuel K.,Massachusetts Institute of Technology | Lin N.,Princeton University | And 2 more authors.
Science | Year: 2014

Integration of models for storms and floods, damages and protections, should aid resilience planning and investments.

Shapira A.,Russell Berrie Nanotechnology Institute | Livney Y.D.,Russell Berrie Nanotechnology Institute | Livney Y.D.,Technion - Israel Institute of Technology | Broxterman H.J.,VU University Amsterdam | Assaraf Y.G.,Technion - Israel Institute of Technology
Drug Resistance Updates | Year: 2011

Anticancer drug resistance almost invariably emerges and poses major obstacles towards curative therapy of various human malignancies. In the current review we will distinguish between mechanisms of chemoresistance that are predominantly mediated by ATP-driven multidrug resistance (MDR) efflux transporters, typically of the ATP-binding cassette (ABC) superfamily, and those that are independent of such drug efflux pumps. In recent years, multiple nanoparticle (NP)-based therapeutic systems have been developed that were rationally designed to overcome drug resistance by neutralizing, evading or exploiting various drug efflux pumps and other resistance mechanisms. NPs are being exploited for selective drug delivery to tumor cells, to cancer stem/tumor initiating cells and/or to the supportive cancer cell microenvironment, i.e. stroma or tumor vasculature. Some of these NPs are currently undergoing preclinical in vivo studies as well as advanced stages of clinical evaluation with promising results. Nanovehicles harboring a payload of therapeutic drug combinations for the selective targeting and elimination of tumor cells as well as the simultaneous overcoming of mechanisms of drug resistance are a subject of intense research efforts, some of which are expected to enter clinical trials in the near future. In the present review we highlight novel approaches to selectively target cancer cells and overcome drug resistance phenomena, through the use of various nanometric drug delivery systems. In the near future, it is anticipated that innovative theragnostic nanovehicles will be developed which will harbor four major components: (1) a selective targeting moiety, (2) a diagnostic imaging aid for the localization of the malignant tumor and its micro- or macrometastases, (3) a cytotoxic, small molecule drug(s) or novel therapeutic biological(s), and (4) a chemosensitizing agent aimed at neutralizing a resistance mechanism, or exploiting a molecular "Achilles hill" of drug resistant cells. We propose to name these envisioned four element-containing nanovehicle platform, "quadrugnostic" nanomedicine. This targeted strategy holds promise in paving the way for the introduction of highly effective nanoscopic vehicles for cancer therapeutics while overcoming drug resistance. © 2011 Elsevier Ltd. All rights reserved.

Philippon M.,VU University Amsterdam | Brun J.-P.,University of Rennes 1 | Gueydan F.,Montpellier University
Tectonophysics | Year: 2012

The Cycladic Blueschist Unit (CBU) represents the northern passive margin of the Adria continental block and ophiolites that are the remnants of the Pindos Ocean, which were affected by high pressure-low temperature metamorphism in the blueschist and eclogite facies during the Eocene. Prior to the Lutetian, the ophiolitic and margin units were thrust towards the SW inside a NE-dipping subduction zone. Two subsequent exhumation stages are characterized by top-to-the-NE senses of shear: i) from mantle depths to lower crustal levels, before 37. Ma, which was accommodated by an extensional inversion of the Vardar suture zone, and ii) from deep crustal levels to the near-surface, between 30 and 20. Ma, which was accommodated by the North Cycladic Detachment. It is during this late stage of ductile exhumation that the central Cyclades Core Complex was exhumed. Segmentation of the CBU by normal faults started at 12. Ma, as recorded by the low temperature thermochronometers, and was coeval with block rotation and folding with NS-trending axes, which were predominantly controlled by the Myrthes-Ikaria strike-slip fault in the centre of the Cyclades. A map restoration of the CBU geometry, prior to segmentation, has been carried out using available structural and paleomagnetic data. The restoration shows that, following the CBU exhumation from mantle depths to crustal levels, a single core complex was exhumed along a single NE dipping detachment. © 2011 Elsevier B.V.

Jamnitski A.,Jan Van Breemen Research Institute READE | Symmons D.,ARC Epidemiology Unit | Peters M.J.L.,VU University Amsterdam | Sattar N.,University of Glasgow | And 2 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective: Data regarding cardiovascular comorbidity and cardiovascular risk factors in patients with psoriatic arthritis (PsA) are limited. To evaluate the cardiovascular risk profile, a systematic literature search was performed to provide an extensive summary of all studies available on cardiovascular risk in PsA. Methods: Medline, EMBASE and the Cochrane library were searched from January 1966 to April 2011 for English language articles on data concerning cardiovascular diseases and cardiovascular risk factors in PsA. Review articles, case reports and studies on psoriasis alone were excluded. Results: Twenty-eight articles were included in this review. Studies on all-cause mortality revealed mixed results. Available data on cardiovascular disease appeared more consistent, indicating an increased cardiovascular mortality and morbidity in PsA. Commensurate with this, surrogate markers of subclinical atherosclerosis, arterial stiffness and cardiovascular risk factors, for example hypertension, dyslipidaemia, obesity and metabolic-related factors, were more prominent in PsA compared with controls. Suppression of inflammation was linked with a favourable effect on cardiovascular surrogate markers, for example carotid intima media thickness and endothelial dysfunction, in several (un) controlled studies. Conclusion: Most studies point towards an increased cardiovascular risk in PsA, broadly on a par with the risk level in rheumatoid arthritis, emphasising the need for similar cardiovascular risk management in both conditions. Further studies are needed to indicate whether inflammatory suppression or modification of traditional cardiovascular risk factors, or both, will reduce cardiovascular risk.

Langer C.J.,University of Pennsylvania | Mok T.,Chinese University of Hong Kong | Postmus P.E.,VU University Amsterdam
Cancer Treatment Reviews | Year: 2013

The prognosis for patients with relapsed/progressive non-small cell lung cancer (NSCLC) remains poor. For first-line therapy, a number of platinum-based regimens are standard; second-line therapies include single-agent docetaxel, pemetrexed, and erlotinib. Treatment options for patients whose tumors have failed to respond to two or more conventional chemotherapy regimens are limited, with erlotinib, which targets the epidermal growth factor receptor, and crizotinib, which targets EML4/ALK, the only agents currently approved in the United States as third-line therapy for patients with advanced/metastatic NSCLC. Among the targeted agents that have undergone evaluation for third-line therapy and beyond are afatinib, apatinib, axitinib, AUY922, pazopanib, sorafenib, sunitinib, and vandetanib. Agents that affect multiple pathways have the potential to provide significant clinical benefits. Identifying molecular characteristics that make tumors more likely to respond to a targeted therapy is crucial. This article reviews the hypotheses and data that provide the rationale for the development of targeted agents for third- and fourth-line treatment of patients with relapsed/refractory NSCLC. © 2012 Elsevier Ltd.

Andersson G.,Linköping University | Andersson G.,Karolinska Institutet | Cuijpers P.,VU University Amsterdam | Carlbring P.,University of Stockholm | And 3 more authors.
World Psychiatry | Year: 2014

Internet-delivered cognitive behavior therapy (ICBT) has been tested in many research trials, but to a lesser extent directly compared to faceto- face delivered cognitive behavior therapy (CBT). We conducted a systematic review and meta-analysis of trials in which guided ICBT was directly compared to face-to-face CBT. Studies on psychiatric and somatic conditions were included. Systematic searches resulted in 13 studies (total N=1053) that met all criteria and were included in the review. There were three studies on social anxiety disorder, three on panic disorder, two on depressive symptoms, two on body dissatisfaction, one on tinnitus, one on male sexual dysfunction, and one on spider phobia. Face-to-face CBT was either in the individual format (n=6) or in the group format (n=7). We also assessed quality and risk of bias. Results showed a pooled effect size (Hedges' g) at post-treatment of -0.01 (95% CI: -0.13 to 0.12), indicating that guided ICBT and face-to-face treatment produce equivalent overall effects. Study quality did not affect outcomes. While the overall results indicate equivalence, there are still few studies for each psychiatric and somatic condition and many conditions for which guided ICBT has not been compared to face-to-face treatment. Thus, more research is needed to establish equivalence of the two treatment formats.

Mentel L.M.,VU University Amsterdam | Mentel L.M.,Pohang University of Science and Technology | Baerends E.J.,VU University Amsterdam | Baerends E.J.,Pohang University of Science and Technology | Baerends E.J.,King Abdulaziz University
Journal of Chemical Theory and Computation | Year: 2014

The basis set superposition effect (BSSE) is a simple concept, and its validity is almost universally accepted. So is the counterpoise method to correct for it. The idea is that the basis set is biased toward the dimer because each monomer in the dimer can "use" the basis functions on the other monomer, which it cannot in a simple monomer calculation. This hypothesis can only be tested if basis set free benchmark numbers are available for monomers and dimer. We are testing the hypothesis on a few systems (in this paper Be2) that are small enough that sufficiently accurate benchmark numbers (basis set free, or close to basis set limit; full CI or close to full CI) are available or can be obtained. We find that the answer to the title question is negative: the standard basis sets of quantum chemistry appear to be biased toward the atom in the sense that basis set errors are larger for the dimer than the monomer. Applying the counterpoise correction increases the imbalance by reducing the already smaller basis set error of the monomer even further. Counterpoise corrected bond energies then deviate more from the basis set limit numbers than uncorrected bond energies. These conclusions hold both at the Hartree-Fock level and (much stronger) at the correlated (CCSD(T), full CI) levels. So the answer to the title question is No. © 2013 American Chemical Society.

Seferovic P.M.,University of Belgrade | Paulus W.J.,VU University Amsterdam
European Heart Journal | Year: 2015

Diabetes mellitus-related cardiomyopathy (DMCMP) was originally described as a dilated phenotype with eccentric left ventricular (LV) remodelling and systolic LV dysfunction. Recently however, clinical studies on DMCMP mainly describe a restrictive phenotype with concentric LV remodelling and diastolic LV dysfunction. Both phenotypes are not successive stages of DMCMP but evolve independently to respectively heart failure with preserved left ventricular ejection fraction (HFPEF) or reduced left ventricular ejection fraction (HFREF). Phenotype-specific pathophysiological mechanisms were recently proposed for LV remodelling and dysfunction in HFPEF and HFREF consisting of coronary microvascular endothelial dysfunction in HFPEF and cardiomyocyte cell death in HFREF. A similar preferential involvement of endothelial or cardiomyocyte cell compartments explains DMCMP development into distinct restrictive/HFPEF or dilated/HFREF phenotypes. Diabetes mellitus (DM)-related metabolic derangements such as hyperglycaemia, lipotoxicity, and hyperinsulinaemia favour development of DMCMP with restrictive/HFPEF phenotype, which is more prevalent in obese type 2 DM patients. In contrast, autoimmunity predisposes to a dilated/HFREF phenotype, which manifests itself more in autoimmune-prone type 1 DM patients. Finally, coronary microvascular rarefaction and advanced glycation end-products deposition are relevant to both phenotypes. Diagnosis of DMCMP requires impaired glucose metabolism and exclusion of coronary, valvular, hypertensive, or congenital heart disease and of viral, toxic, familial, or infiltrative cardiomyopathy. In addition, diagnosis of DMCMP with restrictive/HFPEF phenotype requires normal systolic LV function and diastolic LV dysfunction, whereas diagnosis of DMCMP with dilated/HFREF phenotype requires systolic LV dysfunction. Treatment of DMCMP with restrictive/HFPEF phenotype is limited to diuretics and lifestyle modification, whereas DMCMP with dilated/HFREF phenotype is treated in accordance to HF guidelines. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015.

Broedersz C.P.,Princeton University | Mao X.,University of Pennsylvania | Lubensky T.C.,University of Pennsylvania | MacKintosh F.C.,VU University Amsterdam
Nature Physics | Year: 2011

Disordered fibre networks are the basis of many man-made and natural materials, including structural components of living cells and tissue. The mechanical stability of such networks relies on the bending resistance of the fibres, in contrast to rubbers, which are governed by entropic stretching of polymer segments. Although it is known that fibre networks exhibit collective bending deformations, a fundamental understanding of such deformations and their effects on network mechanics has remained elusive. Here we introduce a lattice-based model of fibrous networks with variable connectivity to elucidate the roles of single-fibre elasticity and network structure. These networks exhibit both a low-connectivity rigidity threshold governed by fibre-bending elasticity and a high-connectivity threshold governed by fibre-stretching elasticity. Whereas the former determines the true onset of network rigidity, we show that the latter exhibits rich zero-temperature critical behaviour, including a crossover between various mechanical regimes along with diverging strain fluctuations and a concomitant diverging correlation length.

Brun J.-P.,University of Rennes 1 | Sokoutis D.,VU University Amsterdam
Geology | Year: 2010

The available seismic anisotropy data in the Aegean shallow mantle and their relationship with crustal deformation are used for deciphering the lithosphere-scale flow pattern driven by rollback of the Hellenic subduction slab. In the north and central Aegean, the directions of mantle seismic anisotropy trend parallel to stretching lineations in core complexes of the overlying crust, suggesting that crust and mantle have undergone the same direction of flow. At the scale of the entire Aegean, crustal extension is controlled by dextral rotation around a pole located at Scutary-Pec, Albania, that is related to the Hellenic trench retreat. The intensity of mantle anisotropy increases as a function of distance from the pole and of amount of rotation. Surface geology reveals that this rotating flow pattern resulted in strains accumulated since 45 Ma. A slab tear model is suggested to integrate the observed variations of geological events in time and space to subduction dynamics. © 2010 Geological Society of America.

VU University Amsterdam, University of Amsterdam, Stichting Voor Fundamenteel Onderzoek Der Materie and ASML Netherlands B.V. | Date: 2015-08-27

Metrology targets are formed on a substrate (W) by a lithographic process. A target (T) comprising one or more grating structures is illuminated with spatially coherent radiation under different conditions. Radiation (650) diffracted by from said target area interferes with reference radiation (652) interferes with to form an interference pattern at an image detector (623). One or more images of said interference pattern are captured. From the captured image(s) and from knowledge of the reference radiation a complex field of the collected scattered radiation at the detector. A synthetic radiometric image (814) of radiation diffracted by each grating is calculated from the complex field. From the synthetic radiometric images (814, 814) of opposite portions of a diffractions spectrum of the grating, a measure of asymmetry in the grating is obtained. Using suitable targets, overlay and other performance parameters of the lithographic process can be calculated from the measured asymmetry.

News Article | October 26, 2015

Indonesian President Joko Widodo, known as “Jokowi,” came to Washington Monday to help elevate his country’s profile and appeal to foreign investors. But as raging forest and peatland fires in Indonesia pour huge amounts of carbon into the atmosphere, he chose to cut short his U.S. visit and will return to address the ongoing ecological disaster at home. Indonesian officials are scrambling to contain fires that, one researcher estimates, have released more carbon dioxide equivalent emissions than Japan does in a year by burning fossil fuels — emissions so voluminous that on several days this year they have surpassed the daily emissions output of the entire U.S. economy. The burning has generated a toxic haze that has settled not only over parts of Indonesia but Malaysia and Singapore as well, and has killed at least 10 people. On Monday the U.S. ambassador to Indonesia, Robert O. Blake Jr., announced in Jakarta the federal government will contribute at least $2.75 million to help Indonesians address the fires and haze and prevent future conflagrations. The White House also issued a fact sheet noting the U.S. was working to improve forest and peatland management on more than 19.7 million acres in the Indonesian provinces of Aceh, Kalimantan, and Papua, and to train Indonesian scientists to inform the nation’s future climate policies. The U.S. funding announced Monday will include money to help respond to haze-related respiratory illnesses, provide protective gear for firefighters and monitoring of the blazes through the U.S. Forest Service’s remote sensing and imaging systems. White House press secretary Josh Earnest said administration officials “stand ready” to discuss additional aid. This year’s El Nino weather pattern, along with the clearing of forests and draining of carbon-rich peatlands has fueled the blazes: On Friday, Widodo said he will ban the commercial destruction of any more peatlands, but it is unclear how easily he can enforce the new policy. “As Presidents Obama and Jokowi meet, much of Indonesia and Southeast Asia will be choking on smoke from fires set to clear forests for farming,” said Nigel Purvis, president and chief executive of the Washington-based consulting firm Climate Advisers. “In 2009, President Jokowi’s predecessor pledged that Indonesia would reduce deforestation dramatically. That hasn’t happened yet. The stars are aligning for President Jokowi to deliver now, and this will be a test of his climate leadership.” Speaking to reporters in the Oval Office, Obama and Widodo both said they were committed to cutting the world’s carbon output. “One of the main topics we discussed was the issue of climate change,” Obama said, “and why it’s so important that large countries like ours work together to arrive at the strongest possible set of targets and international agreements when we arrive in Paris just a little over a month from now.” Widodo said that while both men wanted to address “this issue for the sake of our future generations,” Indonesia was also focused on a more immediate climate concern. “We have peat fires, and the efforts to extinguish it is quite challenging,” he said. Originally scheduled to visit in June, the Indonesian president was elected in July 2014 on a populist platform aimed at the rural poor. The trip was aimed at making the case to business leaders that his country is open to American investment, though Widodo had to scrap a meeting in San Francisco with tech-sector chief executives. He still went ahead with a dinner hosted by the U.S. Chamber of Commerce in Washington Monday. “Indonesia is an open economy,” Widodo told reporters, adding his country intends to join the Trans-Pacific Partnership, a trade accord encompassing a dozen Pacific Rim dozen including the United States. Meredith Miller, vice president at the Albright Stonebridge Group, said in an interview that business outreach is “a huge focus” of his trip, along with the broader goal of projecting that “Indonesia as a strong global player.” “A large part of the importance of this trip is symbolic,” Miller added, noting the very image of Widodo meeting in the Oval Office with Obama — with whom Indonesians feel a special connection — “will send a powerful message. Having that kind of recognition in the White House is very important.” But environmentalists will raise questions about the Indonesian leader’s climate record while he is at the White House. And Widodo’s recent announcement suggests that he is aware of the global scrutiny he will face during his U.S. tour. “People think about climate, they only think about smokestacks and tailpipes, and this is obviously the biggest climate story on the planet right now,” said Rolf Skar, forest campaign director at Greenpeace USA. “What’s urgently needed is a total rethink of the way that the country is doing land management on its peatlands.” Indeed, Indonesia’s current carbon crisis serves as a kind of exclamation point to a long-standing problem in the country — deforestation and other land-use changes contribute much more toward its carbon emissions than do fossil fuels. According to data from the World Resources Institute, in 2012 Indonesia emitted 760 million metric tons of carbon dioxide equivalents if you don’t include the effects of deforestation and other changes to land, but 1,981 million tons (or 1.98 gigatons) if you do. This year, Indonesia’s total emissions will surely be higher than that, as peat fires alone have contributed an estimated 1.6 gigatons. While Indonesia has long ranked among the world’s top 10 emitting countries when deforestation and other non-fossil fuel emissions are taken into account, this year it may rank in the top five or even the top three. (In 2012, according to data compiled by the World Resources Institute, China and the United States led the pack with 10.68 and 5.82 gigatons of total emissions, followed by India and Russia at 2.88 and 2.25 gigatons, respectively.) The core problem is that Indonesia is home to a huge repository of the world’s carbon rich peatlands — 5 percent of them overall, according to one estimate. And when these lands are cleared or drained for agricultural purposes, then the decomposition of peat — and, as in this year, its mass burning — can contribute gigantic volumes of carbon into the atmosphere. One recent study estimated that from 2000 to 2010, the clearing of Indonesian forests for palm oil, timber and other purposes led to 8.59 gigatons of carbon dioxide equivalent emissions due to loss of trees and degradation of peatlands. Moreover, explains VU University Amsterdam global fire expert Guido van der Werf, Indonesia peat fires represent a special kind of carbon problem. In the case of many fires around the world, there is little or no net addition of greenhouse gases to the atmosphere, as trees and vegetation grow back afterward and store carbon once again. But the carbon stored in peat has built up over thousands of years and would not be put back in the same way, at least not any time soon. Thus, for these Indonesian fires, the carbon is, in a sense, headed on a one-way trip to the atmosphere. Wimar Witoelar, an Indonesian political commentator and adjunct professor at Australia’s Deakin University, said Widodo has resolved to get the fires under control. “He’s getting more determined as the fires become worse, because of course he feels very bad, and very guilty, and quite angry,” Witoelar said. But it is unclear how much progress Widodo can make. Many of the world’s most important consumer companies have pledged not to use palm oil associated with deforestation, providing a strong economic incentive for a shift in policy, and Norway already pledged $1 billion to help Indonesia address the problem. Six years ago, Widodo’s predecessor pledged that Indonesia would cut its greenhouse gas emissions between 2005 and 2020 by 26 percent compared with its business-as-usual trajectory, and with sufficient outside aid, it would cut them 41 percent. But according to a Climate Advisers analysis of data from WRI, the European Union and other sources, its forest and land-use patterns have remained largely unchanged between 2004 and 2014. About 1 percent of Indonesia’s tree cover — 3.7 million acres, more than the size of Connecticut — – is removed every year. Skar said that while Widodo’s new peatlands measure has promise, the details of how it is executed is essential. “It has to be acknowledged that Indonesia is facing some serious challenges relating to corruption, chaos and lack of capacity,” he said. Scientists confirm that East Antarctica’s biggest glacier is melting from below Indonesian fires are pouring huge amounts of carbon into the atmosphere Congressional skeptic on global warming demands records from U.S. climate scientists For more, you can sign up for our weekly newsletter here, and follow us on Twitter here.

News Article | December 23, 2015

The hottest papers of 2015 covered topics ranging from cancer risk and autism to mass extinctions and reproducibility in science, according to Altmetric, a London-based company that tracks the attention received by academic publications in the media and on blogs and social networks. Studies in biology, medicine and health dominated its annual top 100 list, as they did last year, but papers about climate and environmental science also pushed their way up the ranking. Nature rounds up a few of the papers on the list. Scientists captured the soul of an artist in a computer to produce eye-catching, artistic images that spread rapidly on social media. Leon Gatys at the University of Tübingen, Germany, and his team developed an algorithm that extracts and combines the content of one image with the style of another — turning an ordinary photograph into a close approximation of a painting by Vincent Van Gogh or Pablo Picasso, for example. The authors write that this algorithm may help to decode how humans create and perceive art. The authors posted their paper on the preprint server arXiv1 in August, and made the model publicly available — inspiring others, such as Kai Sheng Tai, a data scientist at MetaMind in Palo Alto, California, to create their own versions of the program. Andrej Karpathy, a PhD student in computer science at Stanford University in California, tweeted: Computer scientists did more than create art — they say they have solved the perfect game of poker, too. A team led by Michael Bowling at the University of Alberta in Edmonton, Canada, developed an algorithm named Cepheus that can play two-person Texas hold ’em poker — and win every time. It even bluffs, according to the team’s Science2 paper, published in January. Whereas computers are almost unbeatable in games such as draughts (also known as checkers), more complicated games, in which the other player’s pieces aren’t visible to the computer, have been more challenging for developers to solve. But Bowling and his colleagues trained the algorithm to learn from its bad decisions as it played. Iyad Rahwan, a computational social scientist at the Massachusetts Institute of Technology in Cambridge, tweeted: This year started out with a dire outlook on climate. For the world to stay within a limit of 2 °C of warming and prevent catastrophic climate change, scientists warned that nearly 90% of the globe’s remaining coal reserves must remain unburned. Christophe McGlade and Paul Ekins at University College London mined data3 collected by organizations including the US Geological Survey, the US National Petroleum Council and the World Energy Council. They then modelled, by region, how much oil, gas and coal needs to stay in the ground between 2010 and 2050 to meet the 2 °C target. In the absence of new ways to capture and store carbon, the authors found that more than one-third of the world’s oil, more than half of the gas and 88% of coal must remain untouched. Nearly a year after the paper’s publication, the UK Energy Research Centre tweeted a reminder to delegates at the United Nations climate conference (COP21) in Paris: When the clock strikes midnight on New Year’s Eve, consider carefully who you are standing next to. A study showed that 80 million bacteria are transferred between two people during a single kiss. Remco Kort at VU University Amsterdam examined the tongue microbes of 21 couples, and found that partners shared similar tongue microbiomes. The more often the two people reportedly kissed, the more similar were their salivary microbes. When the team asked the couples to kiss for 10 seconds after one person had drunk a yogurt beverage filled with marker bacteria, the researchers found that millions of bacteria moved from one tongue to the other. The paper was published in the journal Microbiome4 in November 2014, but resonated throughout 2015, according to Altmetric. Sarah Hird, a microbial geneticist at the University of California, Davis, wrote on her blog: “So many microbes sloshing around — it’s a little bit gross, a little bit cool, and 100% science.”

Hassabis D.,University College London | Spreng R.N.,Cornell University | Rusu A.A.,VU University Amsterdam | Robbins C.A.,Harvard University | And 2 more authors.
Cerebral Cortex | Year: 2014

The behaviors of other people are often central to envisioning the future. The ability to accurately predict the thoughts and actions of others is essential for successful social interactions, with far reaching consequences. Despite its importance, little is known about how the brain represents people in order to predict behavior. In this functional magnetic resonance imaging study, participants learned the unique personality of 4 protagonists and imagined how each would behave in different scenarios. The protagonists' personalities were composed of 2 traits: Agreeableness and Extraversion. Which protagonist was being imagined was accurately inferred based solely on activity patterns in the medial prefrontal cortex using multivariate pattern classification, providing novel evidence that brain activity can reveal whom someone is thinking about. Lateral temporal and posterior cingulate cortex discriminated between different degrees of agreeableness and extraversion, respectively. Functional connectivity analysis confirmed that regions associated with trait-processing and individual identities were functionally coupled. Activity during the imagination task, and revealed by functional connectivity, was consistent with the default network. Our results suggest that distinct regions code for personality traits, and that the brain combines these traits to represent individuals. The brain then uses this "personality model" to predict the behavior of others in novel situations. © The Author 2013.

Bronkhorst A.W.,TNO | Bronkhorst A.W.,VU University Amsterdam
Attention, Perception, and Psychophysics | Year: 2015

How do we recognize what one person is saying when others are speaking at the same time? This review summarizes widespread research in psychoacoustics, auditory scene analysis, and attention, all dealing with early processing and selection of speech, which has been stimulated by this question. Important effects occurring at the peripheral and brainstem levels are mutual masking of sounds and “unmasking” resulting from binaural listening. Psychoacoustic models have been developed that can predict these effects accurately, albeit using computational approaches rather than approximations of neural processing. Grouping—the segregation and streaming of sounds—represents a subsequent processing stage that interacts closely with attention. Sounds can be easily grouped—and subsequently selected—using primitive features such as spatial location and fundamental frequency. More complex processing is required when lexical, syntactic, or semantic information is used. Whereas it is now clear that such processing can take place preattentively, there also is evidence that the processing depth depends on the task-relevancy of the sound. This is consistent with the presence of a feedback loop in attentional control, triggering enhancement of to-be-selected input. Despite recent progress, there are still many unresolved issues: there is a need for integrative models that are neurophysiologically plausible, for research into grouping based on other than spatial or voice-related cues, for studies explicitly addressing endogenous and exogenous attention, for an explanation of the remarkable sluggishness of attention focused on dynamically changing sounds, and for research elucidating the distinction between binaural speech perception and sound localization. © 2015, The Author(s).

Tol R.S.J.,University of Sussex | Tol R.S.J.,VU University Amsterdam
Journal of Informetrics | Year: 2013

This paper applies the Ijiri-Simon test for systematic deviations from Gibrat's law to citation numbers of economists. It is found that often-cited researchers attract new citation numbers that are disproportionate to the quality of their work. It is also found that this Matthew effect is stronger for economists who started their academic career earlier. © 2013 Elsevier Ltd.

Klug W.S.,University of California at Los Angeles | Roos W.H.,VU University Amsterdam | Wuite G.J.L.,VU University Amsterdam
Physical Review Letters | Year: 2012

The capsids of icosahedral viruses are closed shells assembled from a hexagonal lattice of proteins with fivefold angular defects located at the icosahedral vertices. Elasticity theory predicts that these disclinations are subject to an internal compressive prestress, which provides an explanation for the link between size and shape of capsids. Using a combination of experiment and elasticity theory we investigate the question of whether macromolecular assemblies are subject to residual prestress, due to basic geometric incompatibility of the subunits. Here we report the first direct experimental test of the theory: by controlled removal of protein pentamers from the icosahedral vertices, we measure the mechanical response of so-called "whiffle ball" capsids of herpes simplex virus, and demonstrate the signature of internal prestress locked into wild-type capsids during assembly. © 2012 American Physical Society.

Baumeister R.F.,Florida State University | Baumeister R.F.,King Abdulaziz University | Baumeister R.F.,VU University Amsterdam | Baumeister R.F.,Russell Sage Foundation
Neuropsychologia | Year: 2014

Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it. © 2014 Elsevier Ltd.

Lanas A.,University of Zaragoza | Boers M.,VU University Amsterdam | Nuevo J.,Astrazeneca
Annals of the Rheumatic Diseases | Year: 2013

Objectives: Data concerning rates of gastrointestinal (GI) events in non-steroidal anti-inflammatory drug (NSAID) users derive mainly from clinical trials. The EVIDENCE study quantified the incidence of symptomatic uncomplicated and/or complicated GI events in at-risk European patients treated with NSAIDs in real-life practice. Methods: This non-interventional study assessed 4144 adults with at least one GI risk factor who recently initiated NSAID therapy for osteoarthritis (85%), rheumatoid arthritis (11%), ankylosing spondylitis (3%) or a combination (1%). Patient characteristics and medical history were collected from medical records. GI events (upper and lower) were recorded at in-clinic visits during 6 months' follow-up. Results: Mean time on index NSAID at enrolment was 33 days. The incidence (per 100 person-years) was 18.5 per 100 person-years for uncomplicated GI events and 0.7 per 100 person-years for complicated GI events. Upper GI events were far more common (12%) than lower GI events (1%) during study follow-up (median 182 days (range 61-320)). Other reported rates for cardiovascular, anaemia or non-GI events were much less frequent. A minority (28%) of patients had ongoing proton pump inhibitor use at enrolment, with strong variation by practice and country. Conclusions: EVIDENCE is the largest prospective study of the real-life management of European patients treated with NSAIDs for rheumatic diseases and at increased GI risk. It shows that GI events from the upper GI tract are far more common than those from the lower GI tract. It also shows adherence to guidelines for gastroprotection is generally low. © 2013 BMJ Publishing Group Ltd & European League Against Rheumatism.

Tol R.S.J.,University of Sussex | Tol R.S.J.,VU University Amsterdam
Climatic Change | Year: 2013

The national version of FUND3. 6 is used to backcast the impacts of climate change to the 20th century and extrapolate to the 21st century. Carbon dioxide fertilization of crops and reduced energy demand for heating are the main positive impacts. Climate change had a negative effect on water resources and, in most years, human health. Most countries benefitted from climate change until 1980, but after that the trend is negative for poor countries and positive for rich countries. The global average impact was positive in the 20th century. In the 21st century, impacts turn negative in most countries, rich and poor. Energy demand, water resources, biodiversity and sea level rise are the main negative impacts; the impacts of climate change on human health and agriculture remain positive until 2100. © 2012 Springer Science+Business Media Dordrecht.

van der Knaap M.S.,VU University Amsterdam | Boor I.,VU University Amsterdam | Estevez R.,Physiology Section | Estevez R.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer
The Lancet Neurology | Year: 2012

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterised by chronic white matter oedema. The disease has an infantile onset and leads to slow neurological deterioration in most cases, but, surprisingly, some patients recover. The first disease gene, MLC1, identified in 2001, is mutated in 75% of patients. At that time, nothing was known about MLC1 protein function and the pathophysiology of MLC. More recently, HEPACAM (also called GLIALCAM) has been identified as a second disease gene. GlialCAM serves as an escort for MLC1 and the chloride channel CLC2. The defect in MLC1 has been shown to hamper the cell volume regulation of astrocytes. One of the most important consequences involves the potassium siphoning process, which is essential in brain ion and water homoeostasis. An understanding of the mechanisms of white matter oedema in MLC is emerging. Further insight into the specific function of MLC1 is necessary to find treatment targets. © 2012 Elsevier Ltd.

