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Leiden, Netherlands

Leiden University, located in the city of Leiden, is the oldest university in the Netherlands. The university was founded in 1575 by William, Prince of Orange, leader of the Dutch Revolt in the Eighty Years' War. The royal Dutch House of Orange-Nassau and Leiden University still have a close relationship. The Queens Juliana and Beatrix and crown-prince Willem-Alexander studied at Leiden University. In 2005 Queen Beatrix received a rare honorary degree from Leiden University. Wikipedia.


Koper M.T.M.,Leiden University
Nanoscale | Year: 2011

This review discusses the role of the detailed nanoscale structure of catalytic surfaces on the activity of various electrocatalytic reactions of importance for fuel cells, hydrogen production, and other environmentally important catalytic reactions, such as carbon monoxide oxidation, methanol and ethanol oxidation, ammonia oxidation, nitric oxide reduction, hydrogen evolution, and oxygen reduction. Specifically, results and insights obtained from surface-science single-crystal-based model experiments are linked to experiments on well-defined shape-controlled nanoparticles. A classification of structure sensitive effects in electrocatalysis is suggested, based both on empirical grounds and on quantum-chemical viz. thermochemical considerations. The mutual relation between the two classification schemes is also discussed. The review underscores the relevance of single-crystal modeling of nanoscale effects in catalysis, and points to the special role of two kinds of active sites for electrocatalysis on nanoparticulate surfaces: (i) steps and defects in (111) terraces or facets, and (ii) long-range (100) terraces or facets. © 2011 The Royal Society of Chemistry.


Geluk A.,Leiden University
Leprosy review | Year: 2013

The need for rapid diagnostic tests that can be applied in non-expert settings may now be greater than ever before, due to changes in leprosy control programmes and the decrease in special expertise required for (early) diagnosis of leprosy. However, there is no test available that can detect asymptomatic Mycobacterium leprae infection or predict progression of infection to clinical disease. The characteristics of the leprosy disease spectrum, in which both cellular and humoral immunity against M. leprae determine the outcome of infection, are pre-eminently suitable for development of tests that simultaneously detect biomarkers specific for both types of immune responses, thereby covering the complete immunological leprosy spectrum. Since publication of the M. leprae genome, many research groups have investigated the potential of M. leprae-unique antigens in serologic as well as T cell assays. Despite the early promise of the genome towards identifying antigens that induce M. leprae-specific T cells, it took more than a decade before promising candidates were identified. This review describes recent studies on M. leprae-specific T cell responses and discusses the application of measuring specific cellular mediated immune responses possibly combined with serologic responses in field-friendly tests for early diagnosis of M. leprae exposure and infection.


Ruggi A.,MESA Institute for Nanotechnology | van Leeuwen F.W.B.,Leiden University | Velders A.H.,MESA Institute for Nanotechnology | Velders A.H.,University of Twente
Coordination Chemistry Reviews | Year: 2011

Luminescent transition metal complexes are enjoying a growing interest because of their ubiquitous applications in, e.g., the fields of material science, sensors and (biomedical) diagnostics, and iridium(III) and ruthenium(II) complexes are among the best studied. Due to their long-living excited states, these complexes can have a strong interaction with dioxygen, resulting in luminescence quenching. This oxygen quenching might be regarded as an unwanted effect in luminescence imaging, but, on the other hand, it can be exploited for diagnostic and therapeutic applications as well. After a theoretical introduction concerning the dioxygen quenching mechanism and the parameters involved, in the second part of this review we focus on the possibility of tailoring this quenching by modifying selected properties of a complex (triplet energy, oxidation potential, localization and shielding of the excited state) in order to obtain systems with higher or lower oxygen quenching compared to the archetypical complexes. In the third part of this review an overview of the applications of oxygen quenching of luminescence is offered, with particular attention to biomedical use: diagnostic oxygen sensing, imaging and therapy. © 2011 Elsevier B.V.


Reinders M.E.,Leiden University
Current opinion in organ transplantation | Year: 2013

Despite impressive improvements in short-term survival after solid organ transplantation (SOT), the long-term outcome remains an important challenge. In recent years, it has become evident that ongoing alloreactivity, cellular and/or humoral, may play a critical role in the premature loss of kidney allografts. Clinical trials with mesenchymal stromal cells (MSCs) are currently underway for the treatment of various inflammatory disorders. Due to their immunosuppressive and reparative properties MSC immunotherapy constitutes an attractive intervention for chronic rejection, while avoiding the undesired adverse effects associated with excessive use of immunosuppressive drugs. The immunoregulatory properties of MSCs in both cellular and antibody-mediated inflammatory models and diseases have highlighted their potential to treat chronic rejection after SOT. Moreover, MSCs can also induce tissue regeneration and repair due to their antifibrotic and angiogeneic properties. Studies in experimental animals after SOT support the potential for MSCs to treat or prevent ongoing alloreactivity and the first clinical trials in transplant recipients are underway. MSCs are arising as promising cellular immunotherapy in transplant recipients and carry the potential to prevent or reduce the consequences of chronic or ongoing alloimmune injury.


Berne O.,CSIC - National Institute of Aerospace Technology | Berne O.,Leiden University | Marcelino N.,CSIC - National Institute of Aerospace Technology | Cernicharo J.,CSIC - National Institute of Aerospace Technology
Nature | Year: 2010

Massive stars influence their parental molecular cloud, and it has long been suspected that the development of hydrodynamical instabilities can compress or fragment the cloud1,2. Identifying such instabilities has proved difficult. It has been suggested that elongated structures (such as the pillars of creation3') and other shapes arise because of instabilities 4,5, but alternative explanations are available6,7. One key signature of an instability is a wave-like structure in the gas, which has hitherto not been seen. Here we report the presence of waves' at the surface of the Orion molecular cloud near where massive stars are forming. The waves seem to be a Kelvin-Helmholtz instability that arises during the expansion of the nebula as gas heated and ionized by massive stars is blown over pre-existing molecular gas. © 2010 Macmillan Publishers Limited. All rights reserved.


Papapoulos S.E.,Leiden University
Annals of the Rheumatic Diseases | Year: 2011

In recent years, study of rare bone diseases has led to the identification of signalling pathways that regulate bone formation and provided targets for the development of novel therapeutic agents to stimulate bone formation in patients with osteoporosis. Studies of two bone sclerosing dysplasias, sclerosteosis and van Buchem disease led to the identification of sclerostin, a negative regulator of bone formation. Sclerostin binds to LRP5/6 and inhibits Wnt signalling, but its precise molecular mechanism of action is not yet known. Its expression is restricted in the skeleton to osteocytes and is modified by mechanical loading and parathyroid hormone treatment. Sclerostin deficiency reproduces the findings of the human diseases in mice, while sclerostin excess leads to bone loss and reduced bone strength. An antibody to sclerostin increased bone formation dramatically at all bone envelopes in ovariectomised rats and intact monkeys, without affecting bone resorption and improved bone strength. In initial human studies, a single injection of the antibody to postmenopausal women increased serum P1NP and transiently decreased serum CTX. Clinical phase II studies with this antibody are currently underway.


Witteveen J.E.,Leiden University
European journal of endocrinology / European Federation of Endocrine Societies | Year: 2013

Hungry bone syndrome (HBS) refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone (PTH) levels, which follows parathyroidectomy in patients with severe primary hyperparathyroidism (PHPT) and preoperative high bone turnover. It is a relatively uncommon, but serious adverse effect of parathyroidectomy. We conducted a literature search of all available studies reporting a 'hungry bone syndrome' in patients who had a parathyroidectomy for PHPT, to identify patients at risk and address the pitfalls in their management. The severe hypocalcaemia is believed to be due to increased influx of calcium into bone, due to the sudden removal of the effect of high circulating levels of PTH on osteoclastic resorption, leading to a decrease in the activation frequency of new remodelling sites and to a decrease in remodelling space, although there is no good documentation for this. Various risk factors have been suggested for the development of HBS, including older age, weight/volume of the resected parathyroid glands, radiological evidence of bone disease and vitamin D deficiency. The syndrome is reported in 25-90% of patients with radiological evidence of hyperparathyroid bone disease vs only 0-6% of patients without skeletal involvement. There is insufficient data-based evidence on the best means to treat, minimise or prevent this severe complication of parathyroidectomy. Treatment is aimed at replenishing the severe calcium deficit by using high doses of calcium supplemented by high doses of active metabolites of vitamin D. Adequate correction of magnesium deficiency and normalisation of bone turnover are required for resolution of the hypocalcaemia which may last for a number of months after successful surgery. Preoperative treatment with bisphosphonates has been suggested to reduce post-operative hypocalcaemia, but there are to date no prospective studies addressing this issue.


Snellen I.,Leiden University
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2014

Ground-based high-dispersion spectroscopy could reveal molecular oxygen as a biomarker gas in the atmospheres of twin-Earths transiting red dwarf stars within the next 25 years. The required contrasts are only a factor of 3 lower than that already achieved for carbon monoxide in hot Jupiter atmospheres today but will need much larger telescopes because the target stars will be orders of magnitude fainter. If extraterrestrial life is very common and can therefore be found on planets around the most nearby red dwarf stars, it may be detectable via transmission spectroscopy with the next-generation extremely large telescopes. However, it is likely that significantly more collecting area is required for this. This can be achieved through the development of low-cost flux collector technology, which combines a large collecting area with a low but sufficient image quality for high-dispersion spectroscopy of bright stars. © 2014 The Author(s) Published by the Royal Society.


Harteveld C.L.,Leiden University
Orphanet journal of rare diseases | Year: 2010

Alpha-thalassaemia is inherited as an autosomal recessive disorder characterised by a microcytic hypochromic anaemia, and a clinical phenotype varying from almost asymptomatic to a lethal haemolytic anaemia.It is probably the most common monogenic gene disorder in the world and is especially frequent in Mediterranean countries, South-East Asia, Africa, the Middle East and in the Indian subcontinent. During the last few decades the incidence of alpha thalassaemia in North-European countries and Northern America has increased because of demographic changes. Compound heterozygotes and some homozygotes have a moderate to severe form of alpha thalassaemia called HbH disease. Hb Bart's hydrops foetalis is a lethal form in which no alpha-globin is synthesized. Alpha thalassaemia most frequently results from deletion of one or both alpha genes from the chromosome and can be classified according to its genotype/phenotype correlation. The normal complement of four functional alpha-globin genes may be decreased by 1, 2, 3 or all 4 copies of the genes, explaining the clinical variation and increasing severity of the disease. All affected individuals have a variable degree of anaemia (low Hb), reduced mean corpuscular haemoglobin (MCH/pg), reduced mean corpuscular volume (MCV/fl) and a normal/slightly reduced level of HbA2. Molecular analysis is usually required to confirm the haematological observations (especially in silent alpha-thalassaemia and alpha-thalassaemia trait). The predominant features in HbH disease are anaemia with variable amounts of HbH (0.8-40%). The type of mutation influences the clinical severity of HbH disease. The distinguishing features of the haemoglobin Bart's hydrops foetalis syndrome are the presence of Hb Bart's and the total absence of HbF. The mode of transmission of alpha thalassaemia is autosomal recessive. Genetic counselling is offered to couples at risk for HbH disease or haemoglobin Bart's Hydrops Foetalis Syndrome. Carriers of alpha+- or alpha0-thalassaemia alleles generally do not need treatment. HbH patients may require intermittent transfusion therapy especially during intercurrent illness. Most pregnancies in which the foetus is known to have the haemoglobin Bart's hydrops foetalis syndrome are terminated due to the increased risk of both maternal and foetal morbidity.


Over the last fifteen years, large-scale mining companies have started engaging in Corporate Social Responsibility (CSR), with the aim of contributing to developing local communities affected by their operations. Large-scale mining companies, together with the World Bank, have formulated voluntary principles and benchmarks to guide these company-community relations. Recently, it has been argued that CSR is also crucial in the early stages of exploration. Nowadays, mining consultants propagate a process approach to company-community relations, from early exploration to post-mining planning.This article contributes to these debates by describing: (1) how the Canadian Convention of Prospectors and Developers (PDAC) organises panels on company-community relations and (2) how dynamics in a heterogeneous field of company-community relations in Burkina Faso are influenced by structural aspects such as shifts in alliances and economic trends in the mining industry. The article seeks to assess the value of CSR practices and rhetoric by confronting the professional arena preoccupied with CSR with a social arena of company-community relations. It pays attention to the relationship between the process approach proposed in the frameworks of consultants and the characteristics of social processes on the ground. The confrontation shows that consultants and companies work with concepts of process that disregard some of the structural features of company-community engagements over time. The article scrutinises how consultants deal with discrepancies and shortcomings of the frameworks. It shows how consultants portray their efforts as part of a professional process aimed at improving models. This tactic of deferral is analysed in terms of structural features of development rhetoric. © 2011 Elsevier Ltd.


Pikulin D.I.,Leiden University | Nazarov Y.V.,Technical University of Delft
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

We derive a generic phenomenological model of a Majorana Josephson junction that accounts for avoided crossing of Andreev states, and investigate its dynamics at constant bias voltage to reveal an unexpected pattern of an any-π Josephson effect in the limit of slow decoherence: sharp peaks in noise not related to any definite fraction of Josephson frequency. © 2012 American Physical Society.


Boers-Doets C.B.,Leiden University
Future oncology (London, England) | Year: 2013

With the recent introduction of inhibitors of mammalian target of rapamycin (mTOR) in oncology, distinct cutaneous and oral adverse events have been identified. In fact, stomatitis and rash are documented as the most frequent and potentially dose-limiting side effects. Clinically, mTOR inhibitor-associated stomatitis (mIAS) more closely resembles aphthous stomatitis than oral mucositis due to conventional anticancer therapies. While most cases of mIAS are mild to moderate and self-limiting, more severe and persistent mIAS can become a dose-limiting toxicity. Small ulcerations may cause significant pain and mucosal sensitivity may occur in the absence of clinical changes. Use of clinical assessment tools that are primarily driven by ulceration size may underestimate mIAS, and assessment should include patient-reported outcomes. This article provides an up-to-date review of the clinical presentation, terminology, pathogenesis, assessment and management of mIAS and other mTOR inhibitor-associated oral adverse events. In addition, areas of future research are considered.