Anthoff D.,University of Michigan | Tol R.S.J.,University of Sussex | Tol R.S.J.,VU University Amsterdam
Climatic Change | Year: 2013

We report the results of an uncertainty decomposition analysis of the social cost of carbon as estimated by FUND, a model that has a more detailed representation of the economic impact of climate change than any other model. Some of the parameters particularly influence impacts in the short run whereas other parameters are important in the long run. Some parameters are influential in some regions only. Some parameters are known reasonably well, but others are not. Ethical values, such as the pure rate of time preference and the rate of risk aversion, therefore affect not only the social cost of carbon, but also the importance of the parameters that determine its value. Some parameters, however, are consistently important: cooling energy demand, migration, climate sensitivity, and agriculture. The last two are subject to a large research effort, but the first two are not. © 2013 Springer Science+Business Media Dordrecht.

D'Hooghe M.B.,Nationaal MS Centrum | Nagels G.,Nationaal MS Centrum | Uitdehaag B.M.J.,VU University Amsterdam
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2010

Background: The uncertainty about long-term effects of childbirth presents MS patients with dilemmas. Methods: Based on clinical data of 330 female MS patients, the long-term effects of childbirth were analysed, using a cross-sectional study design. Four groups of patients were distinguished: (1) without children (n = 80), (2) with children born before MS onset (n = 170), (3) with children born after MS onset (n = 61) and (4) with children born before and after MS onset (n = 19). A time-to-event analysis and Cox proportional hazard regression were performed with time from onset to EDSS 6 and age at EDSS 6 as outcome measure. Results: After a mean disease duration of 18 years, 55% had reached EDSS 6. Survival curves show a distinct shift in the time to EDSS 6 between patients with no children after MS onset and patients with children after MS onset in favour of the latter. Cox regression analysis correcting for age at onset shows that patients with children only after MS onset had a reduced risk compared with patients without children (HR 0.61; 95% CI 0.37 to 0.99, p = 0.049). Also, patients who gave birth at any point in time had a reduced risk compared with patients without children (HR 0.66; 95% CI 0.47 to 0.95, p = 0.023). A similar pattern was seen for age at EDSS 6 (HR 0.57, p = 0.027 and HR 0.68, p = 0.032 respectively) Conclusion: Although a bias cannot fully be excluded, these results seem to support a possible favourable long-term effect of childbirth on the course of MS.

Tol R.S.J.,University of Sussex | Tol R.S.J.,VU University Amsterdam
Energy Policy | Year: 2012

The European Commission did not publish a cost-benefit analysis for its 2020 climate package. This paper fills that gap, comparing the marginal costs and benefits of greenhouse gas emission reduction. The uncertainty about the marginal costs of climate change is large and skewed, and estimates partly reflect ethical choices (e.g., the discount rate). The 2010 carbon price in the EU Emissions Trading System can readily be justified by a cost-benefit analysis. Emission reduction is not expensive provided that policy is well-designed, a condition not met by planned EU policy. It is probably twice as expensive as needed, costing one in ten years of economic growth. The EU targets for 2020 are unlikely to meet the benefit-cost test. For a standard discount rate (3% pure rate of time preference), the benefit-cost ratio is rather poor (1/30)-so that benefits need to be very much higher, or costs very much lower than typically assumed to justify the 2020 targets. Only a very low discount rate (0% PRTP) would justify the 20% emission reduction target for 2020. © 2012 Elsevier Ltd.

de Jong Gierveld J.,Netherlands Interdisciplinary Demographic Institute NIDI | van Tilburg T.,VU University Amsterdam
European Journal of Ageing | Year: 2010

Loneliness concerns the subjective evaluation of the situation individuals are involved in, characterized either by a number of relationships with friends and colleagues which is smaller than is considered desirable (social loneliness), as well as situations where the intimacy in confidant relationships one wishes for has not been realized (emotional loneliness). To identify people who are lonely direct questions are not sufficient; loneliness scales are preferred. In this article, the quality of the three-item scale for emotional loneliness and the three-item scale for social loneliness has been investigated for use in the following countries participating in the United Nations "Generations and Gender Surveys": France, Germany, the Netherlands, Russia, Bulgaria, Georgia, and Japan. Sample sizes for the 7 countries varied between 8,158 and 12,828. Translations of the De Jong Gierveld loneliness scale have been tested using reliability and validity tests including a confirmatory factor analysis to test the two-dimensional structure of loneliness. Test outcomes indicated for each of the countries under investigation reliable and valid scales for emotional and social loneliness, respectively. © 2010 The Author(s).

Van Atteveldt N.,Group 47 | Van Atteveldt N.,VU University Amsterdam | Van Atteveldt N.,Maastricht University | Murray M.M.,University of Lausanne | And 4 more authors.
Neuron | Year: 2014

Research into the anatomical substrates and "principles" for integrating inputs from separate sensory surfaces has yielded divergent findings. This suggests that multisensory integration is flexible and context dependent and underlines the need for dynamically adaptive neuronal integration mechanisms. We propose that flexible multisensory integration can be explained by a combination of canonical, population-level integrative operations, such as oscillatory phase resetting and divisive normalization. These canonical operations subsume multisensory integration into a fundamental set of principles as to how the brain integrates all sorts of information, and they are being used proactively and adaptively. We illustrate this proposition by unifying recent findings from different research themes such as timing, behavioral goal, and experience-related differences in integration. van Atteveldt etal. discuss how the flexible, context-dependent manifestations of multisensory integration can be explained by adaptive and proactive interplay of canonical neural operations for cue integration, such as oscillatory phase resetting and divisive normalization. © 2014 Elsevier Inc.

Braakhuis B.J.M.,VU University Amsterdam | Leemans C.R.,VU University Amsterdam | Visser O.,Comprehensive Cancer Center the Netherlands
Oral Oncology | Year: 2014

Background Incidence and survival trends of head and neck squamous cell carcinoma (HNSCC) are essential knowledge for guiding policy making and research. Methods The total population of the Netherlands was studied covering 1989-2011. Two-and five-year survival and age-standardized incidence rates of HNSCC were assessed in relation to site, gender and age (15 years-of-age categories). Results We recorded a statistically significant increase of oral, oropharyngeal and hypopharyngeal carcinoma for males and females of all ages, varying from 0.6% (hypopharynx in males) to 2.7% (oropharynx in females) per year. The incidence of laryngeal carcinoma significantly decreased for males with 2.3% per year; for females the situation was stable. In young adults (below 45 years of age) the incidence figures were different: significant decreasing incidence trends were seen for both genders for carcinomas of the oropharynx, hypopharynx and larynx. Regarding oral carcinoma, no change was observed for the young patient group, but for subsites trends were divergent. Carcinoma of the floor or mouth decreased for both genders, but carcinoma of the tongue rose by a significant 2.8% per year for young males. Five-year survival trends for all ages showed no change for laryngeal carcinoma, a small improvement for oral and hypopharyngeal carcinoma, and a substantial and significant improvement of survival from 36% to 47% survival over the total period for oropharyngeal carcinoma. Conclusion In the Netherlands for the last two decades, the incidence of oral, oropharyngeal and hypopharyngeal squamous cell carcinoma has increased and survival has improved. The incidence of laryngeal carcinoma has decreased in males, and remained unchanged in females; survival from laryngeal carcinoma has not changed. © 2014 Elsevier Ltd. All rights reserved.

Newell P.,University of Sussex | Pattberg P.,VU University Amsterdam | Schroeder H.,University of East Anglia
Annual Review of Environment and Resources | Year: 2012

This review critically assesses a large and growing literature on multiactor environmental governance. The first section provides an historical and conceptual background to the observed increase in such arrangements. The second section describes the diversity of governance arrangements and the related actor constellations to address environmental issues, and the third section offers some explanations for the origins, form, and effectiveness of multiactor governance arrangements. The conclusion reflects on some of the key challenges in advancing and deepening research in this area and suggests some fruitful avenues for future work. © Copyright ©2012 by Annual Reviews. All rights reserved.

Randall T.D.,University of Alabama at Birmingham | Mebius R.E.,VU University Amsterdam
Mucosal Immunology | Year: 2014

Mucosal surfaces are constantly exposed to environmental antigens, colonized by commensal organisms and used by pathogens as points of entry. As a result, the immune system has devoted the bulk of its resources to mucosal sites to maintain symbiosis with commensal organisms, prevent pathogen entry, and avoid unnecessary inflammatory responses to innocuous antigens. These functions are facilitated by a variety of mucosal lymphoid organs that develop during embryogenesis in the absence of microbial stimulation as well as ectopic lymphoid tissues that develop in adults following microbial exposure or inflammation. Each of these lymphoid organs samples antigens from different mucosal sites and contributes to immune homeostasis, commensal containment, and immunity to pathogens. Here we discuss the mechanisms, mostly based on mouse studies, that control the development of mucosal lymphoid organs and how the various lymphoid tissues cooperate to maintain the integrity of the mucosal barrier. © 2014 Society for Mucosal Immunology.

Arbyn M.,Scientific Institute of Public Health | Verdoodt F.,Scientific Institute of Public Health | Snijders P.J.F.,VU University Amsterdam | Verhoef V.M.J.,VU University Amsterdam | And 8 more authors.
The Lancet Oncology | Year: 2014

Background: Screening for human papillomavirus (HPV) infection is more effective in reducing the incidence of cervical cancer than screening using Pap smears. Moreover, HPV testing can be done on a vaginal sample self-taken by a woman, which offers an opportunity to improve screening coverage. However, the clinical accuracy of HPV testing on self-samples is not well-known. We assessed whether HPV testing on self-collected samples is equivalent to HPV testing on samples collected by clinicians. Methods: We identified relevant studies through a search of PubMed, Embase, and CENTRAL. Studies were eligible for inclusion if they fulfilled all of the following selection criteria: a cervical cell sample was self-collected by a woman followed by a sample taken by a clinician; a high-risk HPV test was done on the self-sample (index test) and HPV-testing or cytological interpretation was done on the specimen collected by the clinician (comparator tests); and the presence or absence of cervical intraepithelial neoplasia grade 2 (CIN2) or worse was verified by colposcopy and biopsy in all enrolled women or in women with one or more positive tests. The absolute accuracy for finding CIN2 or worse, or CIN grade 3 (CIN3) or worse of the index and comparator tests as well as the relative accuracy of the index versus the comparator tests were pooled using bivariate normal models and random effect models. Findings: We included data from 36 studies, which altogether enrolled 154 556 women. The absolute accuracy varied by clinical setting. In the context of screening, HPV testing on self-samples detected, on average, 76% (95% CI 69-82) of CIN2 or worse and 84% (72-92) of CIN3 or worse. The pooled absolute specificity to exclude CIN2 or worse was 86% (83-89) and 87% (84-90) to exclude CIN3 or worse. The variation of the relative accuracy of HPV testing on self-samples compared with tests on clinician-taken samples was low across settings, enabling pooling of the relative accuracy over all studies. The pooled sensitivity of HPV testing on self-samples was lower than HPV testing on a clinician-taken sample (ratio 0·88 [95% CI 0·85-0·91] for CIN2 or worse and 0·89 [0·83-0·96] for CIN3 or worse). Also specificity was lower in self-samples versus clinician-taken samples (ratio 0·96 [0·95-0·97] for CIN2 or worse and 0·96 [0·93-0·99] for CIN3 or worse). HPV testing with signal-based assays on self-samples was less sensitive and specific than testing on clinician-based samples. By contrast, some PCR-based HPV tests generally showed similar sensitivity on both self-samples and clinician-based samples. Interpretation: In screening programmes using signal-based assays, sampling by a clinician should be recommended. However, HPV testing on a self-sample can be suggested as an additional strategy to reach women not participating in the regular screening programme. Some PCR-based HPV tests could be considered for routine screening after careful piloting assessing feasibility, logistics, population compliance, and costs. Funding: The 7th Framework Programme of the European Commission, the Belgian Foundation against Cancer, the International Agency for Research on Cancer, and the German Guideline Program in Oncology. © 2014 Elsevier Ltd.

Roos W.H.,VU University Amsterdam | Bruinsma R.,University of California at Los Angeles | Wuite G.J.L.,VU University Amsterdam
Nature Physics | Year: 2010

Viruses are nanosized, genome-filled protein containers with remarkable thermodynamic and mechanical properties. They form by spontaneous self-assembly inside the crowded, heterogeneous cytoplasm of infected cells. Self-assembly of viruses seems to obey the principles of thermodynamically reversible self-assembly but assembled shells ('capsids') strongly resist disassembly. Following assembly, some viral shells pass through a sequence of coordinated maturation steps that progressively strengthen the capsid. Nanoindentation measurements by atomic force microscopy enable tests of the strength of individual viral capsids. They show that concepts borrowed from macroscopic materials science are surprisingly relevant to viral shells. For example, viral shells exhibit 'materials fatigue- and the theory of thin-shell elasticity can account - in part - for atomic-force-microscopy-measured force-deformation curves. Viral shells have effective Young's moduli ranging from that of polyethylene to that of plexiglas. Some of them can withstand internal osmotic pressures that are tens of atmospheres. Comparisons with thin-shell theory also shed light on nonlinear irreversible processes such as plastic deformation and failure. Finally, atomic force microscopy experiments can quantify the mechanical effects of genome encapsidation and capsid protein mutations on viral shells, providing virological insight and suggesting new biotechnological applications. © 2010 Macmillan Publishers Limited. All rights reserved.

Tol R.S.J.,University of Sussex | Tol R.S.J.,VU University Amsterdam
Environmental and Resource Economics | Year: 2012

This paper uses a vote-counting procedure to estimate the probability density function of the total economic impact as a parabolic function of global warming. There is a wide range of uncertainty about the impact of climate change up to 3°C, and the information becomes progressively more diffuse beyond that. Warming greater than 3°C most likely has net negative impacts, and warming greater than 7°C may lead to a total welfare loss. The expected value of the social cost of carbon is about $29/tC in 2015 and rises at roughly 2% per year. © 2012 The Author(s).

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

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

Van Sloten T.T.,Maastricht University | Schram M.T.,Maastricht University | Van Den Hurk K.,VU University Amsterdam | Dekker J.M.,VU University Amsterdam | And 3 more authors.
Journal of the American College of Cardiology | Year: 2014

Objectives This study sought to investigate the association of local and segmental arterial stiffness with incident cardiovascular events and all-cause mortality. Background The association of different stiffness indices, in particular of carotid, brachial, and femoral stiffness, with cardiovascular disease and mortality is currently unknown. Methods In a population-based cohort (n = 579, mean age 67 years, 50% women, 23% with type 2 diabetes [by design]), we assessed local stiffness of carotid, femoral, and brachial arteries (by ultrasonography), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index, and systemic arterial compliance. Results After a median follow-up of 7.6 years, 130 participants had a cardiovascular event and 96 had died. The hazard ratios (HRs) (95% confidence intervals [CIs]) per 1 SD for cardiovascular events and all-cause mortality, respectively, were HR: 1.22 (95% CI: 0.95 to 1.56) and 1.51 (95% CI: 1.11 to 2.06) for lower carotid distensibility; HR: 1.19 (95% CI: 1.00 to 1.41) and 1.28 (95% CI: 1.07 to 1.53) for higher carotid elastic modulus; HR: 1.08 (95% CI: 0.88 to 1.31) and 1.43 (95% CI: 1.10 to 1.86) for lower carotid compliance; HR: 1.39 (95% CI: 1.06 to 1.83) and 1.27 (95% CI: 0.90 to 1.79) for lower femoral distensibility; HR: 1.25 (95% CI: 0.96 to 1.63) and 1.47 (95% CI: 1.01 to 2.13) for lower femoral compliance; and HR: 1.56 (95% CI: 1.23 to 1.98) and 1.13 (95% CI: 0.83 to 1.54) for higher cfPWV. These results were adjusted for age, sex, mean arterial pressure, and cardiovascular risk factors. Mutual adjustments for each of the other stiffness indices did not materially change these results. Brachial stiffness, augmentation index, and systemic arterial compliance were not associated with cardiovascular events or mortality. Conclusions Carotid and femoral stiffness indices are independently associated with incident cardiovascular events and all-cause mortality. The strength of these associations with events may differ per stiffness parameter. © 2014 by the American College of Cardiology Foundation. Published by Elsevier Inc.

Boellaard R.,VU University Amsterdam | Quick H.H.,University of Duisburg - Essen
Seminars in Nuclear Medicine | Year: 2015

Whole-body PET/MR hybrid imaging combines excellent soft tissue contrast and various functional imaging parameters provided by MR with high sensitivity and quantification of radiotracer uptake provided by PET. Although clinical evaluation now is under way, PET/MR demands for new technologies and innovative solutions, currently subject to interdisciplinary research. Attenuation correction (AC) of human soft tissues and of hardware components has to be MR based to maintain quantification of PET imaging as CT attenuation information is missing. MR-based AC is inherently associated with the following challenges: patient tissues are segmented into only few tissue classes, providing discrete attenuation coefficients; bone is substituted as soft tissue in MR-based AC; the limited field of view in MRI leads to truncations in body imaging and, consequently, in MR-based AC; and correct segmentation of lung tissue may be hampered by breathing artifacts. Use of time of flight during PET image acquisition and reconstruction, however, may improve the accuracy of AC. This article provides a status of current image acquisition options in PET/MR hybrid imaging. © 2015 Elsevier Inc.

Van Beijnum J.R.,VU University Amsterdam | Nowak-Sliwinska P.,VU University Amsterdam | Van Den Boezem E.,Maastricht University | Hautvast P.,Maastricht University | And 2 more authors.
Oncogene | Year: 2013

The endothelium plays a pivotal role in the progression of solid tumors and is considered a highly relevant target for therapy. However, it emerges that current clinical angiogenesis inhibitors that act through inhibition of tumor-derived growth factors are prone to inducing drug resistance. Therefore, markers of tumor endothelial cells (ECs) themselves provide attractive novel therapeutic targets. In a screen for markers of tumor angiogenesis, we recently identified high-mobility group box 1 (HMGB1), known to act as proinflammatory cytokine and chromatin-binding molecule. Here we report on the role of HMGB1 in angiogenesis by showing that its overexpression is associated with an increased angiogenic potential of ECs. HMGB1 stimulates the expression of players in vascular endothelial growth factor and platelet-derived growth factor signaling, both in vitro and in vivo. Importantly, we show that HMGB1 triggers and helps to sustain this proangiogenic gene expression program in ECs, additionally characterized by increased activity of matrix metalloproteinases, integrins and nuclear factor-κB. Moreover, we found that HMGB1 is involved in several autocrine and/or paracrine feedback mechanisms resulting in positive enforcement of HMGB1 expression, and that of its receptors, RAGE (receptor for advanced glycation end products) and Toll-like receptor 4 (TLR4). Interference in HMGB1 expression and/or function using knockdown approaches and antibody-mediated targeting to break this vicious circle resulted in inhibited migration and sprouting of ECs. Using different in vivo models, therapeutic efficacy of HMGB1 targeting was confirmed. First, we demonstrated induction of HMGB1 expression in the chicken embryo chorioallantoic membrane (CAM) neovasculature following both photodynamic therapy and tumor challenge. We subsequently showed that anti-HMGB1 antibodies inhibited vessel density in both models, accompanied by a reduced vascular expression of angiogenic growth factor receptors. Collectively, these data identify HMGB1 as an important modulator of tumor angiogenesis and suggest the feasibility of targeting HMGB1 for multi-level cancer treatment. © 2013 Macmillan Publishers Limited All rights reserved.

Diamant M.,VU University Amsterdam | Blaak E.E.,Maastricht University | de Vos W.M.,Wageningen University | de Vos W.M.,University of Helsinki
Obesity Reviews | Year: 2011

The current obesity and type 2 diabetes pandemics have causes beyond changes in eating and exercise habits against a susceptible genetic background. Gut bacteria seem to additionally contribute to the differences in body weight, fat distribution, insulin sensitivity and glucose- and lipid-metabolism. Data, mostly derived from preclinical studies, suggest that gut microbiota play an important role in conditions such as obesity, diabetes, metabolic syndrome and non-alcoholic fatty liver disease. Regulation of energy uptake from the gut, by digesting otherwise indigestible common polysaccharides in our diet, production or activation of signalling molecules involved in host metabolism, modification of gut permeability, the release of gut hormones and inflammation, are among the mechanisms by which gut microbiota may influence the host cardiometabolic phenotype. Recent evidence suggests that quantitative and qualitative differences in gut microbiota exist between lean and obese, and between diabetic and non-diabetic individuals. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may favourably affect host metabolism. Large-scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high-risk populations, are eagerly awaited. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.

Toby Kiers E.,VU University Amsterdam | Palmer T.M.,University of Florida | Ives A.R.,University of Wisconsin - Madison | Bruno J.F.,University of North Carolina at Chapel Hill | Bronstein J.L.,University of Arizona
Ecology Letters | Year: 2010

There is growing concern that rapid environmental degradation threatens mutualistic interactions. Because mutualisms can bind species to a common fate, mutualism breakdown has the potential to expand and accelerate effects of global change on biodiversity loss and ecosystem disruption. The current focus on the ecological dynamics of mutualism under global change has skirted fundamental evolutionary issues. Here, we develop an evolutionary perspective on mutualism breakdown to complement the ecological perspective, by focusing on three processes: (1) shifts from mutualism to antagonism, (2) switches to novel partners and (3) mutualism abandonment. We then identify the evolutionary factors that may make particular classes of mutualisms especially susceptible or resistant to breakdown and discuss how communities harbouring mutualisms may be affected by these evolutionary responses. We propose a template for evolutionary research on mutualism resilience and identify conservation approaches that may help conserve targeted mutualisms in the face of environmental change. © 2010 Blackwell Publishing Ltd/CNRS.

Blacquiere T.,Wageningen University | Smagghe G.,Ghent University | Van Gestel C.A.M.,VU University Amsterdam | Mommaerts V.,Ghent University
Ecotoxicology | Year: 2012

Neonicotinoid insecticides are successfully applied to control pests in a variety of agricultural crops; however, they may not only affect pest insects but also non-target organisms such as pollinators. This review summarizes, for the first time, 15 years of research on the hazards of neonicotinoids to bees including honey bees, bumble bees and solitary bees. The focus of the paper is on three different key aspects determining the risks of neonicotinoid field concentrations for bee populations: (1) the environmental neonicotinoid residue levels in plants, bees and bee products in relation to pesticide application, (2) the reported side-effects with special attention for sublethal effects, and (3) the usefulness for the evaluation of neonicotinoids of an already existing risk assessment scheme for systemic compounds. Although environmental residue levels of neonicotinoids were found to be lower than acute/chronic toxicity levels, there is still a lack of reliable data as most analyses were conducted near the detection limit and for only few crops. Many laboratory studies described lethal and sublethal effects of neonicotinoids on the foraging behavior, and learning and memory abilities of bees, while no effects were observed in field studies at field-realistic dosages. The proposed risk assessment scheme for systemic compounds was shown to be applicable to assess the risk for side-effects of neonicotinoids as it considers the effect on different life stages and different levels of biological organization (organism versus colony). Future research studies should be conducted with field-realistic concentrations, relevant exposure and evaluation durations. Molecular markers may be used to improve risk assessment by a better understanding of the mode of action (interaction with receptors) of neonicotinoids in bees leading to the identification of environmentally safer compounds. © Springer Science+Business Media, LLC 2012.

Heusschen R.,VU University Amsterdam | van Gink M.,Maastricht University | Griffioen A.W.,VU University Amsterdam | Thijssen V.L.,VU University Amsterdam
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2010

Tumor angiogenesis facilitates tumor metastasis and allows malignant tissues to grow beyond a diffusion limited size. It is a complex process that requires endothelial cells to execute specific steps during different phases. miRNAs are small non-coding RNAs that act as molecular switches to redirect the expression profile of a cell. Evidence is emerging that miRNAs are important players in endothelial cell biology and tumor angiogenesis. In this review we summarize the available data of miRNA expression in the endothelium. In addition, we describe the current knowledge regarding the function of miRNAs in endothelial cell biology. Finally, we discuss the potential applications of miRNA based treatment strategies in angiostatic cancer therapy. © 2009 Elsevier B.V. All rights reserved.

Renner F.,Maastricht University | Cuijpers P.,VU University Amsterdam | Huibers M.J.H.,VU University Amsterdam
Psychological Medicine | Year: 2014

Background: Patients with depression often report impairments in social functioning. From a patient perspective, improvements in social functioning might be an important outcome in psychotherapy for depression. Therefore, it is important to examine the effects of psychotherapy on social functioning in patients with depression. Method: We conducted a meta-analysis on studies of psychotherapy for depression that reported results for social functioning at post-treatment. Only studies that compared psychotherapy to a control condition were included (31 studies with 2956 patients). Results: The effect size of psychotherapy on social functioning was small to moderate, before [Hedges' g = 0.46, 95% confidence interval (CI) 0.32-0.60] and after adjusting for publication bias (g = 0.40, 95% CI 0.25-0.55). Univariate moderator analyses revealed that studies using care as usual as a control group versus other control groups yielded lower effect sizes, whereas studies conducted in the USA versus other countries and studies that used clinician-rated instruments versus self-report yielded higher effect sizes. Higher quality studies yielded lower effect sizes whereas the number of treatment sessions and the effect size of depressive symptoms were positively related to the effect size of social functioning. When controlling for these and additional characteristics simultaneously in multivariate meta-regression, the effect size of depressive symptoms, treatment format and number of sessions were significant predictors. The effect size of social functioning remained marginally significant, indicating that improvements in social functioning are not fully explained by improvements in depressive symptoms. Conclusions: Psychotherapy for depression results in small to moderate improvements in social functioning. These improvements are strongly associated with, but not fully explained by, improvements in depressive symptoms. Copyright © Cambridge University Press 2014.

Schulp C.J.E.,VU University Amsterdam | Thuiller W.,CNRS Alpine Ecology Laboratory | Verburg P.H.,VU University Amsterdam
Ecological Economics | Year: 2014

Wild food is an iconic ecosystem service that receives little attention in quantifying, valuating and mapping studies, due to the perceived low importance or due to lack of data. Here, we synthesize available data on the importance of wild food as ecosystem service, its spatial distribution and relations between supply, demand and benefits in the European Union (EU), covering all terrestrial wild food groups. A wide variety of game (38 species), mushrooms (27 species) and vascular plants (81 species) is collected and consumed throughout the EU. Income, age, gender, possibilities for collecting, and cultural factors explain the importance of wild food. While the economic and nutritional values of wild food comprise a few thousands of the GDP or total consumption, over 100. million EU citizens consume wild food. Collecting wild food is an appreciated recreational activity; collecting and consuming wild food provide important cultural ecosystem services, including recreation and sense of place. Because of these benefits, wild food should be included in EU ecosystem service assessments. Better estimates could be made if better data on wild food abundance and production are available and by systematic inventories of participation in wild food collecting. © 2014 Elsevier B.V.

Ter Wee M.M.,VU University Amsterdam | Lems W.F.,VU University Amsterdam | Usan H.,Izmir Alsancak State Hospital | Gulpen A.,Maastricht University | Boonen A.,Caphri Research Institute
Annals of the Rheumatic Diseases | Year: 2012

This study reviewed the effect of biological agents on participation in paid work among patients with rheumatoid arthritis (RA). A systematic literature search was performed to identify published articles reporting the effect of biological agents on employment status, sick leave and/or presenteeism. The quality of included articles was assessed according to the guidelines as proposed by the Dutch Cochrane Centre. Narrative summaries were used to present the data separately for randomised controlled trials (RCTs) as well as controlled and uncontrolled cohort studies. 19 studies (six uncontrolled cohorts, seven controlled cohorts and six RCTs) were included, in which 11 259 patients were treated with biological agents. Employment status improved in four out of 13 studies, absence from work in all 10 studies and presenteeism in seven out of nine studies that reported this outcome. For absenteeism and presenteeism the statistical significance of change or difference was not always provided and results within studies were sometimes conflicting when using different time frames or alternative outcomes. The large heterogeneity in terms of population, design, analyses and most important in outcome measures limits interpretation of the data. RCTs as well as cohort studies showed positive results of biological agents on both absenteeism and presenteeism compared with other disease-modifying antirheumatic drugs (DMARD), continuing the failing DMARD, the general population or the situation before the start of biological agents. The effect on employment status was more conflicting, but 50% of studies that addressed patients with early methotrexate-naive RA showed a positive result on employment status.

Wray N.R.,University of Queensland | Lee S.H.,University of Queensland | Mehta D.,University of Queensland | Vinkhuyzen A.A.E.,University of Queensland | And 2 more authors.
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2014

Background: Despite evidence from twin and family studies for an important contribution of genetic factors to both childhood and adult onset psychiatric disorders, identifying robustly associated specific DNA variants has proved challenging. In the pregenomics era the genetic architecture (number, frequency and effect size of risk variants) of complex genetic disorders was unknown. Empirical evidence for the genetic architecture of psychiatric disorders is emerging from the genetic studies of the last 5 years. Methods and scope: We review the methods investigating the polygenic nature of complex disorders. We provide mini-guides to genomic profile (or polygenic) risk scoring and to estimation of variance (or heritability) from common SNPs; a glossary of key terms is also provided. We review results of applications of the methods to psychiatric disorders and related traits and consider how these methods inform on missing heritability, hidden heritability and still-missing heritability. Findings: Genome-wide genotyping and sequencing studies are providing evidence that psychiatric disorders are truly polygenic, that is they have a genetic architecture of many genetic variants, including risk variants that are both common and rare in the population. Sample sizes published to date are mostly underpowered to detect effect sizes of the magnitude presented by nature, and these effect sizes may be constrained by the biological validity of the diagnostic constructs. Conclusions: Increasing the sample size for genome wide association studies of psychiatric disorders will lead to the identification of more associated genetic variants, as already found for schizophrenia. These loci provide the starting point of functional analyses that might eventually lead to new prevention and treatment options and to improved biological validity of diagnostic constructs. Polygenic analyses will contribute further to our understanding of complex genetic traits as sample sizes increase and as sample resources become richer in phenotypic descriptors, both in terms of clinical symptoms and of nongenetic risk factors. © 2014 Association for Child and Adolescent Mental Health.

Barkhof F.,VU University Amsterdam | Haller S.,University of Geneva | Rombouts S.A.R.B.,Leiden University
Radiology | Year: 2014

Resting-state (RS) functional magnetic resonance (MR) imaging constitutes a novel paradigm that examines spontaneous brain function by using blood oxygen level-dependent contrast in the absence of a task. Spatially distributed networks of temporal synchronization can be detected that can characterize RS networks (RSNs). With a short acquisition time of less than 10 minutes, RS functional MR imaging can be applied in special populations such as children and patients with dementia. Some RSNs are already present in utero, while others mature in childhood. Around 10 major RSNs are consistently found in adults, but their exact spatial extent and strength of coherence are affected by physiologic parameters and drugs. Though the acquisition and analysis methods are still evolving, new disease insights are emerging in a variety of neurologic and psychiatric disorders. The default mode network is affected in Alzheimer disease and various other diseases of cognitive impairment. Alterations in RSNs have been identified in many diseases, in the absence of evident structural modifications, indicating a high sensitivity of the method. Moreover, there is evidence of correlation between RSN alterations and disease progression and severity. However, different diseases often affect the same RSN, illustrating the limited specificity of the findings. This suggests that neurologic and psychiatric diseases are characterized by altered interactions between RSNs and therefore the whole brain should be examined as an integral network (with subnetworks), for example, using graph analysis. A challenge for clinical applications of RS functional MR imaging is the potentially confounding effect of aging, concomitant vascular diseases, or medication on the neurovascular coupling and consequently the functional MR imaging response. Current investigation combines RS functional MR imaging and other methods such as electroencephalography or magnetoencephalography to better understand the vascular and neuronal contributions to alterations in functional connectivity. © RSNA, 2014.