Hurts K.,Leiden University
Transportation Research Part F: Traffic Psychology and Behaviour | Year: 2011

The hypothesis is explored that the precise influence of a secondary, unrelated, spatial reasoning task on driving performance also depends on the specific spatial cues used in this task, compared to those currently emphasized by the primary driving task. In a laboratory experiment, participants were presented with questions about spoken (familiar) city names while driving. The questions either required them to reason spatially about the cities or to process the same city names only acoustically (i.e,; remembering and repeating one of the names). Amount of driver distraction was measured by means of a standardized tool called the Lane-Change Task (LCT) using a PC-based driving simulator. Results of the experiment showed that the spatial reasoning secondary task was more distracting than the acoustic one. In addition, participants performed worse on the LCT when switching to a right lane than when switching to a left lane. It is concluded that the results confirm an interpretation in terms of (in)compatible spatial cues emphasized simultaneously by primary and secondary task, but that alternative interpretations are also possible. The moderating influences of two cognitive ability variables on, and potential practical applications of, these findings are also addressed. © 2011 Elsevier Ltd. All rights reserved.


The popularity of oxytocin (OT) has grown exponentially during the past decade, and so has the number of OT trials in healthy and clinical groups. We take stock of the evidence from these studies to explore potentials and limitations of pharmacotherapeutic applications. In healthy participants, intranasally administered OT leads to better emotion recognition and more trust in conspecifics, but the effects appear to be moderated by context (perceived threat of the 'out-group'), personality and childhood experiences. In individuals with untoward childhood experiences, positive behavioral or neurobiological effects seem lowered or absent. In 19 clinical trials, covering autism, social anxiety, postnatal depression, obsessive-compulsive problems, schizophrenia, borderline personality disorder and post-traumatic stress, the effects of OT administration were tested, with doses ranging from 15 IU to more than 7000 IU. The combined effect size was d=0.32 (N=304; 95% confidence interval (CI): 0.18-0.47; P<0.01). However, of all disorders, only studies on autism spectrum disorder showed a significant combined effect size (d=0.57; N=68; 95% CI: 0.15-0.99; P<0.01). We hypothesize that for some of the other disorders, etiological factors rooted in negative childhood experiences may also have a role in the diminished effectiveness of treatment with OT.


Sousa K.,University of the Basque Country | Ortiz P.,Leiden University
Journal of Cosmology and Astroparticle Physics | Year: 2015

We consider the perturbative stability of non-supersymmetric configurations in =1 supergravity models with a spectator sector not involved in supersymmetry breaking. Motivated by the supergravity description of complex structure moduli in Large Volume Compactifications of type IIB-superstrings, we concentrate on models where the interactions are consistent with the supersymmetric truncation of the spectator fields, and we describe their couplings by a random ensemble of generic supergravity theories. We characterise the mass spectrum of the spectator fields in terms of the statistical parameters of the ensemble and the geometry of the scalar manifold. Our results show that the non-generic couplings between the spectator and the supersymmetry breaking sectors can stabilise all the tachyons which typically appear in the spectator sector before including the supersymmetry breaking effects, and we find large regions of the parameter space where the supersymmetric sector remains stable with probability close to one. We discuss these results about the stability of the supersymmetric sector in two physically relevant situations: non-supersymmetric Minkowski vacua, and slow-roll inflation driven by the supersymmetry breaking sector. For the class of models we consider, we have reproduced the regimes in which the KKLT and Large Volume Scenarios stabilise all supersymmetric moduli. We have also identified a new regime in which the supersymmetric sector is stabilised at a very robust type of dS minimum without invoking a large mass hierarchy.


ten Cate C.,Leiden University
Current opinion in neurobiology | Year: 2014

Like speech and language, the songs of many songbirds consist of learned, rapidly produced, structured sequences of distinct vocal units, originating from an interplay between experience and learning biases. Songs are species specific, but also show considerable within species variation in elements or element sequencing. This variation implies that birds possess mechanisms to identify, categorize and combine sounds. I review the abilities for speech sound perception and categorization, as well as for grammatical rule learning by birds. Speech sound perception in birds is in many ways comparable to human speech perception. Birds can also detect and generalize patterns underlying artificially arranged strings of vocal elements. However, there is a need for more comparative studies to examine the limits of their rule learning abilities and how they relate to those of humans. Copyright © 2014 Elsevier Ltd. All rights reserved.


von Lindern J.S.,Leiden University
Archives of disease in childhood. Fetal and neonatal edition | Year: 2012

To study whether the incidence of intraventricular haemorrhage (IVH) in very premature infants (<32 weeks gestation) with thrombocytopaenia is lower when using a liberal platelet-transfusion guideline compared with a restrictive guideline. A retrospective cohort study comparing the incidence of IVH in very premature infants with thrombocytopaenia (platelet count <150×10(9)/l) admitted between 2007 and 2008 to two neonatal intensive care unit in The Netherlands. The restrictive platelet-transfusion unit (N=353 infants <32 weeks gestation) transfused only in case of active haemorrhage and a platelet count <50×10(9)/l. The liberal-transfusion unit (N=326 infants <32 weeks gestation) transfused according to predefined platelet count thresholds. Primary outcome was the incidence and severity of IVH in infants with thrombocytopaenia in both units. The number of infants with thrombocytopaenia that received a platelet transfusion was significantly lower in the restrictive-transfusion unit compared with the liberal-transfusion unit, 15% (21/145) versus 31% (41/141), (p<0.001). The incidence of IVH in infants with thrombocytopaenia in the restrictive-transfusion and liberal-transfusion units was 30% (44/145) and 29% (41/141), respectively (p=0.81). The incidence of severe IVH (grade 3 or 4) in the restrictive-transfusion and liberal-transfusion units was 8% (12/145) and 11% (16/141), respectively (p=0.38). In the restrictive-transfusion unit, the rate of platelet transfusions was significantly lower, but the incidence and severity of IVH was similar to the liberal-transfusion unit.


Adolescence is a time of many cognitive and social-affective changes that are important for rapid behavioral adjustment to a variety of environmental demands and social contexts. Performance monitoring is one of the most important processes for behavioral adjustment; it allows individuals to evaluate outcomes of actions and change behavior accordingly. Neuroimaging studies have demonstrated that dorsal and ventral subregions of the medial frontal cortex are differentially engaged in performance monitoring, depending on the cognitive or social-affective dimensions of a task. Based on a review of neuroimaging, ERP, and heart rate studies, the implications of these modality-dependent contributions are discussed for the development of performance monitoring in adolescence. © 2014 Society for Psychophysiological Research.


van Reine W.F.P.,Leiden University
Taxon | Year: 2011

It is recommended that the name Dasya baillouviana not be conserved with a conserved type; the committee is undecided on the proposal to conserve Achnanthes brevipes against A. adnata, A. bacillarioides, and A. dubia, and is seeking more comments by diatom specialists. Sycidium and Sykidion were considered not sufficiently alike to be confused, but the committee is undecided on the confusability of Sycidiaceae with Sykidiaceae and Sycidiales with Sykidiales. Recommendations are made on the membership of the Special Committee on Harmonization of the Nomenclature of Cyanophyta/Cyanobacteria established in 2005 but yet to be set up. The Committee's views on some modifications to the ICBN are presented including some proposals that might be made from the floor at the forthcoming Congress in Melbourne.


Podolsky D.,Technion - Israel Institute of Technology | Sachdev S.,Harvard University | Sachdev S.,Leiden University
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

We study the Higgs excitation in the Goldstone phase of the relativistic O(N) model in two spatial dimensions at zero temperature. The response functions of the order parameter, and its magnitude squared, become universal functions of frequency in the vicinity of the quantum critical point described by the Wilson-Fisher fixed point, and we compute them to next-to-leading order in 1/N. The Higgs particle has an infrared singular decay to gapless Goldstone excitations, and its response functions are characterized by a pole in the lower half of the complex frequency plane. The pole acquires a nonzero real part only at next-to-leading order in 1/N, demonstrating that the Higgs excitation has an oscillatory component even in the scaling limit. Both the real and imaginary parts of the pole position vanish with the correlation length exponent ν upon approaching the critical point. We present evidence that the spectral density of the O(N)-invariant amplitude-squared of the order parameter has a peak at a nonzero frequency in the scaling limit. We connect our results to recent experimental studies of the superfluid-insulator quantum phase transition of ultracold bosonic atoms in optical lattices. © 2012 American Physical Society.


Poletiek F.H.,Leiden University
Behavioral and Brain Sciences | Year: 2011

Mercier and Sperber's (M&S's) theory of reasoning cannot predict reasoning in the absence of an argumentative context. Applying the theory to hypothesis testing behavior, I propose that hypothesis testing is often motivated by determining the true inference and that reasoning models should account for utilities (affected by various motives, including the wish to convince) of reasoning outcomes. © 2011 Cambridge University Press.


Wuhrer M.,Leiden University
Glycoconjugate Journal | Year: 2013

Mass spectrometry plays an increasingly important role in structural glycomics. This review provides an overview on currently used mass spectrometric approaches such as the characterization of glycans, the analysis of glycopeptides obtained by proteolytic cleavage of proteins and the analysis of glycosphingolipids. The given examples are demonstrating the application of mass spectrometry to study glycosylation changes associated with congenital disorders of glycosylation, lysosomal storage diseases, autoimmune diseases and cancer. © 2012 The Author(s).


Trouw L.A.,Leiden University | Mahler M.,INOVA Diagnostics Inc.
Autoimmunity Reviews | Year: 2012

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and damage of the joints affecting about 0.5% of the general population. Early treatment in RA is important as it can prevent disease progression and irreversible damage of the joints. Despite the high diagnostic value of anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF), there is a strong demand for novel serological biomarkers to further improve the diagnosis of this abundant disease. During the last decades, several autoantigens have been described in RA including Ra33 (hnRNP A2), fibrinogen, fibronectin, alpha-enolase, type II collagen, immunoglobulin binding protein (BiP), annexins and viral citrullinated peptide (VCP) derived from Epstein Barr Virus-encoded protein (EBNA-2). More recent discoveries include antibodies to carbamylated antigens (anti-CarP), to peptidyl arginine deiminase type 4 (PAD4), to BRAF (v raf murine sarcoma viral oncogene homologue B1) and to 14 autoantigens identified by phage display technology. This review provides a current overview of novel biomarkers for RA and discusses their future potential to improve the diagnosis of the disease. © 2012 Elsevier B.V.


Adoptive cell therapy (ACT) by infusion of autologous or redirected tumor-specific T-cells has had a major impact on the treatment of several metastasized malignancies that were until now hardly treatable. Recent findings provide a more profound knowledge on the underlying mechanisms of success and allow the optimization of the ACT protocol with respect to (1) the treatment related side-effects, (2) the quality and specificity of infused T-cells, and (3) the immunosuppressive phenotype of the tumor environment. In this review, the results and insights in the success of ACT as well as the possibilities to improve ACT and its exploitation as treatment option for various metastatic cancer types, will be discussed. © 2016 Elsevier Ltd.


Papapoulos S.E.,Leiden University
Annals of the New York Academy of Sciences | Year: 2011

Bisphosphonates are widely used in the treatment of postmenopausal osteoporosis. They decrease the rate of bone turnover, maintain or improve structural and material properties of bone, and increase bone mineral density and thereby decrease the risk of fractures. Available potent bisphosphonates can be given to patients by different dosing regimens that range from daily oral administration to yearly intravenous infusions. Controlled studies, extending to 10 years of continuous treatment, provide information about long-term efficacy and safety and can help in the planning of long-term treatment strategies. Selection of bisphosphonates for the treatment of individuals should be based on a careful review of efficacy data, a risk profile of the bisphosphonate, and values and preferences of the patient. © 2010 New York Academy of Sciences.


Meijer A.H.,Leiden University
Seminars in Immunopathology | Year: 2016

Zebrafish has earned its place among animal models of tuberculosis. Its natural pathogen, Mycobacterium marinum, shares major virulence factors with the human pathogen Mycobacterium tuberculosis. In adult zebrafish, which possess recombination-activated adaptive immunity, it can cause acute infection or a chronic progressive disease with containment of mycobacteria in well-structured, caseating granulomas. In addition, a low-dose model that closely mimics human latent infection has recently been developed. These models are used alongside infection of optically transparent zebrafish embryos and larvae that rely on innate immunity and permit non-invasive visualization of the early stages of developing granulomas that are inaccessible in other animal models. By microinjecting mycobacteria intravenously or into different tissues, systemic and localized infections can be induced, each useful for studying particular aspects of early pathogenesis, such as phagocyte recruitment, granuloma expansion and maintenance, vascularization of granulomas, and the phagocyte-mediated dissemination of mycobacteria. This has contributed to new insights into the mycobacteria-driven mechanisms that promote granuloma formation, the double-edged role of inflammation, the mechanisms of macrophage cell death that favor disease progression, and the host-protective role of autophagy. As a result, zebrafish models are now increasingly used to explore strategies for adjunctive therapy of tuberculosis with host-directed drugs. © 2015, The Author(s).


A new species from the Indian eastern Himalaya, Miliusa codonantha, is described and illustrated. It chiefly differs from M. macrocarpa, its most morphologically similar species, in having smaller flowers and considerably fewer stamens and carpels per flower. In addition, a new combination is made for another species of Miliusa also occurring on the Indian subcontinent: M. dioeca (basionym: Uvaria dioeca). The two species as well as M. macrocarpa are placed in the previously recognized M. campanulata group. The names U. dioeca and its heterotypic synonym M. wallichiana are lectotypified. © 2013 BGBM Berlin-Dahlem.


van Bergen E.,Leiden University
Proceedings. Biological sciences / The Royal Society | Year: 2013

Inbreeding depression results from mating among genetically related individuals and impairs reproductive success. The decrease in male mating success is usually attributed to an impact on multiple fitness-related traits that reduce the general condition of inbred males. Here, we find that the production of the male sex pheromone is reduced significantly by inbreeding in the butterfly Bicyclus anynana. Other traits indicative of the general condition, including flight performance, are also negatively affected in male butterflies by inbreeding. Yet, we unambiguously show that only the production of male pheromones affects mating success. Thus, this pheromone signal informs females about the inbreeding status of their mating partners. We also identify the specific chemical component (hexadecanal) probably responsible for the decrease in male mating success. Our results advocate giving increased attention to olfactory communication as a major causal factor of mate-choice decisions and sexual selection.


Reitsma P.H.,Leiden University
Hamostaseologie | Year: 2015

Venous thromboembolism (VTE) poses a worldwide health burden affecting millions of people each year. The annual incidence of symptomatic VTE, the collective term used here for deep venous thrombosis, pulmonary embolism or both, is 2-3 per thousand inhabitants. The one-year mortality is 20% after a first VTE. Of the surviving patients 15-25% will experience a recurrent episode of VTE in the three years after the first event. Primary and secondary prevention is key to reducing death and disability from VTE. How to make use of our current knowledge of inherited risk of VTE for primary and secondary disease prevention is not straightforward. This despite the fact that in the past two or three decades we have made major strides in enlarging our understanding of inherited VTE risk, and that new inherited risk factors continue to be identified. For primary prevention of VTE genetic testing is not likely to play a role in the future. Genetic variations also determine recurrence risk, albeit that the effect sizes for individual genetic variations are invariably lower than those for first VTE events. Multilocus genetic risk scores improve risk classification, and it is now possible to stratify patients who have had a first venous thrombosis, into subgroups with a high and low risk of recurrence. Whether this approach can be used to tailor intensity and duration of treatment remains to be established. © Schattauer 2015.


Van Der Heijde D.,Leiden University
Annals of the Rheumatic Diseases | Year: 2011

Both erosions and joint space narrowing (JSN) are aspects of structural damage in rheumatoid arthritis. Most information is available on structural damage as one concept. However, the differential aspect of the effects on bone and cartilage could yield interesting information. Comparative information of these aspects can be based only on radiographic data on erosions and JSN. Both erosions and JSN are the consequence of inflammation, and their progression is inhibited by drugs that inhibit inflammation. These two processes often occur in parallel but joints in which erosions are present show a preference for progression of erosions and, to a lesser extent, development of JSN. The reverse is true for joints with JSN present, where there is a preference for worsening of JSN over development of erosions. Repair is possible for erosions as well as JSN and this is related to the absence of inflammation and effective treatment (especially methotrexate in combination with a tumour necrosis factor blocker).


Scott D.L.,Kings College London | Wolfe F.,University of Kansas | Huizinga T.W.J.,Leiden University
The Lancet | Year: 2010

Rheumatoid arthritis is characterised by persistent synovitis, systemic inflammation, and autoantibodies (particularly to rheumatoid factor and citrullinated peptide). 50 of the risk for development of rheumatoid arthritis is attributable to genetic factors. Smoking is the main environmental risk. In industrialised countries, rheumatoid arthritis affects 0·5-1·0 of adults, with 5-50 per 100 000 new cases annually. The disorder is most typical in women and elderly people. Uncontrolled active rheumatoid arthritis causes joint damage, disability, decreased quality of life, and cardiovascular and other comorbidities. Disease-modifying antirheumatic drugs (DMARDs), the key therapeutic agents, reduce synovitis and systemic inflammation and improve function. The leading DMARD is methotrexate, which can be combined with other drugs of this type. Biological agents are used when arthritis is uncontrolled or toxic effects arise with DMARDs. Tumour necrosis factor inhibitors were the first biological agents, followed by abatacept, rituximab, and tocilizumab. Infections and high costs restrict prescription of biological agents. Long-term remission induced by intensive, short-term treatment selected by biomarker profiles is the ultimate goal. © 2010 Elsevier Ltd.


Selman M.H.,Leiden University
Molecular & cellular proteomics : MCP | Year: 2012

Antibody effector functions have been shown to be influenced by the structure of the Fc N-glycans. Here we studied the changes in plasma or serum IgG Fc N-glycosylation upon vaccination of 10 Caucasian adults and 10 African children. Serum/plasma IgG was purified by affinity chromatography prior to and at two time points after vaccination. Fc N-glycosylation profiles of individual IgG subclasses were determined for both total IgG and affinity-purified anti-vaccine IgG using a recently developed fast nanoliquid chromatography-electrospray ionization MS (LC-ESI-MS) method. While vaccination had no effect on the glycosylation of total IgG, anti-vaccine IgG showed increased levels of galactosylation and sialylation upon active immunization. Interestingly, the number of sialic acids per galactose increased during the vaccination time course, suggesting a distinct regulation of galactosylation and sialylation. In addition we observed a decrease in the level of IgG1 bisecting N-acetylglucosamine whereas no significant changes were observed for the level of fucosylation. Our data indicate that dependent on the vaccination time point the infectious agent will encounter IgGs with different glycosylation profiles, which are expected to influence the antibody effector functions relevant in immunity.


Brandts A.,Leiden University
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine | Year: 2010

The purpose of this study was to determine the ability of 7 T cardiac magnetic resonance imaging (MRI) to quantitatively assess left ventricular volumes, mass, and function from cine short-axis series and left ventricular diastolic filling from velocity-encoded MRI in 10 healthy volunteers. As comparative "gold standard," the corresponding measures obtained at 1.5 T were taken. Left ventricular volumes, function, and mass were obtained by manual image segmentation. Trans-mitral flow graphs were obtained from 2D one-directional through-plane velocity-encoded MRI planned at the mitral valve in end-systole. Imaging at 7 T MRI was successful in 80% of the examinations. Assessment of left ventricular volumes, function, and mass at 7 T showed good agreement with 1.5 T (no significant differences between variables describing volumes, function, and mass with intraclass correlation coefficients ranging from 0.77 to 0.96). Trans-mitral stroke volume and the ratio between early and atrial peak filling rate showed strong agreement at both field strengths (no significant differences between stroke volumes and filling ratios with intraclass correlation coefficients 0.92 for stroke volumes and 0.77 for peak filling ratios). In conclusion, this study shows that assessing left ventricular volumes, function, and flow is feasible at 7 T MRI and that standardized MRI protocols provide similar quantitative results when compared with 1.5 T MRI. Copyright © 2010 Wiley-Liss, Inc.


Ghaly M.,Leiden University
Bioethics | Year: 2012

When Muslims thought of establishing milk banks, religious reservations were raised. These reservations were based on the concept that women's milk creates 'milk kinship' believed to impede marriage in Islamic Law. This type of kinship is, however, a distinctive phenomenon of Arab tradition and relatively unknown in Western cultures. This article is a pioneer study which fathoms out the contemporary discussions of Muslim scholars on this issue. The main focus here is a religious guideline (fatwa) issued in 1983, referred to in this article as 'one text', by the Egyptian scholar Yūsuf al-Qaradāwī who saw no religious problem in establishing or using these banks. After a number of introductory remarks on the 'Western' phenomenon of milk banks and the 'Islamic' phenomenon of 'milk kinship', this article analyses the fatwa of al-Qaradāwī'one text' and investigates the 'two contexts' in which this fatwa was discussed, namely, the context of the Muslim world and that of Muslim minorities living in the West. The first context led to rejecting the fatwa and refusing to introduce the milk banking system in the Muslim world. The second context led to accepting this system and thus allowing Muslims living in the West to donate and receive milk from these banks. Besides its relevance to specialists in the fields of Islamic studies, anthropology and medical ethics, this article will also be helpful to physicians and nurses who deal with patients of Islamic background. © 2010 Blackwell Publishing Ltd.


Mul K.,Leiden University
Current Opinion in Neurology | Year: 2016

PURPOSE OF REVIEW: This review gives an overview of the currently known key clinical and (epi)genetic aspects of facioscapulohumeral muscular dystrophy (FSHD) and provides perspectives to facilitate future research. RECENT FINDINGS: Clinically, imaging studies have contributed to a detailed characterization of the FSHD phenotype, and a model is proposed with five stages of disease progression. A number of clinical trials have been conducted regarding exercise and diet aiming to reduce symptoms. Genetically, at least two different mechanisms (FSHD1 and FSHD2) lead to double homeobox 4 (DUX4) expression in skeletal myocytes, which is expected to be necessary for the disease. Disease severity is most likely determined by a combination of the D4Z4 repeat size and its epigenetic state. SUMMARY: FSHD is one of the most common muscular dystrophies and is characterized by a typical distribution of muscle weakness. Progress has been made on clinical as well as on (epi)genetic aspects of the disease. Currently, there is no cure available for FSHD. For successful development of new treatments targeting the disease process, integration of clinical and pathogenetic knowledge is essential. A clinical trial toolbox that consists of patient registries, biomarkers and clinical outcome measures will be required to effectively conduct future clinical trials. Copyright © 2016 Wolters Kluwer Health, Inc. All rights resereved.


Roep B.O.,Leiden University | Tree T.I.M.,Kings College London
Nature Reviews Endocrinology | Year: 2014

Type 1 diabetes mellitus (T1DM) is the result of autoimmune destruction of pancreatic β cells in genetically predisposed individuals with impaired immune regulation. The insufficiency in the modulation of immune attacks on the β cells might be partly due to genetic causes; indeed, several of the genetic variants that predispose individuals to T1DM have functional features of impaired immune regulation. Whilst defects in immune regulation in patients with T1DM have been identified, many patients seem to have immune regulatory capacities that are indistinguishable from those of healthy individuals. Insight into the regulation of islet autoimmunity might enable us to restore immune imbalances with therapeutic interventions. In this Review, we discuss the current knowledge on immune regulation and dysfunction in humans that is the basis of tissue-specific immune regulation as an alternative to generalized immune suppression.


Rodriguez P.,University of Birmingham | Koper M.T.M.,Leiden University
Physical Chemistry Chemical Physics | Year: 2014

This perspective article reviews recent advances in the study of important catalytic reactions on gold electrodes. The paper discusses both oxidation and reduction reactions: the oxidation of carbon monoxide and alcohols as well as the oxygen reduction reaction on gold electrodes and also a brief discussion of other interesting reactions on gold electrodes such as the amine borane oxidation and the CO2 reduction. A common theme in electrocatalysis on gold is the sensitive dependence of various reaction rates on pH and gold surface structure. The electrocatalysis of redox reactions on gold is highly pH dependent, often preferring alkaline media, due to the prominent role of negatively charged reaction intermediates related to the fact that gold does not bind the neutral intermediates strongly enough. Gold also tends to be a selective catalyst, again due to its weak adsorption properties, as on gold the reaction often stops when a difficult bond breaking or making event will be the necessary next step. This journal is © the Partner Organisations 2014.


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

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


Vertegaal A.C.O.,Leiden University
Biochemical Society Transactions | Year: 2010

Ubiquitin and ubiquitin-like proteins are conjugated to a wide variety of target proteins that play roles in all biological processes. Target proteins are conjugated to ubiquitin monomers or to ubiquitin polymers that form via all seven internal lysine residues of ubiquitin. The fate of these target proteins is controlled in a chain architecture-dependent manner. SUMO (small ubiquitin-related modifier) shares the ability of ubiquitin to form chains via internal SUMOylation sites. Interestingly, a SUMO-binding site in Ubc9 is important for SUMO chain synthesis. Similar to ubiquitin-polymer cleavage by USPs (ubiquitin-specific proteases), SUMO chain formation is reversible. SUMO polymers are cleaved by the SUMO proteases SENP6 [SUMO/sentrin/SMT3 (suppressor of mif two 3)-specific peptidase 6], SENP7 and Ulp2 (ubiquitin-like protease 2). SUMO chain-binding proteins including ZIP1, SLX5/8 (synthetic lethal of unknown function 5/8), RNF4 (RING finger protein 4) and CENP-E (centromere-associated protein E) have been identified that interact non-covalently with SUMO chains, thereby regulating target proteins that are conjugated to SUMO multimers. SUMO chains play roles in replication, in the turnover of SUMO targets by the proteasome and during mitosis and meiosis. Thus signalling via polymers is an exciting feature of the SUMO family. © The Authors Journal compilation.


Strijbos J.-W.,Leiden University
IEEE Transactions on Learning Technologies | Year: 2011

Within the (Computer-Supported) Collaborative Learning (CS)CL research community, there has been an extensive dialogue on theories and perspectives on learning from collaboration, approaches to scaffold (script) the collaborative process, and most recently research methodology. In contrast, the issue of assessment of collaborative learning has received much less attention. This article discusses how assessment of collaborative learning has been addressed, provides a perspective on what could be assessed, and highlights limitations of current approaches. Since assessment of collaborative learning is a demanding experience for teachers and students alike, they require adequate computer-supported and intelligent tools for monitoring and assessment. A roadmap for the role and application of intelligent tools for assessment of (CS)CL is presented. © 2011 IEEE.


Bower R.G.,Durham University | Benson A.J.,California Institute of Technology | Crain R.A.,Swinburne University of Technology | Crain R.A.,Leiden University
Monthly Notices of the Royal Astronomical Society | Year: 2012

The observed stellar mass function (SMF) is very different to the halo mass function predicted by Λ cold dark matter (ΛCDM), and it is widely accepted that this is due to energy feedback from supernovae and black holes. However, the strength and form of this feedback is not understood. In this paper, we use the phenomenological model galform to explore how galaxy formation depends on the strength and halo mass dependence of feedback. We focus on 'expulsion' models in which the wind mass loading, β, is proportional to with n= 0, 1, 2 and contrast these models with the successful Bower et al. model (B8W7), for which A crucial development is that our code explicitly accounts for the recapture of expelled gas as the system's halo mass (and thus gravitational potential) increases. While models with high wind speed and mass loading result in a poor match to the observed SMF, a model with slower wind speed matches the flat portion of the SMF at M {black star}∼ 10 9-10 11h -1M ⊙. When combined with active galactic nucleus feedback, the model provides a good description of the observed SMF above 10 9h -1M ⊙. In order to explore the impact of different feedback schemes further, we examine how the expulsion models compare with a further range of observational data, contrasting the results with the B8W7 model. In the expulsion models, the brightest galaxies are assembled more recently, and the specific star formation rates of galaxies decrease strongly with decreasing stellar mass. The expulsion models tend to have a cosmic star formation density that is dominated by lower mass galaxies at z= 1-3, and dominated by high-mass galaxies at low redshift. These trends are in conflict with observational data, but the comparison highlights some deficiencies of the B8W7 model also. The experiments in this paper not only give us important physical insight into the impact of the feedback process on the formation histories of galaxies, but the strong mass dependence of feedback adopted in B8W7 still appears to provide the most promising description of the observed Universe. © 2012 The Authors Monthly Notices of the Royal Astronomical Society © 2012 RAS.


Nichol K.,Leiden University | Daniels K.E.,North Carolina State University
Physical Review Letters | Year: 2012

Experiments quantifying the rotational and translational motion of particles in a dense, driven, 2D granular gas floating on an air table reveal that kinetic energy is divided equally between the two translational and one rotational degrees of freedom. This equipartition persists when the particle properties, confining pressure, packing density, or spatial ordering are changed. While the translational velocity distributions are the same for both large and small particles, the angular velocity distributions scale with the particle radius. The probability distributions of all particle velocities have approximately exponential tails. Additionally, we find that the system can be described with a granular Boyle's law with a van der Waals-like equation of state. These results demonstrate ways in which conventional statistical mechanics can unexpectedly apply to nonequilibrium systems. © 2012 American Physical Society.


van Baardewijk L.J.,Leiden University
International orthopaedics | Year: 2013

Despite adequate treatment 5-30% of bone fracture patients experience delayed union. During normal fracture union, bone morphogenetic proteins (BMPs) induce healing through a sequential cascade of events. Improved fracture healing after BMP-2 or -7 supplementation in patients with impaired fracture union suggests a deficiency of one or more of these factors. We postulated that low levels of circulating BMPs may result in delayed bone healing. The aim of this study was to quantify differences in levels of circulating BMP-2, -4, -6, -7, and -9 in patients that have demonstrated normal or delayed fracture healing. Blood samples were collected from an unselected cohort of 65 patients that had been treated for a diaphyseal tibia or femur fracture. Patients were divided into a group with fracture healing within nine months after injury and a group with delayed fracture union. BMP plasma concentrations were quantified using ELISAs and compared between these two groups. Circulating plasma levels of BMP-2, -4, -6, and -7 did not differ between 34 patients with normal fracture healing and 31 patients with delayed fracture healing. Also the median BMP-9 plasma levels were not statistically different between the two groups of patients. However, the distribution in the patients with normal union showed a wider range (72-2496 pg/ml) compared with the delayed union group (120-816 pg/ml). In general, circulating BMP concentrations are not statistically different between patients who demonstrated normal or delayed fracture healing. High circulating BMP-9 levels seem to be associated with faster fracture healing, but are apparently not decisive.