Young C.M.,University of Florida | Kingma S.D.K.,VU University Amsterdam | Neu J.,University of Florida
Journal of Pediatrics | Year: 2011

We review research relating ischemia/reperfusion to injury in the neonatal intestine. Epidemiologic evidence suggests that the most common form of necrotizing enterocolitis is not triggered by a primary hypoxic-ischemic event. Its late occurrence, lack of preceding ischemic events, and evidence for microbial and inflammatory processes preclude a major role for primary hypoxic ischemia as the sentinel pathogenic event. However, term infants, especially those with congenital heart disease who have development of intestinal necrosis, and those preterm infants with spontaneous intestinal perforations, are more likely to have intestinal ischemia as a primary component of their disease pathogenesis. © 2011 Mosby Inc. All rights reserved.

Klein-Nulend J.,VU University Amsterdam | Bakker A.D.,VU University Amsterdam | Bacabac R.G.,University of San Carlos | Vatsa A.,Suffolk University | Weinbaum S.,City College of New York
Bone | Year: 2013

The human skeleton is a miracle of engineering, combining both toughness and light weight. It does so because bones possess cellular mechanisms wherein external mechanical loads are sensed. These mechanical loads are transformed into biological signals, which ultimately direct bone formation and/or bone resorption. Osteocytes, since they are ubiquitous in the mineralized matrix, are the cells that sense mechanical loads and transduce the mechanical signals into a chemical response. The osteocytes then release signaling molecules, which orchestrate the recruitment and activity of osteoblasts or osteoclasts, resulting in the adaptation of bone mass and structure. In this review, we highlight current insights in bone adaptation to external mechanical loading, with an emphasis on how a mechanical load placed on whole bones is translated and amplified into a mechanical signal that is subsequently sensed by the osteocytes. This article is part of a Special Issue entitled "The Osteocyte". © 2012 Elsevier Inc.

Van Der Burg L.R.A.,Maastricht University | Ter Wee M.M.,VU University Amsterdam | Boonen A.,Maastricht University
Annals of the Rheumatic Diseases | Year: 2012

Objectives: To review systematically the effect of biological treatment in patients with ankylosing spondylitis (AS) on three work outcomes: work status, absence from paid work and at-work productivity. Methods: A systematic literature search was performed (Pubmed, Embase, Cochrane Library) to identify relevant articles. Risk of bias of included studies was assessed using the Cochrane guidelines for cohorts and randomised controlled trials (RCTs). Data were extracted using a self-composed data extraction form. Owing to extensive interstudy heterogeneity, narrative summaries were used to present the data. Results: Nine studies were included (six uncontrolled cohorts, one population-controlled cohort and two RCTs) that reported on 39 comparisons. Overall, 961 patients were treated with three different tumour necrosis factor α inhibitors (etanercept, infliximab, adalimumab). For presenteeism and absence from work, most comparisons showed improvement in favour of biological agents, but not all comparisons were statistically significant and they usually concerned before-after analyses. For work status, changes were less often positive, but studies dealt with patients with longstanding AS, lacked power and had a relatively short follow-up. Conclusions: Although trends towards beneficial effects of biological agents in longstanding AS were seen on all work outcomes, the methodological limitations in the studies included hampers clear conclusions. Since the majority of studies were (extensions of) controlled trials, the generalisability of the effect of biological agents on work participation in real life should be further studied in larger (population-controlled) studies. The effect of biological agents in patients with early disease has not yet been examined.

Visser M.,VU University Amsterdam | Koster A.,Maastricht University
BMC Geriatrics | Year: 2013

Background: There is currently no validated questionnaire available to assess total sedentary time in older adults. Most studies only used TV viewing time as an indicator of sedentary time. The first aim of our study was to investigate the self-reported time spent by older persons on a set of sedentary activities, and to compare this with objective sedentary time measured by accelerometry. The second aim was to determine what set of self-reported sedentary activities should be used to validly rank people's total sedentary time. Finally we tested the reliability of our newly developed questionnaire using the best performing set of sedentary activities. Methods. The study sample included 83 men and women aged 65-92 y, a random sample of Longitudinal Aging Study Amsterdam participants, who completed a questionnaire including ten sedentary activities and wore an Actigraph GT3X accelerometer for 8 days. Spearman correlation coefficients were calculated to examine the association between self-reported time and objective sedentary time. The test-retest reliability was calculated using the intraclass correlation coefficient (ICC). Results: Mean total self-reported sedentary time was 10.4 (SD 3.5) h/d and was not significantly different from mean total objective sedentary time (10.2 (1.2) h/d, p = 0.63). Total self-reported sedentary time on an average day (sum of ten activities) correlated moderately (Spearman's r = 0.35, p < 0.01) with total objective sedentary time. The correlation improved when using the sum of six activities (r = 0.46, p < 0.01), and was much higher than when using TV watching only (r = 0.22, p = 0.05). The test-retest reliability of the sum of six sedentary activities was 0.71 (95% CI 0.57-0.81). Conclusions: A questionnaire including six sedentary activities was moderately associated with accelerometry-derived sedentary time and can be used to reliably rank sedentary time in older persons. © 2013 Visser and Koster; licensee BioMed Central Ltd.

Goulas A.,Maastricht University | Uylings H.B.M.,VU University Amsterdam | Stiers P.,Maastricht University
Cerebral Cortex | Year: 2014

A consensus on the prefrontal cortex (PFC) holds that it is pivotal for flexible behavior and the integration of the cognitive, affective, and motivational domains. Certain models have been put forth and a dominant model postulates a hierarchical anterior-posterior gradient. The structural connectivity principles of this model dictate that increasingly anterior PFC regions exhibit more efferent connections toward posterior ones than vice versa. Such hierarchical asymmetry principles are thought to pertain to the macaque PFC. Additionally, the laminar patterns of the connectivity of PFC regions can be used for defining hierarchies. In the current study, we formally tested the asymmetry-based hierarchical principles of the anterior-posterior model by employing an exhaustive dataset on macaque PFC connectivity and tools from network science. On the one hand, the asymmetry-based principles and predictions of the hierarchical anterior-posterior model were not confirmed. The wiring of the macaque PFC does not fully correspond to the principles of the model, and its asymmetry-based hierarchical layout does not follow a strict anterior-posterior gradient. On the other hand, our results suggest that the laminar-based hierarchy seems a more tenable working hypothesis for models advocating an anterior-posterior gradient. Our results can inform models of the human PFC. © 2012 The Author.

Snellenburg J.J.,VU University Amsterdam | Laptenok S.,French Institute of Health and Medical Research | Seger R.,University of Augsburg | Mullen K.M.,U.S. National Institute of Standards and Technology | van Stokkum I.H.M.,VU University Amsterdam
Journal of Statistical Software | Year: 2012

In this work the software application called Glotaran is introduced as a Java-based graphical user interface to the R package TIMP, a problem solving environment for fitting superposition models to multi-dimensional data. TIMP uses a command-line user interface for the interaction with data, the specification of models and viewing of analysis results. Instead, Glotaran provides a graphical user interface which features interactive and dynamic data inspection, easier -- assisted by the user interface -- model specification and interactive viewing of results. The interactivity component is especially helpful when working with large, multi-dimensional datasets as often result from time-resolved spectroscopy measurements, allowing the user to easily pre-select and manipulate data before analysis and to quickly zoom in to regions of interest in the analysis results. Glotaran has been developed on top of the NetBeans rich client platform and communicates with R through the Java-to-R interface Rserve. The background and the functionality of the application are described here. In addition, the design, development and implementation process of Glotaran is documented in a generic way.

Mishra A.K.,University of Birmingham | Driessen N.N.,VU University Amsterdam | Appelmelk B.J.,VU University Amsterdam | Besra G.S.,University of Birmingham
FEMS Microbiology Reviews | Year: 2011

Approximately one third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. This bacterium has an unusual lipid-rich cell wall containing a vast repertoire of antigens, providing a hydrophobic impermeable barrier against chemical drugs, thus representing an attractive target for vaccine and drug development. Apart from the mycolyl-arabinogalactan-peptidoglycan complex, mycobacteria possess several immunomodulatory constituents, notably lipomannan and lipoarabinomannan. The availability of whole-genome sequences of M. tuberculosis and related bacilli over the past decade has led to the identification and functional characterization of various enzymes and the potential drug targets involved in the biosynthesis of these glycoconjugates. Both lipomannan and lipoarabinomannan possess highly variable chemical structures, which interact with different receptors of the immune system during host-pathogen interactions, such as Toll-like receptors-2 and C-type lectins. Recently, the availability of mutants defective in the synthesis of these glycoconjugates in mycobacteria and the closely related bacterium, Corynebacterium glutamicum, has paved the way for host-pathogen interaction studies, as well as, providing attenuated strains of mycobacteria for the development of new vaccine candidates. This review provides a comprehensive account of the structure, biosynthesis and immunomodulatory properties of these important glycoconjugates. Biosynthesis and immunomodulatory properties of mycobacterial lipoarabinomannan © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd.

Sanduleanu S.,Maastricht University | Masclee A.M.,Maastricht University | Meijer G.A.,VU University Amsterdam
Nature Reviews Gastroenterology and Hepatology | Year: 2012

Several studies have raised warnings about the limited effectiveness of colonoscopy for the prevention of colorectal cancer (CRC), especially of the proximal colon. Two major categories of factors might be responsible for the development of interval cancers, namely technical, endoscopist-dependent factors and biological characteristics of the cancer that lead to more rapid tumour progression. Recognition of endoscopist-dependent factors is critical, as these factors are probably amenable to correction through improved awareness and education of endoscopists, using quality metrics (such as adenoma detection rates and cecal intubation rates) for objective evaluation and feedback. In this article, the current literature regarding the incidence of, and potential explanations for, interval CRCs is outlined. Although there is probably an interaction between technical and biology-related factors-and an attempt to dissect the biology from the technology might be fraught with difficulties-a structured analysis of individual cases of interval cancer might help in the continuous monitoring of the quality of colonoscopy, and ultimately might reduce the number of interval CRCs. © 2012 Macmillan Publishers Limited. All rights reserved.

Koster A.,Maastricht University | Schaap L.A.,VU University Amsterdam
Clinics in geriatric medicine | Year: 2015

This review describes the effect of type 2 diabetes on fat mass, fat distribution, and lean mass, and changes in these parameters, in older adults, focusing on observational studies. Studies show that type 2 diabetes is associated with an unfavorable body composition characterized by more visceral fat, less thigh subcutaneous fat, and more fat infiltration in the muscle compared with persons without the disease. Longitudinal studies found an accelerated decline in muscle mass in older persons with type 2 diabetes. Studies are needed to examine the consequences of these changes in body composition on physical functioning, morbidity, and mortality risk. Copyright © 2015 Elsevier Inc. All rights reserved.

Jordan A.,University of East Anglia | Huitema D.,VU University Amsterdam
Environmental Politics | Year: 2014

Academics and practitioners have responded to the gridlock in the international climate-change regime by more actively exploring the ability of individuals and/or groups of states to fill in the associated ‘governance gaps’ by engaging in policy innovation at the level of the nation state, including its regional and local emanations. Here, we draw together the findings of a collection that, for the first time, explores policy innovation at this level from three key perspectives: the source of new policy elements (‘invention’), their wider entry into use (‘diffusion’), and their projected and/or real effects (‘evaluation’). After critically reviewing the findings of the contributions from these perspectives, we explore new directions for definitional, conceptual-theoretical, and empirical work in this field. Finally, we explore how a more systematic analysis of policy innovation dynamics can inform a much fuller understanding of climate policy and governance across different sites and scales. © 2014, © 2014 The Author(s). Published by Taylor & Francis.

Jordan A.,University of East Anglia | Huitema D.,VU University Amsterdam | Huitema D.,University of Management and Technology
Global Environmental Change | Year: 2014

States have been widely criticized for failing to advance the international climate regime. Many observers now believe that a "new" climate governance is emerging through transnational and/or local forms of action that will eventually plug the resulting governance gaps. Yet states, which remain oddly absent from most discussions of the "new" governance, will remain key players as governance becomes more polycentric. This paper introduces a special issue that explores the ability of states to rise to these interconnected challenges through the analytical prism of policy innovation. It reveals that policy innovation is much more multi-dimensional than is often thought; it encompasses three vital activities: invention (centering on the 'source' of new policy elements), diffusion (that produces different 'patterns' of policy adoption), and the evaluation of the 'effects' that such innovations create in reality. The papers, which range from qualitative case studies to large '. n' quantitative studies, offer new insights into the varied roles that states play in relation to all three. They show, for instance that: the policy activity of states has risen dramatically in the past decade; that state innovation is affected to similar degrees by internal and external factors; and that policies that offer flexibility to target groups on how to meet policy goals are most effective but that voluntary reporting requirements are ineffective. This paper draws upon these and many other insights to offer a much more nuanced reflection on the future of climate governance; one that deservedly puts states at the front and center of analysis. © 2014 The Authors.

Lems W.F.,VU University Amsterdam | Geusens P.,Maastricht University | Geusens P.,Hasselt University
Current Opinion in Rheumatology | Year: 2014

PURPOSE OF REVIEW: The aim of treatment in patients at high risk for fractures is to reduce the risk of a first or a subsequent fracture. New data are available on the antifracture effects and side-effects of antiresorptive and osteoanabolic drugs, and new emerging therapies with new modes of action are on the horizon. RECENT FINDINGS: Calcium and vitamin D intake should be sufficient, but not too high. Vertebral, nonvertebral (including hip fracture) prevention with antiresorptive drugs such as bisphosphonates (alendronate, risedronate and zoledronic acid) and denosumab exceeds the risk of rare side-effects such as atypical femur fracture and osteonecrosis of the jaw. Teriparatide is an osteoanabolic drug that improves quality of life in severe osteoporosis. Strontium ranelate decreases dynamic parameters of bone formation during the first year of treatment, and could increase the risk of cardiovascular events in high-risk patients. Initiation of and adherence to fracture prevention drugs are still low. New potential developments in antiresorptive drugs include odanacatib, a selective inhibitor of cathepsin K, and, in osteoanabolic drugs, monoclonal antibodies against sclerostin. SUMMARY: These recent data indicate that fracture prevention with antiresorptives and teriparatide is effective with a reasonable safety profile. Odanacatib and antisclerostin are promising new drugs with new mechanisms of action, as they are able to disconnect the normal coupling between bone resorption and bone formation. © 2014 Wolters Kluwer Health.

Schaap L.A.,VU University Amsterdam | Koster A.,Maastricht University | Visser M.,VU University Amsterdam
Epidemiologic Reviews | Year: 2013

Aging is associated with changes in body composition and muscle strength. This review aimed to determine the relation between different body composition measures and muscle strength measures and functional decline in older men and women. By use of relevant databases (PubMed, Embase, and CINAHL) and keywords in a search from 1976 to April 2012, 50 articles were reviewed that met the inclusion criteria (written in English, a prospective, longitudinal design, involving older persons aged 65 years or more, and at least one of the measures that follow: body mass index (BMI), waist circumference, waist/hip ratio, midarm circumference, fat mass, muscle fat infiltration, muscle mass, or strength as independent variables and a measure of functional decline as outcome measure). Meta-analyses were performed and revealed that BMI ≥30 and low muscle strength were associated with functional decline (pooled odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.43, 1.80, for BMI ≥30 and OR = 1.86, 95% CI: 1.32, 2.64, for muscle strength). Low muscle mass was not significantly associated with functional decline (pooled OR = 1.19, 95% CI: 0.98, 1.45). Future intervention research should focus on positive changes in body composition to prevent onset or worsening of functional decline in old age. © 2013 The Author. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

Agency: GTR | Branch: AHRC | Program: | Phase: Research Grant | Award Amount: 37.73K | Year: 2016

Research Context. Waste is a significant problem facing a rapidly urbanising world, with challenges at every stage including waste prevention, treatment/management, recycling and reuse, and the health and ecosystem impacts of poorly managed waste. Rising to these challenges, particularly in relation to sustainable cities, is high on the policy agenda at local, national and international levels. For example a recent (2013) UK Government report on waste noted that: We need to develop further the concept of a circular economy, where one persons waste becomes anothers valuable resource...Making the changes needed may require innovation and creative thinking... Aims and Objectives The aim of the Network is to develop a forum for knowledge exchange and debate across art & humanities and science disciplines and subject areas with a common focus on waste treatment, management and innovation. This will seek to develop responses to the question: how can arts based approaches inform waste management innovation techniques and processes; and secondly, (how) does place (local context, identity, culture, governance) make a difference to waste generation, waste innovation delivery and uptake? This aim will be met through the following objectives: i)To establish an interdisciplinary network of Europe-wide academics, artists, scientists, practitioners, stakeholders, and interested end-users. We will run four workshops in 4 European cities (London, Amsterdam, Maastricht, Bangor in Wales) to explore and develop ideas, issues and possible solutions and learn from each other, and also run a number of pop-up events piloting arts-based approaches to public engagement and waste. A wiki style open source website will provide network support. ii) to identify particular sorts of waste (e.g. industrial/domestic, organic/manufactured, chemicals/metals, waste-energy, water) and to identify specific intervention points, which have good potential for creative interdisciplinary innovation. Applications and Benefits Bringing together different disciplines and different communities of place and practice to address a common problem will have the primary benefit of structured knowledge exchange and capacity building across a number of divides (e.g. academic/practitioner, geographical, artists and scientists). The process of creating and participating in the network will therefore be its key outcome/benefit. The network will also make connections (through the pop up events and through the website) with the general public, enabling local and lay expertise to inform the network. We aim to identify, through an iterative process of workshops and facilitated discussion, not only how good practice in one area can be uptaken in another, but to identify what sorts of waste, and what sorts of intervention points, may be best suited for taking forward creative interdisciplinary solutions, and to seek future funding to develop these, ensuring a legacy for the network. We also anticipate a number of smaller spin off innovations, which may be quite simple, such as better recycling leaflet design and event management. We aim for the long term benefits to be more sustainable waste management and treatment innovation systems and improved governance including citizen participation, enabling waste to be more sustainably treated and for more value to be extracted from waste streams. This would have clear benefits for the health, wealth and wellbeing of cities and their citizens.

University of Manchester, U.S. National Institute on Aging, Hospital District Of Helsinki And Uusimaa, VU University Amsterdam, Ucl Business Plc and University of Cardiff | Date: 2012-08-31

The present invention relates to methods of assessing whether a subject has or is likely to develop a neurodegenerative disease comprising determining whether the subject has a mutation in the C9orf72 gene wherein said mutation prevents or disrupts C9orf72 expression relative to expression in a reference from subjects without the mutation.

Korolnek T.,University of Maryland University College | Zhang J.,University of Maryland University College | Beardsley S.,University of Maryland University College | Scheffer G.L.,VU University Amsterdam | Hamza I.,University of Maryland University College
Cell Metabolism | Year: 2014

Several lines of evidence predict that specific pathways must exist in metazoans for the escorted movement of heme, an essential but cytotoxic iron-containing organic ring, within and between cells and tissues, but these pathways remain obscure. In Caenorhabditis elegans, embryonic development is inextricably dependent on both maternally derived heme and environmentally acquired heme. Here, we show that the multidrug resistance protein MRP-5/ABCC5 likely acts as a heme exporter, and targeted depletion of mrp-5 in the intestine causes embryonic lethality. Transient knockdown of mrp5 in zebrafish leads to morphological defects and failure to hemoglobinize red blood cells. MRP5 resides on the plasma membrane and endosomal compartments and regulates export of cytosolic heme. Together, our genetic studies in worms, yeast, zebrafish, and mammalian cells identify a conserved, physiological role for a multidrug resistance protein in regulating systemic heme homeostasis. We envision other MRP family members may play similar unanticipated physiological roles in animal development. © 2014 Elsevier Inc.

Mirtschink A.,VU University Amsterdam | Seidl M.,University of Regensburg | Gori-Giorgi P.,VU University Amsterdam
Physical Review Letters | Year: 2013

We generalize the exact strong-interaction limit of the exchange-correlation energy of Kohn-Sham density functional theory to open systems with fluctuating particle numbers. When used in the self-consistent Kohn-Sham procedure on strongly interacting systems, this functional yields exact features crucial for important applications such as quantum transport. In particular, the steplike structure of the highest-occupied Kohn-Sham eigenvalue is very well captured, with accurate quantitative agreement with exact many-body chemical potentials. While it can be shown that a sharp derivative discontinuity is present only in the infinitely strongly correlated limit, at finite correlation regimes we observe a slightly smoothened discontinuity, with qualitative and quantitative features that improve with increasing correlation. From the fundamental point of view, our results obtain the derivative discontinuity without making the assumptions used in its standard derivation, offering independent support for its existence. © 2013 American Physical Society.

Veerhuis R.,VU University Amsterdam | Nielsen H.M.,Skåne University Hospital | Tenner A.J.,University of California at Irvine
Molecular Immunology | Year: 2011

The brain is considered to be an immune privileged site, because the blood-brain barrier limits entry of blood borne cells and proteins into the central nervous system (CNS). As a result, the detection and clearance of invading microorganisms and senescent cells as well as surplus neurotransmitters, aged and glycated proteins, in order to maintain a healthy environment for neuronal and glial cells, is largely confined to the innate immune system. In recent years it has become clear that many factors of innate immunity are expressed throughout the brain. Neuronal and glial cells express Toll like receptors as well as complement receptors, and virtually all complement components can be locally produced in the brain, often in response to injury or developmental cues. However, as inflammatory reactions could interfere with proper functioning of the brain, tight and fine tuned regulatory mechanisms are warranted. In age related diseases, such as Alzheimer's disease (AD), accumulating amyloid proteins elicit complement activation and a local, chronic inflammatory response that leads to attraction and activation of glial cells that, under such activation conditions, can produce neurotoxic substances, including pro-inflammatory cytokines and oxygen radicals. This process may be exacerbated by a disturbed balance between complement activators and complement regulatory proteins such as occurs in AD, as the local synthesis of these proteins is differentially regulated by pro-inflammatory cytokines. Much knowledge about the role of complement in neurodegenerative diseases has been derived from animal studies with transgenic overexpressing or knockout mice for specific complement factors or receptors. These studies have provided insight into the potential therapeutic use of complement regulators and complement receptor antagonists in chronic neurodegenerative diseases as well as in acute conditions, such as stroke. Interestingly, recent animal studies have also indicated that complement activation products are involved in brain development and synapse formation. Not only are these findings important for the understanding of how brain development and neural network formation is organized, it may also give insights into the role of complement in processes of neurodegeneration and neuroprotection in the injured or aged and diseased adult central nervous system, and thus aid in identifying novel and specific targets for therapeutic intervention. © 2011 Elsevier Ltd.

Cloetingh S.,VU University Amsterdam | Burov E.,University Pierre and Marie Curie
Basin Research | Year: 2011

Lithospheric folding is an important mode of basin formation in compressional intraplate settings. Basins formed by lithospheric folding are characterized by distinct features in subsidence history. A comparison with extensional basins, foreland basins, intracratonic basins and pull-apart basins provides criteria for the discrimination between these modes of basin formation. These findings are important in deciphering the feedbacks between tectonics and surface processes. In addition, inferences on accommodation space and thermal regime have important consequences for hydrocarbon maturity. Lithospheric folding is coupled to compressional reactivation of basins and faults, and therefore, strongly affects reservoir characteristics of sedimentary basins. © 2010 The Authors. Basin Research © 2010 Blackwell Publishing Ltd, European Association of Geoscientists & Engineers and International Association of Sedimentologists.

Guo M.,Harvard University | Ehrlicher A.J.,Harvard University | Ehrlicher A.J.,Beth Israel Deaconess Medical Center | Ehrlicher A.J.,McGill University | And 8 more authors.
Cell | Year: 2014

Molecular motors in cells typically produce highly directed motion; however, the aggregate, incoherent effect of all active processes also creates randomly fluctuating forces, which drive diffusive-like, nonthermal motion. Here, we introduce force-spectrum-microscopy (FSM) to directly quantify random forces within the cytoplasm of cells and thereby probe stochastic motor activity. This technique combines measurements of the random motion of probe particles with independent micromechanical measurements of the cytoplasm to quantify the spectrum of force fluctuations. Using FSM, we show that force fluctuations substantially enhance intracellular movement of small and large components. The fluctuations are three times larger in malignant cells than in their benign counterparts. We further demonstrate that vimentin acts globally to anchor organelles against randomly fluctuating forces in the cytoplasm, with no effect on their magnitude. Thus, FSM has broad applications for understanding the cytoplasm and its intracellular processes in relation to cell physiology in healthy and diseased states. © 2014 Elsevier Inc.

van Gelder J.-L.,Netherlands Institute for the Study of Crime and Law Enforcement NSCR | de Vries R.E.,VU University Amsterdam
Journal of Quantitative Criminology | Year: 2014

Objectives: Test the hypothesis that dispositional self-control and morality relate to criminal decision making via different mental processing modes, a 'hot' affective mode and a 'cool' cognitive one. Methods: Structural equation modeling in two studies under separate samples of undergraduate students using scenarios describing two different types of crime, illegal downloading and insurance fraud. Both self-control and morality are operationalized through the HEXACO model of personality (Lee and Ashton in Multivariate Behav Res 39(2):329-358, 2004).Results: In Study 1, negative state affect, i.e., feelings of fear and worry evoked by a criminal prospect, and perceived risk of sanction were found to mediate the relations between both dispositions and criminal choice. In Study 2, processing mode was manipulated by having participants rely on either their thinking or on their feelings prior to deciding on whether or not to make a criminal choice. Activating a cognitive mode strengthened the relation between perceived risk and criminal choice, whereas activating an affective mode strengthened the relation between negative affect and criminal choice.Conclusion: In conjunction, these results extend research that links stable individual dispositions to proximal states that operate in the moment of decision making. The results also add to dispositional perspectives of crime by using a structure of personality that incorporates both self-control and morality. Contributions to the proximal, state, perspectives reside in the use of a new hot/cool perspective of criminal decision making that extends rational choice frameworks. © 2013 Springer Science+Business Media New York.

Sheinman M.,VU University Amsterdam | Sheinman M.,Technion - Israel Institute of Technology | Benichou O.,University Pierre and Marie Curie | Kafri Y.,Technion - Israel Institute of Technology | Voituriez R.,University Pierre and Marie Curie
Reports on Progress in Physics | Year: 2012

Problems of search and recognition appear over different scales in biological systems. In this review we focus on the challenges posed by interactions between proteins, in particular transcription factors, and DNA and possible mechanisms which allow for fast and selective target location. Initially we argue that DNA-binding proteins can be classified, broadly, into three distinct classes which we illustrate using experimental data. Each class calls for a different search process and we discuss the possible application of different search mechanisms proposed over the years to each class. The main thrust of this review is a new mechanism which is based on barrier discrimination. We introduce the model and analyze in detail its consequences. It is shown that this mechanism applies to all classes of transcription factors and can lead to a fast and specific search. Moreover, it is shown that the mechanism has interesting transient features which allow for stability at the target despite rapid binding and unbinding of the transcription factor from the target. © 2012 IOP Publishing Ltd.

O'Higgins T.G.,Scottish Association for Marine Science | Gilbert A.J.,VU University Amsterdam
Estuarine, Coastal and Shelf Science | Year: 2014

The introduction of the Marine Strategy Framework Directive (MSFD) with its focus on an Ecosystem Approach places an emphasis on the human dimensions of environmental problems. Human activities may be the source of marine degradation, but may also be adversely affected should degradation compromise the provision of ecosystem services. The MSFD marks a shift away from management aiming to restore past, undegraded states toward management for Good Environmental Status (GEnS) based on delivery of marine goods and services. An example relating ecosystem services to criteria for Good Environmental Status is presented for eutrophication, a long recognised problem in many parts of Europe's seas and specifically targeted by descriptors for GEnS. Taking the North Sea as a case study the relationships between the eutrophication criteria of the MSFD and final and intermediate marine ecosystem services are examined. Ecosystem services are valued, where possible in monetary terms, in order to illustrate how eutrophication affects human welfare (economic externalities) through its multiple effects on ecosystem services. © 2013 Elsevier Ltd.

Duhamel M.,French National Center for Scientific Research | Duhamel M.,VU University Amsterdam | Vandenkoornhuyse P.,French National Center for Scientific Research
Trends in Plant Science | Year: 2013

Food demand will increase concomitantly with human population. Food production therefore needs to be high enough and, at the same time, minimize damage to the environment. This equation cannot be solved with current strategies. Based on recent findings, new trajectories for agriculture and plant breeding which take into account the belowground compartment and evolution of mutualistic strategy, are proposed in this opinion article. In this context, we argue that plant breeders have the opportunity to make use of native arbuscular mycorrhizal (AM) symbiosis in an innovative ecologically intensive agriculture. © 2013 Elsevier Ltd.

Giglio L.,University of Maryland University College | Randerson J.T.,University of California at Irvine | Van Der Werf G.R.,VU University Amsterdam
Journal of Geophysical Research: Biogeosciences | Year: 2013

We describe the fourth generation of the Global Fire Emissions Database (GFED4) burned area data set, which provides global monthly burned area at 0.25° spatial resolution from mid-1995 through the present and daily burned area for the time series extending back to August 2000. We produced the full data set by combining 500 m MODIS burned area maps with active fire data from the Tropical Rainfall Measuring Mission (TRMM) Visible and Infrared Scanner (VIRS) and the Along-Track Scanning Radiometer (ATSR) family of sensors. We found that the global annual area burned for the years 1997 through 2011 varied from 301 to 377Mha, with an average of 348Mha. We assessed the interannual variability and trends in burned area on the basis of a region-specific definition of fire years. With respect to trends, we found a gradual decrease of 1.7Mhayr - 1 (- 1.4%yr - 1) in Northern Hemisphere Africa since 2000, a gradual increase of 2.3Mhayr - 1 (+1.8%yr - 1) in Southern Hemisphere Africa also since 2000, a slight increase of 0.2Mhayr - 1 (+2.5%yr - 1) in Southeast Asia since 1997, and a rapid decrease of approximately 5.5Mhayr - 1 (- 10.7%yr - 1) from 2001 through 2011 in Australia, followed by a major upsurge in 2011 that exceeded the annual area burned in at least the previous 14 years. The net trend in global burned area from 2000 to 2012 was a modest decrease of 4.3Mhayr - 1 (- 1.2%yr - 1). We also performed a spectral analysis of the daily burned area time series and found no vestiges of the 16 day MODIS repeat cycle. Key pointsThe area of the land surface burned annually has been decreasing since 2000.This trend is in part due to a decline in burning in Northern-Hemisphere Africa.The area burned in some regions has been increasing, however. ©2013. American Geophysical Union. All Rights Reserved.

Ballesteros-Gomez A.,University of Cordoba, Spain | Rubio S.,University of Cordoba, Spain | van Leeuwen S.,VU University Amsterdam
Journal of Chromatography A | Year: 2010

A new solvent extraction system was developed for extraction of PFCs from food. The extraction is carried out with 75:25 (v/v) tetrahydrofuran:water, a solvent mixture that provides an appropriate balance of hydrogen bonding, dispersion and dipole-dipole interactions to efficiently extract PFCs with chains containing 4-14 carbon atoms from foods. This mixture provided recoveries above 85% from foods including vegetables, fruits, fish, meat and bread; and above 75% from cheese. Clean-up with a weak anion exchange resin and Envi-carb SPE, which were coupled in line for simplicity, was found to minimize matrix effects (viz. enhancement or suppression of electrospray ionization). The target analytes (PFCs) were resolved on a perfluorooctyl phase column that proved effective in separating mass interferences for perfluorooctane sulfonate (PFOS) in fish and meat samples. The mass spectrometer was operated in the negative electrospray ionization mode and used to record two transitions per analyte and one per mass-labeled method internal standard. The target PFCs were quantified from solvent based calibration curves. The limits of detection (LODs) were as low as 1-5pganalyteg-1 food; by exception, those for C4 and C5 PFCs were somewhat higher (25-30pgg-1) owing to their less favourable mass response. To the best of our knowledge these are among the best LODs for PFCs in foods reported to date. The analysis of a variety of foods revealed contamination with PFCs at levels from 4.5 to 75pgg-1 in 25% of samples (fish and packaged spinach). C10-C14 PFCs were found in fish, which testifies to the need to control long-chain PFCs in this type of food. The proposed method is a useful tool for the development of a large-scale database for the presence of PFCs in foods. © 2010 Elsevier B.V.