Hu H.H.,University of Southern California | Kan H.E.,Leiden University
NMR in Biomedicine | Year: 2013

Accurate, precise and reliable techniques for the quantification of body and organ fat distributions are important tools in physiology research. They are critically needed in studies of obesity and diseases involving excess fat accumulation. Proton MR methods address this need by providing an array of relaxometry-based (T1, T2) and chemical shift-based approaches. These techniques can generate informative visualizations of regional and whole-body fat distributions, yield measurements of fat volumes within specific body depots and quantify fat accumulation in abdominal organs and muscles. MR methods are commonly used to investigate the role of fat in nutrition and metabolism, to measure the efficacy of short- and long-term dietary and exercise interventions, to study the implications of fat in organ steatosis and muscular dystrophies and to elucidate pathophysiological mechanisms in the context of obesity and its comorbidities. The purpose of this review is to provide a summary of mainstream MR strategies for fat quantification. The article succinctly describes the principles that differentiate water and fat proton signals, summarizes the advantages and limitations of various techniques and offers a few illustrative examples. The article also highlights recent efforts in the MR of brown adipose tissue and concludes by briefly discussing some future research directions. © 2013 John Wiley & Sons, Ltd.


Hensen E.F.,VU University Amsterdam | Bayley J.-P.,Leiden University
Familial Cancer | Year: 2011

The last 10 years have seen enormous progress in the field of paraganglioma and pheochromocytoma genetics. The identification of the first gene related to paraganglioma, SDHD, encoding a subunit of mitochondrial succinate dehydrogenase (SDH), was quickly followed by the identification of mutations in SDHC and SDHB. Very recently several new SDH-related genes have been discovered. The SDHAF2 gene encodes an SDH co-factor related to the function of the SDHA subunit, and is currently exclusively associated with head and neck paragangliomas. SDHA itself has now also been identified as a paraganglioma gene, with the recent identification of the first mutation in a patient with extra-adrenal paraganglioma. Another SDH-related co-factor, SDHAF1, is not currently known to be a tumor suppressor, but may shed some light on the mechanisms of tumorigenesis. An entirely novel gene associated with adrenal pheochromocytoma, TMEM127, suggests that other new paraganglioma susceptibility genes may await discovery. In addition to these recent discoveries, new techniques related to mutation analysis, including genetic analysis algorithms, SDHB immunohistochemistry, and deletion analysis by MLPA have improved the efficiency and accuracy of genetic analysis. However, many intriguing questions remain, such as the striking differences in the clinical phenotype of genes that encode proteins with an apparently very close functional relationship, and the lack of expression of SDHD and SDHAF2 mutations when inherited via the maternal line. Little is still known of the origins and causes of truly sporadic tumors, and the role of oxygen in the relationships between high-altitude, familial and truly sporadic paragangliomas remains to be elucidated. © 2010 The Author(s).


Webb A.,Leiden University
Progress in Nuclear Magnetic Resonance Spectroscopy | Year: 2014

Cavity resonators are widely used in electron paramagnetic resonance, very high field magnetic resonance microimaging and also in high field human imaging. The basic principles and designs of different forms of cavity resonators including rectangular, cylindrical, re-entrant, cavity magnetrons, toroidal cavities and dielectric resonators are reviewed. Applications in EPR and MRI are summarized, and finally the topic of traveling wave MRI using the magnet bore as a waveguide is discussed. © 2014 Elsevier Ltd. All rights reserved.


The design and catalytic implementation of tandem reactions to selectively create nitrogen-containing products under mild conditions has encountered numerous challenges in synthetic chemistry. Several known classes of homogeneously catalyzed carbon-nitrogen bond formation including hydroamination, hydroamidation, hydroaminoalkylation, hydroaminomethylation and reductive amination were reported in the literature. More recently, a new class of C-N bond formation consisting of hydroamidomethylation and reductive amidation extended the applicability of these synthetic methodologies. The tandem reactions do considerably impact on the selectivity and efficiency of synthetic strategies. This review highlights and compares selected examples of the hydroaminomethylation, reductive amination, hydroamidomethylation and reductive amidation reactions, and thus consequently reveals their potential applications in synthetic chemistry as well as chemical industries. This journal is © the Partner Organisations 2014.


Mydosh J.A.,Leiden University | Oppeneer P.M.,Uppsala University
Philosophical Magazine | Year: 2014

Throughout the past three decades, the hidden order (HO) problem in URu2Si2 has remained a hot topic in the physics of strongly correlated electron systems with well over 600 publications related to this subject. Presently in 2014, there has been significant progress in combining various experimental results embedded within electronic structure calculations using density functional theory (DFT) to give a consistent description of the itinerant behaviour of the HO transition and its low temperature state. Here, we review six different experiments: ARPES, quantum oscillations, neutron scattering, RXD, optical spectroscopy and STM/STS. We then establish the consistencies among these experiments when viewed through the Fermi-surface nesting, folding and gapping framework as predicted by DFT. We also discuss a group of other experiments (torque, cyclotron resonance, NMR and XRD) that are more controversial and are presently in a transition state regarding their interpretation as rotational symmetry breaking and dotriacontapole formation. There are also a series of recent exotic experiments (Raman scattering, polar Kerr effect and ultrasonics) that require verification, yet they offer new insights into the HO symmetry breaking and order parameter. We conclude with some constraining comments on the microscopic models that rely on localized 5f-U states and strong Ising anisotropy for explaining the HO transition, and with an examination of different models in the light of recent experiments. © 2014 Taylor & Francis.


Kortekaas K.A.,Leiden University
European journal of heart failure | Year: 2013

Systemic complications after cardiac surgery are common in heart failure patients. However, the pathophysiological mechanisms, such as a different local inflammatory response of failing hearts, remain in question. This study examines whether failing hearts respond differently to cardioplegic arrest and reperfusion compared with non-failing hearts (controls). The inflammatory response was evaluated in samples collected simultaneously from the radial artery and coronary sinus, and myocardial tissue in 62 patients undergoing cardiac surgery. No myocardial release of inflammatory mediators was observed upon reperfusion in controls (n = 19). In contrast, in patients with heart failure, reperfusion was characterized by a myocardial release of several cytokines. Myocardial interleukin-6 was 115% increased in non-ischaemic heart failure (n = 18, P = 0.002) as compared with a 117% increase in patients with ischaemic heart failure (n = 25, P = 0.01). Furthermore, a myocardial release of monocyte chemoattractant protein-1 was observed in both patient groups: a 109% (P = 0.001) and 114% (P = 0.01) increase in patients with non-ischaemic heart failure and ischaemic heart failure, respectively. Post-operative myocardial damage, expression of inflammatory mediators, and p65-nuclear factor-κB activity were similar in all patient groups. Inflammatory cell content was increased in early ischaemic myocardial tissue in both heart failure groups compared with controls. Heart failure patients show a clear myocardial inflammatory response upon reperfusion, probably explained by degranulation of infiltrated inflammatory cells. Results in controls indicate that they better withstand cardioplegic arrest and reperfusion without an explicit myocardial inflammatory response.


De Gruijl F.R.,Leiden University
Photochemistry and Photobiology | Year: 2011

Next to the adverse effects of solar UV exposure, the beneficial effects mediated by vitamin D3 have come into the limelight. The question then is "how much sun exposure do we actually need?" Estimates have been made, but the data are not quite adequate. The groups of Drs. Rhodes and Webb bridged the gap between experiments and everyday life by a study in which 109 volunteers were exposed in mid-winter to simulated solar UV radiation in summertime clothing at dosages of 1.3 SED three times a week. Thus, 90% reached sufficiently high vitamin D statuses (>50 nmol L-1). In this issue, these researchers transpose these experimental exposures in a cabinet to summertime noon exposures of people walking around for about half an hour in open terrain on a clear day in Manchester, UK. This result is an improvement over earlier estimates and shows that casual mid-day summer sun exposure should indeed suffice. Artificial UV exposures of volunteers needed to be translated to real-life sun exposures to assess adequate exposures for vitamin D. Simple translation to sun exposure of a horizontal flat surface is easy, but that does not represent common sun exposure of people. Therefore, Drs. Webb and Rhodes and coworkers constructed a 3D dynamic model in which a person moves around upright in the midday summer sun in Manchester, turning all sides of the body randomly to all cardinal directions. Thus, they found that exposures of half an hour 3 per week should be sufficient © 2011 The Author. Photochemistry and Photobiology © 2011 The American Society of Photobiology.


Koper M.T.M.,Leiden University | Koper M.T.M.,Hokkaido University
Chemical Science | Year: 2013

This perspective article outlines a simple but general theoretical analysis for multiple proton-electron transfer reactions, based on the microscopic theory of proton-coupled electron transfer reactions, recent developments in the thermodynamic theory of multi-step electron transfer reactions, and the experimental realization that many multiple proton-coupled electron transfer reactions feature decoupled proton-electron steps in their mechanism. It is shown that decoupling of proton and electron transfer leads to a strong pH dependence of the overall catalytic reaction, implying an optimal pH for high catalytic turnover, and an associated optimal catalyst at the optimal pH. When more than one catalytic intermediate is involved, scaling relationships between intermediates may dictate the optimal catalyst and limit the extent of reversibility that may be achievable for a multiple proton-electron transfer reaction. The theory is discussed in relation to the experimental results for a number of redox reactions that are of importance for sustainable energy conversion, primarily focusing on their pH dependence. © 2013 The Royal Society of Chemistry.


Van Stein D.,Leiden University
British Journal of Haematology | Year: 2015

Transfusion-related acute lung injury (TRALI), a syndrome of respiratory distress caused by blood transfusion, is the leading cause of transfusion-related mortality. The majority of TRALI cases have been related to passive infusion of human leucocyte antigen (HLA) and human neutrophil antigen (HNA) antibodies in donor blood. In vitro, ex vivo and in vivo animal models have provided insight in TRALI pathogenesis. The various classes of antibodies implicated in TRALI appear to have different pathophysiological mechanisms for the induction of TRALI involving endothelial cells, neutrophils, monocytes and, as very recently has been discovered, lymphocytes. The HLA and HNA-antibodies are found mainly in blood from multiparous women as they have become sensitized during pregnancy. The incidence of TRALI has decreased rapidly following the introduction of a male-only strategy for plasma donation. This review focuses on pre-clinical and clinical studies investigating the pathophysiology of antibody-mediated TRALI. © 2015 John Wiley & Sons Ltd.


Colins O.F.,Leiden University | Andershed H.,Orebro University
Law and Human Behavior | Year: 2015

The new DSM-5 specifier 'with Limited Prosocial Emotions' (LPE) is expected to provide greater information about impairment of children and adolescents with conduct disorder (CD). This study examined the clinical utility of the LPE specifier symptom threshold among female adolescents being detained in Belgium (n = 191 girls; ages 12-17). Standardized questionnaires and a structured diagnostic interview were used to assess the LPE specifier, CD, and variables of interest. Approximately 62% (n = 118) of the girls met criteria for CD. Depending on the instrument that was used to assess the LPE specifier criteria, 26% to 37% of the girls with CD met criteria for the LPE specifier symptom threshold (CD + LPE). Overall, CD + LPE girls were not significantly different from CD-only girls regarding psychiatric morbidity (i.e., attention-deficit/hyperactivity disorder, oppositional defiant disorder, substance use disorder, major depression, and anxiety disorders). However, CD + LPE girls were more aggressive, rule-breaking, delinquent, and had higher levels of psychopathic traits than CD-only girls. This study supports the view that the LPE specifier identifies a group of seriously antisocial individuals, but could not replicate previous findings that the LPE specifier symptom threshold identifies CD individuals who exhibit more psychiatric morbidity than CD individuals who are without the specifier symptom threshold. These findings altogether suggest that the clinical usefulness of the DSM-5 specifier for the diagnosis of CD is restricted, at least in detained girls. © 2015 American Psychological Association.


Lindeman J.H.,Leiden University
Expert Review of Cardiovascular Therapy | Year: 2015

An aneurysm of the abdominal aorta is a common pathology and a major cause of sudden death in the elderly. Currently, abdominal aortic aneurysms (AAAs) can only be treated by surgery and an effective medical therapy is urgently missing. The pathophysiology of AAAs is complex and is believed to be best described as a comprehensive inflammatory response with an accompanying proteolytic imbalance; the latter being held responsible for the progressive weakening of the aortic wall. Remarkably, while interference in inflammatory and/or proteolytic cascades proves highly effective in preclinical studies, emerging clinical studies consistently fail to show a benefit. In fact, some anti-inflammatory interventions appear to adversely influence the disease process. Altogether, recent clinical observations not only challenge the prevailing concepts of AAA progression, but also raise doubt on the translatability of findings from rodent models for growing AAA. © 2015 Informa UK, Ltd.


Marijnen C.A.M.,Leiden University
The Lancet Oncology | Year: 2015

Improved treatment strategies have eliminated local control as the major problem in rectal cancer. With increasing awareness of long-term toxic effects in survivors of rectal cancer, organ-preservation strategies are becoming more popular. After chemoradiotherapy, both watchful waiting and local excision are used as possible alternatives for radical surgery. Although these seem attractive strategies, many issues about the safety of organ preservation remain. Additionally, radiotherapy strategies are mainly aimed at intermediate and high-risk rectal tumours, and adaptation of this standard practice for a completely new treatment indication has yet to start. This Review will discuss the options and problems of organ preservation, and address the research questions that need to be answered in the coming years, with a specific focus on radiotherapy. © 2015 Elsevier Ltd.


Doxiadis I.I.N.,Leiden University
Frontiers in Immunology | Year: 2012

Long lasting debates in the past questioned the relevance of any sort of compatibility in post mortal kidney transplantation. It is for no say that fully compatible transplants have the highest chances for a long patient and graft survival. In the present report the use of HLA-DR as a representative of the Major Histocompatibility Complex class II genes in the allocation of organs is discussed. The major arguments are the easiness to offer to patients a compatible graft in a relatively short waiting time, an increase in graft survival, the less sensitization during the transplantation period, and the lower waiting time for a retransplant. Even if the number of organ donors remains the same a lowering of the mean waiting time is expected because of the longer period of graft survival. © 2012 Doxiadis.


Holkers M.,Leiden University
Nature Methods | Year: 2014

Engineered sequence-specific nucleases and donor DNA templates can be customized to edit mammalian genomes via the homologous recombination (HR) pathway. Here we report that the nature of the donor DNA greatly affects the specificity and accuracy of the editing process following site-specific genomic cleavage by transcription activator-like effector nucleases (TALENs) and clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 nucleases. By applying these designer nucleases together with donor DNA delivered as protein-capped adenoviral vector (AdV), free-ended integrase-defective lentiviral vector or nonviral vector templates, we found that the vast majority of AdV-modified human cells underwent scarless homology-directed genome editing. In contrast, a significant proportion of cells exposed to free-ended or to covalently closed HR substrates were subjected to random and illegitimate recombination events. These findings are particularly relevant for genome engineering approaches aiming at high-fidelity genetic modification of human cells.


van Belzen M.,Leiden University
European Journal of Human Genetics | Year: 2016

Whole-exome sequencing of a patient with intellectual disability and without recognisable phenotype yielded a mutation in the intron20 splice donor site of CREBBP. Mutations at different positions within the same intron20 splice donor site were observed in three patients clinically suspected as having Rubinstein-Taybi syndrome (RSTS). All mutations were de novo and likely disease-causing. To investigate a putative difference in splicing between the patient without RSTS phenotype and the three patients with the RSTS phenotype, we analysed the effects of these mutations on splicing of the pre-mRNA of CREBBP. As no RNA of patients was available, we generated a new and improved exon-trap vector, pCDNAGHE, and tested the effect of the various mutations on splicing in vitro. All mutations lead to skipping of exon20. In one of the patients with an RSTS phenotype, there was also some normal splicing detectable. We conclude that the splicing pattern obtained by exon-trapping cannot explain the difference in phenotype between the patient without the RSTS phenotype and the patients with clinical RSTS. Patient or tissue-specific splice effects as well as modifying genes likely will explain the difference in phenotype.European Journal of Human Genetics advance online publication, 11 May 2016; doi:10.1038/ejhg.2016.47. © 2016 Macmillan Publishers Limited


Paltansing S.,Leiden University
Emerging infectious diseases | Year: 2013

A prospective cohort study was performed among travelers from the Netherlands to investigate the acquisition of carbapenemase-producing Enterobacteriaceae (CP-E) and extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) and associated risk factors. Questionnaires were administered and rectal swab samples were collected and tested before and after traveler return. Of 370 travelers, 32 (8.6%) were colonized with ESBL-E before trave,; 113 (30.5%) acquired an ESBL-E during travel, and 26 were still colonized 6 months after return. No CP-E were found. Independent risk factors for ESBL-E acquisition were travel to South and East Asia. Multilocus sequence typing showed extensive genetic diversity among Escherichia coli. Predominant ESBLs were CTX-M enzymes. The acquisition rate, 30.5%, of ESBL-E in travelers from the Netherlands to all destinations studied was high. Active surveillance for ESBL-E and CP-E and contact isolation precautions may be recommended at admission to medical facilities for patients who traveled to Asia during the previous 6 months.


While disruption of alternative splicing underlies many diseases, modulation of splicing using antisense oligonucleotides (AONs) can have therapeutic implications. The most notable example is Duchenne muscular dystrophy (DMD), where antisense-mediated exon skipping can restore the open reading frame and allow the synthesis of partly functional dystrophin proteins instead of non-functional ones. This approach is currently tested in early phase clinical trials. In this review the development of the exon skipping approach in patient-derived cell cultures, animal models and patients is described and hurdles that have to be overcome to make this personalized medicine type approach widely applicable are discussed. © 2010 Landes Bioscience.


Spieksma F.M.,Leiden University
Probability in the Engineering and Informational Sciences | Year: 2015

The existence of a moment function satisfying a drift function condition is well known to guarantee non-explosiveness of the associated minimal Markov process (cf. [1,9]), under standard technical conditions. Surprisingly, the reverse is true as well for a countable space Markov process. We prove this result by showing that recurrence of an associated jump process, that we call the α-jump process, is equivalent to non-explosiveness. Non-explosiveness corresponds in a natural way to the validity of the Kolmogorov integral relation for the function identically equal to 1. In particular, we show that positive recurrence of the α-jump chain implies that all bounded functions satisfy the Kolmogorov integral relation. We present a drift function criterion characterizing positive recurrence of this α-jump chain. Suppose that to a drift function V there corresponds another drift function W, which is a moment with respect to V. Via a transformation argument, the above relations hold for the transformed process with respect to V. Transferring the results back to the original process, allows to characterize the V-bounded functions that satisfy the Kolmogorov forward equation. © 2015 Cambridge University Press.


Hypoxia-inducing transcription factor-1α (HIF-1α) in hypoxic tumors induces the TNF receptor family member CD137 on tumor-infi ltrating lymphocytes. This can be exploited for intratumoral low-dose injection of effective systemic immunotherapy with agonist CD137-specifi c monoclonal antibodies that induce circulation of systemic tumor-specifi c effector T cells capable of eradicating distant metastases. © 2012 American Association for Cancer Research.


Brinks V.,University Utrecht | Jiskoot W.,Leiden University | Schellekens H.,University Utrecht
Pharmaceutical Research | Year: 2011

Immunogenicity of therapeutic proteins lowers patient well-being and drastically increases therapeutic costs. Preventing immunogenicity is an important issue to consider when developing novel therapeutic proteins and applying them in the clinic. Animal models are increasingly used to study immunogenicity of therapeutic proteins. They are employed as predictive tools to assess different aspects of immunogenicity during drug development and have become vital in studying the mechanisms underlying immunogenicity of therapeutic proteins. However, the use of animal models needs critical evaluation. Because of species differences, predictive value of such models is limited, and mechanistic studies can be restricted. This review addresses the suitability of animal models for immunogenicity prediction and summarizes the insights in immunogenicity that they have given so far. © 2011 The Author(s).


Hugen N.,Radboud University Nijmegen | Van de Velde C.J.H.,Leiden University | De Wilt J.H.W.,Radboud University Nijmegen | Nagtegaal I.D.,Radboud University Nijmegen
Annals of Oncology | Year: 2014

Background: Clinical studies regarding colorectal cancer (CRC) have suggested differences in metastatic patterns between mucinous adenocarcinoma (MC), signet-ring cell carcinoma (SRCC) and the more common adenocarcinoma (AC). The current study systematically evaluates metastatic patterns of different histological subtypes in CRC patients and analyzes metastatic disease upon primary tumor localization. Patients and methods: A nationwide retrospective review of pathological records of 5817 patients diagnosed with CRC who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch pathology registry (PALGA). To substantiate clinical relevance, metastatic patterns were compared with the prospective randomized multicenter Total Mesorectal Excision (TME) trial, which investigated efficacy of preoperative radiotherapy in rectal cancer patients. Results: In the autopsy study, 1675 patients had metastatic disease. MC and SRCC patients more frequently had metastatic disease (33.9% and 61.2% versus 27.6%; P < 0.0001) and had metastases at multiple sites more often compared with AC patients (58.6% and 70.7% versus 49.9%; P = 0.001). AC predominantly metastasized to the liver, and MC and SRCC more frequently had peritoneal metastases. Metastatic patterns were also related to the primary tumor site, with a high rate of abdominal metastases in colon cancer patients, whereas rectal cancer patients more often had metastases at extra-abdominal sites. Results from the TME trial confirmed findings in rectal cancer patients from the autopsy study. Conclusion: There are profound differences in metastatic patterns between histological subtypes and the localization of the primary tumor in CRC. Findings from this study should encourage to take these factors into account for follow-up strategies and future studies. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Markers for longevity that reflect the health condition and predict healthy aging are extremely scarce. Such markers are, however, valuable in aging research. It has been shown previously that the N-glycosylation pattern of human immunoglobulin G (IgG) is age-dependent. Here we investigate whether N-linked glycans reflect early features of human longevity. The Leiden Longevity Study (LLS) consists of nonagenarian sibling pairs, their offspring, and partners of the offspring serving as control. IgG subclass specific glycosylation patterns were obtained from 1967 participants in the LLS by MALDI-TOF-MS analysis of tryptic IgG Fc glycopeptides. Several regression strategies were applied to evaluate the association of IgG glycosylation with age, sex, and longevity. The degree of galactosylation of IgG decreased with increasing age. For the galactosylated glycoforms the incidence of bisecting GlcNAc increased as a function of age. Sex-related differences were observed at ages below 60 years. Compared to males, younger females had higher galactosylation, which decreased stronger with increasing age, resulting in similar galactosylation for both sexes from 60 onwards. In younger participants (<60 years of age), but not in the older age group (>60 years), decreased levels of non-galactosylated glycoforms containing a bisecting GlcNAc reflected early features of longevity. We here describe IgG glycoforms associated with calendar age at all ages and the propensity for longevity before middle age. As modulation of IgG effector functions has been described for various IgG glycosylation features, a modulatory effect may be expected for the longevity marker described in this study.


Willemze R.,Leiden University
Giornale Italiano di Dermatologia e Venereologia | Year: 2012

Primary cutaneous lymphomas are a heterogeneous group of T-cell and B-cell neoplasms that present in the skin without any evidence of extracutaneous disease at the time of diagnosis. In 1980 primary cutaneous lymphomas other than mycosis fungoides, Sezary syndrome and some related disorders, collectively termed cutaneous T-cell lymphoma had not yet been recognized. This historic review describes the history of cutaneous lymphoma research in Europe over the last thirty years. European collaborative studies by dermatologists and pathologists, often coordinated by the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Group, resulted in the definition of new types of cutaneous T-cell lymphomas (CTCL) and cutaneous B-cell lymphomas (CBCL), and the development of consensus classifications for primary cutaneous lymphomas (EORTC classification; WHO-EORTC classification; WHO classification 2008), which resulted in better diagnosis and treatment of these diseases. More recent activities described herein are the development of guidelines for staging, treatment and the design of clinical trials, often in close collaboration with the International Society for Cutaneous Lymphomas, the formation of an EORTC CTCL trials platform and attempts to translate the results of molecular genetic studies into clinical practise. In this review the importance of a multidisciplinary approach and continued international collaboration not only in clinical trials and guideline development, but also in basic research is emphasized.


Bot I.,Leiden University | Biessen E.A.L.,Maastricht University
Thrombosis and Haemostasis | Year: 2011

The mast cell, a potent inflammatory cell type, is widely distributed over several tissues, but particularly prominent at the interface exposed to the environment to act in the first line of defense against pathogens. Upon activation mast cells release granules, which contain a large panel of mediators, including neutral proteases (e.g. chymase and tryptase), cathepsins, heparin, histamine and a variety of cytokines and growth factors. While mast cells have been demonstrated to be critically involved in a number of Th2 dominated diseases such as asthma and allergy, recent investigations have now also implicated mast cells in the pathogenesis of atherosclerosis and acute cardiovascular syndromes. In this review, we will discuss the contribution of mast cells to the initiation and progression of atherosclerosis and gauge the therapeutic opportunities of mast cell targeted intervention in acute cardiovascular syndromes. © Schattauer 2011.


Hoeben R.C.,Leiden University
Cold Spring Harbor Perspectives in Biology | Year: 2013

Adenoviruses have attracted much attention as probes to study biological processes such as DNA replication, transcription, splicing, and cellular transformation. More recently these viruses have been used as gene-transfer vectors and oncolytic agents. On the other hand, adenoviruses are notorious pathogens in people with compromised immune functions. This article will briefly summarize the basic replication strategy of adenoviruses and the key proteins involved and will deal with the new developments since 2006. In addition, we will cover the development of antivirals that interfere with human adenovirus (HAdV) rep-lication and the impact of HAdV on human disease. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Verra W.C.,Leiden University
The Cochrane database of systematic reviews | Year: 2013

The functional and clinical basis on which to choose whether or not to retain the posterior cruciate ligament during total knee arthroplasty surgery remained unclear after a Cochrane systematic review and statistically significant differences between the groups. In the subgroup analyses that allowed pooling of the results of the different studies, no homogeneous statistically significant differences were identified. The methodological quality and the quality of reporting of the studies were highly variable. With respect to range of motion, pain, clinical, and radiological outcomes, no clinically relevant differences were found between total knee arthroplasty with retention or sacrifice of the posterior cruciate ligament. Two statistically significant differences were found; range of motion was 2.4 ° higher in the posterior cruciate ligament sacrificing group, however results were heterogeneous; and the mean functional Knee Society Score was 2.3 points higher in the posterior cruciate ligament sacrificing group. These differences are clinically not relevant.


McCarthy J.F.,Australian National University | Vel J.A.C.,Leiden University | Afiff S.,University of Indonesia
Journal of Peasant Studies | Year: 2012

While the size and speculative nature of land transactions in the wake of energy, food and climate crises have surprised observers, the reasons for partial implementation of many land developments remain largely unexamined. This contribution investigates trajectories of land acquisition and enclosure by analyzing four acquisition processes in Indonesia - those associated with rice, oil palm, Jatropha and carbon sequestration - considering their implications for comparative studies elsewhere. The paper finds that current patterns of land use change represent a continuation of ongoing land transformation processes. It describes the logic leading to partial realization of large-scale schemes. Highlighting the importance of interactions between formal and vernacular rural land development processes, the essay concludes that many large-scale schemes are better understood as virtual land acquisitions. © 2012 Copyright Taylor and Francis Group, LLC.