Gori-Giorgi P.,VU University Amsterdam | Seidl M.,University of Regensburg
Physical Chemistry Chemical Physics | Year: 2010

Improving the accuracy and thus broadening the applicability of electronic density functional theory (DFT) is crucial to many research areas, from material science, to theoretical chemistry, biophysics and biochemistry. In the last three years, the mathematical structure of the strong-interaction limit of density functional theory has been uncovered, and exact information on this limit has started to become available. The aim of this paper is to give a perspective on how this new piece of exact information can be used to treat situations that are problematic for standard Kohn-Sham DFT. One way to use the strong-interaction limit, more relevant for solid-state physical devices, is to define a new framework to do practical, non-conventional, DFT calculations in which a strong-interacting reference system is used instead of the traditional non-interacting one of Kohn and Sham. Another way to proceed, more related to chemical applications, is to include the exact treatment of the strong-interaction limit into approximate exchange-correlation energy density functionals in order to describe difficult situations such as the breaking of the chemical bond. © 2010 the Owner Societies.

Van Heeswijk W.C.,VU University Amsterdam | Westerhoff H.V.,VU University Amsterdam | Westerhoff H.V.,University of Manchester | Westerhoff H.V.,University of Amsterdam | Boogerd F.C.,VU University Amsterdam
Microbiology and Molecular Biology Reviews | Year: 2013

We present a comprehensive overview of the hierarchical network of intracellular processes revolving around central nitrogen metabolism in Escherichia coli. The hierarchy intertwines transport, metabolism, signaling leading to posttranslational modification, and transcription. The protein components of the network include an ammonium transporter (AmtB), a glutamine transporter (GlnHPQ), two ammonium assimilation pathways (glutamine synthetase [GS]-glutamate synthase [glutamine 2-oxoglutarate amidotransferase {GOGAT}] and glutamate dehydrogenase [GDH]), the two bifunctional enzymes adenylyl transferase/ adenylyl-removing enzyme (ATase) and uridylyl transferase/uridylyl- removing enzyme (UTase), the two trimeric signal transduction proteins (GlnB and GlnK), the two-component regulatory system composed of the histidine protein kinase nitrogen regulator 2 (NRII) and the response nitrogen regulator 1 (NRI), three global transcriptional regulators called nitrogen assimilation control (Nac) protein, leucine-responsive regulatory protein (Lrp), and cyclicAMP(cAMP) receptor protein (Crp), the glutaminases, and the nitrogen-phosphotransferase system. First, the structural and molecular knowledge on these proteins is reviewed. Thereafter, the activities of the components as they engage together in transport, metabolism, signal transduction, and transcription and their regulation are discussed. Next, old and new molecular data and physiological data are put into a common perspective on integral cellular functioning, especially with the aim of resolving counterintuitive or paradoxical processes featured in nitrogen assimilation. Finally, we articulate what still remains to be discovered and what general lessons can be learned from the vast amounts of data that are available now. © 2013, American Society for Microbiology. All Rights Reserved.

Joost M.,CNRS Laboratory for Basic and Applied Heterochemistry | Joost M.,VU University Amsterdam | Amgoune A.,CNRS Laboratory for Basic and Applied Heterochemistry | Bourissou D.,CNRS Laboratory for Basic and Applied Heterochemistry
Angewandte Chemie - International Edition | Year: 2015

For a while, the reactivity of gold complexes was largely dominated by their Lewis acid behavior. In contrast to the other transition metals, the elementary steps of organometallic chemistry - oxidative addition, reductive elimination, transmetallation, migratory insertion - have scarcely been studied in the case of gold or even remained unprecedented until recently. However, within the last few years, the ability of gold complexes to undergo these fundamental reactions has been unambiguously demonstrated, and the reactivity of gold complexes was shown to extend well beyond π-activation. In this Review, the main achievements described in this area are presented in a historical context. Particular emphasis is set on mechanistic studies and structure determination of key intermediates. The electronic and structural parameters delineating the reactivity of gold complexes are discussed, as well as the remaining challenges. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rasanen E.,University of Jyväskylä | Seidl M.,University of Regensburg | Gori-Giorgi P.,VU University Amsterdam
Physical Review B - Condensed Matter and Materials Physics | Year: 2011

We study the energetic properties of finite but internally homogeneous D-dimensional electron droplets in the strict-correlation limit. The indirect Coulomb interaction is found to increase as a function of the electron number, approaching the tighter forms of the Lieb-Oxford bound recently proposed by Räsänen [Phys. Rev. Lett.PRLTAO0031-900710.1103/PhysRevLett.102.206406 102, 206406 (2009)]. The bound is satisfied in three-, two-, and one-dimensional droplets, and in the latter case it is reached exactly-regardless of the type of interaction considered. Our results provide useful reference data for delocalized strongly correlated systems, and they can be used in the development and testing of exchange-correlation density functionals in the framework of density-functional theory. © 2011 American Physical Society.

Rabinovich G.A.,CONICET | Rabinovich G.A.,University of Buenos Aires | van Kooyk Y.,VU University Amsterdam | Cobb B.A.,Case Western Reserve University
Annals of the New York Academy of Sciences | Year: 2012

Unlike their protein "roommates" and their nucleic acid "cousins," carbohydrates remain an enigmatic arm of biology. The central reason for the difficulty in fully understanding how carbohydrate structure and biological function are tied is the nontemplate nature of their synthesis and the resulting heterogeneity. The goal of this collection of expert reviews is to highlight what is known about how carbohydrates and their binding partners-the microbial (non-self), tumor (altered-self), and host (self)-cooperate within the immune system, while also identifying areas of opportunity to those willing to take up the challenge of understanding more about how carbohydrates influence immune responses. In the end, these reviews will serve as specific examples of how carbohydrates are as integral to biology as are proteins, nucleic acids, and lipids. Here, we attempt to summarize general concepts on glycans and glycan-binding proteins (mainly C-type lectins, siglecs, and galectins) and their contributions to the biology of immune responses in physiologic and pathologic settings. © 2012 New York Academy of Sciences.

Broedersz C.P.,Princeton University | Broedersz C.P.,VU University Amsterdam | Mackintosh F.C.,Princeton University | Mackintosh F.C.,VU University Amsterdam
Reviews of Modern Physics | Year: 2014

This is an overview of theoretical approaches to semiflexible polymers and their networks. Such semiflexible polymers have large bending rigidities that can compete with the entropic tendency of a chain to crumple up into a random coil. Many studies on semiflexible polymers and their assemblies have been motivated by their importance in biology. Indeed, cross-linked networks of semiflexible polymers form a major structural component of tissue and living cells. Reconstituted networks of such biopolymers have emerged as a new class of biological soft matter systems with remarkable material properties, which have spurred many of the theoretical developments discussed here. Starting from the mechanics and dynamics of individual semiflexible polymers, the physics of semiflexible bundles, entangled solutions, and disordered cross-linked networks are reviewed. Finally, recent developments on marginally stable fibrous networks, which exhibit critical behavior similar to other marginal systems such as jammed soft matter, are discussed. © 2014 American Physical Society.

Stjernschantz E.,VU University Amsterdam | Oostenbrink C.,VU University Amsterdam | Oostenbrink C.,University of Natural Resources and Life Sciences, Vienna
Biophysical Journal | Year: 2010

Accurate ligand-protein binding affinity prediction, for a set of similar binders, is a major challenge in the lead optimization stage in drug development. In general, docking and scoring functions perform unsatisfactorily in this application. Docking calculations, followed by molecular dynamics simulations and free energy calculations can be applied to improve the predictions. However, for targets with large, flexible binding sites, with no experimentally determined binding modes for a set of ligands, insufficient sampling can decrease the accuracy of the free energy calculations. Cytochrome P450s, a protein family of major importance for drug metabolism, is an example of a challenging target for binding affinity predictions. As a result, the choice of starting structure from the docking solutions becomes crucial. In this study, an iterative scheme is introduced that includes multiple independent molecular dynamics simulations to obtain weighted ensemble averages to be used in the linear interaction energy method. The proposed scheme makes the initial pose selection less crucial for further simulation, as it automatically calculates the relative weights of the various poses. It also properly takes into account the possibility that multiple binding modes contribute similarly to the overall affinity, or of similar compounds occupying very different poses. The method was applied to a set of 12 compounds binding to cytochrome P450 2C9 and it displayed a root mean-square error of 2.9 kJ/mol. © 2010 by the Biophysical Society.

Sheinman M.,VU University Amsterdam | Broedersz C.P.,Princeton University | MacKintosh F.C.,VU University Amsterdam
Physical Review Letters | Year: 2012

We study the effects of motor-generated stresses in disordered three-dimensional fiber networks using a combination of a mean-field theory, scaling analysis, and a computational model. We find that motor activity controls the elasticity in an anomalous fashion close to the point of marginal stability by coupling to critical network fluctuations. We also show that motor stresses can stabilize initially floppy networks, extending the range of critical behavior to a broad regime of network connectivities below the marginal point. Away from this regime, or at high stress, motors give rise to a linear increase in stiffness with stress. Finally, we demonstrate that our results are captured by a simple, constitutive scaling relation highlighting the important role of nonaffine strain fluctuations as a susceptibility to motor stress. © 2012 American Physical Society.

Manfredini D.,University of Padua | Lobbezoo F.,VU University Amsterdam
Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology | Year: 2010

Objectives: The present paper aims to systematically review the literature on the temporomandibular disorders (TMD)-bruxism relationship published from 1998 to 2008. Study design: A systematic search in the National Library of Medicine's PubMed database was performed to identify all studies on humans assessing the relationship between TMD symptoms and bruxism diagnosed with any different approach. The selected articles were assessed independently by the 2 authors according to a structured reading of articles format (PICO). Results: A total of 46 articles were included for discussion in the review and grouped into questionnaire/self-report (n = 21), clinical assessment (n = 7), experimental (n = 7), tooth wear (n = 5), polysomnographic (n = 4), or electromyographic (n = 2) studies. In several studies, the level of evidence was negatively influenced by a low level of specificity for the assessment of the bruxism-TMD relationship, because of the low prevalence of severe TMD patients in the studied samples and because of the use of self-report diagnosis of bruxism with some potential diagnostic bias. Conclusions: Investigations based on self-report or clinical bruxism diagnosis showed a positive association with TMD pain, but they are characterized by some potential bias and confounders at the diagnostic level (eg, pain as a criterion for bruxism diagnosis). Studies based on more quantitative and specific methods to diagnose bruxism showed much lower association with TMD symptoms. Anterior tooth wear was not found to be a major risk factor for TMD. Experimental sustained jaw clenching may provoke acute muscle tenderness, but it is not analogous to myogenous TMD pain, so such studies may not help clarify the clinical relationship between bruxism and TMD. © 2010 Mosby, Inc. All rights reserved.

Jansen P.,VU University Amsterdam | Xu L.-H.,University of New Brunswick | Kleiner I.,University Paris Diderot | Ubachs W.,VU University Amsterdam | Bethlem H.L.,VU University Amsterdam
Physical Review Letters | Year: 2011

The 6.7 and 12.2 GHz masers, corresponding to the 51→6 0A+ and 20→3-1E transitions in methanol (CH3OH), respectively, are among the brightest radio objects in the sky. We present calculations for the sensitivity of these and other transitions in the ground state of methanol to a variation of the proton-to-electron mass ratio. We show that the sensitivity is greatly enhanced due to a cancellation of energies associated with the hindered internal rotation and the overall rotation of the molecule. We find sensitivities of K μ=-42 and Kμ=-33, for the 51→6 0A+ and 20→3-1E transitions, respectively. The sensitivities of other transitions in the different isotopologues of methanol range from -88 to 330. This makes methanol a sensitive probe for spatial and temporal variations of the proton-to-electron mass ratio. © 2011 American Physical Society.

Kiers E.T.,VU University Amsterdam | Denison R.F.,University of Minnesota
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Trade-offs between individual fitness and the collective performance of crop and below-ground symbiont communities are common in agriculture. Plant competitiveness for light and soil resources is key to individual fitness, but higher investments in stems and roots by a plant community to compete for those resources ultimately reduce crop yields. Similarly, rhizobia and mycorrhizal fungi may increase their individual fitness by diverting resources to their own reproduction, even if they could have benefited collectively by providing their shared crop host with more nitrogen and phosphorus, respectively. Past selection for inclusive fitness (benefits to others, weighted by their relatedness) is unlikely to have favoured community performance over individual fitness. The limited evidence for kin recognition in plants and microbes changes this conclusion only slightly. We therefore argue that there is still ample opportunity for human-imposed selection to improve cooperation among crop plants and their symbionts so that they use limited resources more efficiently. This evolutionarily informed approach will require a better understanding of how interactions among crops, and interactions with their symbionts, affected their inclusive fitness in the past and what that implies for current interactions. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Vonk Noordegraaf A.,VU University Amsterdam | Haddad F.,Stanford University | Bogaard H.J.,VU University Amsterdam | Hassoun P.M.,Johns Hopkins University
Circulation | Year: 2015

We predict that cardiac MRI and PET will significantly contribute to a better understanding of the pathophysiological processes that lead to the development of chronic RV failure in PAH. Imaging studies have demonstrated that, in the setting of chronic pressure overload, the RV compensates enduringly to sustain CO by an increase in wall mass, dilatation, and contractility and marked changes in the RV shape. With the passage of time, these compensatory mechanisms fail, resulting in increased wall stress and impaired global RV function. Other factors that might contribute to disturbed RV function are a reduced wall deformation and an inefficient RV contraction pattern. The resulting interventricular asynchrony is associated with leftward septum bowing, impaired LV filling, and decreased stroke volume. Furthermore, the RV becomes mechanically insufficient: More oxygen is required for a comparable power output. At the same time, RV oxygen delivery is impaired and tissue oxygenation is reduced. Alterations in myocardial metabolism have been observed in PAH, but their overall relevance and whether they represent cause or consequence of RV failure remain unclear. With the current evidence, it can confidently be stated that RV imaging parameters measured at baseline correlate with exercise capacity and functional class and predict survival.69,136 Moreover, RV imaging parameters have been shown to respond to treatment,35,137 and changes in these parameters after treatment reflect altered exercise capacity138 and predict subsequent survival.12 What is lacking at this point, however, is the demonstration of reliable monitoring and improved overall clinical outcome when a treatment strategy based on specific imaging parameters is used. In the near future, it can be expected that the importance of changes in cellular functions and signaling pathways will become clearer and the changes will be "imageable." This might allow a regional and quantifiable analysis of processes such as angiogenesis, apoptosis, and neurohormonal factors. Table 5 provides an overview of currently available clinical imaging tracers that could be relevant for the assessment of molecular processes of RV diseases in patients. In addition, recent developments in (hybrid) PET and MRI might allow an integrated RV assessment in vivo. They will likely provide an important basis for simultaneous measurements of multiple myocardial disease processes. © 2015 American Heart Association, Inc.

Wierman A.,California Institute of Technology | Zwart B.,VU University Amsterdam
Operations Research | Year: 2012

This paper focuses on the competitive analysis of scheduling disciplines in a large deviations setting. Although there are policies that are known to optimize the sojourn time tail under a large class of heavy-tailed job sizes (e.g., processor sharing and shortest remaining processing time) and there are policies known to optimize the sojourn time tail in the case of light-tailed job sizes (e.g., first come first served), no policies are known that can optimize the sojourn time tail across both light- and heavy-tailed job size distributions. We prove that no such work-conserving, nonanticipatory, nonlearning policy exists, and thus that a policy must learn (or know) the job size distribution in order to optimize the sojourn time tail. © 2012 INFORMS.

Steensma T.D.,VU University Amsterdam | McGuire J.K.,Washington State University | Kreukels B.P.C.,VU University Amsterdam | Beekman A.J.,VU University Amsterdam | Cohen-Kettenis P.T.,VU University Amsterdam
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2013

Objective: To examine the factors associated with the persistence of childhood gender dysphoria (GD), and to assess the feelings of GD, body image, and sexual orientation in adolescence. Method: The sample consisted of 127 adolescents (79 boys, 48 girls), who were referred for GD in childhood (<12 years of age) and followed up in adolescence. We examined childhood differences among persisters and desisters in demographics, psychological functioning, quality of peer relations and childhood GD, and adolescent reports of GD, body image, and sexual orientation. We examined contributions of childhood factors on the probability of persistence of GD into adolescence. Results: We found a link between the intensity of GD in childhood and persistence of GD, as well as a higher probability of persistence among natal girls. Psychological functioning and the quality of peer relations did not predict the persistence of childhood GD. Formerly nonsignificant (age at childhood assessment) and unstudied factors (a cognitive and/or affective cross-gender identification and a social role transition) were associated with the persistence of childhood GD, and varied among natal boys and girls. Conclusion: Intensity of early GD appears to be an important predictor of persistence of GD. Clinical recommendations for the support of children with GD may need to be developed independently for natal boys and for girls, as the presentation of boys and girls with GD is different, and different factors are predictive for the persistence of GD. © 2013 American Academy of Child and Adolescent Psychiatry.

Buttazzo G.,University of Pisa | De Pascale L.,University of Pisa | Gori-Giorgi P.,VU University Amsterdam
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2012

The most challenging scenario for Kohn-Sham density-functional theory, that is, when the electrons move relatively slowly trying to avoid each other as much as possible because of their repulsion (strong-interaction limit), is reformulated here as an optimal transport (or mass transportation theory) problem, a well-established field of mathematics and economics. In practice, we show that to solve the problem of finding the minimum possible internal repulsion energy for N electrons in a given density ρ(r) is equivalent to find the optimal way of transporting N-1 times the density ρ into itself, with the cost function given by the Coulomb repulsion. We use this link to set the strong-interaction limit of density-functional theory on firm ground and to discuss the potential practical aspects of this reformulation. © 2012 American Physical Society.

Conti M.,University of Padua | Willemsen J.,VU University Amsterdam | Crispo B.,University of Trento
IEEE Communications Surveys and Tutorials | Year: 2013

Wireless sensor networks (WSNs) consist of numerous small nodes that can sense, collect, and disseminate information for many different types of applications. One of these applications is subject tracking and monitoring, in which the monitored subjects often need protection. For instance, a WSN can be deployed to monitor the movement of a panda in a national park. The panda needs protection from different adversaries, such as hunters and poachers. An adversary might trace the messages in the WSN to find the source node that sensed the panda, with the final aim of killing the panda. Hence the question is: how do we hide the location of the source node from the adversary? This question is relevant in several of the scenarios related to this application, such as patient monitoring and battlefield surveillance. In other words, the problem is to provide privacy to the source node: source location privacy. In this paper, we provide a survey of the state of the art in source location privacy. We first discuss the key concepts in source location privacy, such as anonymity, unobservability, safety period, and capture likelihood. Then, we present an overview of the solutions that provide source location privacy within a WSN, in relation to the assumptions about the adversary's capabilities. In particular, we summarize the concepts and solutions, which are categorized based on the core techniques used to provide source location privacy. We mention the limitations of the algorithms as found in the literature, classify the solutions based on their approach, and provide an overview of the assumptions on the adversarial capabilities related to each solution. © 2009-2012 IEEE.

Dieckmann P.,Medical Simulation | Krage R.,VU University Amsterdam
Current Opinion in Anaesthesiology | Year: 2013

PURPOSE OF REVIEW: Psychology is relevant for improving the use of simulation in anesthesiology, as it allows us to describe, explain and optimize the interactions of learners and instructors as well as the design of simulation scenarios and debriefings. Much psychological expertise is not used for simulation in healthcare. This article aims to help bridging the gap between professions. RECENT FINDINGS: The evidence is building that simulation is effective for learning. Recent psychological work improves the understanding of why this is the case - or why not. Publications range from the elements to be simulated, to optimizing the presentation of scenarios and debriefings to an organizational overview of how simulation can contribute to patient safety, healthcare worker well-beings and quality of care. The psychological analysis helps in capturing the salient characteristics of the tasks to be simulated and in implementing them in a relevant learning setting. SUMMARY: Using psychology in simulation allows us to create, recognize and use learning opportunities. The motivations of those involved can be taken into account and the simulation activity can be channeled into a goal-oriented direction. VIDEO ABSTRACT AVAILABLE: See the Video Supplementary Digital Content 1 ( COAN/A26). Copyright © Lippincott Williams & Wilkins.

de Jong M.C.,VU University Amsterdam | Kors W.A.,VU University Amsterdam | de Graaf P.,VU University Amsterdam | Castelijns J.A.,VU University Amsterdam | And 2 more authors.
The Lancet Oncology | Year: 2014

Background: About 5% of children with retinoblastoma from germline mutation of the RB1 gene are at risk of developing trilateral retinoblastoma-intraocular retinoblastoma combined with a histologically similar brain tumour, most commonly in the pineal gland. We aimed to provide a systematic overview of published data for trilateral retinoblastoma, and to analyse how survival has changed. Methods: We searched Medline and Embase for scientific literature published between Jan 1, 1966, and April 14, 2014, that assessed trilateral retinoblastoma cases. We undertook a meta-analysis of survival with the Kaplan-Meier method and Cox proportional hazards regression, stratified on the basis of the original study, to account for between-study heterogeneity. Findings: We included 90 studies, with 174 patients with trilateral retinoblastoma. 5-year survival after pineal trilateral retinoblastoma increased from 6% (95% CI 2-15) in patients diagnosed before 1995, to 44% (26-61; p<0·0001) in those diagnosed from 1995 onwards. Before 1995, no patients with non-pineal trilateral retinoblastoma survived, but from 1995 onwards, 5-year survival was 57% (30-77; p=0·035). Hazard ratios (HR) adjusted for the presence of leptomeningeal metastases and trilateral retinoblastoma location, suggested that both conventional (HR 0·059, 95% CI 0·016-0·226; p<0·0001) and high-dose chemotherapy with stem-cell rescue (0·013, 0·002-0·064; p<0·0001) most strongly contributed to this improvement. Absence of leptomeningeal metastases (HR 2·13, 95% CI 0·98-4·60; p=0·055) were associated with improved survival. Non-pineal trilateral retinoblastomas were larger than pineal tumours (median 30 mm [range 6-100] vs 22 mm [7-60]; p=0·012), but both had similar outcomes since 1995. Interpretation: Our results suggest that improvements in overall survival are attributable to improved chemotherapy regimens and early detection of pineal trilateral retinoblastoma. As such, successful treatment of trilateral retinoblastoma should include screening at least at the time of retinoblastoma diagnosis and chemotherapy, which would preferably be a high-dose regimen with autologous stem-cell rescue. Funding: None. © 2014 Elsevier Ltd.

Parinussa R.M.,U.S. Department of Agriculture | Holmes T.R.H.,U.S. Department of Agriculture | De Jeu R.A.M.,VU University Amsterdam
IEEE Transactions on Geoscience and Remote Sensing | Year: 2012

An existing methodology to derive surface soil moisture from passive microwave satellite observations is applied to the WindSat multifrequency polarimetric microwave radiometer. The methodology is a radiative-transfer-based model that has successfully been applied to a series of (historical) satellite sensors, including the Advanced Microwave Scanning Radiometer for Earth Observing System (AMSR-E). Brightness temperature observations from the WindSat and AMSR-E radiometers were compared, and the WindSat observations were adjusted to overcome small sensor differences (e.g., frequency, bandwidth, incidence angle, and original sensor calibration procedure). The method to relate Ka-band brightness temperature observations to land surface temperature was adapted to the overpass times of WindSat. Statistical analysis with both satellite-observed and in situ soil moistures indicates that the quality of the newly derived WindSat soil moisture product is similar to that obtained with AMSR-E after the adjustment of the WindSat brightness temperature observations. The average correlation coefficients (R) between satellite soil moisture and in situ observations are similar for the two satellites with average values of R = 0.60 for WindSat and R = 0.62 for AMSR-E as calculated from 33 sites. On a global scale, the average correlation coefficient between the two satellite soil moisture products is high with a value of R = 0.83. The results of this study demonstrate that soil moisture from WindSat is consistent with existing soil moisture products derived from AMSR-E using the land parameter retrieval model. Therefore, the soil moisture retrievals from these two satellites could easily be combined to increase the temporal resolution of satellite-derived soil moisture observations. © 2011 IEEE.

Mulder P.,VU University Amsterdam | de Groot H.L.F.,VU University Amsterdam | de Groot H.L.F.,Tinbergen Institute
Energy Economics | Year: 2012

This paper uses new and unique data derived from a consistent framework of national accounts to compute and evaluate energy intensity developments across 18 OECD countries and 50 sectors over the period 1970-2005. We find that across countries energy intensity levels tend to decrease in most Manufacturing sectors. In the Service sector, energy intensity decreases at a relatively slow rate, with diverse trends across sub-sectors. A decomposition analysis reveals that changes in the sectoral composition of the economy explain a considerable and increasing part of aggregate energy intensity dynamics. A convergence analysis reveals that only after 1995 cross-country variation in aggregate energy intensity levels clearly tends to decrease, driven by a strong and robust trend break in Manufacturing and enhanced convergence in Services. Moreover, we find evidence for the hypothesis that across sectors lagging countries are catching-up with leading countries, with rates of convergence that are on average higher in Services than in Manufacturing. Aggregate convergence patterns are almost exclusively caused by convergence of within-sector energy intensity levels, and not by convergence of the sectoral composition of economies. © 2012 Elsevier B.V.

Denison R.F.,University of Minnesota | Kiers E.T.,VU University Amsterdam
Current Biology | Year: 2011

Research on life history strategies of microbial symbionts is key to understanding the evolution of cooperation with hosts, but also their survival between hosts. Rhizobia are soil bacteria known for fixing nitrogen inside legume root nodules. Arbuscular mycorrhizal (AM) fungi are ubiquitous root symbionts that provide plants with nutrients and other benefits. Both kinds of symbionts employ strategies to reproduce during symbiosis using host resources; to repopulate the soil; to survive in the soil between hosts; and to find and infect new hosts. Here we focus on the fitness of the microbial symbionts and how interactions at each of these stages has shaped microbial life-history strategies. During symbiosis, microbial fitness could be increased by diverting more resources to individual reproduction, but that may trigger fitness-reducing host sanctions. To survive in the soil, symbionts employ sophisticated strategies, such as persister formation for rhizobia and reversal of spore germination by mycorrhizae. Interactions among symbionts, from rhizobial quorum sensing to fusion of genetically distinct fungal hyphae, increase adaptive plasticity. The evolutionary implications of these interactions and of microbial strategies to repopulate and survive in the soil are largely unexplored. © 2011 Elsevier Ltd. All rights reserved.

Geurts J.J.G.,VU University Amsterdam | Calabrese M.,University of Padua | Fisher E.,Cleveland Clinic | Rudick R.A.,Cleveland Clinic
The Lancet Neurology | Year: 2012

During the past 10 years, the intense involvement of the grey matter of the CNS in the pathology of multiple sclerosis has become evident. On gross inspection, demyelination in the grey matter is rather inconspicuous, and lesions in the grey matter are mostly undetectable with traditional MRI sequences. However, the results of immunohistochemical studies have shown extensive involvement of grey matter, and researchers have developed and applied new MRI acquisition methods as a result. Imaging techniques specifically developed to visualise grey matter lesions indicate early involvement, and image analysis techniques designed to measure the volume of grey matter show progressive loss. Together, these techniques have shown that grey matter pathology is associated with neurological and neuropsychological disability, and the strength of this association exceeds that related to white matter lesions or whole brain atrophy. By focusing on the latest insights into the in-vivo measurement of grey matter lesions and atrophy, we can assess their clinical effects. © 2012 Elsevier Ltd.

Cristea I.A.,Babes - Bolyai University | Cristea I.A.,University of Pisa | Kok R.N.,VU University Amsterdam | Kok R.N.,Australian National University | And 2 more authors.
British Journal of Psychiatry | Year: 2015

Background Cognitive bias modification (CBM) interventions are strongly advocated in research and clinical practice.Aims To examine the efficiency of CBM for clinically relevant outcomes, along with study quality, publication bias and potential moderators.Method We included randomised controlled trials (RCTs) of CBM interventions that reported clinically relevant outcomes assessed with standardised instruments.Results We identified 49 trials and grouped outcomes into anxiety and depression. Effect sizes were small considering all the samples, and mostly non-significant for patient samples. Effect sizes became non-significant when outliers were excluded and after adjustment for publication bias. The quality of the RCTs was suboptimal.Conclusions CBM may have small effects on mental health problems, but it is also very well possible that there are no significant clinically relevant effects. Research in this field is hampered by small and low-quality trials, and by risk of publication bias. Many positive outcomes are driven by extreme outliers.