Kroes G.-J.,Leiden University | Diaz C.,Autonomous University of Madrid
Chemical Society Reviews | Year: 2016

We review the state-of-the art in dynamics calculations on the reactive scattering of H2 from metal surfaces, which is an important model system of an elementary reaction that is relevant to heterogeneous catalysis. In many applications, quantum dynamics and classical trajectory calculations are performed within the Born-Oppenheimer static surface model. However, ab initio molecular dynamics (AIMD) is finding increased use in applications aimed at modeling the effect of surface phonons on the dynamics. Molecular dynamics with electronic friction has been used to model the effect of electron-hole pair excitation. Most applications are still based on potential energy surfaces (PESs) or forces computed with density functional theory (DFT), using a density functional within the generalized gradient approximation to the exchange-correlation energy. A new development is the use of a semi-empirical version of DFT (the specific reaction parameter (SRP) approach to DFT). We also discuss the accurate methods that have become available to represent electronic structure data for the molecule-surface interaction in global PESs. It has now become possible to describe highly activated H2 + metal surface reactions with chemical accuracy using the SRP-DFT approach, as has been shown for H2 + Cu(111) and Cu(100). However, chemical accuracy with SRP-DFT has yet to be demonstrated for weakly activated systems like H2 + Ru(0001) and non-activated systems like H2 + Pd(111), for which SRP DFs are not yet available. There is now considerable evidence that electron-hole pair (ehp) excitation does not need to be modeled to achieve the (chemically) accurate calculation of dissociative chemisorption and scattering probabilities. Dynamics calculations show that phonons can be safely neglected in the chemically accurate calculation of sticking probabilities on cold metal surfaces for activated systems, and in the calculation of a number of other observables. However, there is now sufficient evidence to suggest that the decision on whether or not to neglect phonons should be taken with care, with appropriate consideration of the observable to be computed and of the relevant surface temperature. AIMD calculations have provided valuable insights into the mechanisms that are operative in the dissociative adsorption and absorption of hydrogen on/in precovered metal surfaces. Classical and quantum dynamics calculations have shown that the reaction probability of H2 on Pt surfaces consisting of (100) steps and (111) terraces can to a very good approximation be computed as a weighted average of the reactivities on the steps and terraces. Progress obtained with dynamics calculations on the scattering of H2 from alloys and from simple low index metal surfaces is also reported. Insights that may be obtained on the reactivity of a metal surface from the prominent presence of out-of-plane diffraction or, conversely, the complete absence of diffraction, are discussed. A new field has been opened up by experiments on H2 scattering from surfaces at fast grazing incidence, and we discuss new predictions regarding diffraction and dissociative scattering of H2 under such conditions. © 2016 The Royal Society of Chemistry.


Noordenbos G.,Leiden University
Eating Disorders | Year: 2011

In the treatment of eating disorders (ED), no consensus exists on relevant criteria for recovery and goals for treatment. Which criteria do ED patients and therapists evaluate as most relevant for recovery? And do patients and therapists differ in their evaluations? This article presents a review of research on the opinions about recovery criteria of former patients and therapists. Criteria most often mentioned by the patients could be divided into the following themes: eating and drinking; physical activity and exercising; attitude towards food and weight; body evaluation; relaxation; physical recovery; psychological recovery; emotion regulation; social relations; sexual attitude; and comorbidity. Only slight differences were found between the opinions of former patients and therapists. © Taylor & Francis Group, LLC.


Assendelft W.J.,Leiden University
Cochrane database of systematic reviews (Online) | Year: 2013

Low-back pain is a costly illness for which spinal manipulative therapy is commonly recommended. Previous systematic reviews and practice guidelines have reached discordant results on the effectiveness of this therapy for low-back pain. To resolve the discrepancies related to the use of spinal manipulative therapy and to update previous estimates of effectiveness, by comparing spinal manipulative therapy with other therapies and then incorporating data from recent high-quality randomized, controlled trials (RCTs) into the analysis. The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and CINAHL were electronically searched from their respective beginning to January 2000, using the Back Group search strategy; references from previous systematic reviews were also screened. Randomized, controlled trials (RCT) that evaluated spinal manipulative therapy for patients with low-back pain, with at least one day of follow-up, and at least one clinically-relevant outcome measure. Two authors, who served as the authors for all stages of the meta-analysis, independently extracted data from unmasked articles. Comparison treatments were classified into the following seven categories: sham, conventional general practitioner care, analgesics, physical therapy, exercises, back school, or a collection of therapies judged to be ineffective or even harmful (traction, corset, bed rest, home care, topical gel, no treatment, diathermy, and minimal massage). Thirty-nine RCTs were identified. Meta-regression models were developed for acute or chronic pain and short-term and long-term pain and function. For patients with acute low-back pain, spinal manipulative therapy was superior only to sham therapy (10-mm difference [95% CI, 2 to 17 mm] on a 100-mm visual analogue scale) or therapies judged to be ineffective or even harmful. Spinal manipulative therapy had no statistically or clinically significant advantage over general practitioner care, analgesics, physical therapy, exercises, or back school. Results for patients with chronic low-back pain were similar. Radiation of pain, study quality, profession of manipulator, and use of manipulation alone or in combination with other therapies did not affect these results. There is no evidence that spinal manipulative therapy is superior to other standard treatments for patients with acute or chronic low-back pain.


Visser J.,Leiden University
The Cochrane database of systematic reviews | Year: 2013

Adequate contraceptive advice is important in both women with diabetes mellitus type 1 and type 2 to reduce the risk of maternal and infant morbidity and mortality in unplanned pregnancies. A wide variety of contraceptives are available for these women. However, hormonal contraceptives might influence carbohydrate and lipid metabolism and increase micro- and macrovascular complications, so caution in selecting a contraceptive method is required. To investigate whether progestogen-only, combined estrogen and progestogen or non-hormonal contraceptives differ in terms of effectiveness in preventing pregnancy, in their side effects on carbohydrate and lipid metabolism, and in long-term complications such as micro- and macrovascular disease when used in women with diabetes mellitus. The search was performed in CENTRAL, MEDLINE, EMBASE, POPLINE, CINAHL, WorldCat, ECO, ArticleFirst, the Science Citation Index, the British Library Inside, and reference lists of relevant articles. The last search was performed in January 2013. In addition, experts in the field and pharmaceutical companies marketing contraceptives were contacted to identify published, unpublished or ongoing studies. Randomised and quasi-randomised controlled trials that studied women with diabetes mellitus comparing: 1. hormonal versus non-hormonal contraceptives; 2. progestogen-only versus estrogen and progestogen contraceptives; 3. contraceptives containing < 50 μg estrogen versus contraceptives containing ≥ 50 μg estrogen; and 4. contraceptives containing first-, second- and third-generation progestogens, drospirenone and cyproterone acetate. The principal outcomes were contraceptive effectiveness, diabetes control, lipid metabolism and micro- and macrovascular complications. Two investigators evaluated the titles and abstracts identified from the literature search. Quality assessment was performed independently with discrepancies resolved by discussion or consulting a third review author. Because the trials differed in studied contraceptives, participant characteristics and methodological quality, we could not combine the data in a meta-analysis. The trials were therefore examined on an individual basis and narrative summaries were provided. Four randomised controlled trials were included. No unintended pregnancies were reported during the study periods. Only one trial was of good methodological quality. It compared the influence of a levonorgestrel-releasing intrauterine device (IUD) versus a copper IUD on carbohydrate metabolism in women with type 1 diabetes mellitus. No significant difference was found between the two groups. The other three trials were of limited methodological quality. Two compared progestogen-only pills with different estrogen and progestogen combinations, and one also included the levonorgestrel-releasing IUD and copper IUD. The trials reported that blood glucose levels remained stable during treatment with most regimens. Only high-dose combined oral contraceptives and 30 μg ethinylestradiol + 75 μg gestodene were identified as slightly impairing glucose homeostasis. The three studies found conflicting results regarding lipid metabolism. Some combined oral contraceptives appeared to have a minor adverse effect while others appeared to slightly improve lipid metabolism. The copper IUD and progestogen-only oral contraceptives also slightly improved lipid metabolism and no influence was seen while using the levonorgestel-releasing IUD. Only one study reported on micro- and macrovascular complications. It observed no signs or symptoms of thromboembolic incidents or visual disturbances, however study duration was short. Only minor adverse effects were reported in two studies. The four included randomised controlled trials in this systematic review provided insufficient evidence to assess whether progestogen-only and combined contraceptives differ from non-hormonal contraceptives in diabetes control, lipid metabolism and complications. Three of the four studies were of limited methodological quality, sponsored by pharmaceutical companies and described surrogate outcomes. Ideally, an adequately reported, high-quality randomised controlled trial analysing both intermediate outcomes (that is glucose and lipid metabolism) and true clinical endpoints (micro- and macrovascular disease) in users of combined, progestogen-only and non-hormonal contraceptives should be conducted. However, due to the low incidence of micro- and macrovascular disease and accordingly the large sample size and long follow-up period needed to observe differences in risk, a randomised controlled trial might not be the ideal design.


Breedveld F.C.,Leiden University | Combe B.,Montpellier University Hospital Center
Arthritis Research and Therapy | Year: 2011

Treatment strategies for rheumatoid arthritis (RA) will continue to evolve as new drugs are developed, as new data become available, and as our potential to achieve greater and more consistent outcomes becomes more routine. Many patients will find both symptom relief and modest control of their disease with disease-modifying antirheumatic drugs (DMARDs), yet this course of therapy is clearly not effective in all patients. In fact, despite strong evidence that intensive treatment in the early stages of RA can slow or stop disease progression and may prevent disability, many patients continue to be managed in a stepwise manner and are treated with an ongoing monotherapy regimen with DMARDs. There is now a large body of evidence demonstrating the success of treating RA patients with anti-TNF therapy, usually in combination with methotrexate. As a result of the increased use of anti-TNF therapy, treatment paradigms have changed - and our practice is beginning to reflect this change. In the present review, we summarize the salient points of several recently proposed and emerging treatment paradigms with an emphasis on how these strategies may impact future practice. © 2011 Breedveld and Combe; licensee BioMed Central Ltd.


Jozwiak M.,Leiden University
The Cochrane database of systematic reviews | Year: 2013

Induction of labour is a common obstetric intervention, with between 20% and 30% of births reported to occur following induction of labour. Women with a prior caesarean delivery have an increased risk of uterine rupture, particularly when labour is induced. For women who have had a previous caesarean birth and who require induction of labour in a subsequent pregnancy, it is unclear which method of cervical ripening and labour induction is preferable. To assess the benefits and harms associated with different methods used to induce labour in women who have had a previous caesarean birth and require induction of labour in a subsequent pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2012) and reference lists of retrieved studies. All randomised controlled trials comparing any method of third trimester cervical ripening or labour induction, with placebo/no treatment or other methods in women with prior caesarean section requiring labour induction in a subsequent pregnancy were included.Methods of cervical ripening or labour induction could include: prostaglandin medication (including oral or vaginal prostaglandin E2 (PGE2) and misoprostol); mifepristone; mechanical methods (including Foley catheters and double balloon catheters); oxytocin, or placebo. The two review authors independently assessed studies for inclusion and trial quality. Any disagreement was resolved by discussion. Both review authors independently extracted data and data were checked for accuracy. Two studies (involving a total of 80 women) were included. However, the two included studies used different methods and thus, meta-analysis was not appropriate. The two included studies compared 2.5 mg vaginal PGE2 inserts versus oxytocin (Taylor and colleagues) and misoprostol versus oxytocin (Wing and colleagues). Risk of bias in the included studies was judged 'low' and 'unclear' respectively.Vaginal PGE2 inserts versus oxytocin - Taylor and colleagues included 42 women, equally distributed over both groups. Baseline characteristics, and reasons for labour induction were comparable between the groups. There were no significant differences in any of the outcome measures reported (caesarean section, instrumental vaginal deliveries, epidural analgesia, Apgar score, perinatal death). One uterine rupture occurred in the prostaglandin group, after the use of prostaglandins and oxytocin, while no ruptures occurred in the oxytocin group (one study, 42 women; risk ratio (RR) 3.00, 95% confidence interval (CI) 0.13 to 69.70).Misoprostol versus oxytocin - the study conducted by Wing and colleagues was stopped prematurely due to safety concerns after the inclusion of 38 women. Seventeen women had been included in the misoprostol group, and 21 women in the oxytocin group. There were no significant difference in the only outcome measure reported by the authors, uterine rupture, which occurred twice in the misoprostol group, and did not occur in the oxytocin group (one study; 38 women; RR 6.11, 95% CI 0.31 to 119.33). There is insufficient information available from randomised controlled trials on which to base clinical decisions regarding the optimal method of induction of labour in women with a prior caesarean birth.


To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term. Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT)). Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008. Pregnant women who had a singleton pregnancy beyond 36+0 weeks' gestation with suspected intrauterine growth restriction. Induction of labour or expectant monitoring. The primary outcome was a composite measure of adverse neonatal outcome, defined as death before hospital discharge, five minute Apgar score of less than 7, umbilical artery pH of less than 7.05, or admission to the intensive care unit. Operative delivery (vaginal instrumental delivery or caesarean section) was a secondary outcome. Analysis was by intention to treat, with confidence intervals calculated for the differences in percentages or means. 321 pregnant women were randomly allocated to induction and 329 to expectant monitoring. Induction group infants were delivered 10 days earlier (mean difference -9.9 days, 95% CI -11.3 to -8.6) and weighed 130 g less (mean difference -130 g, 95% CI -188 g to -71 g) than babies in the expectant monitoring group. A total of 17 (5.3%) infants in the induction group experienced the composite adverse neonatal outcome, compared with 20 (6.1%) in the expectant monitoring group (difference -0.8%, 95% CI -4.3% to 3.2%). Caesarean sections were performed on 45 (14.0%) mothers in the induction group and 45 (13.7%) in the expectant monitoring group (difference 0.3%, 95% CI -5.0% to 5.6%). In women with suspected intrauterine growth restriction at term, we found no important differences in adverse outcomes between induction of labour and expectant monitoring. Patients who are keen on non-intervention can safely choose expectant management with intensive maternal and fetal monitoring; however, it is rational to choose induction to prevent possible neonatal morbidity and stillbirth. International Standard Randomised Controlled Trial number ISRCTN10363217.


Aartsma-Rus A.,Leiden University
Methods in Molecular Biology | Year: 2012

Antisense-mediated exon skipping to restore the disrupted dystrophin reading frame is currently in clinical trials for Duchenne muscular dystrophy. This chapter describes the rationale of this approach and gives an overview of in vitro and in vivo experiments with antisense oligonucleotides and antisense genes. Finally, an overview of clinical trials is given and outstanding questions and hurdles are discussed. © 2012 Springer Science+Business Media, LLC.


Aartsma-Rus A.,Leiden University
Methods in Molecular Biology | Year: 2012

Antisense-mediated exon skipping is an attractive tool to study gene function as well as a promising therapeutic application for a number of diseases. In order for antisense oligonucleotides (AONs) to induce effective exon skipping during pre-mRNA splicing, they have to fulfill certain criteria. These include resistance against endo-and exonucleases and RNase H-induced cleavage and suitable thermodynamic properties. Furthermore, the AON-target sequence needs to be accessible and should contain sequence motives that are essential for proper inclusion of the exon into the mRNA. For most genes, only a few AONs have been designed, with the exception of the DMD gene, for which over 400 AONs targeting the majority of DMD exons have been reported. This allows retrospective analysis of effective and ineffective AONs to obtain guidelines to optimize future AON design. © 2012 Springer Science+Business Media, LLC.


Sevink A.,Leiden University | Schmid F.,Johannes Gutenberg University Mainz
Macromolecules | Year: 2011

We present a hybrid numerical method to introduce hydrodynamics in dynamic self-consistent field (SCF) studies of inhomogeneous polymer systems. It solves a set of coupled dynamical equations: The Navier-Stokes equations for the fluid flow, and SCF-based convection-diffusion equations for the evolution of the local monomer compositions. The Navier-Stokes equations are simulated by the lattice Boltzmann method and the dynamic self-consistent field equations are solved by a finite difference scheme. Two applications are presented: First, we study microphase separation in symmetric and asymmetric block copolymer melts with various values of shear and bulk viscosities, comparing the results to those obtained with purely diffusive dynamics. Second, we investigate the effect of hydrodynamics on vesicle formation in amphiphilic block copolymer solutions. In agreement with previous studies, hydrodynamic interactions are found to have little effect on the microphase separation at early times, but they substantially accelerate the process of structure formation at later times. Furthermore, they also contribute to selecting the pathway of vesicle formation, favoring spherical intermediates over aspherical (disklike) ones. © 2011 American Chemical Society.


Context: Studies on 24-hour growth hormone (GH) secretion are rare. The influence of sex, age and adiposity are well recognized but generally derived from specific selected subject groups, not spanning sexes, many age decades, and a range of body weights. Objective: The goal was to investigate GH dynamics in a group of 130 healthy adult subjects, both men and women, across 5 age decades, and a 2.5 fold range of body mass index (BMI). Methods: GH was measured by a sensitive immunofluorometric assay. Secretion parameters were quantified by automated deconvolution and relative pattern randomness by approximate entropy (ApEn). Results: Median age was 40, range 20-77 year. Median BMI was 26, range 18.3-49.8 kg/m2. Pulsatile 24-hour GH secretion was negatively correlated with age (p = 0.002) and BMI (p < 0.0001). Basal GH secretion negatively correlated with BMI (p = 0.003) and not with age. The sex-dependent GH secretion (larger in women) was no longer detectable after 50 year. IGF-1 levels were lower in women after 50 year compared with men of similar age. ApEn showed age-related increase in both sexes and was higher in premenopausal and postmenopausal women than men of comparable age (p < 0.0001). A single fasting GH measurement is non-informative of 24-hour GH secretion. Conclusion: BMI dominates the negative regulation of 24-hour GH secretion across 5 decades of age in this till now largest cohort of healthy adults, who underwent 24-hour blood sampling. Sex also impacts GH secretion before age 50 year and its regularity at all ages. Serum IGF-I differences partly depend on pre- or postmenopausal state. Finally, a single GH measurement is not informative of 24-hour GH secretion. © 2015 S. Karger AG, Basel Copyright © 2015, S. Karger AG. All rights reserved.


Costas R.,Leiden University | Bordons M.,Institute Estudios Documentales sobre Ciencia y Tecnologia IEDCYT
Scientometrics | Year: 2011

Scientific authorship has important implications in science since it reflects the contribution to research of the different individual scientists and it is considered by evaluation committees in research assessment processes. This study analyses the order of authorship in the scientific output of 1,064 permanent scientists at the Spanish CSIC (WoS, 1994-2004). The influence of age, professional rank and bibliometric profile of scientists over the position of their names in the byline of publications is explored in three different research areas: Biology and Biomedicine, Materials Science and Natural Resources. There is a strong trend for signatures of younger researchers and those in the lower professional ranks to appear in the first position (junior signing pattern), while more veteran or highly-ranked ones, who tend to play supervisory functions in research, are proportionally more likely to sign in the last position (senior signing pattern). Professional rank and age have an effect on authorship order in the three fields analysed, but there are inter-field differences. Authorship patterns are especially marked in the most collaboration-intensive field (i.e. Biology and Biomedicine), where professional rank seems to be more significant than age in determining the role of scientists in research as seen through their authorship patterns, while age has a more significant effect in the least collaboration-intensive field (Natural Resources). © 2011 The Author(s).


Mydosh J.A.,Leiden University | Oppeneer P.M.,Uppsala University
Reviews of Modern Physics | Year: 2011

This Colloquium reviews the 25 year quest to understand the continuous (second-order), mean-field-like phase transition occurring at 17.5 K in URu 2Si2. About ten years ago, the term "hidden order" (HO) was coined and has since been utilized to describe the unknown ordered state, whose origin cannot be disclosed by conventional solid-state probes, such as x rays, neutrons, or muons. The HO is able to support superconductivity at lower temperatures (Tc 1.5K), and when magnetism is developed with increasing pressure both the HO and the superconductivity are destroyed. Other ways of probing the HO are via Rh doping and large magnetic fields. During the last few years a variety of advanced techniques have been tested to probe the HO state and these attempts will be summarized. A digest of recent theoretical developments is also included. It is the objective of this Colloquium to shed additional light on the HO state and its associated phases in other materials. © 2011 American Physical Society.


Van Der Heijde D.,Leiden University | Maksymowych W.P.,University of Alberta
Annals of the Rheumatic Diseases | Year: 2010

Advances in the understanding of this group of arthritides over the past decade can be considered transformational from the perspective of basic mechanisms as well as clinical research focusing on the development of imaging technologies and a spectrum of standardised clinical outcomes that aim at a more comprehensive understanding of disease activity, functioning and disability, and prognosis. Prior to this decade, treatment was unsatisfactory and limited to physical modalities and non-steroidal anti-inflammatory agents, while diagnostic ascertainment primarily focused on clinical evaluation and plain radiography. Today, patients with spondyloarthritis (SpA) can look forward to earlier diagnosis and more effective treatment but significant challenges remain. This review will summarise the past decade's major accomplishments in the understanding of the basic mechanisms contributing to the development of SpA, outline those advances in clinical and imaging outcomes that have enabled major therapeutic advances and now permit a broader understanding of the early development of disease and its impact on patient well-being, and will describe new approaches to the development of diagnostic criteria that incorporate advances in imaging.


van Iterson M.,Leiden University
Statistical applications in genetics and molecular biology | Year: 2012

Among the most commonly applied microarray normalization methods are intensity-dependent normalization methods such as lowess or loess algorithms. Their computational complexity makes them slow and thus less suitable for normalization of large datasets. Current implementations try to circumvent this problem by using a random subset of the data for normalization, but the impact of this modification has not been previously assessed. We developed a novel intensity-dependent normalization method for microarrays that is fast, simple and can include weighing of observations. Our normalization method is based on the P-spline scatterplot smoother using all data points for normalization. We show that using a random subset of the data for normalization should be avoided as unstable results can be produced. However, in certain cases normalization based on an invariant subset is desirable, for example, when groups of samples before and after intervention are compared. We show in the context of DNA methylation arrays that a constant weighted P-spline normalization yields a more reliable normalization curve than the one obtained by normalization on the invariant subset only. Our novel intensity-dependent normalization method is simpler and faster than current loess algorithms, and can be applied to one- and two-colour array data, similar to normalization based on loess. An implementation of the method is currently available as an R package called TurboNorm from www.bioconductor.org.


Ramautar R.,Leiden University | De Jong G.J.,University Utrecht
Bioanalysis | Year: 2014

Metabolomics is the comprehensive analysis of low molecular weight compounds in biological samples such as cells, body fluids and tissues. Comprehensive profiling of metabolites in complex sample matrices with the current analytical toolbox remains a huge challenge. Over the past few years, liquid chromatography-mass spectrometry (LC-MS) and capillary electrophoresis-mass spectrometry (CE-MS) have emerged as powerful complementary analytical techniques in the field of metabolomics. This Review provides an update of the most recent developments in LC-MS and CE-MS for metabolomics. Concerning LC-MS, attention is paid to developments in column technology and miniaturized systems, while strategies are discussed to improve the reproducibility and the concentration sensitivity of CE-MS for metabolomics studies. Novel interfacing techniques for coupling CE to MS are also considered. Representative examples illustrate the potential of the recent developments in LC-MS and CE-MS for metabolomics. Finally, some conclusions and perspectives are provided. © 2014 Future Science Ltd.


Streets A.J.,University of Sheffield | Wessely O.,Cleveland Clinic | Peters D.J.,Leiden University | Ong A.C.,University of Sheffield
Human Molecular Genetics | Year: 2013

Mutations in PKD1 (85%) or PKD2 (15%) account for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). The ADPKD proteins, termed as polycystin-1 (PC1) and polycystin-2 (PC2), interact via their C-termini to form a receptor-ion channel complex whose function and regulation are not fully understood. Here, we report the first phosphorylated residue (Ser829) in PC2, whose dephosphorylation is mediated by PC1 binding through the recruitment of protein phosphatase-1 alpha (PP1α). Using a new phosphospecific antibody (pPC2) to this site, we demonstrate that Ser829 is phosphorylated by Protein kinase A (PKA) but remains constitutively phosphorylated in cells and tissues lacking PC1. cAMP increased pSer829 basolateral localization in MDCK cells in a time dependent manner and was essential for pronephric development in Xenopus embryos. When constitutively expressed, a complex phenotype associated with enhanced ATP-dependent ER Ca2+ release and loss of growth suppression was observed in cycling cells. These results reveal a reciprocal functional link between PC1 and PC2 which is critically dependent on their interaction. Unopposed cAMP stimulated hyperphosphorylation of PC2 in the absence of functional PC1 could contribute to cyst initiation in PKD1 patients and represents a new molecular paradigm in understanding ADPKD pathogenesis. © The Author 2013. Published by Oxford University Press. All rights reserved.


Marra V.,University of Heidelberg | Amendola L.,University of Heidelberg | Sawicki I.,University of Heidelberg | Valkenburg W.,University of Heidelberg | Valkenburg W.,Leiden University
Physical Review Letters | Year: 2013

There is an approximately 9% discrepancy, corresponding to 2.4σ, between two independent constraints on the expansion rate of the Universe: one indirectly arising from the cosmic microwave background and baryon acoustic oscillations and one more directly obtained from local measurements of the relation between redshifts and distances to sources. We argue that by taking into account the local gravitational potential at the position of the observer this tension - strengthened by the recent Planck results - is partially relieved and the concordance of the Standard Model of cosmology increased. We estimate that measurements of the local Hubble constant are subject to a cosmic variance of about 2.4% (limiting the local sample to redshifts z>0.010) or 1.3% (limiting it to z>0.023), a more significant correction than that taken into account already. Nonetheless, we show that one would need a very rare fluctuation to fully explain the offset in the Hubble rates. If this tension is further strengthened, a cosmology beyond the Standard Model may prove necessary. © 2013 American Physical Society.


Schram R.D.,Leiden University
Journal of Computational Physics | Year: 2013

We created an efficient algorithm suitable for graphics processing units (GPUs) to perform Monte Carlo simulations on a subset of reaction-diffusion models. The set of reaction-diffusion models that the algorithm is applied to represents a seemingly simplistic set of problems on a one-dimensional lattice, where each site contains either a particle or is empty. However, these systems exhibit non-equilibrium phase transitions, with very large finite-time corrections, which mandates a fast algorithm to simulate them. The algorithm presented here uses techniques that are specific to GPU programming, and combines these with multispin coding to create one of the fastest algorithms for reaction-diffusion models. As an example, the algorithm is applied to the pair contact process with diffusion (PCPD). Compared to a simple algorithm on the CPU, our GPU algorithm is approximately 4000 times faster. The GPU algorithm is roughly 55 times faster than an optimized version for the CPU. © 2013 Elsevier Inc.


Cavalli S.,CIBER ISCIII | Cavalli S.,Barcelona Institute for Research in Biomedicine | Albericio F.,CIBER ISCIII | Albericio F.,Barcelona Institute for Research in Biomedicine | And 2 more authors.
Chemical Society Reviews | Year: 2010

Peptides are particularly attractive as molecular building blocks in the bottom-up fabrication of supramolecular structures based on self-assembly and have potential in many important applications in the fields of biotechnology and bioengineering. In the first part of this critical review the main categories of peptide-based amphiphiles will be discussed by showing some relevant examples, which demonstrate the importance of amphiphilic peptides as molecular building blocks for nanostructures. In the second part of this review we will review the cross-disciplinary role of peptide-based supramolecular nanoarchitectures ranging from chemistry to biology, medicine, materials science, and engineering through discussing several examples of applied nanomaterials (216 references). © 2010 The Royal Society of Chemistry.


Van Den Broek P.,Leiden University | Van Den Broek P.,University of Minnesota
Science | Year: 2010

Texts form a powerful tool in teaching concepts and principles in science. How do readers extract information from a text, and what are the limitations in this process? Central to comprehension of and learning from a text is the construction of a coherent mental representation that integrates the textual information and relevant background knowledge. This representation engenders learning if it expands the reader's existing knowledge base or if it corrects misconceptions in this knowledge base. The Landscape Model captures the reading process and the influences of reader characteristics (such as working-memory capacity, reading goal, prior knowledge, and inferential skills) and text characteristics (such as content/structure of presented information, processing demands, and textual cues). The model suggests factors that can optimize-or jeopardize-learning science from text.