News Article | October 23, 2015

In the last month, there’s been much attention to a cool patch in the North Atlantic Ocean, where record cold temperatures over the past eight months present a stark contrast to a globe that is experiencing record warmth. And although there is certainly no consensus on the matter yet, some scientists think this pattern may be a sign of one long-feared consequence of climate change — a slowing of North Atlantic ocean circulation, due to a freshening of surface waters. The cause, goes the thinking, would be the rapidly melting Greenland ice sheet, whose large freshwater flows may weaken ocean “overturning” by reducing the density of cold surface waters (colder, salty water is denser). If cold, salty waters don’t sink in the North Atlantic and flow back southward toward Antarctica at depth, then warm surface waters won’t flow northward to take their place. The result could be a significant change to northern hemisphere climate, as less ocean-borne heat reaches higher latitudes. [Why some scientists are worried about a surprisingly cold ‘blob’ in the North Atlantic Ocean] Now, two new studies just out in Nature Geoscience help to underscore why scientists have a good reason to think this sort of thing can happen — namely, because it appears to have happened in the Earth’s distant past. And not just once but on multiple occasions. For a long time scientists have been trying to figure out a funny thing about glacial periods of Earth’s history. These periods are not, you see, uniformly cold. Rather, they show an alternation between so-called stadials — long periods featuring quite cold temperatures — and interstadials, which are relatively rapidly occurring warmer periods during glacials. So what causes this oscillation in glacial temperatures? A leading theory is that this all has something to do with changes in the circulation of the oceans. The idea is that large flows of ice into the ocean in the North Atlantic cause freshening at the surface. This could then weaken Atlantic ocean circulation, lessen northward heat transport, and ultimately cause a cold period — another stadial. The first study in Nature Geoscience seems to confirm as much by looking at a deep sea core from the middle of the South Atlantic Ocean, off the coast of South America in waters that aren’t far from the beginning of the Southern Ocean and, then, Antarctica. The research, led by Julia Gottschalk of the University of Cambridge in collaboration with other researchers from Cambridge, the United States, Australia and France, finds “a very tight link between abrupt changes in the ocean circulation, and these events, these transitions between cold climate states and warm climate states during the last glacial period,” as Gottschalk puts it. But how could the researchers know this from a single cylinder of mud extracted from more than two miles beneath the ocean? The trick, Gottschalk says, is that the core was taken from a region where very different water masses, characteristic of the North and South Atlantic, meet. “The waters formed in the north are preserving, so they’re less corrosive,” Gottschalk says. “And the waters from the south are more corrosive because they have more CO2, more acid basically.” And these water characteristics have an effect on the dissolution of the shells of tiny microorganisms called foraminifera, which fall to the seafloor and become part of the core sample that the scientists examined. Thus, by examining these shells, the researchers were able to tell when the area was bathing in waters that had traveled southward from the North Atlantic — so-called North Atlantic Deep Water, a key part of the overturning circulation — and when that circulation was weaker and South Atlantic waters occupied the area instead. The results, Gottschalk says, are something that scientists studying glacial changes and their causes have lacked — namely, “a clear deep ocean record that really shows these abrupt changes in ocean circulation.” Indeed, the record showed that during “nearly every” warm or interstadial period, deep water from the North Atlantic made its way southward toward Antarctica — precisely what you would expect if overturning ocean circulation increased in the North Atlantic, snapping back from a more slowed-down state. “Our core site is really very sensitive to these ocean circulation changes, and we could really draw this conclusion that abrupt climate change in the past is really closely coupled to changes in the overturning, or to deepwater mass formation,” Gottschalk says. More specifically, Gottschalk says, the last 115,000 years featured some 25 abrupt cold-to-warm shifts in the North Atlantic. And “at least during the last 70,000 years these climate shifts were in some way or the other tightly linked with significant changes of the deep Atlantic ocean circulation, in particular with deep water circulating from the North to the South Atlantic.” The second study, meanwhile, seeks to explain the Younger Dryas, a cold period that began abruptly 12,900 years ago, as the planet was actually coming out of a glacial period and entering the present interglacial. Suddenly, though, temperatures swung back and became quite cold again for more than a thousand years, leading glaciers and ice sheets to rebuild. And once again, a change in Atlantic ocean circulation has long been a leading suspect in causing this dramatic, sudden event. “The start of the Younger Dryas was in a couple of years, really five years or so,” says Hans Renssen of VU University Amsterdam in the Netherlands, who led the research, along with scientists from Belgium, France, the United Kingdom, Norway and Switzerland. Using climate change models, the researchers tried to reproduce the cooling of the Younger Dryas period. And they found that simulating a full shutdown of the Atlantic’s overturning circulation actually made things too cold — but combining together a more moderate ocean circulation slowdown (losing about half of its force) with a concurrent reduction in solar radiation reaching the Earth’s surface and a change in atmospheric circulation patterns did a very good job of simulating the cool down. Slowing the Atlantic ocean’s circulation thus “plays an important role, but it’s not the only mechanism,” Renssen says. When it comes to modern day implications of the research, however, “it shows that climate is sensitive to changes in the freshwater balance of the ocean,” Renssen says. “So I would not expect a Younger Dryas, or a thousand year-long cold period, but I think there’s still a serious risk of the ocean circulation to weaken, and even abruptly.” Granted, it’s important to distinguish between past periods, like the Younger Dryas, and where we are today. For the Younger Dryas, the trigger event is thought to be a gigantic freshwater flow from the huge Lake Agassiz, which had been previously hemmed in by the Laurentide Ice Sheet — a vast ice sheet that covered much of North America during the last glacial period. But neither Lake Agassiz nor the Laurentide Ice Sheet exists today. So whatever they did in the past could be quite different from the effects of large ice loss from Greenland in the present. The gist of the new research, then, is that the idea of abrupt climate changes brought on by ocean circulation changes is very much alive and well in climate change research. Whether what we’re currently seeing matches what happened in the past is another matter — but the past certainly gives ample reason for concern. Why scientists are so worried about the ice shelves of Antarctica Scientists say a dramatic worldwide coral bleaching event is now underway The U.S. needs a solar energy revolution. But it’s laying off solar energy researchers For more, you can sign up for our weekly newsletter here, and follow us on Twitter here.

News Article | October 23, 2015

Last week, I noted a staggering statistic: Raging fires in Indonesia — the result of both this year’s El Nino event and the clearing of forests and draining of peatlands — have apparently given off as much carbon dioxide to the atmosphere as Germany does in a year by burning fossil fuels. The key reason is that about half of the fires are burning on carbon packed peatlands. “Taken together, the impact of peat fires on global warming may be more than 200 times greater than fires on other lands,” wrote four researchers with the World Resources Institute recently. Unfortunately, it appears that since last week, the fire situation in Indonesia has only worsened — and so have the emissions. Forget Germany, the emissions are now equal to Japan’s, based on estimates by Guido van der Werf, an expert on wildfire emissions at VU University Amsterdam in the Netherlands. Here’s a figure from van der Werf, showing the latest calculations: Based on van der Werf’s methodology — which estimates fire emissions to the atmosphere based on satellite imagery of the fires and of vegetation — Indonesian fires have now emitted roughly 1.35 gigatons of carbon dioxide equivalents. A gigaton is a billion metric tons, and the planet is estimated have less than 1,000 gigatons of carbon dioxide left to emit to have a two-thirds chance of keeping global warming below 2 degrees Celsius above pre-industrial levels. You can also see that this year’s fires are about to surpass the estimated emissions from fires in 2006, which would make them the second worst in this record. Reaching the catastrophic levels of 1997 (which like 2006 was also another El Nino) is still a ways away — it saw more than 4 gigatons of emissions, based on van der Werf’s calculations. The fire emissions from Indonesia probably won’t reach those levels this year, but it seems more than possible that Indonesian fire emissions this year could exceed India’s fossil fuel emissions. “It is mostly that in 2006, daily emissions were leveling off big time right now which is not the case this year,” says van der Werf. Indonesia’s fire emissions have, needless to say, long since blown away Indonesia’s own emissions from fossil fuels. Four researchers from the World Resources Institute presented the data recently in another way — showing that on more than 20 days this year, fire emissions from Indonesia were greater than fossil fuel emissions from the entire, gigantic U.S. economy. However you slice it, Indonesia’s fire emissions are a particularly noteworthy problem  leading into this year’s high stakes climate meeting in Paris. There, world leaders will focus on the planet’s emissions from burning fossil fuels. But the Indonesia story shows why carbon emissions related to land use changes, brought on by deforestation and the many other ways that humans alter their environments, remain an urgent part of the story.

Teunissen C.E.,VU University Amsterdam | Khalil M.,Medical University of Graz
Multiple Sclerosis Journal | Year: 2012

Neurodegeneration is the correlate of disease progression in multiple sclerosis (MS) and thus biological biomarkers that sensitively reflect this process are much needed. Neurofilament protein subunits are potential cerebrospinal fluid (CSF) biomarkers for disease progression in MS. We argue that the neurofilament light subunit can reflect acute axonal damage mediated by inflammatory mechanisms and can imply prognostic value for conversion from clinically isolated syndrome (CIS) to definite MS. The neurofilament heavy subunit may rather reflect chronic irreversible damage and has prognostic value for disease progression or disability. The neurofilament intermediate subunit has not yet been studied. Recent studies showing higher neurofilament light or heavy subunit levels to be altered upon treatment regimes indicate their potential clinical value in monitoring treatment or side effects. Future studies should be aimed at the optimisation, standardisation and interlaboratory implementation of the assays and address the predictive value of these biomarkers. © The Author(s) 2012.

Desoye G.,Medical University of Graz | Van Poppel M.,VU University Amsterdam
Best Practice and Research: Clinical Obstetrics and Gynaecology | Year: 2015

Recent studies have established that the neonate born to a pregnancy with maternal diabetes or obesity ('diabesity') is characterized by increased fat accumulation. The neonatal fat is the result of triglyceride synthesis and deposition stimulated by elevated fetal insulin levels combined with insulin's mitogenic activity directly stimulating the growth of the white adipocytes. Fetal insulin levels are determined by fetal glucose and some amino acids such as arginine. Although the placenta plays a key role in providing maternally derived nutrients to the growing fetus, there is currently no evidence that it actively contributes to an excessive maternal-to-fetal glucose flux at the end of gestation. Early in gestation, the maternal environment in diabesity, and in particular the glucose-insulin axis, can modify placental growth and development, which may contribute to an enhanced glucose flux to the fetus already early in pregnancy. This may have long-lasting effects on the fetal pancreas and accelerate beta-cell maturation. The association of fetal and neonatal insulin levels and the proportion of body fat with obesity later in the offspring's life calls for interventions during pregnancy to prevent or reduce fetal hyperinsulinaemia. Dietary and/or physical activity interventions initiated before or in early pregnancy would likely be most effective. Results from the very few studies with fetal insulin as the outcome are inconsistent. However, there is a major lack of randomized intervention trials on this topic. © 2014 Elsevier Ltd. All rights reserved.

Van Der Heijden M.G.A.,ART Agroscope Reckenholz Tänikon | Van Der Heijden M.G.A.,VU University Amsterdam
Ecology | Year: 2010

Nutrient loss from ecosystems is among the top environmental threats to ecosystems worldwide, leading to reduced plant productivity in nutrient-poor ecosystems and eutrophication of surface water near nutrient-rich ecosystems. Hence, it is of pivotal importance to understand which factors influence nutrient loss. Here it is demonstrated that arbuscular mycorrhizal (AM) fungi, widespread soil fungi that form mutualistic relationships with the majority of land plants, reduce nutrient loss from grassland microcosms during raininduced leaching events. Grassland microcosms with AM fungi lost 60% less phosphorus and 7.5% less ammonium compared to control microcosms without AM fungi. Similar results were obtained for microcosms planted with each of three different grass species. In contrast, nitrate leaching was not affected by AM. fungi but depended on the amount of nutrients supplied to the microcosms. Moreover, fertilization of the microcosms reduced the abundance of AM fungi and their ability to reduce phosphorus leaching losses. Extrapolation of these results suggests that the disruption of the mycorrhizal symbiosis is one of the reasons for enhanced phosphorus loss from fertilized ecosystems. The microcosms contained a sandy soil, a soil type vulnerable to leaching losses. The reduction of phosphorus leaching by AM fungi may, therefore, represent an upper limit. Advantages and limitations of the experimental setup for assessing the impact of AM fungi on nutrient cycling are discussed. The results indicate that AM fungi contribute to ecosystem sustainability by promoting a closed phosphorus cycle and reducing phosphorus leaching losses. © 2010 by the Ecological Society of America.

McGill J.,University of Iowa | Van Rooijen N.,VU University Amsterdam | Legge K.L.,University of Iowa
Journal of Experimental Medicine | Year: 2010

We have recently demonstrated that peripheral CD8 T cells require two separate activation hits to accumulate to high numbers in the lungs after influenza virus infection: a primary interaction with mature, antigen-bearing dendritic cells (DCs) in the lymph node, and a second, previously unrecognized interaction with MHC I-viral antigen-bearing pulmonary DCs in the lungs. We demonstrate that in the absence of lung-resident DC subsets, virus-specific CD8 T cells undergo significantly increased levels of apoptosis in the lungs; however, reconstitution with pulmonary plasmacytoid DCs and CD8α + DCs promotes increased T cell survival and accumulation in the lungs. Further, our results show that the absence of DCs after influenza virus infection results in significantly reduced levels of IL-15 in the lungs and that pulmonary DC-mediated rescue of virus-specific CD8 T cell responses in the lungs requires trans-presentation of IL-15 via DC-expressed IL-15Rα. This study demonstrates a key, novel requirement for DC trans-presented IL-15 in promoting effector CD8 T cell survival in the respiratory tract after virus infection, and suggests that this trans-presentation could be an important target for the development of unique antiviral therapies and more effective vaccine strategies. © 2010 McGill et al.

Goltl F.,Ecole Normale Superieure de Lyon | Bulo R.E.,Ecole Normale Superieure de Lyon | Bulo R.E.,VU University Amsterdam | Hafner J.,University of Vienna | Sautet P.,Ecole Normale Superieure de Lyon
Journal of Physical Chemistry Letters | Year: 2013

Recently, the outstanding properties of Cu-SSZ-13 (a zeolite in the chabazite structure) for the selective catalytic reduction of nitrous oxides were discovered. However, the true nature of the active site is still not answered satisfactorily. In this work, we identify the active site for the given reaction from first-principles simulations of the total energy of Cu(II) ions in various positions in combination with previously published catalytic activity as a function of the copper exchange level. This attribution is confirmed by the simulation of vibrational properties of CO adsorbed to the reduced Cu(I) species. The relation between energetic considerations, vibrational calculations, and experiment allows a clear statement about the distribution of active sites in the catalyst. We furthermore discuss the structural properties of the active site leading to the high stability under reaction conditions over a large temperature range. The insights from this work allow a more targeted catalyst design and represent a step toward an industrial application of copper-exchanged zeolites in cleaning car exhaust gases. © 2013 American Chemical Society.

Fineman M.S.,Elcelyx Therapeutics | Cirincione B.B.,Amylin Pharmaceuticals Inc. | Maggs D.,Amylin Pharmaceuticals Inc. | Diamant M.,VU University Amsterdam
Diabetes, Obesity and Metabolism | Year: 2012

Glucagon-like peptide-1 (GLP-1), a gut-derived hormone secreted in response to nutrients, has several glucose and weight regulating actions including enhancement of glucose-stimulated insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduction in food intake. Because of these multiple effects, the GLP-1 receptor system has become an attractive target for type 2 diabetes therapies. However, GLP-1 has significant limitations as a therapeutic due to its rapid degradation (plasma half-life of 1-2 min) by dipeptidyl peptidase-4 (DPP-4). Two main classes of GLP-1-mediated therapies are now in use: DPP-4 inhibitors that reduce the degradation of GLP-1 and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists. The GLP-1R agonists can be further divided into short- and long-acting formulations which have differential effects on their mechanisms of action, ultimately resulting in differential effects on their fasting and postprandial glucose lowering potential. This review summarizes the similarities and differences among DPP-4 inhibitors, short-acting GLP-1R agonists and long-acting GLP-1R agonists. We propose that these different GLP-1-mediated therapies are all necessary tools for the treatment of type 2 diabetes and that the choice of which one to use should depend on the specific needs of the patient. This is analogous to the current use of modern insulins, as short-, intermediate- and long-acting versions are all used to optimize the 24-h plasma glucose profile as needed. Given that GLP-1-mediated therapies have advantages over insulins in terms of hypoglycaemic risk and weight gain, optimized use of these compounds could represent a significant paradigm shift for the treatment of type 2 diabetes. © 2012 Blackwell Publishing Ltd.

Roet K.C.D.,An Institute of the Royal Netherlands Academy of Arts and science | Verhaagen J.,An Institute of the Royal Netherlands Academy of Arts and science | Verhaagen J.,VU University Amsterdam
Experimental Neurology | Year: 2014

Olfactory ensheathing glial cells (OECs) are a specialized type of glia that form a continuously aligned cellular pathway that actively supports unprecedented regeneration of primary olfactory axons from the periphery into the central nervous system. Implantation of OECs stimulates neural repair in experimental models of spinal cord, brain and peripheral nerve injury and delays disease progression in animal models for neurodegenerative diseases like amyotrophic lateral sclerosis. OECs implanted in the injured spinal cord display a plethora of pro-regenerative effects; they promote axonal regeneration, reorganize the glial scar, remyelinate axons, stimulate blood vessel formation, have phagocytic properties and modulate the immune response. Recently genome wide transcriptional profiling and proteomics analysis combined with classical or larger scale "medium-throughput" bioassays have provided novel insights into the molecular mechanism that endow OECs with their pro-regenerative properties. Here we review these studies and show that the gaps that existed in our understanding of the molecular basis of the reparative properties of OECs are narrowing. OECs express functionally connected sets of genes that can be linked to at least 10 distinct processes directly relevant to neural repair. The data indicate that OECs exhibit a range of synergistic cellular activities, including active and passive stimulation of axon regeneration (by secretion of growth factors, axon guidance molecules and basement membrane components) and critical aspects of tissue repair (by structural remodeling and support, modulation of the immune system, enhancement of neurotrophic and antigenic stimuli and by metabolizing toxic macromolecules). Future experimentation will have to further explore the newly acquired knowledge to enhance the therapeutic potential of OECs. © 2014 Elsevier Inc.

Houben E.N.G.,VU University Amsterdam | Korotkov K.V.,University of Kentucky | Bitter W.,VU University Amsterdam
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2014

Mycobacteria use type VII secretion (T7S) systems to secrete proteins across their complex cell envelope. Pathogenic mycobacteria, such as the notorious pathogen Mycobacterium tuberculosis, have up to five of these secretion systems, named ESX-1 to ESX-5. At least three of these secretion systems are essential for mycobacterial virulence and/or viability. Elucidating T7S is therefore essential to understand the success of M. tuberculosis and other pathogenic mycobacteria as pathogens, and could be instrumental to identify novel targets for drug- and vaccine-development. Recently, significant progress has been achieved in the identification of T7S substrates and a general secretion motif. In addition, a start has been made with unraveling the mechanism of secretion and the structural analysis of the different subunits. This review summarizes these recent findings, which are incorporated in a working model of this complex machinery. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey. © 2013 Elsevier B.V.

Munoz R.F.,San Francisco General Hospital | Cuijpers P.,VU University Amsterdam | Smit F.,VU University Amsterdam | Barrera A.Z.,Palo Alto University | Leykin Y.,San Francisco General Hospital
Annual Review of Clinical Psychology | Year: 2010

Before the 1980s, no randomized controlled trials had been carried out to test whether major depressive episodes could be prevented. In the past 30 years, several trials have reported success in reducing the incidence (the number of new cases) of major depressive episodes. These studies suggest that major depression can be prevented. Given the large burden of disease caused by major depression, it is time for substantial systematic efforts to replicate these studies, carry out multisite trials, and widely disseminate prevention interventions found to be effective. The present review examines the conceptual and practical differences between treatment and prevention trials and the importance of identifying groups at high short-term risk for major depressive episodes to make prevention trials feasible. We also list the randomized controlled prevention trials that have been carried out to date and discuss the need for prevention interventions that go beyond the limits of traditional face-to-face interventions. Copyright © 2010 by Annual Reviews. All rights reserved.

Penninx B.W.J.H.,VU University Amsterdam | Milaneschi Y.,VU University Amsterdam | Lamers F.,National Health Research Institute | Vogelzangs N.,VU University Amsterdam
BMC Medicine | Year: 2013

Depression is the most common psychiatric disorder worldwide. The burden of disease for depression goes beyond functioning and quality of life and extends to somatic health. Depression has been shown to subsequently increase the risk of, for example, cardiovascular, stroke, diabetes and obesity morbidity. These somatic consequences could partly be due to metabolic, immuno-inflammatory, autonomic and hypothalamic-pituitary-adrenal (HPA)-axis dysregulations which have been suggested to be more often present among depressed patients. Evidence linking depression to metabolic syndrome abnormalities indicates that depression is especially associated with its obesity-related components (for example, abdominal obesity and dyslipidemia). In addition, systemic inflammation and hyperactivity of the HPA-axis have been consistently observed among depressed patients. Slightly less consistent observations are for autonomic dysregulation among depressed patients. The heterogeneity of the depression concept seems to play a differentiating role: metabolic syndrome and inflammation up-regulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression. This review finishes with potential treatment implications for the downward spiral in which different depressive symptom profiles and biological dysregulations may impact on each other and interact with somatic health decline. © 2013 Penninx et al.; licensee BioMed Central Ltd.

Rijkaart D.C.,VU University Amsterdam | Berkhof J.,VU University Amsterdam | Rozendaal L.,VU University Amsterdam | van Kemenade F.J.,VU University Amsterdam | And 6 more authors.
The Lancet Oncology | Year: 2012

Background: Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed. The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening. Methods: In this randomised trial, women aged 29-56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002. Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken. At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment. The primary endpoint was the number of CIN grade 3 or worse detected. Analysis was done by intention to screen. The trial is now finished and is registered, number ISRCTN20781131. Findings: 22 420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20 106 in the control group were eligible for analysis at the first screen. At the second screen, 19 579 women in the intervention group and 19 731 in the control group were eligible, of whom 16 750 and 16 743, respectively, attended the second screen. In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19 731 in the control group; relative risk 0·73, 95% CI 0·55-0·96; p=0·023). Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19 731; 0·29, 0·10-0·87; p=0·031). In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20 106; 1·15, 0·92-1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19 286 vs 12 of 19 373; 2·85, 1·47-5·49; p=0·001). Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20 106; 1·25, 1·05-1·50; p=0·015). In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27-0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57-1·72; p=1·00). The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20 106; 0·96, 0·81-1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20 106; 1·08, 0·94-1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29-33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74-1·27; CIN grade 2 or worse in women aged 29-33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81-1·26; CIN grade 3 or worse in women aged 34-56 years: 157 of 16 860 vs 167 of 16 978; 0·95, 0·76-1·18; CIN grade 2 or worse in women aged 34-56 years: 274 of 16 860 vs 248 of 16 978; 1·11, 0·94-1·32). Interpretation: Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer. Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit. Our results lend support to the use of HPV DNA testing for all women aged 29 years and older. Funding: Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development). © 2012 Elsevier Ltd.

Paulus W.J.,VU University Amsterdam | Tschope C.,Franklin University
Journal of the American College of Cardiology | Year: 2013

Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity. © 2013 by the American College of Cardiology Foundation.

Palma D.,VU University Amsterdam | Palma D.,University of Western Ontario | Senan S.,VU University Amsterdam
Current Opinion in Oncology | Year: 2011

Purpose Of Review: To review recent developments in stereotactic body radiation therapy (SBRT) for stage I nonsmall cell lung cancer (NSCLC). Recent findings: In stage I tumors measuring up to 5 cm in diameter, SBRT can achieve local tumor control rates of up to 97%. SBRT has a favorable toxicity profile and has been safely applied in elderly patients, after previous pneumonectomy, or with severe chronic obstructive airways disease. Population studies indicate that the introduction of SBRT was associated with increased treatment rates for elderly patients and improved overall survival. Summary: In patients with stage I NSCLC who do not undergo surgery, SBRT achieves superior survival as compared to treatment using conventionally fractionated radiotherapy. The role of SBRT in operable patients remains to be defined within randomized trials. In patients identified to be at high risk for surgical complications, SBRT appears to provide an effective alternative with low risks of hospitalization and 30-day mortality. Future treatment algorithms should include individualized assessment of surgical risks, and the consideration of SBRT for high-risk patients, in order to develop a personalized treatment approach. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Polderman T.J.C.,VU University Amsterdam | Benyamin B.,University of Queensland | De Leeuw C.A.,VU University Amsterdam | De Leeuw C.A.,Radboud University Nijmegen | And 5 more authors.
Nature Genetics | Year: 2015

Despite a century of research on complex traits in humans, the relative importance and specific nature of the influences of genes and environment on human traits remain controversial. We report a meta-analysis of twin correlations and reported variance components for 17,804 traits from 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits. Estimates of heritability cluster strongly within functional domains, and across all traits the reported heritability is 49%. For a majority (69%) of traits, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. The data are inconsistent with substantial influences from shared environment or non-additive genetic variation. This study provides the most comprehensive analysis of the causes of individual differences in human traits thus far and will guide future gene-mapping efforts. All the results can be visualized using the MaTCH webtool. © 2015 Nature America, Inc. All rights reserved.

van der Ent A.,University of Queensland | Baker A.J.M.,University of Melbourne | Pollard A.J.,Furman University | Schat H.,VU University Amsterdam
Plant and Soil | Year: 2013

Background: Plants that accumulate metal and metalloid trace elements to extraordinarily high concentrations in their living biomass have inspired much research worldwide during the last decades. Hyperaccumulators have been recorded and experimentally confirmed for elements such as nickel, zinc, cadmium, manganese, arsenic and selenium. However, to date, hyperaccumulation of lead, copper, cobalt, chromium and thallium remain largely unconfirmed. Recent uses of the term in relation to rare-earth elements require critical evaluation. Scope: Since the mid-1970s the term 'hyperaccumulator' has been used millions of times by thousands of people, with varying degrees of precision, aptness and understanding that have not always corresponded with the views of the originators of the terminology and of the present authors. There is therefore a need to clarify the circumstances in which the term 'hyperaccumulator' is appropriate and to set out the conditions that should be met when the terms are used. We outline here the main considerations for establishing metal or metalloid hyperaccumulation status of plants, (re)define some of the terminology and note potential pitfalls. Conclusions: Unambiguous communication will require the international scientific community to adopt standard terminology and methods for confirming the reliability of analytical data in relation to metal and metalloid hyperaccumulators. © 2012 Springer Science+Business Media B.V.

Van Den Hooff B.,VU University Amsterdam | De Winter M.,Accenture
European Journal of Information Systems | Year: 2011

In this paper, a social capital perspective is applied to the relationship between the IT department and the Business organization. IT and Business are conceptualized as different occupational communities, with different understandings of their work. Our focus is on the level of social capital and the process of knowledge sharing between these occupational communities. We analyze the role that these factors play in reaching a mutual understanding within the process of IS development, and the influence this has on the perceived performance of the IT organization. Our study, combining qualitative and quantitative methods, points out that a lack of social capital (structural, relational as well as cognitive) can serve as an explanation for the often problematic relationship between these communities. Our analyses also show that social capital is especially relevant for the Business organization's perception of IT performance, whereas the IT department's perception is that performance is primarily dependent on the exchange of information. © 2011 Operational Research Society Ltd. All rights reserved.

Cornelissen J.H.C.,VU University Amsterdam | Cornwell W.K.,VU University Amsterdam | Cornwell W.K.,University of New South Wales
Journal of Ecology | Year: 2014

The time is now ripe for ecologists and evolutionary biologists together to tackle a huge and important new challenge: mapping plant species effects on ecosystem functions onto the Tree of Life. This new research agenda is now tractable because of major recent advances in (i) screening plant species world-wide for the traits that support these functions, as well as in our understanding of how these traits support these functions; (ii) genetic screening and bioinformatics to build huge molecular plant phylogenies; and (iii) the comparative methods tools to analyse traits and phylogenies together. Understanding the evolutionary dynamics of traits related to biogeochemical cycling requires concerted research activity at a range of different phylogenetic scales, from analyses that consider data from all land plants to micro-evolution and other sources of intraspecific variation. This effort also requires study of the different plant organs involved in carbon and nutrient uptake, processing and transport, including the coordination between them. This overall effort should reveal (i) which lineages are associated with fast and which with slow turnover of carbon and nutrients (and water); (ii) how they are associated with fast versus slow turnover in terms of the traits involved; (iii) when in evolutionary history key transitions between fast and slow occurred; and (iv) what were and are the consequences of such variation in plant carbon and nutrient traits and turnover rates for past, present and future ecosystem functioning and services. Here, we introduce seven papers that together help set up this research agenda, each at a different phylogenetic level and resolution, and for different plant organs. Recent studies have begun to reveal evolutionary patterns in traits that matter to carbon and nutrient cycling for other groups of organisms, such as decomposing fungi and macrodetritivores and herbivorous animals. Ultimately such studies will all help towards the goal of mapping effects of organisms on biogeochemical cycling onto the entire Tree of Life. © 2014 British Ecological Society.

Van Der Vaart A.,VU University Amsterdam | Van Zanten H.,TU Eindhoven
Journal of Machine Learning Research | Year: 2011

We consider the quality of learning a response function by a nonparametric Bayesian approach using a Gaussian process (GP) prior on the response function. We upper bound the quadratic risk of the learning procedure, which in turn is an upper bound on the Kullback-Leibler information between the predictive and true data distribution. The upper bound is expressed in small ball probabilities and concentration measures of the GP prior. We illustrate the computation of the upper bound for the Matérn and squared exponential kernels. For these priors the risk, and hence the information criterion, tends to zero for all continuous response functions. However, the rate at which this happens depends on the combination of true response function and Gaussian prior, and is expressible in a certain concentration function. In particular, the results show that for good performance, the regularity of the GP prior should match the regularity of the unknown response function. © 2011 Aad van der Vaart and Harry van Zanten.

Johnson N.C.,Northern Arizona University | Angelard C.,University of Lausanne | Sanders I.R.,University of Lausanne | Kiers E.T.,VU University Amsterdam
Ecology Letters | Year: 2013

Mycorrhizal symbioses link the biosphere with the lithosphere by mediating nutrient cycles and energy flow though terrestrial ecosystems. A more mechanistic understanding of these plant-fungal associations may help ameliorate anthropogenic changes to C and N cycles and biotic communities. We explore three interacting principles: (1) optimal allocation, (2) biotic context and (3) fungal adaptability that may help predict mycorrhizal responses to carbon dioxide enrichment, nitrogen eutrophication, invasive species and land-use changes. Plant-microbial feedbacks and thresholds are discussed in light of these principles with the goal of generating testable hypotheses. Ideas to develop large-scale collaborative research efforts are presented. It is our hope that mycorrhizal symbioses can be effectively integrated into global change models and eventually their ecology will be understood well enough so that they can be managed to help offset some of the detrimental effects of anthropogenic environmental change. © 2013 John Wiley & Sons Ltd/CNRS.

Hoen A.,PBL Netherlands Environmental Assessment Agency | Koetse M.J.,VU University Amsterdam
Transportation Research Part A: Policy and Practice | Year: 2014

This paper presents results of an online stated choice experiment on preferences of Dutch private car owners for alternative fuel vehicles (AFVs) and their characteristics. Results show that negative preferences for alternative fuel vehicles are large, especially for the electric and fuel cell car, mostly as a result of their limited driving range and considerable refueling times. Preference for AFVs increases considerably with improvements on driving range, refueling time and fuel availability. Negative AFV preferences remain, however, also with substantial improvements in AFV characteristics; the remaining willingness to accept is on average € 10,000-€ 20,000 per AFV. Results from a mixed logit model show that consumer preferences for AFVs and AFV characteristics are heterogeneous to a large extent, in particular for the electric car, additional detour time and fuel time for the electric and fuel cell car. An interaction model reveals that annual mileage is by far the most important factor that determines heterogeneity in preferences for the electric and fuel cell car. When annual mileage increases, the preference for electric and fuel cell cars decreases substantially, whilst the willingness to pay for driving range increases substantially. Other variables such as using the car for holidays abroad and the daily commute also appear to be relevant for car choice. © 2014 Elsevier Ltd.

Gooren L.,Emeritus Medical Center | Lips P.,VU University Amsterdam
Journal of Sexual Medicine | Year: 2014

Introduction: Guidelines for cross-sex hormone treatment of transsexual people are now in place. However, little attention has been paid to the issue of treatment suitability for older people. Does existing treatment need to be adapted as subjects age, and does it make a difference if treatment is only started when the subject is already older? Aim: To assess the necessity of adapting cross-sex hormone administration for elderly transsexual people. Main Outcome Measures: Risks/benefits of continued use of cross-sex hormones with regard to bone health, cardiovascular risks, and malignancies. Methods: Due to lack of data on the subject population, sex hormone treatment of other conditions in older non-transsexual people has been taken as the best available analogy to determine the extent to which these might be applicable to comparable transsexual persons. Findings in transsexual people receiving cross-sex hormone treatment sometimes modified the above approach of applying guidelines for the elderly to the aging transsexual population. Results: Testosterone administration to female-to-male transsexual persons (FtoM) carries little risk with regard to cardiovascular disease and cancer. For those with high hematocrit or cardiac insufficiency the dose can be reduced. Administration of estrogens to male-to-female transsexual persons (MtoF), particularly when combined with progestins, does significantly increase the risk of developing cardiovascular disease (almost a twofold incidence compared with the general population). This may require dose adjustment or changing from oral to safer transdermal estrogens. Tumors of the breasts, prostate and pituitary may occur. In FtoM, breast cancer can occur even after breast ablation. Older subjects can commence cross-sex hormone treatment without disproportionate risks. Conclusion: Cross-sex hormones may be continued into old age but monitoring for cardiovascular disease and malignancies, both of the old and new sex, is recommended. MtoF will have more health complications in old age than FtoM requiring adaptations of treatment. Gooren L and Lips P. Conjectures concerning cross-sex hormone treatment of aging transsexual persons. J Sex Med 2014;11:2012-2019. © 2014 International Society for Sexual Medicine.

Dennison M.,VU University Amsterdam | Sheinman M.,VU University Amsterdam | Storm C.,TU Eindhoven | Mackintosh F.C.,VU University Amsterdam
Physical Review Letters | Year: 2013

We study the elastic properties of thermal networks of Hookean springs. In the purely mechanical limit, such systems are known to have a vanishing rigidity when their connectivity falls below a critical, isostatic value. In this work, we show that thermal networks exhibit a nonzero shear modulus G well below the isostatic point and that this modulus exhibits an anomalous, sublinear dependence on temperature T. At the isostatic point, G increases as the square root of T, while we find GaTα below the isostatic point, where α 0.8. We show that this anomalous T dependence is entropic in origin. © 2013 American Physical Society.

Tybur J.M.,VU University Amsterdam | Gangestad S.W.,University of New Mexico
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Mate preferences may operate in part to mitigate the threats posed by infectious disease. In this paper, we outline various ways in which preferring healthy mates can offer direct benefits in terms of pathogen avoidance and indirect benefits in terms of heritable immunity to offspring, as well as the costs that may constrain mate preferences for health. We then pay special attention to empirical work on mate preferences in humans given the depth and breadth of research on human mating. We review this literature and comment on the degree to which human mate preferences may reflect preferences for health. © 2011 The Royal Society.

Ravena R.,TU Eindhoven | Schota J.,TU Eindhoven | Berkhoutb F.,VU University Amsterdam
Environmental Innovation and Societal Transitions | Year: 2012

The multi-level perspective (MLP) is a widely adopted framework for analysing stability, change and transitions in socio-technical systems. Key to explanations of change is the interaction between nested levels (niche, regime, landscape) constituting socio-technical systems over time. This paper proposes a second generation, multi-scalar MLP that explicitly incorporates a spatial scale. Recent developments in innovation studies and contributions from regional studies and geography are reviewed. We draw on notions of space as being relational, fluid and contested by institutionally situated actors. Dynamics in socio-technical systems are explained not only by interactions between modes of structuration and developments over time, but also by interactions between actors and institutions situated across different levels of spatial scale. The paper explores the kinds of insights that might emerge from adopting a second generation MLP to socio-technical systems with a case study of biomass gasification in India. © 2012 Elsevier B.V.

Sijbrandij M.,VU University Amsterdam | Kleiboer A.,VU University Amsterdam | Bisson J.I.,University of Cardiff | Barbui C.,University of Verona | Cuijpers P.,VU University Amsterdam
The Lancet Psychiatry | Year: 2015

Background: An increasing number of studies have investigated the pharmacological prevention of post-traumatic stress disorder (PTSD) and acute stress disorder (ASD). This is the first systematic review to examine the effects of pharmacotherapies (eg, β blockers, hydrocortisone, and selective serotonin re-uptake inhibitors) given within the first month after a traumatic or aversive event to prevent PTSD or ASD compared with no pharmacotherapy or placebo control. Methods: A systematic literature search in PubMed, PsycINFO, Embase, and the Cochrane database of randomised trials was done. Studies included randomised controlled trials, controlled clinical trials, and cohort studies; their overall quality was low to moderate. We computed the pooled incidence risk ratio (IRR): the risk of incidence of PTSD or ASD in the pharmacotherapy groups relative to the incidence of PTSD or ASD in the control groups. Additionally, we computed Hedges' g effect sizes for PTSD or ASD continuous outcomes. Findings: 15 studies met inclusion criteria (1765 individuals). Pharmacotherapy was more effective in preventing PTSD or ASD than placebo or no intervention (14 studies, 1705 individuals, IRR 0·65, 95% CI 0·55-0·78; number needed to treat 11·36), although no effect was found when only randomised controlled trials were included (ten studies, 300 individuals, IRR 0·69, 95% CI 0·40-1·21). Hydrocortisone showed a large effect in reducing the risk of PTSD (five studies, 164 individuals, IRR 0·38, 95% CI 0·16-0·92). Interpretation: No firm evidence was found for the efficacy of all early pharmacotherapies in the prevention of PTSD or ASD, but hydrocortisone reduced the risk of developing PTSD. The small number of studies and their limited methodological quality cast uncertainty about the effects. © 2015 Elsevier Ltd.

de Vries R.E.,VU University Amsterdam | Zettler I.,University of Tübingen | Hilbig B.E.,University of Mannheim
Assessment | Year: 2014

Numerous researchers have noted that, instead of response sets or styles, most social desirability scales seem to measure personality traits instead. In two studies, we investigated the substantive interpretation of the Balanced Inventory of Desirable Responding in terms of the HEXACO model of personality. Because of its focus on honesty and integrity, the Impression Management (IM) scale was hypothesized to be mainly related to HEXACO Honesty-Humility. In the main study among 1,106 students and well-acquainted others (friends, family, or partners), positive self-other agreement correlations were found for both IM (r =.45) and Self-Deceptive Enhancement (SDE; r =.34), supporting a trait conception of IM and SDE. In both self- and other ratings, the most important predictors of SDE were (low) Emotionality, Extraversion, and Conscientiousness. IM was associated with Conscientiousness and Agreeableness, but Honesty-Humility was by far its most important predictor. In a subsample (n = 465), Honesty-Humility and IM were unrelated to GPA. © The Author(s) 2013.

Van Bastelaar K.M.P.,VU University Amsterdam | Pouwer F.,University of Tilburg | Cuijpers P.,VU University Amsterdam | Riper H.,Netherlands Institute of Mental Health and Addiction Trimbos | Snoek F.J.,VU University Amsterdam
Diabetes Care | Year: 2011

OBJECTIVE - Comorbid depression is common in patients with type 1 and type 2 diabetes, adversely affecting quality of life, diabetes outcomes, and mortality. Depression can be effectively treated with cognitive behavior therapy (CBT). The Internet is a new and attractive method for delivering CBT intervention on a large scale at relatively low costs. This study evaluated the effectiveness of Web-based CBT for depression treatment in adults with type 1 or type 2 diabetes, with minimal guidance. RESEARCH DESIGN ANDMETHODS - A randomized controlled trial was conducted in the Netherlands in 255 adult diabetic patients with elevated depressive symptoms. Primary outcomes were depressive symptoms. Secondary outcomes were diabetes-specific emotional distress and glycemic control. Assessments were at baseline, after treatment, and at the 1-month follow-up. RESULTS - The Web-based CBT was effective in reducing depressive symptoms by intention-to-treat analyses (P = 0.04, d = 0.29; clinical improvement 41% vs. 24% P < 0.001) and by perprotocol analyses (P < 0.001, d = 0.70; clinical improvement, 56% vs. 24% P < 0.001). The intervention reduced diabetes-specific emotional distress (P = 0.03) but had no beneficial effect on glycemic control (P > 0.05). CONCLUSIONS - Web-based CBT depression treatment is effective in reducing depressive symptoms in adults with type 1 and type 2 diabetes. In addition, the intervention reduces diabetes-specific emotional distress in depressed patients. © 2011 by the American Diabetes Association.

Laughlin D.C.,University of Waikato | Joshi C.,University of Waikato | van Bodegom P.M.,VU University Amsterdam | Bastow Z.A.,Northern Arizona University | Fule P.Z.,Northern Arizona University
Ecology Letters | Year: 2012

Community assembly involves two antagonistic processes that select functional traits in opposite directions. Environmental filtering tends to increase the functional similarity of species within communities leading to trait convergence, whereas competition tends to limit the functional similarity of species within communities leading to trait divergence. Here, we introduce a new hierarchical Bayesian model that incorporates intraspecific trait variation into a predictive framework to unify classic coexistence theory and evolutionary biology with recent trait-based approaches. Model predictions exhibited a significant positive correlation (r = 0.66) with observed relative abundances along a 10 °C gradient in mean annual temperature. The model predicted the correct dominant species in half of the plots, and accurately reproduced species' temperature optimums. The framework is generalizable to any ecosystem as it can accommodate any species pool, any set of functional traits and multiple environmental gradients, and it eliminates some of the criticisms associated with recent trait-based community assembly models. © 2012 Blackwell Publishing Ltd/CNRS.

News Article | November 17, 2015

This story has been updated. A surprising new scientific paper suggests that the pattern of global wildfires varies based on the day of the week — with considerably fewer fires globally on Sunday than on other days. And not only that: It partly attributes this pattern not to anything natural about ecosystems, but rather to human behavioral patterns — including weekly rituals that are ultimately rooted in culture and faith. “Our weekly routines are based on religion originally,” says Nick Earl of the University of Melbourne in Australia, who published the research in Geophysical Research Letters with two colleagues. “And you can see that in the weekly cycle of fires.” To show as much, the researchers used NASA satellite imagery to look at all global fires from 2001 to 2013, with images taken four times each day. The images were then scanned by an algorithm to detect large fires, which can occur both for natural reasons — i.e., lightning — but also due to human causes, including arson and accidents, deliberate forest management, and the lighting of fires for forest clearing and agriculture (the apparent source of the Indonesian peat fire catastrophe that occurred this year). This appears to have been the first time that researchers tried to detect a weekly cycle in the occurrence of global fires — which, if fires were a purely natural phenomenon, shouldn’t exist. “There’s nothing in nature that’s on a weekly cycle,” Earl says. Yet after applying various statistical tests to the very large set of data, the researchers found that while patterns varied by region, the results on a global scale showed a considerable drop in fires on Sunday, as well as a weekly peak on Tuesday. “There were a total of 104 million Sunday fires globally over 2001–2013, this being 9 million (8%) fewer than the Tuesday total,” the researchers noted. This pattern was particularly pronounced in some parts of the world, including the United States, and less so in others. “Globally, there’s a very clear weekly cycle of fires, Sunday being the minimum,” Earl says. As he notes, the data include all the naturally caused fires too, from sources like lightning strikes, which would tend to suppress any human signal. Here’s an image Earl provided, visualizing some of the results (click to enlarge): Of course, it’s one thing to find such a pattern, and another to interpret it. Still it’s hard to ignore that Sunday isn’t just any day — it is the day of rest in many societies around the world. Sure enough, the paper makes the attribution to religion directly: “Our results show that weekly cycles in active fires are highly pronounced for many parts of the world, and these cycles are strongly influenced by the working week and particularly the day(s) of rest linked to religion,” the authors write. Asked if he is confident in this attribution, Earl simply said that he’s trying to explain the data and doesn’t see another way of doing so. “If someone comes up with a different idea, that’s great, because I can’t think of one,” he said. “I can’t think of any other reason for it.” Guido van der Werf, an expert on global fires at VU University Amsterdam, praised the study in a comment to the Post, noting that “It confirms the important role of humans in starting fires in the tropics.” “Keep in mind that an important role for humans in starting fires does not mean that without these human ignitions there would be no fires, new research indicates the opposite may be true,” said van der Werf. The research also hinted that, while fires on a global scale go down on Sunday, there might be regional variations, also tied to faith — including different practices in non-Christian countries. For instance, Earl points to predominantly Muslim Kazakhstan, where the fire minimum was actually on Thursday and Friday. “Areas with a higher Muslim population like the Kazakhstan region have minima on Thursday and Friday,” a fact sheet provided by Earl notes. “This is likely to be because Friday is ‘the day of assembly’ and prayer for the Muslim faith, so there is less industrial activity on these days.” However, it’s not clear how far you can take this: The paper notes that the data for Kazakhstan were not statistically significant, although it also suggested some reasons “any significant signal may be being masked.” Another predominantly Muslim country that sees many fires, Indonesia, also failed to show a statistically significant late week minimum. When it comes to such countries, then, the data provide just a “hint that it goes against sort of the global pattern,” Earl says. All of which suggests both that there are other factors involved across countries that determine patterns of fires, and that there may be limits to the technique and the inferences that can be made from it. The study’s strongest finding, then, is simply the global picture, as well as the presence of weekly cycles in a number of regions. If the research is correct, it wouldn’t just be a surprising observation — it would have consequences. For even as humans shape weekly fire cycles, says Earl, those weekly fire cycles feed back and shape the weather we all experience. Fires, after all, emit large volumes of aerosol particles, which can have complex atmospheric effects that can affect both temperature and rainfall. The most striking result, though, remains the attribution of fire patterns, at least in part, to culture and religion. Asked if this means we can see human religion from space, Earl put it like this: “I never actually thought of it like that before. You kind of are.”

News Article | December 18, 2015

Green fluorescent proteins (GFPs) revolutionized scientists’ ability to monitor happenings inside cells. But the glowing proteins have a serious limitation that prevents them from helping scientists watch biological phenomena in whole, living animals. The wavelengths of light used to excite GFPs are readily absorbed by animal tissue, making it difficult for researchers to peer past the surface of an organism. To overcome that limitation, some scientists have engineered fluorescent proteins that absorb and emit near-infrared (near-IR) light, which can penetrate through tissue. On Tuesday at the 7th International Chemical Congress of Pacific Basin Societies, or Pacifichem, in Honolulu, scientists reported a newly engineered near-IR fluorescent protein that could improve whole-organism imaging of biological processes. The new protein is the brightest in a bacterial class of phytochrome fluorescent proteins, and it emits close to the edge of the near-IR spectra. These features could enhance the sensitivity and ease of imaging experiments that monitor multiple biological processes at once. Phytochrome fluorescent proteins bind near-IR absorbing tetrapyrroles called bilins. But the native proteins “are not meant to fluoresce,” explains biophysicist John T. M. Kennis of VU University Amsterdam, who was not involved in the new work. “They are signaling proteins that have evolved to detect near-IR light and give off a signal to the organism to act in certain ways. So these proteins have to be engineered to become fluorescent.” Vladislav Verkhusha and Daria Shcherbakova of Albert Einstein College of Medicine have been working on engineering the proteins to absorb and emit light from different stretches of the near-IR spectrum. Proteins with different spectral properties allow scientists to tag more than one type of cell, tissue, or organ so they can image them simultaneously. Recently, Verkhusha, Shcherbakova, and coworkers found that they could tune the proteins’ spectral properties by changing the amino acid residue to which a bilin called biliverdin attaches to the protein. Their best success to date is a protein they call BphP1-FP (Chem. Biol. 2015, DOI: 10.1016/j.chembiol.2015.10.007). The emission of the new protein is blue-shifted by about 40 nm compared to native and previously engineered phytochrome proteins—from over 700 nm to 669 nm, near the edge of the near-IR region. BphP1-FP also has a fluorescence quantum yield, a measure that contributes to the protein’s brightness, of 13%, “which is the highest ever reported for bacterial phytochromes,” Kennis says. He notes that the first reported near-IR bacterial phytochrome fluorescent protein, developed in 2009, had a quantum yield of about 7% and that there have been few improvements on that in the past six years. Verkhusha and Shcherbakova’s team used BphP1-FP and a spectrally distinct phytochrome protein for multicolor imaging of different compartments in human cells. The group’s work suggests that “the ideal of the transparent mouse comes within reach,” Kennis says.

News Article | November 2, 2016

Highly dependent on the different aspects of global change, variations in ecosystem services supply can also have direct impacts on human well being. A new article published in the open access journal One Ecosystem assesses the relationships between climate and land use change and ecosystem services supply in Europe, to pave the way on research connecting them to adaptation and human well being in a changing world. Ecosystem services arise when ecological structures or functions contribute toward meeting a human demand. With global change impacting biodiversity and ecosystems properties, ecosystem services supply are also likely to be affected, consequently impacting various aspects of human well being. In this context, assessing the possible bio-physical impacts of the ongoing and future changes in climate and land use becomes highly relevant for designing mitigation and adaptation policies. While undergoing a comprehensive climate and land use impact assessment continues to be a demanding research challenge due to the large knowledge gaps, in their new paper, the team of scientists from the European Commission's Joint Research Centre, Ispra, Italy and the Institute for Environmental Studies at the VU University Amsterdam, the Netherlands, present a first of its kind spatially explicit preliminary assessment of the changes in ecosystem services supply as a function of these global change drivers. Carried out for the mainland of the 28 Member States of the European Union, the focus of this analysis is on regulating ecosystem services, due to their direct dependency on the proper functioning of ecosystems. Focusing on three regulating services: air quality regulation, soil erosion control, and water flow regulation, the new research presents an assessment of changes related to global change and their projected impacts, positive or negative, on human well being in the different European regions. "Considering both land use projections and climate change scenarios in our research, in principle, enabled us to capture the main pressures acting on ecosystems and their services, thus enhancing the suitability of this approach to generate policy-relevant information," explains the authors. "Yet, this study is only preliminary and a stepping stone for further research, needed not only to expand the analysis to other ES, but also to incorporate processes and scaling properties of the systems considered as they become available, and to account for spatial dependencies." Polce C, Maes J, Brander L, Cescatti A, Baranzelli C, Lavalle C, Zulian G (2016) Global change impacts on ecosystem services: a spatially explicit assessment for Europe. One Ecosystem 1: e9990. https:/

Kwakkel G.,VU University Amsterdam | Kwakkel G.,Amsterdam Rehabilitation Research Center | Veerbeek J.M.,VU University Amsterdam | van Wegen E.E.H.,VU University Amsterdam | Wolf S.L.,Atlanta Center for Visual and Neurocognitive Rehabilitation
The Lancet Neurology | Year: 2015

Constraint-induced movement therapy (CIMT) was developed to overcome upper limb impairments after stroke and is the most investigated intervention for the rehabilitation of patients. Original CIMT includes constraining of the non-paretic arm and task-oriented training. Modified versions also apply constraining of the non-paretic arm, but not as intensive as original CIMT. Behavioural strategies are mostly absent for both modified and original CIMT. With forced use therapy, only constraining of the non-paretic arm is applied. The original and modified types of CIMT have beneficial effects on motor function, arm-hand activities, and self-reported arm-hand functioning in daily life, immediately after treatment and at long-term follow-up, whereas there is no evidence for the efficacy of constraint alone (as used in forced use therapy). The type of CIMT, timing, or intensity of practice do not seem to affect patient outcomes. Although the underlying mechanisms that drive modified and original CIMT are still poorly understood, findings from kinematic studies suggest that improvements are mainly based on adaptations through learning to optimise the use of intact end-effectors in patients with some voluntary motor control of wrist and finger extensors after stroke. © 2015 Elsevier Ltd.

Posthuma D.,Center for Neurogenomics and Cognitive Research | Posthuma D.,VU University Amsterdam | Posthuma D.,Erasmus University Rotterdam | Polderman T.J.C.,Center for Neurogenomics and Cognitive Research
Current Opinion in Neurology | Year: 2013

Purpose of Review: The relative influence of genes and environment on the liability to neurodevelopmental disorders (NDDs) can be investigated using a twin design. This review highlights the results of the most recent twin studies of NDDs. Purpose of Review: Recent twin studies have confirmed that NDDs show moderate-to-high heritability, and that from an etiological viewpoint both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are best regarded as the extremes on a continuous liability distribution. Both ASD and ADHD show high heritability in childhood and a substantial drop in heritability in adulthood, which is likely explained by the use of different assessment strategies in childhood versus adulthood, or by a complex mechanism of gene-by-environment interaction. NDDs show substantial comorbidity among each other, and with other mental health problems, which is partly because of a shared genetic etiology between different disorders. Summary: The findings of twin studies implicate substantial heritability of NDDs, and warrant large-scale molecular genetic studies for such traits. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Polman C.H.,VU University Amsterdam | Rudick R.A.,Cleveland Clinic
Neurology | Year: 2010

Background: The Multiple Sclerosis Functional Composite (MSFC) provides a focused and sensi-tive evaluation of disability in patients with multiple sclerosis (MS) that may be more responsive to change than that provided by the Expanded Disability Status Scale. Expert Clinical Opinion: The MSFC is a 3-part quantitative instrument that measures arm, leg, and cognitive function with the 9-Hole Peg Test (arm/hand dexterity), the Timed 25-Foot Walk (leg function), and the Paced Auditory Serial Addition Test (3-second version, PASAT3; cognition). The MSFC has excellent test-retest reliability. Construct validity was supported by expected differ-ences in scores between patients with primary or secondary progressive MS compared with relapsing-remitting MS. Concurrent validity was demonstrated by significant correlations with the Expanded Disability Status Scale, the Sickness Impact Profile, and the Short Form-36, partic-ularly on the physical components of the latter 2 scales. MSFC scores also correlate with MRI changes. Limitations of the MSFC include practice effects with the PASAT and to a lesser extent the 9-Hole Peg Test, variations in the reference populations used to calculate Z-scores, and the lack of an accepted definition of a clinically meaningful change. Future Directions: Future research should be directed at adding a test that measures visual func-tion (e.g., contrast acuity), at replacing the PASAT by a cognition test that has better measurement characteristics, and at developing methods to better understand the clinical relevance of changes in MSFC scores. Copyright © 2010 by AAN Enterprises, Inc. All rights reserved.

Price M.E.,Brunel University | Van Vugt M.,VU University Amsterdam | Van Vugt M.,University of Oxford
Frontiers in Human Neuroscience | Year: 2014

We describe the service-for-prestige theory of leadership, which proposes that voluntary leader-follower relations evolved in humans via a process of reciprocal exchange that generated adaptive benefits for both leaders and followers. We propose that although leader-follower relations first emerged in the human lineage to solve problems related to information sharing and social coordination, they ultimately evolved into exchange relationships whereby followers could compensate leaders for services which would otherwise have been prohibitively costly for leaders to provide. In this exchange, leaders incur costs to provide followers with public goods, and in return, followers incur costs to provide leaders with prestige (and associated fitness benefits). Because whole groups of followers tend to gain from leader-provided public goods, and because prestige is costly for followers to produce, the provisioning of prestige to leaders requires solutions to the "free rider" problem of disrespectful followers (who benefit from leader services without sharing the costs of producing prestige). Thus service-for-prestige makes the unique prediction that disrespectful followers of beneficial leaders will be targeted by other followers for punitive sentiment and/or social exclusion. Leader-follower relations should be more reciprocal and mutually beneficial when leaders and followers have more equal social bargaining power. However, as leaders gain more relative power, and their high status becomes less dependent on their willingness to pay the costs of benefitting followers, service-for-prestige predicts that leader-follower relations will become based more on leaders' ability to dominate and exploit rather than benefit followers. We review evidential support for a set of predictions made by service-for-prestige, and discuss how service-for-prestige relates to social neuroscience research on leadership. © 2014 Price and Van Vugt.

Cohen J.A.,Cleveland Clinic | Reingold S.C.,Scientific and Clinical Review Associates | Polman C.H.,VU University Amsterdam | Wolinsky J.S.,University of Texas Health Science Center at Houston
The Lancet Neurology | Year: 2012

Many of the available disability outcome measures used in clinical trials of multiple sclerosis are insensitive to change over time, inadequately validated, or insensitive to patient-perceived health status or quality of life. Increasing focus on therapies that slow or reverse disability progression makes it essential to refine existing measures or to develop new tools. Major changes to the expanded disability status scale should be avoided to prevent the loss of acceptance by regulators as a measure for primary outcomes in trials that provide substantial evidence of effectiveness. Rather, we recommend practical refinements. Conversely, although substantial data support the multiple sclerosis functional composite as an alternative measure, changes to its component tests and scoring method are needed. Novel approaches, including the use of composite endpoints, patient-reported outcomes, and measurement of biomarkers, show promise as adjuncts to the current disability measures, but are insufficiently validated to serve as substitutes. A collaborative approach that involves academic experts, regulators, industry representitives, and funding agencies is needed to most effectively develop disability outcome measures. © 2012 Elsevier Ltd.

Kuilman T.,Netherlands Cancer Institute | Kuilman T.,Cancer Research UK Research Institute | Michaloglou C.,Netherlands Cancer Institute | Michaloglou C.,Novartis | And 2 more authors.
Genes and Development | Year: 2010

Almost half a century after the first reports describing the limited replicative potential of primary cells in culture, there is now overwhelming evidence for the existence of "cellular senescence" in vivo. It is being recognized as a critical feature of mammalian cells to suppress tumorigenesis, acting alongside cell death programs. Here, we review the various features of cellular senescence and discuss their contribution to tumor suppression. Additionally, we highlight the power and limitations of the biomarkers currently used to identify senescent cells in vitro and in vivo. © 2010 by Cold Spring Harbor Laboratory Press.

Vriend I.,VeiligheidNL | Coehoorn I.,VeiligheidNL | Verhagen E.,VU University Amsterdam
British Journal of Sports Medicine | Year: 2015

Background/aim: The contemporary electronic media is regarded as a practical tool in the dissemination of preventive measures and interventions. For this purpose an App (free of charge) was developed including an efficacious programme for the prevention of ankle sprain recurrences. This study evaluated the implementation effectiveness of this 'Versterk je Enkel' App. Methods: The App was evaluated within its practical context using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) Framework. The launch of the App was accompanied by a press release, website banners, as well as online and offline advertisements. Data for the evaluation of the App were objectively registered through Google analytics. Data were obtained in February 2013 based on 25 781 users resulting in follow-ups of 18 months (iOS version) and 15 months (Android version), respectively. Users questionnaires provided a qualitative view of the objectively assessed measures (n=82) to gain insight into the demographics of users, reasons to download, user experience and how the information was used. Results: The App reached only 2.6% of the projected target population. User ratings for the App's relevancy, clarity, usefulness, appeal, information and reliability were high. App usage indicates that compliance with the embedded programme was low. Conclusions: Although the App was well received by the users, targeted efforts are required to ensure proper uptake and usage of the App by the target population. This also holds true for eHealth and mHealth efforts aimed at athlete care and injury prevention in general. © 2015, BMJ Publishing Group. All rights reserved.

Anna J.M.,University of Toronto | Scholes G.D.,University of Toronto | Van Grondelle R.,VU University Amsterdam
BioScience | Year: 2014

How could quantum mechanics possibly be important in biology We will discuss this question in the light of recent experiments that suggest that quantum mechanics - or at least coherence - is at play after photosynthesis is initiated by light. First, we give a brief description of light harvesting in photosynthesis. We follow this with an introduction to two-dimensional electronic spectroscopy, in which we demonstrate how this spectroscopic technique can be used to indicate coherent contributions to energy transfer dynamics. As a final point, we focus on the possible role that coherence may play in photosynthetic biological systems. © 2013 The Author(s) 2013. Published by Oxford University Press on behalf of the American Institute of Biological Sciences. All rights reserved. For Permissions, please e-mail:

Min R.,University of Bern | Di Marzo V.,National Research Council Italy | Mansvelder H.D.,VU University Amsterdam
Neuroscientist | Year: 2010

Hippocampal depolarization-induced suppression of inhibition (DSI) is a robust form of short-term synaptic plasticity. DSI is mediated by endocannabinoid signaling. Since this discovery, pinning down the endogenous cannabinoid receptor ligand that mediates DSI has been problematic. Blocking degradation of the endocannabinoid 2-arachidonoyl glycerol (2-AG) lengthens DSI, which seems to indicate that 2-AG mediates DSI. In contrast, pharmacological inhibition of the 2-AG-synthesizing enzyme diacylglycerol lipase (DAGL) has yielded conflicting results: DAGL inhibitors often fail to block hippocampal DSI. Recently, 2 studies seem to have cornered this problem using DAGL knockout mice. Hippocampal DSI is absent in DAGL-α knockout mice, pointing to a key role for 2-AG in DSI. However, these studies do not reconcile the discrepancy with pharmacological experiments. Here, we argue that the seeming contradiction between results from pharmacological and genetic approaches may be explained in several ways. We suggest that the contradiction may be resolved by taking a different perspective on endocannabinoid signaling: in some forms of endocannabinoid-mediated signaling endocannabinoids might not be necessarily produced "on demand" but presynthesized and stored until needed. © The Author(s) 2010.

Scholes G.D.,University of Toronto | Fleming G.R.,University of California at Berkeley | Fleming G.R.,Lawrence Berkeley National Laboratory | Olaya-Castro A.,University College London | Van Grondelle R.,VU University Amsterdam
Nature Chemistry | Year: 2011

Solar fuel production often starts with the energy from light being absorbed by an assembly of molecules; this electronic excitation is subsequently transferred to a suitable acceptor. For example, in photosynthesis, antenna complexes capture sunlight and direct the energy to reaction centres that then carry out the associated chemistry. In this Review, we describe the principles learned from studies of various natural antenna complexes and suggest how to elucidate strategies for designing light-harvesting systems. We envisage that such systems will be used for solar fuel production, to direct and regulate excitation energy flow using molecular organizations that facilitate feedback and control, or to transfer excitons over long distances. Also described are the notable properties of light-harvesting chromophores, spatial-energetic landscapes, the roles of excitonic states and quantum coherence, as well as how antennas are regulated and photoprotected. © 2011 Macmillan Publishers Ltd.

Nieuwenhuis S.,Leiden University | De Geus E.J.,VU University Amsterdam | Aston-Jones G.,Medical University of South Carolina
Psychophysiology | Year: 2011

Many psychophysiologists have noted the striking similarities between the antecedent conditions for the P3 component of the event-related potential and the orienting response: both are typically elicited by salient, unexpected, novel, task-relevant, and other motivationally significant stimuli. Although the close coupling of the P3 and orienting response has been well documented, the neural basis and functional role of this relationship is still poorly understood. Here we propose that the simultaneous occurrence of the P3 and autonomic components of the orienting response reflects the co-activation of the locus coeruleus-norepinephrine system and the peripheral sympathetic nervous system by their common major afferent: the rostral ventrolateral medulla, a key sympathoexcitatory region. A comparison of the functional significance of the locus coeruleus-norepinephrine system and the peripheral sympathetic nervous system suggests that the P3 and orienting response reflect complementary cognitive and physical contributions to the mobilization for action following motivationally significant stimuli. Copyright © 2010 Society for Psychophysiological Research.

Thijssen V.L.,VU University Amsterdam | Rabinovich G.A.,CONICET | Rabinovich G.A.,University of Buenos Aires | Griffioen A.W.,VU University Amsterdam
Cytokine and Growth Factor Reviews | Year: 2013

Galectins are a family of carbohydrate binding proteins with a broad range of cytokine and growth factor-like functions in multiple steps of cancer progression. They contribute to tumor cell transformation, promote tumor angiogenesis, hamper the anti-tumor immune response, and facilitate tumor metastasis. Consequently, galectins are considered as multifunctional targets for cancer therapy. Interestingly, many of the functions related to tumor progression can be linked to galectins expressed by endothelial cells in the tumor vascular bed. Since the tumor vasculature is an easily accessible target for cancer therapy, understanding how galectins in the tumor endothelium influence cancer progression is important for the translational development of galectin-targeting therapies. © 2013 Elsevier Ltd.

Driessen E.,VU University Amsterdam | Hollon S.D.,Vanderbilt University
Psychiatric Clinics of North America | Year: 2010

Cognitive behavioral therapy (CBT) is efficacious in the acute treatment of depression and may provide a viable alternative to antidepressant medication (ADM) for even more severely depressed unipolar patients when implemented in a competent fashion. CBT also may be of use as an adjunct to medication treatment of bipolar patients, although there have been few studies and they are not wholly consistent. CBT does seem to have an enduring effect that protects against subsequent relapse and recurrence following the end of active treatment, which is not the case for medications. Single studies that require replication suggest that patients who are married or unemployed or who have more antecedent life events may do better in CBT than in ADM, as might patients who are free from comorbid Axis II disorders, whereas patients with comorbid Axis II disorders seem to do better in ADM than in CBT. There also are indications that CBT may work through processes specified by theory to produce change in cognition that in turn mediate subsequent change in depression and freedom from relapse following treatment termination, although evidence in that regard is not yet conclusive. © 2010 Elsevier Inc.

Smits N.,VU University Amsterdam | Finkelman M.D.,Tufts University
Statistics in Medicine | Year: 2014

Health questionnaires are often built up from sets of questions that are totaled to obtain a sum score. An important consideration in designing questionnaires is to minimize respondent burden. An increasingly popular method for efficient measurement is computerized adaptive testing; unfortunately, many health questionnaires do not meet the requirements for this method. In this paper, a new sequential method for efficiently obtaining sum scores via the computer is introduced, which does not have such requirements and is based on the ordinal regression model. In the assessment, future scores are predicted from past responses, and when an acceptable level of uncertainty is achieved, the procedure is terminated. Two simulation studies were performed to illustrate the usefulness of the procedure. The first used artificially generated symptom scores, and the second was a post hoc simulation using real responses on the Center for Epidemiologic Studies Depression scale. In both studies, the sequential method substantially reduced the respondent burden while maintaining a high sum score quality. Benefits and limitations of this new methodology are discussed. © 2013 John Wiley & Sons, Ltd.

Calabrese M.,University of Verona | Magliozzi R.,Imperial College London | Magliozzi R.,Instituto Superiore Of Sanita | Ciccarelli O.,University College London | And 3 more authors.
Nature Reviews Neuroscience | Year: 2015

Multiple sclerosis is characterized at the gross pathological level by the presence of widespread focal demyelinating lesions of the myelin-rich white matter. However, it is becoming clear that grey matter is not spared, even during the earliest phases of the disease. Furthermore, grey matter damage may have an important role both in physical and cognitive disability. Grey matter pathology involves both inflammatory and neurodegenerative mechanisms, but the relationship between the two is unclear. Histological, immunological and neuroimaging studies have provided new insight in this rapidly expanding field, and form the basis of the most recent hypotheses on the pathogenesis of grey matter damage. © 2015 Macmillan Publishers Limited. All rights reserved.

Dulac O.,University of Paris Descartes | Dulac O.,CEA Saclay Nuclear Research Center | Plecko B.,University of Zürich | Wolf N.I.,VU University Amsterdam
The Lancet Neurology | Year: 2014

Seizures are a common paediatric problem, with inborn errors of metabolism being a rare underlying aetiology. The clinical presentation of inborn errors of metabolism is often associated with other neurological symptoms, such as hypotonia, movement disorders, and cognitive disturbances. However, the occurrence of epilepsy associated with inborn errors of metabolism represents a major challenge that needs to be identified quickly; for some cases, specific treatments are available, metabolic decompensation might be avoided, and accurate counselling can be given about recurrence risk. Some clinical presentations are more likely than others to point to an inborn error of metabolism as the cause of seizures. Knowledge of important findings at examination, and appropriate biochemical investigation of children with seizures of uncertain cause, can aid the diagnosis of an inborn error of metabolism and ascertain whether or not the seizures are amenable to specific metabolic treatment. © 2014 Elsevier Ltd.

Pegtel D.M.,VU University Amsterdam | Peferoen L.,VU University Amsterdam | Amor S.,Queen Mary, University of London
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

Homeostasis relies heavily on effective cell-to-cell communication. In the central nervous system (CNS), probably more so than in other organs, such communication is crucial to support and protect neurons especially during ageing, as well as to control inflammation, remove debris and infectious agents. Emerging evidence indicates that extracellular vesicles (EVs) including endosome-derived exosomes and fragments of the cellular plasma membrane play a key role in intercellular communication by transporting messenger RNA, microRNA (miRNA) and proteins. In neurodegenerative diseases, secreted vesicles not only remove misfolded proteins, but also transfer aggregated proteins and prions and are thus thought to perpetuate diseases by 'infecting' neighbouring cells with these pathogenic proteins. Conversely, in other CNS disorders signals from stressed cells may help control inflammation and inhibit degeneration. EVs may also reflect the status of the CNS and are present in the cerebrospinal fluid indicating that exosomes may act as biomarkers of disease. That extracellular RNA and in particular miRNA, can be transferred by EV also indicates that these vesicles could be used as carriers to specifically target the CNS to deliver immune modulatory drugs, neuroprotective agents and anti-cancer drugs. Here, we discuss the recent evidence indicating the potential role of exosomes in neurological disorders and how knowledge of their biology may enable a Trojan-horse approach to deliver drugs into the CNS and treat neurodegenerative and other disorders of the CNS. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Mohrmann R.,Max Planck Institute for Biophysical Chemistry | Mohrmann R.,Saarland University | De Wit H.,VU University Amsterdam | Verhage M.,VU University Amsterdam | And 3 more authors.
Science | Year: 2010

Exocytosis requires formation of SNARE [soluble N-ethylmaleimide - sensitive factor attachment protein (SNAP) receptor] complexes between vesicle and target membranes. Recent assessments in reduced model systems have produced divergent estimates of the number of SNARE complexes needed for fusion. Here, we used a titration approach to answer this question in intact, cultured chromaffin cells. Simultaneous expression of wild-type SNAP-25 and a mutant unable to support exocytosis progressively altered fusion kinetics and fusion-pore opening, indicating that both proteins assemble into heteromeric fusion complexes. Expressing different wild-type:mutant ratios revealed a third-power relation for fast (synchronous) fusion and a near-linear relation for overall release. Thus, fast fusion typically observed in synapses and neurosecretory cells requires at least three functional SNARE complexes, whereas slower release might occur with fewer complexes. Heterogeneity in SNARE-complex number may explain heterogeneity in vesicular release probability.

Amor S.,VU University Amsterdam | Amor S.,Queen Mary, University of London | Woodroofe M.N.,Sheffield Hallam University
Immunology | Year: 2014

Emerging evidence suggests important roles of the innate and adaptive immune responses in the central nervous system (CNS) in neurodegenerative diseases. In this special review issue, five leading researchers discuss the evidence for the beneficial as well as the detrimental impact of the immune system in the CNS in disorders including Alzheimer's disease, multiple sclerosis and CNS injury. Several common pathological mechanisms emerge indicating that these pathways could provide important targets for manipulating the immune reposes in neurodegenerative disorders. The articles highlight the role of the traditional resident immune cell of the CNS - the microglia - as well as the role of other glia astrocytes and oligodendrocytes in immune responses and their interplay with other immune cells including, mast cells, T cells and B cells. Future research should lead to new discoveries which highlight targets for therapeutic interventions which may be applicable to a range of neurodegenerative diseases. © 2013 John Wiley & Sons Ltd.

Kozuch J.,TU Berlin | Steinem C.,University of Gottingen | Hildebrandt P.,TU Berlin | Millo D.,VU University Amsterdam
Angewandte Chemie - International Edition | Year: 2012

Support from the support: Tethered bilayer lipid membranes containing the cation-channel-forming peptide gramicidin A were assembled on nanostructured Au films. The combination of surface-enhanced infrared absorption (SEIRA) and electrochemical impedance spectroscopy (EIS) was used for the in situ structural and functional characterization of gramicidin A in the same device. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Eleveld M.A.,VU University Amsterdam | Van der Wal D.,Netherlands Institute for Sea Research | Van Kessel T.,Deltares
Remote Sensing of Environment | Year: 2014

Optical data from a sun-synchronous satellite were used to investigate how large-scale estuarine suspended particulate matter (SPM) concentrations were affected by tidal and bulk meteorological drivers, and how retrieved SPM is biased by tidal aliasing and sampling under clear sky conditions. Local absorption and scattering properties were used to derive surface SPM maps from 84 cloud-free ENVISAT MERIS FR reflectance images of the Westerschelde estuary (51° 30' N, 3° 30' E) for the period 2006-2008, and validated with in situ SPM at fixed stations (r. = 0.89 for geometric means). The distinctly different SPM maps were categorized for different tidal and seasonal conditions. Resulting composites reveal spatial patterns in SPM as a function of semi-diurnal tidal phase, fortnightly tidal phase, or season. For the estuary proper, tidal and seasonal effects on the variation of SPM are similar in magnitude. Observed controls for surface SPM are distance to shallow source area, tidal current velocity, and advection of North Sea and estuarine surface waters. Turbidity maxima appear only during favourable tidal and meteorological conditions. For the Westerschelde, the bias introduced by sun-synchronous sampling causes low water image acquisitions to uniquely coincide with spring tides, and high water images with neap tides. Cloud-free images were associated with low wind velocities. Simulations from a mud transport model confirmed the overestimation of geometric mean SPM from the tidal aliasing, and underestimation from fair weather. This resulted in a net relative error of -. 8% at the wave-exposed mouth, but biases cancelled out in the upper estuary. We argue that local biases should be considered when interpreting water quality products for estuaries and coasts around the world. © 2014 Elsevier Inc.

Heusschen R.,VU University Amsterdam | Heusschen R.,University of Liège | Griffioen A.W.,VU University Amsterdam | Thijssen V.L.,VU University Amsterdam
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2013

Galectin family members have been shown to exert multiple roles in the context of tumor biology. Several recent findings support a similar multi-faceted role for galectin-9. Galectin-9 expression is frequently altered in cancer as compared to normal tissues. In addition, an increasing amount of evidence suggests that galectin-9 is involved in several aspects of tumor progression, including tumor cell adhesion and survival, immune escape and angiogenesis. Also, galectin-9 shows potential as a prognostic marker and a therapeutic target for several malignancies. In this review we summarize both the established and the emerging roles of galectin-9 in tumor biology and discuss the potential application of galectin-9 in anti-cancer therapy. © 2013 Elsevier B.V.

Van Ewijk R.,University of Mainz | Van Ewijk R.,VU University Amsterdam
Journal of Health Economics | Year: 2011

Each year, many pregnant Muslim women fast during Ramadan. Using Indonesian cross-sectional data and building upon work of Almond and Mazumder (2011), I show that people who were prenatally exposed to Ramadan fasting have a poorer general health than others. As predicted by medical theory, this effect is especially pronounced among older people, who also more often report symptoms indicative of coronary heart problems and type 2 diabetes. Among exposed Muslims the share of males is lower, which is most likely caused by death before birth. I show that these effects are unlikely the result of common health shocks correlated to the occurrence of Ramadan, or of fasting mainly occurring among women who would have had unhealthier children anyway. © 2011 Elsevier B.V.

Estrada F.,National Autonomous University of Mexico | Estrada F.,VU University Amsterdam | Estrada F.,Boston University | Perron P.,Boston University | Martinez-Lopez B.,National Autonomous University of Mexico
Nature Geoscience | Year: 2013

The warming of the climate system is unequivocal as evidenced by an increase in global temperatures by 0.8C over the past century. However, the attribution of the observed warming to human activities remains less clear, particularly because of the apparent slow-down in warming since the late 1990s. Here we analyse radiative forcing and temperature time series with state-of-the-art statistical methods to address this question without climate model simulations. We show that long-term trends in total radiative forcing and temperatures have largely been determined by atmospheric greenhouse gas concentrations, and modulated by other radiative factors. We identify a pronounced increase in the growth rates of both temperatures and radiative forcing around 1960, which marks the onset of sustained global warming. Our analyses also reveal a contribution of human interventions to two periods when global warming slowed down. Our statistical analysis suggests that the reduction in the emissions of ozone-depleting substances under the Montreal Protocol, as well as a reduction in methane emissions, contributed to the lower rate of warming since the 1990s. Furthermore, we identify a contribution from the two world wars and the Great Depression to the documented cooling in the mid-twentieth century, through lower carbon dioxide emissions. We conclude that reductions in greenhouse gas emissions are effective in slowing the rate of warming in the short term. © 2013 Macmillan Publishers Limited.

Thijssen V.L.,VU University Amsterdam | Heusschen R.,University of Liège | Caers J.,University of Liège | Griffioen A.W.,VU University Amsterdam
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2015

Galectins are a family of proteins that bind to specific glycans thereby deciphering the information captured within the glycome. In the last two decades, several galectin family members have emerged as versatile modulators of tumor progression. This has initiated the development and preclinical assessment of galectin-targeting compounds. With the first compounds now entering clinical trials it is pivotal to gain insight in the diagnostic and prognostic value of galectins in cancer as this will allow a more rational selection of the patients that might benefit most from galectin-targeted therapies. Here, we present a systematic review of galectin expression in human cancer patients. Malignant transformation is frequently associated with altered galectin expression, most notably of galectin-1 and galectin-3. In most cancers, increased galectin-1 expression is associated with poor prognosis while elevated galectin-9 expression is emerging as a marker of favorable disease outcome. The prognostic value of galectin-3 appears to be tumor type dependent and the other galectins require further investigation. Regarding the latter, additional studies using larger patient cohorts are essential to fully unravel the diagnostic and prognostic value of galectin expression. Furthermore, to better compare different findings, consensus should be reached on how to assess galectin expression, not only with regard to localization within the tissue and within cellular compartments but also regarding alternative splicing and genomic variations. Finally, linking galectin expression and function to aberrant glycosylation in cancer cells will improve our understanding of how these versatile proteins can be exploited for diagnostic, prognostic and even therapeutic purposes in cancer patients. © 2015 Elsevier B.V.

Lieberman D.L.,University of Miami | Tybur J.M.,VU University Amsterdam | Latner J.D.,University of Hawaii at Manoa
Obesity | Year: 2012

Recent research has established a link between disgust sensitivity and stigmatizing reactions to various groups, including obese individuals. However, previous research has overlooked disgust's multiple evolved functions. Here, we investigated whether the link between disgust sensitivity and obesity stigma is specific to pathogen disgust, or whether sexual disgust and moral disgusttwo separate functional domainsalso relate to negative attitudes toward obese individuals. Additionally, we investigated whether sex differences exist in the manner disgust sensitivity predicts obesity stigma, whether the sexes differ across the subtypes of obesity bias independent of disgust sensitivity, and last, the association between participants' BMI and different subtypes of obesity stigma. In study 1 (N = 92), we established that obesity elicits pathogen, sexual, and moral disgust. In study 2, we investigated the relationship between these types of disgust sensitivity and obesity stigma. Participants (N = 387) reported their level of disgust toward various pathogen, sexual, and moral acts and their attitudes toward obese individuals. For women, but not men, increased pathogen disgust sensitivity predicted more negative attitudes toward obese individuals. Men reported more negative general attitudes toward obese individuals whereas women reported greater fear of becoming obese. The sexes also differed in how their own BMI related to the subtypes of obesity stigma. These findings indicate that pathogen disgust sensitivity plays a role in obesity stigma, specifically for women. Defining the scope of disgust's activation in response to obesity and its relationship with other variables can help identify possible mechanisms for understanding and ultimately alleviating prejudice and discrimination. © 2011 The Obesity Society.

Rooney A.G.,Western General Hospital | Brown P.D.,University of Texas M. D. Anderson Cancer Center | Reijneveld J.C.,VU University Amsterdam | Grant R.,Western General Hospital
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2014

Depression is one of the leading causes of global disability, and a considerable hidden morbidity among patients with glioma. In this narrative review, we summarise what is currently known about depression in glioma, the main unanswered questions and the types of studies that should be prioritised in order to find out. We conclude by calling for a prospective Phase II study of antidepressants in depressed glioma patients, to test methodologies for a multicentre randomised controlled trial.

Roche D.M.,VU University Amsterdam | Wiersma A.P.,Deltares | Renssen H.,VU University Amsterdam
Climate Dynamics | Year: 2010

The first comparative and systematic climate model study of the sensitivity of the climate response under Last Glacial Maximum (LGM) conditions to freshwater perturbations at various locations that are known to have received significant amounts of freshwater during the LGM (21 kyr BP) climate conditions is presented. A series of ten regions representative of those receiving most of the meltwater from decaying ice-sheets during the deglaciation is defined, comprising the border of LGM ice-sheets, outlets of rivers draining part of the melting ice-sheets and iceberg melt zones. The effect of several given freshwater fluxes applied separately in each of these regions on regional and global climate is subsequently tested. The climate response is then analysed both for the atmosphere and oceans. Amongst the regions defined, it is found that the area close by and dynamically upstream to the main deep water formation zone in the North Atlantic are most sensitive to freshwater pulses, as is expected. However, some important differences between Arctic freshwater forcing and Nordic Seas forcing are found, the former having a longer term response linked to sea-ice formation and advection whereas the latter exhibits more direct influence of direct freshening of the deep water formation sites. Combining the common surface temperature response for each respective zone, we fingerprint the particular surface temperature response obtained by adding freshwater in a particular location. This is done to examine if a surface climate response can be used to determine the origin of a meltwater flux, which is relevant for the interpretation of proxy data. We show that it is indeed possible to generally classify the fingerprints by their origin in terms of sea-ice modification and modification of deep-water formation. Whilst the latter is not an unambiguous characterization of each zone, it nonetheless provides important clues on the physical mechanisms at work. In particular, it is shown that in order to obtain a consistent see-saw temperature pattern, addition of freshwater in the Northern Hemisphere at sites dynamically close to the deep water formation zones is needed. Finally a preliminary data-model comparison for the time of the Heinrich event 1 suggests that those sites are indeed the most favourable to explain the pattern of climate variability recorded in proxy data for this period. More importantly, this model-data comparison enables us to clearly reject a substantial fraction of the zones tested as potential source for large freshwater entering the ocean at that time. © 2009 The Author(s).

Petzold A.,VU University Amsterdam | Petzold A.,University College London
Journal of Neuroimmunology | Year: 2013

The diagnosis of multiple sclerosis is based on dissemination in time and space. Before 2010 lack of evidence for dissemination in space could be substituted by a paraclinical test, cerebrospinal fluid (CSF) oligoclonal bands (OCBs). The present meta-analysis (13,467 patients) shows that the diagnostic specificity of OCB drops from 94% to 61% if inflammatory etiologies are considered. Importantly, this was not caused by poor laboratory practice. This review on CSF OCB further illustrates the conceptional problem of substituting dissemination in space with a biomarker. The potential prognostic value of intrathecal OCB will need to be tested prospectively. © 2013 Elsevier B.V.

Garaude J.,Mount Sinai School of Medicine | Garaude J.,French Institute of Health and Medical Research | Kent A.,Mount Sinai School of Medicine | Van Rooijen N.,VU University Amsterdam | Blander J.M.,Mount Sinai School of Medicine
Science Translational Medicine | Year: 2012

Toll-like receptor (TLR) ligands are increasingly being used as adjuvants in cancer vaccine trials to harness innate immunity and prime effective antitumor immune responses. Despite some success, enhancing tumor antigen presentation, promoting a protective antitumor response, and overcoming the immunosuppressive tumor microenvironment pose considerable challenges that necessitate further improvements in vaccine design. Here, we show that expression of the TLR ligand flagellin within tumor cells constitutes an effective antitumor vaccination strategy that relies on simultaneous engagement of TLR5 and the Nod-like receptors (NLRs) NLRC4/NAIP5 (neuronal apoptosis inhibitory protein 5) by flagellin along with associative recognition of tumor antigen for optimal antigen presentation to T cells. Although TLR5 signaling was critical for mediating rapid macrophage-dependent clearance of flagellin-expressing tumor cells in vivo, TLR5 and NLRC4/NAIP5 were equally important for priming antitumor CD4 + and CD8 + T cells and suppressing tumor growth. Vaccination with irradiated flagellin-expressing tumor cells prevented tumor development, and disrupting flagellin recognition by TLR5 or NLRC4/NAIP5 impaired protective immunization against an existing or subsequent tumor. Our findings delineate a new strategy to induce anticancer immune responses consisting of introducing microbial structures with dual TLR and NLR stimulatory activity into tumor cells. This ensures recognition of tumor-derived antigen within the inflammatory context of microbial recognition and additionally activates both the phagocytic and the cytosolic pathways of innate immune defense against the tumor.

Batenburg A.,VU University Amsterdam | Das E.,Radboud University Nijmegen
Journal of Medical Internet Research | Year: 2014

Background: Due to mixed findings in research on the effect of online peer-to-peer support on psychological well-being, there is a need for studies explaining why and when online support communities are beneficial for cancer patients. Objective: Previous studies have typically not taken into account individual coping differences, despite the fact that patients have different strategies to cope with cancer-related emotions. In the current study, it was predicted that the effects of online support group participation would partly depend on patients' ability to cope with thoughts and emotions regarding the illness. Methods: For this study, 184 Dutch breast cancer patients filled out a questionnaire assessing activity within a peer-led online support community, coping with emotions and thoughts regarding the illness (cognitive avoidance, emotional processing, and expression) and psychological well-being (depression, breast cancer-related concerns, and emotional well-being). Of these, 163 patients were visiting an online peer-led support community. Results: Results showed interactions of the intensity of support group participation and coping style on psychological well-being. Specifically, we found an interaction of online activity and emotional expression on depression (beta=-.17, P=.030), a marginally significant interaction of online activity and emotional expression on emotional well-being (beta=.14, P=.089), and an interaction of online activity and cognitive avoidance on breast cancer-related concerns (beta=.15, P=.027). For patients who actively dealt with their emotions and thoughts, active online support group participation was positively related to psychological well-being. For patients high on avoidance of illness-related thoughts or low on emotional expression, active participation was negatively related to measures of well-being. Conclusions: The current study revealed the role of individual differences in coping in online support group participation. Results suggest that breast cancer patients' ability to cope with emotions and thoughts regarding the illness influence the relationship between online support group participation and psychological well-being.

Michie S.,University College London | van Stralen M.M.,VU University Amsterdam | West R.,University College London
Implementation Science | Year: 2011

Background: Improving the design and implementation of evidence-based practice depends on successful behaviour change interventions. This requires an appropriate method for characterising interventions and linking them to an analysis of the targeted behaviour. There exists a plethora of frameworks of behaviour change interventions, but it is not clear how well they serve this purpose. This paper evaluates these frameworks, and develops and evaluates a new framework aimed at overcoming their limitations.Methods: A systematic search of electronic databases and consultation with behaviour change experts were used to identify frameworks of behaviour change interventions. These were evaluated according to three criteria: comprehensiveness, coherence, and a clear link to an overarching model of behaviour. A new framework was developed to meet these criteria. The reliability with which it could be applied was examined in two domains of behaviour change: tobacco control and obesity.Results: Nineteen frameworks were identified covering nine intervention functions and seven policy categories that could enable those interventions. None of the frameworks reviewed covered the full range of intervention functions or policies, and only a minority met the criteria of coherence or linkage to a model of behaviour. At the centre of a proposed new framework is a 'behaviour system' involving three essential conditions: capability, opportunity, and motivation (what we term the 'COM-B system'). This forms the hub of a 'behaviour change wheel' (BCW) around which are positioned the nine intervention functions aimed at addressing deficits in one or more of these conditions; around this are placed seven categories of policy that could enable those interventions to occur. The BCW was used reliably to characterise interventions within the English Department of Health's 2010 tobacco control strategy and the National Institute of Health and Clinical Excellence's guidance on reducing obesity.Conclusions: Interventions and policies to change behaviour can be usefully characterised by means of a BCW comprising: a 'behaviour system' at the hub, encircled by intervention functions and then by policy categories. Research is needed to establish how far the BCW can lead to more efficient design of effective interventions. © 2011 Michie et al; licensee BioMed Central Ltd.

Seelaar H.,Erasmus Medical Center | Rohrer J.D.,University College London | Pijnenburg Y.A.L.,VU University Amsterdam | Fox N.C.,University College London | Van Swieten J.C.,Erasmus Medical Center
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2011

Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30e50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2e21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for diseasespecific therapeutic trials in the future.

Hammer A.,HU University of Applied Sciences Utrecht | Coene M.,VU University Amsterdam
Ear and Hearing | Year: 2016

Objective: In this study, the acquisition of Dutch finite verb morphology is investigated in children with cochlear implants (CIs) with profound hearing loss and in children with hearing AIDS (HAs) with moderate to severe hearing loss. Comparing these two groups of children increases our insight into how hearing experience and audibility affect the acquisition of morphosyntax. Design: Spontaneous speech samples were analyzed of 48 children with CIs and 29 children with HAs, ages 4 to 7 years. These language samples were analyzed by means of standardized language analysis involving mean length of utterance, the number of finite verbs produced, and target-like subject verb agreement. The outcomes were interpreted relative to expectations based on the performance of typically developing peers with normal hearing. Outcomes of all measures were correlated with hearing level in the group of HA users and age at implantation in the group of CI users. Results: For both groups, the number of finite verbs that were produced in 50-utterance sample was on par with mean length of utterance and at the lower bound of the normal distribution. No significant differences were found between children with CIs and HAs on any of the measures under investigation. Yet, both groups produced more subject verb agreement errors than are to be expected for typically developing hearing peers. No significant correlation was found between the hearing level of the children and the relevant measures of verb morphology, both with respect to the overall number of verbs that were used and the number of errors that children made. Within the group of CI users, the outcomes were significantly correlated with age at implantation. Conclusion: When producing finite verb morphology, profoundly deaf children wearing CIs perform similarly to their peers with moderate-tosevere hearing loss wearing HAs. Hearing loss negatively affects the acquisition of subject verb agreement regardless of the hearing device (CI or HA) that the child is wearing. The results are of importance for speech-language pathologists who are working with children with a hearing impairment indicating the need to focus on subject verb agreement in speech-language therapy. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Van der Flier W.M.,VU University Amsterdam | Cordonnier C.,University of Lille Nord de France
Experimental Gerontology | Year: 2012

Microbleeds are small dot-like lesions which can be appreciated on gradient echo, T2*-weighted magnetic resonance images as hypointensities. They are considered as an expression of small vessel disease on MRI, next to lacunes and white matter hyperintensities (WMH). Microbleeds are relatively common in vascular dementia, with reported prevalences between 35% and 85%. In the context of vascular dementia, microbleeds are mainly thought to result from hypertensive vasculopathy, but the frequent co-occurrence of lobar microbleeds suggests that neurodegenerative pathology and/or cerebral amyloid angiopathy is also of importance. The presence of multiple microbleeds in vascular dementia or in patients with vascular cognitive impairment is related to worse performance on cognitive tests, mainly in psychomotor speed and executive functioning. They may have some predictive value in terms of predicting development of (vascular) dementia, mortality and disability. Data on the occurrence of stroke and post-stroke dementia in patients with microbleeds are to date not available. New definitions and diagnostic criteria for vascular dementia and vascular cognitive impairment are needed and should take into account microbleeds. © 2012 Elsevier Inc.

Batenburg A.,VU University Amsterdam | Das E.,Radboud University Nijmegen
Journal of Medical Internet Research | Year: 2014

Background: Previous research on the effects of online peer support on psychological well-being of patients with cancer showed mixed findings. There is a need for longitudinal studies explaining if and when online peer-led support groups are beneficial. How patients cope with emotions that come along with the cancer diagnosis might influence effectiveness of online participation. Emotional approach coping is a construct encompassing the intentional use of emotional processing and emotional expression in efforts to manage adverse circumstances. Objective: In this longitudinal study, we hypothesize that mixed findings in previous research are partly caused by individual differences in coping with emotions, which may moderate the effects of online support group participation on patients' well-being. Methods: A total of 133 Dutch patients with breast cancer filled out a baseline (T0) and a follow-up (T1, 6 months later) questionnaire assessing intensity of online participation within the online support community, emotional approach coping (ie, actively processing and expressing emotions), and psychological well-being (depression, emotional well-being, and breast cancer-related concerns). There were 109 patients who visited an online support community at both points in time. Repeated measures ANOVAs assessed change in well-being over time. Results: Results showed 3-way interactions of time, online intensity of participation, and emotional approach coping on emotional well-being (F1,89=4.232, P=.04, η2 ρ=.045) and depression (F1,88=8.167, P=.005, η2 ρ=.085). Online support group participation increased emotional well-being over time for patients who scored low on emotional approach coping at T0, provided that they were highly active online. Patients who were highly active online with a high score on emotional approach coping reported no change in sense of well-being, but showed the highest score on well-being overall. Participating less frequently online was only beneficial for patients who scored high on emotional approach coping, showing an increase in well-being over time. Patients participating less frequently and with a low score on emotional approach coping reported no significant change in well-being over time. Conclusions: This study extends previous findings on the effects of online peer support in two ways: by testing changes in well-being as a function of intensity of online support group participation and by examining the role of individual differences in emotional coping styles. Findings showed no negative effects of intense support group participation. Participating frequently online was especially helpful for patients who approach their emotions less actively; their emotional well-being increased over time. In contrast, frequent online users who actively approach their emotions experienced no change in well-being, reporting highest levels of well-being overall. For patients who participate less intensively within the support community, coping style seems to outweigh effects of online participation; over time, patients who actively approached emotions experienced an increase in psychological well-being, whereas patients with a low score on emotional approach coping reported no change in depression and emotional well-being. ©Anika Batenburg, Enny Das.

Lindau D.,Nijmegen Center for Molecular Life science | Gielen P.,Nijmegen Center for Molecular Life science | Kroesen M.,Nijmegen Center for Molecular Life science | Wesseling P.,Radboud University Nijmegen | And 2 more authors.
Immunology | Year: 2013

Myeloid-derived suppressor cells (MDSC) and regulatory T (Treg) cells are major components of the immune suppressive tumour microenvironment (TME). Both cell types expand systematically in preclinical tumour models and promote T-cell dysfunction that in turn favours tumour progression. Clinical reports show a positive correlation between elevated levels of both suppressors and tumour burden. Recent studies further revealed that MDSCs can modulate the de novo development and induction of Treg cells. The overlapping target cell population of Treg cells and MDSCs is indicative for the importance and flexibility of immune suppression under pathological conditions. It also suggests the existence of common pathways that can be used for clinical interventions aiming to manipulate the TME. Elimination or reprogramming of the immune suppressive TME is one of the major current challenges in immunotherapy of cancer. Interestingly, recent findings suggest that natural killer T (NKT) cells can acquire the ability to convert immunosuppressive MDSCs into immunity-promoting antigen-presenting cells. Here we will review the cross-talk between MDSCs and other immune cells, focusing on Treg cells and NKT cells. We will consider its impact on basic and applied cancer research and discuss how targeting MDSCs may pave the way for future immunocombination therapies. © 2012 Nijmegen Centre for Molecular Life Sciences Immunology © 2012 Blackwell Publishing Ltd.

Alvarado J.,FOM Institute for Atomic and Molecular Physics | Sheinman M.,VU University Amsterdam | Sharma A.,VU University Amsterdam | Mackintosh F.C.,VU University Amsterdam | Koenderink G.H.,FOM Institute for Atomic and Molecular Physics
Nature Physics | Year: 2013

Living systems naturally exhibit internal driving: active, molecular processes drive non-equilibrium phenomena such as metabolism or migration. Active gels constitute a fascinating class of internally driven matter, in which molecular motors exert localized stresses inside polymer networks. There is evidence that network crosslinking is required to allow motors to induce macroscopic contraction. Yet a quantitative understanding of how network connectivity enables contraction is lacking. Here we show experimentally that myosin motors contract crosslinked actin polymer networks to clusters with a scale-free size distribution. This critical behaviour occurs over an unexpectedly broad range of crosslink concentrations. To understand this robustness, we developed a quantitative model of contractile networks that takes into account network restructuring: motors reduce connectivity by forcing crosslinks to unbind. Paradoxically, to coordinate global contractions, motor activity should be low. Otherwise, motors drive initially well-connected networks to a critical state where ruptures form across the entire network. © 2013 Macmillan Publishers Limited.

Huitema D.,VU University Amsterdam | Meijerink S.,Radboud University Nijmegen
Ecology and Society | Year: 2010

This special feature aims to further our understanding of the way in which transitions occur in water management. We contend that if we want to understand such transitions, we need to understand policy change and its opposite, policy stability. These issues have attracted considerable academic attention. Our interest is, however, very specific and thereby unique: we review the role that (groups of) individuals play in the process of preparing, instigating, and implementing policy change. In this article, a review of the literature on policy change provides the basis from which we extract a set of strategies which are available to policy entrepreneurs. The questions for the rest of this special feature are first, can we detect the influence of policy entrepreneurs in actual cases of major policy change, and second, which strategies have they actually used to affect policy change? © 2010 by the author(s).

Van Hooff J.C.,VU University Amsterdam | Ford R.M.,Griffith University
Brain Research | Year: 2011

The present study examined the electrophysiological correlates of intentional forgetting using the item-method directed forgetting paradigm. Participants (N = 23) studied a series of words each followed by either a "remember" cue (TBR) or a "forget" cue (TBF) and then undertook an old/new recognition memory test for which they were requested to endorse studied items regardless of original remember/forget status. Event-related potentials time locked to the cues were examined as a function of subsequent recognition-memory accuracy. Results showed that TBR and TBF cues elicited Dm or subsequent memory effects that differed in scalp distribution and polarity, suggesting activation of fundamentally different encoding operations for the respective sets of items. Additionally, analyses that examined the processes underlying successful implementations of intentions to forget (i.e., TBF-miss vs. TBR-miss) and intentions to remember (i.e., TBR-hit vs. TBF-hit) revealed that in case of unwanted information a frontal inhibition mechanism is engaged to stop processes associated with intentional memory formation. These results counter the possibility that directed forgetting reflects only the more elaborate encoding of TBR than TBF words and, instead, implicate the existence of an active inhibitory mechanism directed at TBF words once the forget cue is presented. © 2011 Elsevier B.V.

MacKintosh F.C.,VU University Amsterdam | Schmidt C.F.,University of Gottingen
Current Opinion in Cell Biology | Year: 2010

The materials cells are made of are strikingly different from man-made materials. Metabolism keeps cells out of equilibrium. Motor proteins and energy-consuming polymerization drive shape changes and motion. In contrast to macroscopic machines, though, there is no clear distinction between the force generators and the structural elements. Rather, the force-generating motor proteins are mixed with the elementary building blocks of cell structure on a molecular scale. The composite ensemble presents a new type of active material which is at the focus of intense current research. Simple model systems have been used successfully in exploring fundamental phenomena. Theoretical models are extending conventional soft matter approaches, and pioneering studies strive to analyze the complex nonequilibrium dynamics of living cells. © 2010 Elsevier Ltd. All rights reserved.

Frost J.,VU University Amsterdam | Vermeulen I.E.,VU University Amsterdam | Beekers N.,National IT Institute for Healthcare
Journal of Medical Internet Research | Year: 2014

Background: Active sharing in online cancer communities benefits patients. However, many patients refrain from sharing health information online due to privacy concerns. Existing research on privacy emphasizes data security and confidentiality, largely focusing on electronic medical records. Patient preferences around information sharing in online communities remain poorly understood. Consistent with the privacy calculus perspective adopted from e-commerce research, we suggest that patients approach online information sharing instrumentally, weighing privacy costs against participation benefits when deciding whether to share certain information. Consequently, we argue that patients prefer sharing clinical information over daily life and identity information that potentially compromises anonymity. Furthermore, we explore whether patients' prior experiences, age, health, and gender affect perceived privacy costs and thus willingness to share information. Objective: The goal of the present study is to document patient preferences for sharing information within online health platforms. Methods: A total of 115 cancer patients reported sharing intentions for 15 different types of information, demographics, health status, prior privacy experiences, expected community utility, and privacy concerns. Results: Factor analysis on the 15 information types revealed 3 factors coinciding with 3 proposed information categories: clinical, daily life, and identity information. A within-subject ANOVA showed a strong preference for sharing clinical information compared to daily life and identity information (F1, 114=135.59, P=.001, η2=.93). Also, adverse online privacy experiences, age, and health status negatively affected information-sharing intentions. Female patients shared information less willingly. Conclusions: Respondents'information-sharing intentions depend on dispositional and situational factors. Patients share medical details more willingly than daily life or identity information. The results suggest the need to focus on anonymity rather than privacy in online communities.

Meijerink S.,Radboud University Nijmegen | Huitema D.,VU University Amsterdam
Ecology and Society | Year: 2010

This paper focuses on the role of policy entrepreneurs in realizing water policy transitions. The central questions are to what extent have policy entrepreneurs played a role in realizing major change in water policies, who are these policy entrepreneurs, and what strategies have they used to bring about change? The policy science literature suggests that policy entrepreneurs have an arsenal of possible strategies for achieving change. Based on a comparative analysis of water policy changes in 15 countries around the globe and the European Union, we investigate which strategies have in practice been used by policy entrepreneurs, to what effect, and which lessons for managing water transitions we can draw from this. The comparative case analysis shows that individuals play complementary roles; hence, entrepreneurship in water management is often collective entrepreneurship. Strategies of coalition building, the manipulation of decision making forums, and the strategic framing of issues and windows are crucial to understanding water policy change, which suggests that the management of water policy transitions is a highly political game. We conclude by listing recommendations for those who would like to direct water policy change. © 2010 by the author(s).

Kok P.,Radboud University Nijmegen | Failing M.F.,Radboud University Nijmegen | Failing M.F.,VU University Amsterdam | de Lange F.P.,Radboud University Nijmegen
Journal of Cognitive Neuroscience | Year: 2014

Sensory processing is strongly influenced by prior expectations. Valid expectations have been shown to lead to improvements in perception as well as in the quality of sensory representations in primary visual cortex. However, very little is known about the neural correlates of the expectations themselves. Previous studies have demonstrated increased activity in sensory cortex following the omission of an expected stimulus, yet it is unclear whether this increased activity constitutes a general surprise signal or rather has representational content. One intriguing possibility is that top-down expectation leads to the formation of a template of the expected stimulus in visual cortex, which can then be compared with subsequent bottom-up input. To test this hypothesis, we used fMRI to noninvasively measure neural activity patterns in early visual cortex of human participants during expected but omitted visual stimuli. Our results show that prior expectation of a specific visual stimulus evokes a feature-specific pattern of activity in the primary visual cortex (V1) similar to that evoked by the corresponding actual stimulus. These results are in line with the notion that prior expectation triggers the formation of specific stimulus templates to efficiently process expected sensory inputs. © 2014 Massachusetts Institute of Technology.

Hohlfeld R.,Institute for Clinical Neuroimmunology | Barkhof F.,VU University Amsterdam | Polman C.,VU University Amsterdam
Neurology | Year: 2011

The limitations of established therapies for multiple sclerosis (MS) are well-known and include the need for injections, treatment adherence and convenience issues, partial efficacy, and, in some cases, a risk of potentially life-threatening adverse events, such as progressive multifocal leukoencephalopathy. Recently, attention has focused on developing more effective therapies that are administered orally and target neurodegeneration as well as inflammation. In this review, we provide an outlook on the future clinical challenges for MS treatment and management, and focus specifically on the emerging sphingosine 1-phosphate receptor (S1PR) modulators. We highlight the importance of improving our understanding of the neurobiological basis of MS to develop well-tolerated targeted therapies and the need to include advanced MRI assessments that quantify neurodegeneration in interventional studies in MS. As more treatments become available, often with complex pharmacodynamic actions, objective assessment of benefit-to-risk profiles becomes increasingly important to ensure that patients receive appropriate care. Pharmacovigilance and immune monitoring will become important aspects of patient treatment and management in the future. With respect to S1PR modulation, we review the experimental agents that are in clinical development for MS and summarize the steps taken in postmarketing surveillance to ensure that fingolimod (FTY720) has a well-characterized safety profile. ©2011 American Academy of Neurology.

Cordonnier C.,University of Lille Nord de France | Van Der Flier W.M.,VU University Amsterdam
Brain | Year: 2011

Brain microbleeds are small dot-like lesions appearing as hyposignals on gradient echo T*2magnetic resonance sequences. In Alzheimer's disease, brain microbleeds are of special interest as they may play a crucial role in the pathophysiology. They may be a missing link between two important theories on the neuropathogenesis of Alzheimer's disease - the amyloid cascade hypothesis and the vascular hypothesis. Moreover, they may affect the clinical course of the disease and may have therapeutic consequences. The aim of this article is to review available data to understand the meaning of brain microbleeds in clinical terms and underlying pathology in the context of Alzheimer's disease. We also review the available evidence and highlight the pitfalls of our current knowledge on brain microbleeds in the setting of clinical trials design. © 2011 The Author.

Van Horssen J.,VU University Amsterdam | Witte M.E.,VU University Amsterdam | Ciccarelli O.,University College London
Multiple Sclerosis Journal | Year: 2012

Axonal injury is a key feature of multiple sclerosis (MS) pathology and is currently seen as the main correlate for permanent clinical disability. Although little is known about the pathogenetic mechanisms that drive axonal damage and loss, there is accumulating evidence highlighting the central role of mitochondrial dysfunction in axonal degeneration and associated neurodegeneration. The aim of this topical review is to provide a concise overview on the involvement of mitochondrial dysfunction in axonal damage and destruction in MS. Hereto, we will discuss putative pathological mechanisms leading to mitochondrial dysfunction and recent imaging studies performed in vivo in patients with MS. Moreover, we will focus on molecular mechanisms and novel imaging studies that address the role of mitochondrial metabolism in tissue repair. Finally, we will briefly review therapeutic strategies aimed at improving mitochondrial metabolism and function under neuroinflammatory conditions. © The Author(s) 2012.

Buffart L.M.,VU University Amsterdam | Galvao D.A.,Edith Cowan University | Brug J.,VU University Amsterdam | Chinapaw M.J.M.,VU University Amsterdam | Newton R.U.,Edith Cowan University
Cancer Treatment Reviews | Year: 2014

Physical activity during and after cancer treatment has beneficial effects on a number of physical and psychosocial outcomes. This paper aims to discuss the existing physical activity guidelines for cancer survivors and to describe future research directions to optimize prescriptions. Studies on physical activity during and after cancer treatment were searched in PubMed,, Australian New Zealand Clinical Trials Registry, and Dutch Trial registry. Physical activity guidelines for cancer survivors suggest that physical activity should be an integral and continuous part of care for all cancer survivors. However, the development of these guidelines has been limited by the research conducted. To be able to develop more specific guidelines, future studies should focus on identifying clinical, personal, physical, psychosocial, and intervention moderators explaining 'for whom' or 'under what circumstances' interventions work. Further, more insight into the working mechanisms of exercise interventions on health outcomes in cancer survivors is needed to improve the efficacy and efficiency of interventions. Finally, existing programs should embrace interests and preferences of patients to facilitate optimal uptake of interventions. In conclusion, current physical activity guidelines for cancer survivors are generic, and research is needed to develop more personalized physical activity guidelines. © 2013 Elsevier Ltd.

Petzold A.,VU University Amsterdam | Petzold A.,University College London
Brain Research | Year: 2015

This review on the role of glial fibrillary acidic protein (GFAP) as a biomarker for astroglial pathology in neurological diseases provides background to protein synthesis, assembly, function and degeneration. Qualitative and quantitative analytical techniques for the investigation of human tissue and biological fluid samples are discussed including partial lack of parallelism and multiplexing capabilities. Pathological implications are reviewed in view of immunocytochemical, cell-culture and genetic findings. Particular emphasis is given to neurodegeneration related to autoimmune astrocytopathies and to genetic gain of function mutations. The current literature on body fluid levels of GFAP in human disease is summarised and illustrated by disease specific meta-analyses. In addition to the role of GFAP as a diagnostic biomarker for chronic disease, there are important data on the prognostic value for acute conditions. The published evidence permits to classify the dominant GFAP signatures in biological fluids. This classification may serve as a template for supporting diagnostic criteria of autoimmune astrocytopathies, monitoring disease progression in toxic gain of function mutations, clinical treatment trials (secondary outcome and toxicity biomarker) and provide prognostic information in neurocritical care if used within well defined time-frames. © 2014 Elsevier B.V. All rights reserved.

Hagenaars M.A.,Leiden University | Stins J.F.,VU University Amsterdam | Roelofs K.,Leiden University | Roelofs K.,Radboud University Nijmegen
Journal of Experimental Psychology: General | Year: 2012

In the present study, we investigated the effect of prior aversive life events on freezing-like responses. Fifty healthy females were presented neutral, pleasant, and unpleasant images from the International Affective Picture System while standing on a stabilometric platform and wearing a polar band to assess body sway and heart rate. In the total sample, only unpleasant pictures elicited reduced body sway and reduced heart rate (freezing). Moreover, participants who had experienced 1 or more aversive life events showed greater reductions in heart rate for unpleasant versus pleasant pictures than those who had experienced no such event. In addition, relative to no-event participants, single-event participants showed reduced body sway to unpleasant pictures, while multiple-event participants showed reduced body sway in response to all picture categories. These results indicate that aversive life events affect automatic freezing responses and may indicate the cumulative effect of multiple trauma. The experimental paradigm presented is a promising method to study freezing as a primary defense response in trauma-related disorders. © 2011 American Psychological Association.

News Article | December 18, 2015

"Don't tell me what happens!" Spoilers do reduce enjoyment, but not as much as you might think, research shows. More The much-anticipated film "Star Wars: The Force Awakens" opens in U.S. theaters Friday (Dec. 18), and if you're not already waiting in line to see the very first screenings, you might be worried about spoilers ruining the experience. And now you've got science to support your fears. A recent study found that spoilers — or giving away key plot details — may not ruin an experience entirely, but can reduce suspense and decrease overall enjoyment. "Our study is the first to show that people's widespread beliefs about spoilers being harmful are actually well-founded and not a myth," the study's corresponding author, Benjamin Johnson, an assistant professor of communication science at VU University Amsterdam in the Netherlands, said in a statement. [15 Weird Things Humans Do Every Day, and Why] Johnson and his colleagues asked 412 university students to read several short stories that they had never seen before. Before reading, the students were given summaries, some of which revealed spoilers. The students then rated the stories, describing whether or not they found the tales engaging, moving and suspenseful. The scientists said they were curious to find if their tests would corroborate results from a 2011 study published in the journal Psychological Science. That research, somewhat unexpectedly, suggested that people actually enjoy an experience more, at least some of the time, after hearing spoilers. In fact, the new research showed the opposite. "What we expected was to see that some outcomes would be improved by spoilers, in keeping with the earlier study," Johnson told Live Science. "Instead, we surprisingly found that for all the outcomes, spoilers were detrimental." In the new study, stories that had been "spoiled" were rated as less moving, less thought provoking, and less successful at drawing the reader into a narrative world and providing an immersive experience. In fact, the effects of story spoilers were "consistently negative," Johnson said in a statement. In other words, when people don't know how a story will turn out, they experience more enjoyment and appreciation, the researchers found. For big entertainment events like "The Force Awakens," the long-awaited seventh movie in the "Star Wars" franchise, and the first "Star Wars" movie released since 2005, audiences have a lot of anticipation. Many dedicated fans have been queuing for more than a week, eager to be among the first to see what surprises the filmmakers have in store. However, a far greater number of moviegoers are more likely to catch the film over the weekend, or even a couple of weeks after opening, hoping to avoid long lines and sold-out screenings. But waiting to see the movie comes with the possibility of sacrificing a little enjoyment. The longer you postpone the experience, the more likely you are to run across a spoiler that reveals critical details. Even carefully limiting Internet use and TV viewing to avoid movie reviews or related articles could be derailed by an unexpected encounter with a social media post or a stray remark that would ruin everything. Or would it? Johnson was quick to add that the study also discovered some good news about spoilers: They're not as bad as some people think they are. Even if, in spite of all your efforts, you hear some vital detail before you're ready, you'll still get plenty of satisfaction from your experience with the story, the researchers learned. [Top 10 Scariest Movies Ever] Johnson explained that, even when a story is "spoiled," there's plenty of evidence to suggest that an emotional payoff is still possible. "We know from previous research that people can feel suspense even if they know how the story ends," Johnson told Live Science. "You might watch a film for the fifth or sixth time, and even though you know all the beats, all the twists and turns, you can still feel anxiety or worry for characters," he said. Still, he warned, people shouldn't take this as a go-ahead to spoil stories for others, as spoilers can and do negatively affect people's experiences. The next steps for the researchers will include investigating the dynamics of social interaction in enjoying, and spoiling, media enjoyment. Johnson told Live Science that he and his colleagues have been gathering data related to four leaked episodes of the HBO series "Game of Thrones," which were widely downloaded and viewed before the Season 5 premiere in early 2015. Johnson said they hope to learn how the social networks that accompany viewing experiences may inform viewing pleasure — and increase the chances of encountering spoilers.

Tewarie P.,VU University Amsterdam | van Dellen E.,VU University Amsterdam | van Dellen E.,University Utrecht | Hillebrand A.,VU University Amsterdam | Stam C.J.,VU University Amsterdam
NeuroImage | Year: 2015

The brain is increasingly studied with graph theoretical approaches, which can be used to characterize network topology. However, studies on brain networks have reported contradictory findings, and do not easily converge to a clear concept of the structural and functional network organization of the brain. It has recently been suggested that the minimum spanning tree (MST) may help to increase comparability between studies. The MST is an acyclic sub-network that connects all nodes and may solve several methodological limitations of previous work, such as sensitivity to alterations in connection strength (for weighted networks) or link density (for unweighted networks), which may occur concomitantly with alterations in network topology under empirical conditions. If analysis of MSTs avoids these methodological limitations, understanding the relationship between MST characteristics and conventional network measures is crucial for interpreting MST brain network studies. Here, we firstly demonstrated that the MST is insensitive to alterations in connection strength or link density. We then explored the behavior of MST and conventional network-characteristics for simulated regular and scale-free networks that were gradually rewired to random networks. Surprisingly, although most connections are discarded during construction of the MST, MST characteristics were equally sensitive to alterations in network topology as the conventional graph theoretical measures. The MST characteristics diameter and leaf fraction were very strongly related to changes in the characteristic path length when the network changed from a regular to a random configuration. Similarly, MST degree, diameter, and leaf fraction were very strongly related to the degree of scale-free networks that were rewired to random networks. Analysis of the MST is especially suitable for the comparison of brain networks, as it avoids methodological biases. Even though the MST does not utilize all the connections in the network, it still provides a, mathematically defined and unbiased, sub-network with characteristics that can provide similar information about network topology as conventional graph measures. © 2014 Elsevier Inc.

van Beers R.J.,VU University Amsterdam | van Beers R.J.,University Utrecht
PLoS ONE | Year: 2012

Motor learning is driven by movement errors. The speed of learning can be quantified by the learning rate, which is the proportion of an error that is corrected for in the planning of the next movement. Previous studies have shown that the learning rate depends on the reliability of the error signal and on the uncertainty of the motor system's own state. These dependences are in agreement with the predictions of the Kalman filter, which is a state estimator that can be used to determine the optimal learning rate for each movement such that the expected movement error is minimized. Here we test whether not only the average behaviour is optimal, as the previous studies showed, but if the learning rate is chosen optimally in every individual movement. Subjects made repeated movements to visual targets with their unseen hand. They received visual feedback about their endpoint error immediately after each movement. The reliability of these error-signals was varied across three conditions. The results are inconsistent with the predictions of the Kalman filter because correction for large errors in the beginning of a series of movements to a fixed target was not as fast as predicted and the learning rates for the extent and the direction of the movements did not differ in the way predicted by the Kalman filter. Instead, a simpler model that uses the same learning rate for all movements with the same error-signal reliability can explain the data. We conclude that our brain does not apply state estimation to determine the optimal planning correction for every individual movement, but it employs a simpler strategy of using a fixed learning rate for all movements with the same level of error-signal reliability. © 2012 Robert J.

Buma F.,University Utrecht | Kwakkel G.,University Utrecht | Kwakkel G.,VU University Amsterdam | Ramsey N.,University Utrecht
Restorative Neurology and Neuroscience | Year: 2013

This review addresses what is currently known about the time course of skill reacquisition after stroke. There is growing evidence that the natural logarithmic pattern of functional recovery can be modified by intensive task-oriented practice preferably initiated within 6 months after stroke. However, the impact of practice on the learning-dependent and intrinsic spontaneous mechanisms of neurological recovery is poorly understood. At least four probably interrelated mechanisms have been identified that drive motor and recovery after stroke: (1) salvation of penumbral tissue in the first days to weeks after stroke; (2) alleviation of diaschisis; (3) homeostatic and learning-dependent (Hebbian) neuroplasticity; (4) behavioral compensation strategies. These mechanisms underlying recovery are highly interactive, and operate in different, sometimes limited, time-windows after stroke onset. In line with these mechanisms of improvement after stroke, we present a hypothetical phenomenological model for understanding skill reacquisition after stroke. Translational research is important at this point to improve our knowledge about the neural correlates of what and how patients learn when they show functional improvement after stroke. This knowledge should serve as a basis to optimize the timing, focus and intensity of evidence-based rehabilitation interventions and to design innovative strategies to enhance motor recovery after stroke. © 2013-IOS Press and the authors.

Niewerth D.,VU University Amsterdam | Creutzig U.,University of Munster | Bierings M.B.,University Utrecht | Kaspers G.J.L.,VU University Amsterdam
Blood | Year: 2010

Survival of pediatric acute myeloid leukemia (AML) has improved considerably over the past decades. Since 1985, allogeneic stem cell transplantation (allo-SCT) is widely recommended for patients who have a matched sibling donor. However, it remains controversial whether allo-SCT is superior to chemotherapy for children with newly diagnosed AML. This review summarizes phase 3 clinical trials that compared allo-SCT with chemotherapy (including autologous SCT) in pediatric AML, excluding studies that did not use the intention-to-treat analysis or correct for time-to-transplantation. Although allo-SCT might prevent more relapses than chemotherapy, the number needed for transplantation (with allo-SCT) to prevent one relapse is in the order of 10 patients. Moreover, overall survival is similar with both methods in most recent studies, apparently because of increased salvagability of a relapse when initial therapy concerned chemotherapy only, and because of a higher treatment-related mortality with allo-SCT. Because allo-SCT also gives more severe side effects and results more often in secondary malignancies than chemotherapy, we do not recommend allo-SCT in first remission for pediatric AML in general. Further research should focus on the possibility that subgroups might benefit from allo-SCT, aiming at further improvements in the prognosis of pediatric AML. © 2010 by The American Society of Hematology.

Verhaar H.J.,University Utrecht | Lems W.F.,VU University Amsterdam
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: At present there are two parathyroid hormone (PTH) analogues (PTH 1 34 and PTH 1 84) registered for the treatment of established osteoporosis in postmenopausal women (PTH 1 34 and PTH 1 84) and in men (PTH 1 34 only) who are at increased risk of having a fracture. Areas covered in this review: The efficacy and safety of PTH 1 34 and PTH 1 84 in the management of osteoporosis is evaluated by reviewing published literature and presentations from scientific meetings through to 2010. What the reader will gain: This review focuses on data on fracture risk reduction and safety endpoints of PTH analogues. The adverse reactions reported most are nausea, pain in the extremities, headache and dizziness. Take home message: Exogenous PTH analogues, given as daily subcutaneous injections, stimulate bone formation, increase bone mass and bone strength, and improve calcium balance. In postmenopausal women with osteoporosis, PTH analogues reduced the risk of vertebral (PTH 1 34 and PTH 1 84) and non-vertebral fractures (only PTH 1 34). In men and women with glucocorticosteroid-induced osteoporosis, PTH 1 34 reduced the risk of vertebral fractures. In general, PTH analogues are well tolerated with an acceptable safety profile: they can be used for the prevention and treatment of fractures in postmenopausal women with severe, established osteoporosis. © 2010 Informa UK, Ltd.

Muller M.,VU University Amsterdam | Muller M.,University Utrecht | Van Der Graaf Y.,University Utrecht | Visseren F.L.,University Utrecht | And 2 more authors.
Annals of Neurology | Year: 2012

Objective: Cerebral hypoperfusion is among the mechanisms that may explain the association of high blood pressure (BP) with dementia. However, few data are available on the longitudinal association of hypertension and cerebral perfusion. Methods: We examined the longitudinal association of hypertension, BP, and antihypertensive drugs with change in parenchymal cerebral blood flow (pCBF) in 575 patients with manifest atherosclerotic disease (mean age, 57 6 10 years) from the SMART-MR study. Total CBF was measured at baseline and at follow-up with magnetic resonance (MR) angiography and was expressed per 100ml brain volume as an indicator of cerebral perfusion. Automated brain segmentation was used to quantify brain tissue volumes and cerebrospinal fluid on MR imaging. Results: Mean (standard deviation [SD]) baseline pCBF was 52.3 (9.8) ml/min/100ml and after 3.9 years (range, 3.0-5.8 years) of follow-up declined to 50.7 (10.3) ml/min/100ml. Regression analyses adjusted for age, sex, follow-up time, and vascular risk showed that untreated and poorly controlled hypertension and higher levels of systolic and diastolic BP (per SD) were significantly associated with a decline in pCBF; mean differences in decline (95% confidence interval) were -2.2 (-4.4 to 0.0), -1.0 (-1.8 to -0.1), and -1.0 (-1.8 to -0.2) ml/min/100ml. In addition, within hypertensive patients (n = 469), patients using angiotensin receptor blockers (ARBs) did not show a decline in pCBF, whereas patients using other antihypertensive drugs did show a decline in pCBF. Interpretation: Untreated hypertension, poorly controlled hypertension, and high BP levels are associated with a decline in pCBF. In addition, treatment with ARBs might result in less decline in pCBF than other antihypertensive treatment. © 2012 American Neurological Association.

Vlaar T.,VU University Amsterdam | Cioc R.C.,VU University Amsterdam | Mampuys P.,University of Antwerp | Maes B.U.W.,University of Antwerp | And 2 more authors.
Angewandte Chemie - International Edition | Year: 2012

Heterocycles containing a guanidine moiety are of great importance in medicinal chemistry (Scheme 1).[1] As a result, several methods for the synthesis of these "privileged scaffolds" have been reported.[2, 3] Classical approaches, such as the addition of diamines to isothiocyanates followed by condensation and the coupling of diamines with cyanogen bromide,[2, 4] have some clear limitations, such as the availability and toxicity of reagents. Moreover, these procedures suffer from poor atom and/or step efficiency, thus making them unattractive from a sustainability point of view. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Belopolsky A.V.,VU University Amsterdam | Van der Stigchel S.,University Utrecht
Journal of Neurophysiology | Year: 2013

The oculomotor system serves as the basis for representing concurrently competing motor programs. Here, we examine whether the oculomotor system also keeps track of the outcome of competition between target and distractor on the previous trial. Participants had to perform a simple task of making a saccade toward a predefined direction. On two-thirds of the trials, an irrelevant distractor was presented to either the left or right of the fixation. On one-third of the trials, no distractor was present. The results show that on trials without a distractor, saccades curved away from the empty location that was occupied by a distractor on the previous trial. This result was replicated and extended to cases when different saccade directions were used. In addition, we show that repetition of distractor location on the distractor- present trials results in a stronger curvature away and in a shorter saccade latency to the target. Taken together, these results provide strong evidence that the oculomotor system automatically codes and retains locations that had been ignored in the past to bias future behavior. © 2013 the American Physiological Society.

Onwuteaka-Philipsen B.D.,VU University Amsterdam | Brinkman-Stoppelenburg A.,Rotterdam University | Gwen C.P.,Statistics Netherlands | De Jong-Krul J.F.,Statistics Netherlands | And 2 more authors.
The Lancet | Year: 2012

Background In 2002, the euthanasia act came into eff ect in the Netherlands, which was followed by a slight decrease in the euthanasia frequency. We assessed frequency and characteristics of euthanasia, physician-assisted suicide, and other end-of-life practices in 2010, and assessed trends since 1990. Methods In 1990, 1995, 2001, 2005, and 2010 we did nationwide studies of a stratifi ed sample from the death registry of Statistics Netherlands, to which all deaths and causes were reported. We mailed questionnaires to physicians attending these deaths (2010: n=8496 deaths). All cases were weighted to adjust for the stratifi cation procedure and for diff erences in response rates in relation to the age, sex, marital status, region of residence, and cause and place of death. Findings In 2010, of all deaths in the Netherlands, 28% (95% CI 25-32; 475 of 6861) were the result of euthanasia. This rate is higher than the 17% (15-18; 294 of 9965) in 2005, but comparable with those in 2001 and 1995. Distribution of sex, age, and diagnosis was stable between 1990 and 2010. In 2010, 77% (3136 of 4050) of all cases of euthanasia or physician-assisted suicide were reported to a review committee (80% [1933 of 2425] in 2005). Ending of life without an explicit patient request in 2010 occurred less often (02%; 95% CI 01-03; 13 of 6861) than in 2005, 2001, 1995, and 1990 (08%; 06-11; 45 of 5197). Continuous deep sedation until death occurred more frequently in 2010 (123% [116-131; 789 of 6861]) than in 2005 (82% [78-86; 521 of 9965]). Of all deaths in 2010, 04% (03-06; 18 of 6861) were the result of the patient's decision to stop eating and drinking to end life; in half of these cases the patient had made a euthanasia request that was not granted. Interpretation Our study provides insight in consequences of regulating euthanasia and physician-assisted suicide within the broader context of end-of-life practices. In the Netherlands the euthanasia law resulted in a relatively transparent practice. Although translating these results to other countries is not straightforward, they can inform the debate on legalisation of assisted dying in other countries.

Kearney M.R.,University of Melbourne | Simpson S.J.,University of Sydney | Raubenheimer D.,Massey University | Kooijman S.A.L.M.,VU University Amsterdam
Functional Ecology | Year: 2013

Models of the regulatory behaviour of organisms are fundamental to a strong physiologically-based understanding of species' responses to global environmental change. Biophysical models of heat and water exchange in organisms (biophysical ecology) and nutritionally-explicit models for understanding feeding behaviour and its fitness consequences (the Geometric Framework of nutrition, GF) are providing such an underpinning. However, temperature, water and nutrition interact in fundamental ways in influencing the responses of the organism to their environment, and a priority is to develop an integrated approach for conceptualising and measuring these interactions. Ideally, such an approach would be based on a thermodynamically-formalized energy and mass budgeting approach that is sparsely parameterised and sufficiently general to apply across a range of situations and organisms. Here we illustrate how mass-balance aspects of Dynamic Energy Budget theory can be applied to obtain first-principles estimates of fluxes of O2, CO2, H2O and nitrogenous waste. Then, using an herbivorous lizard (Egernia cunninghami) as a case study, we demonstrate how these estimates can be integrated with heat/water exchange models and environmental data to provide a holistic understanding of how foraging strategy, food availability, habitat and weather interact with heat, water and nutrient/energy budgets across the life-cycle. The analysis shows the potential importance of the water balance in affecting the energy budgets of ' dry skinned' ectotherms, especially early in ontogeny, and highlights a significant gap in our knowledge of the physiological and behavioural traits that affect water balance when compared with our knowledge of thermal traits. In general, the modelling approach we describe can provide the thermodynamically-constrained stage on which other evolutionary and ecological interactions play out; the 'thermodynamic niche'. This in turn provides a solid foundation from which to tackle key questions about organismal responses to environmental change. © 2012 British Ecological Society.

Langhorne P.,University of Glasgow | Langhorne P.,Institute of Cardiovascular and Medical science | Bernhardt J.,Florey Neuroscience Institutes | Bernhardt J.,La Trobe University | And 2 more authors.
The Lancet | Year: 2011

Stroke is a common, serious, and disabling global health-care problem, and rehabilitation is a major part of patient care. There is evidence to support rehabilitation in well coordinated multidisciplinary stroke units or through provision of early supported provision of discharge teams. Potentially beneficial treatment options for motor recovery of the arm include constraint-induced movement therapy and robotics. Promising interventions that could be beneficial to improve aspects of gait include fitness training, high-intensity therapy, and repetitive-task training. Repetitive-task training might also improve transfer functions. Occupational therapy can improve activities of daily living; however, information about the clinical effect of various strategies of cognitive rehabilitation and strategies for aphasia and dysarthria is scarce. Several large trials of rehabilitation practice and of novel therapies (eg, stem-cell therapy, repetitive transcranial magnetic stimulation, virtual reality, robotic therapies, and drug augmentation) are underway to inform future practice. © 2011 Elsevier Ltd.

Figgen D.,Massey University | Koers A.,VU University Amsterdam | Schwerdtfeger P.,Massey University
Angewandte Chemie - International Edition | Year: 2010

(Figure Presented) Small but mighty: An unprecedented large parity-violation energy difference of 0.7 Hz for the N-W stretching frequency of N≡WHCII, which conveniently lies in the CO 2 laser frequency range, is predicted from relativistic density functional theory. This result could lead to the first successful detection of such effects in chiral molecules. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.