Westenberg J.J.M.,Leiden University
Current Cardiovascular Imaging Reports | Year: 2011

Prevalence of heart failure with preserved left ventricular ejection fraction amounts to 50% of all cases with heart failure. Diagnosis assessment requires evidence of left ventricular diastolic dysfunction. Currently, echocardiography is the method of choice for diastolic function testing in clinical practice. Various applications are in use and recommended criteria are followed for classifying the severity of dysfunction. Cardiovascular magnetic resonance (CMR) offers a variety of alternative applications for evaluation of diastolic function, some superior to echocardiography in accuracy and reproducibility, some being complementary. In this article, the role of the available CMR applications for diastolic function testing in clinical practice and research is reviewed and compared to echocardiography. © 2011 The Author(s).


van Zuuren E.J.,Leiden University
The Cochrane database of systematic reviews | Year: 2013

Sickle cell disease is one of the most common and severe genetic disorders in the world. It can be broadly divided into two distinct clinical phenotypes characterized by either haemolysis or vaso-occlusion. Pain is the most prominent symptom of vaso-occlusion, and hypercoagulability is a well-established pathogenic phenomenon in people with sickle cell disease. Low-molecular-weight heparins might control this hypercoagulable state through their anticoagulant effect. To assess the effects of low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches. We also searched abstract books of conference proceedings and several online trials registries for ongoing trials.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 6 December 2012. Randomised controlled clinical trials and controlled clinical trials that assessed the effects of low-molecular-weight heparins in the management of vaso-occlusive crises in people with sickle cell disease. Study selection, data extraction, assessment of risk of bias and analyses were carried out independently by the two review authors. One study (with an overall unclear to high risk of bias) comprising 253 participants was included. This study, with limited data, reported that pain severity at day two and day three was lower in the tinzaparin group than in the placebo group (P < 0.01, analysis of variance (ANOVA)) and additionally at day 4 (P < 0.05 (ANOVA)). Thus tinzaparin resulted in more rapid resolution of pain, as measured with a numerical pain scale. The mean difference in duration of painful crises was statistically significant at -1.78 days in favour of the tinzaparin group (95% confidence interval -1.94 to -1.62). Participants treated with tinzaparin had statistically significantly fewer hospitalisation days than participants in the group treated with placebo, with a mean difference of -4.98 days (95% confidence interval -5.48 to -4.48). Two minor bleeding events were reported as adverse events in the tinzaparin group, and none were reported in the placebo group. Based on the results of one study, evidence is incomplete to support or refute the effectiveness of low-molecular-weight heparins in people with sickle cell disease. Vaso-occlusive crises are extremely debilitating for sufferers of sickle cell disease; therefore well-designed placebo-controlled studies with other types of low-molecular-weight heparins, and in participants with different genotypes of sickle cell disease, still need to be carried out to confirm or dismiss the results of this single study.


van Zuuren E.J.,Leiden University
The Cochrane database of systematic reviews | Year: 2013

Hashimoto's thyroiditis is a common auto-immune disorder. The most common presenting symptoms may include anxiety, negative mood, depression, dry skin, cold intolerance, puffy eyes, muscle cramps and fatigue, deep voice, constipation, slow thinking and poor memory. Clinical manifestations of the disease are defined primarily by low levels of thyroid hormones; therefore it is treated by hormone replacement therapy, which usually consists of levothyroxine (LT4). Selenium might reduce antibody levels and result in a decreased dosage of LT4 and may provide other beneficial effects (e.g. on mood and health-related quality of life). To assess the effects of selenium supplementation on Hashimoto's thyroiditis. We searched the following databases up to 2 October 2012: CENTRAL in The Cochrane Library (2012, Issue 10), MEDLINE, EMBASE, and Web of Science; we also screened reference lists of included studies and searched several online trial registries for ongoing trials (5 November 2012). Randomised controlled clinical trials that assessed the effects of selenium supplementation for adults diagnosed with Hashimoto's thyroiditis. Study selection, data extraction, assessment of risk of bias, and analyses were carried out by two independent review authors. We assessed the quality of the evidence of included studies using GRADE. We were unable to conduct a meta-analysis because clinical heterogeneity between interventions that were investigated is substantial. Four studies at unclear to high risk of bias comprising 463 participants were included. The mean study duration was 7.5 months (range 3 to 18 months). One of our primary outcomes'change from baseline in health related quality of life'and two of our secondary outcomes'change from baseline in LT4 replacement dosage at end of the study' and 'economic costs'were not assessed in any of the studies. One study at high risk of bias showed statistically significant improvement in subjective well-being with sodium selenite 200 μg plus titrated LT4 compared with placebo plus titrated LT4 (relative risk (RR) 4.67, 95% confidence interval (CI) 1.61 to 13.50; P = 0.004; 36 participants; number needed to treat (NNT) = 2 (95% CI 2 to 3)).Selenomethionine 200 μg reduced the serum levels of anti-thyroid peroxidase antibodies compared with placebo in two studies (mean difference (MD) -917 U/mL, 95% CI -1056 to -778; P < 0.001; 85 participants) and (MD -345 IU/mL, 95% CI -359 to -331; P < 0.001; 169 participants). Pooling of the studies was not feasible due to marked clinical heterogeneity (I(2) = 99%). In a further comparison within the first study where selenomethionine was combined with LT4 the reduction in TPO antibodies was even more noticeable (MD -1508 U/mL, 95% CI -1671 to -1345; P < 0.001; 86 participants). In a third study, where LT4 was added to both intervention arms, a reduction in serum levels of anti-thyroid peroxidase antibodies favoured the selenomethionine arm as well (MD -235 IU/mL, 95% CI -374 to -95; P = 0.001; 88 participants). Although the changes from baseline were statistically significant in these three studies, their clinical relevance is unclear. Serum antibodies were not statistically significantly affected in the study comparing sodium selenite 200 μg plus titrated LT4 with placebo plus titrated LT4 (MD -25, 95% CI -181 to 131; P = 0.75; 36 participants).Adverse events were reported in two studies (1 of 85 and 1 of 88 participants, respectively). Selenium supplementation did not appear to have a statistically significant impact on the incidence of adverse events (RR 2.93, 95% CI 0.12 to 70.00; and RR 2.63, 95% CI 0.11 to 62.95). Results of these four studies show that evidence to support or refute the efficacy of selenium supplementation in people with Hashimoto's thyroiditis is incomplete. The current level of evidence for the efficacy of selenium supplementation in the management of people with Hashimoto's thyroiditis is based on four randomised controlled trials assessed at unclear to high risk of bias; this does not at present allow confident decision making about the use of selenium supplementation for Hashimoto's thyroiditis. This review highlights the need for randomised placebo-controlled trials to evaluate the effects of selenium in people with Hashimoto's thyroiditis and can ultimately provide reliable evidence to help inform clinical decision making.


Bayley J.P.,Leiden University
Current opinion in oncology | Year: 2012

A revival of interest in tumor metabolism is underway and here we discuss recent results with a focus on the central theme of the Warburg effect, aerobic glycolysis. The M2 tumor-specific isoform of pyruvate kinase has generated much interest, but it has now been reported that PKM2 is not specific to tumors. Despite this setback, the reciprocal regulation of PKM2, prolyl hydroxylase 3 and HIF-1 in a positive feedback loop shows that PKM2 is important to tumor metabolism. Hexokinase II was reported to be a crucial regulator of glycolysis in glioblastoma multiforme, and the importance of lactate dehydrogenase was underlined by evidence that a 'lactate-based dialog' exists between cancer cells and endothelial cells. A growing appreciation of the role of oncogenes and tumor suppressor genes in the Warburg effect was reflected in reports of the regulation of glutamine metabolism by p53, the role of c-Myc in the high glucose uptake of tumors, and the regulation of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) and ATP consumption by AKT. The sirtuins, SIRT3 and SIRT6, were also shown to play central roles in aerobic glycolysis and other aspects of tumor metabolism. The results discussed illustrate the growing integration of the previously distinct fields of molecular biological and metabolic cancer research and show that this synergy is beginning to yield a more complete and comprehensive understanding of the tumor cell.


De Marchi G.,European Space Agency | Paresce F.,Istituto di Astrofisica Spaziale e Fisica Cosmica | Zwart S.P.,Leiden University
Astrophysical Journal | Year: 2010

We show that we can obtain a good fit to the present-day stellar mass functions (MFs) of a large sample of young and old Galactic clusters in the range 0.1-10 M⊙ with a tapered power-law distribution function with an exponential truncation of the form dN/dm ∞ mα [1 - e-(m/mc)β]. The average value of the power-law index α is ∼ - 2, that of β is ∼2.5, whereas the characteristic mass mc is in the range 0.1-0.8 M⊙ and does not seem to vary in any systematic way with the present cluster parameters such as metal abundance, total cluster mass, or central concentration. However, mc shows a remarkable correlation with the dynamical age of the cluster, namely, mc/M⊙ 0.15 + 0.5 × τ3/4 dyn, where τdyn is the dynamical age taken as the ratio of cluster age and dissolution time. The small scatter seen around this correlation is consistent with the uncertainties in the estimated value of τdyn. We attribute the observed trend to the onset of mass segregation via two-body relaxation in a tidal environment, causing the preferential loss of low-mass stars from the cluster and hence a drift of the characteristic mass mc toward higher values. If dynamical evolution is indeed at the origin of the observed trend, it would seem plausible that high-concentration globular clusters, now with median mc 0.33 M⊙, were born with a stellar MF very similar to that measured today in the youngest Galactic clusters and with a value of mc 0.15 M⊙. This hypothesis is consistent with the absence of a turnover in the MF of the Galactic bulge down to the observational limit at ∼0.2 M⊙ and, if correct, it would carry the implication that the characteristic mass is not set by the thermal Jeans mass of the cloud. © 2010. The American Astronomical Society. All rights reserved.


Kunst M.J.J.,Leiden University
International Journal of Law and Psychiatry | Year: 2011

Feelings of revenge have often been found to correlate with symptoms of posttraumatic stress disorder (PTSD). Which PTSD symptom cluster prevails in this association is, however, unknown. Furthermore, previous studies suggest that revenge may be satisfied by perceptions of perpetrator punishment severity, but did not control for concurrent symptoms of PTSD. Therefore, this study explored associations between PTSD symptom clusters, feelings of revenge, and perceived perpetrator punishment severity in a sample of victims of interpersonal violence. Results indicated that the re-experiencing/intrusion symptom cluster was the only index of PTSD which was related to victims' feelings of revenge (n= 207). Revenge correlated negatively with perceptions of punishment severity in victim who knew that the perpetrator had been sentenced, but not after adjustment for PTSD symptoms (n= 96). © 2011 Elsevier Ltd.


Gurm H.S.,University of Michigan | Seth M.,University of Michigan | Kooiman J.,Leiden University | Share D.,Blue Cross Blue Shield of Michigan
Journal of the American College of Cardiology | Year: 2013

Objectives The aim of the study was to develop and validate a tool for predicting risk of contrast-induced nephropathy (CIN) in patients undergoing contemporary percutaneous coronary intervention (PCI). Background CIN is a common complication of PCI and is associated with adverse short- and long-term outcomes. Previously described risk scores for predicting CIN either have modest discrimination or include procedural variables and thus cannot be applied for pre-procedural risk stratification. Methods Random forest models were developed using 46 pre-procedural clinical and laboratory variables to estimate the risk of CIN in patients undergoing PCI. The 15 most influential variables were selected for inclusion in a reduced model. Model performance estimating risk of CIN and new requirement for dialysis (NRD) was evaluated in an independent validation data set using area under the receiver-operating characteristic curve (AUC), with net reclassification improvement used to compare full and reduced model CIN prediction after grouping in low-, intermediate-, and high-risk categories. Results Our study cohort comprised 68,573 PCI procedures performed at 46 hospitals between January 2010 and June 2012 in Michigan, of which 48,001 (70%) were randomly selected for training the models and 20,572 (30%) for validation. The models demonstrated excellent calibration and discrimination for both endpoints (CIN AUC for full model 0.85 and for reduced model 0.84, p for difference <0.01; NRD AUC for both models 0.88, p for difference = 0.82; net reclassification improvement for CIN 2.92%, p = 0.06). Conclusions The risk of CIN and NRD among patients undergoing PCI can be reliably calculated using a novel easy-to-use computational tool (https://bmc2.org/calculators/cin). This risk prediction algorithm may prove useful for both bedside clinical decision making and risk adjustment for assessment of quality. © 2013 by the American College of Cardiology Foundation.


Gonzalez-Covarrubias V.,Leiden University | Gonzalez-Covarrubias V.,Instituto Nacional Of Medicina Genomica Inmegen
Biogerontology | Year: 2013

The role of classical lipids in aging diseases and human longevity has been widely acknowledged. Triglyceride and cholesterol concentrations are clinically assessed to infer the risk of cardiovascular disease while larger lipoprotein particle size and low triglyceride levels have been identified as markers of human longevity. The rise of lipidomics as a branch of metabolomics has provided an additional layer of accuracy to pinpoint specific lipids and its association with aging diseases and longevity. The molecular composition and concentration of lipid species determine their cellular localization, metabolism, and consequently, their impact in disease and health. For example, low density lipoproteins are the main carriers of sphingomyelins and ceramides, while high density lipoproteins are mostly loaded with ether phosphocholines, partly explaining their opposing roles in atherogenesis. Moreover, the identification of specific lipid species in aging diseases and longevity would aid to clarify how these lipids alter health and influence longevity. For instance, ether phosphocholines PC (O-34:1) and PC (O-34:3) have been positively associated with longevity and negatively with diabetes, and hypertension, but other species of phosphocholines show no effect or an opposite association with these traits confirming the relevance of the identification of molecular lipid species to tackle our understanding of healthy aging and disease. Up-to-date, a minor fraction of the human plasma lipidome has been associated to healthy aging and longevity, further research would pinpoint toward specific lipidomic profiles as potential markers of healthy aging and metabolic diseases. © 2013 Springer Science+Business Media Dordrecht.


Koning F.,Leiden University
Seminars in Immunopathology | Year: 2012

Celiac disease (CD) is caused by uncontrolled immune responses to the gluten proteins in wheat and related cereals. Gluten is a complex mixture of gliadin and glutenin proteins and most modern wheat varieties contain up to 100 highly related, but distinct gluten proteins. Invariably, these gliadin and glutenin proteins contain immunogenic peptides, particularly so after the peptides have been modified by the enzyme tissue transglutaminase (TG2). This modification results in the conversion of glutamine residues in the gluten peptides into the negatively charged glutamic acid. This generates peptides that bind strongly to the disease predisposing HLA-DQ2.5 or -DQ8 molecules and this facilitates the induction of diseaseinducing CD4 T cell responses, a hallmark of CD. It is wellknown that the HLA-DQ genotype determines the risk of disease development. Moreover, the abundance of immunogenic peptides in the gluten proteins is likely linked to the observation that polyclonal T cell responses to multiple gluten peptides are usually found in patients with CD. However, not all patients respond to the same set of peptides. Here, I propose a model that integrates these observations and links them to the highly variable clinical spectrum of symptoms that are associated with CD. Moreover, I discuss whether it is feasible to alter wheat and/or gluten to make it suitable for consumption by CD patients. © Springer-Verlag 2012.


Roelfsema F.,Leiden University | Veldhuis J.D.,Endocrine Research Unit
Endocrine Reviews | Year: 2013

Thyroid hormones are extremely important for metabolism, development, and growth during the lifetime. The hypothalamo-pituitary-thyroid axis is precisely regulated for these purposes. Much of our knowledge of this hormonal axis is derived from experiments in animals and mutations in man. This review examines the hypothalamo- pituitary-thyroid axis particularly in relation to the regulated 24-hour serumTSHconcentration profiles in physiological and pathophysiological conditions, including obesity, primary hypothyroidism, pituitary diseases, psychiatric disorders, and selected neurological diseases. Diurnal TSH rhythms can be analyzed with novel and precise techniques, eg, operator-independent deconvolution and approximate entropy. These approaches provide indirect insight in the regulatory components in pathophysiological conditions. © 2013 The Endocrine Society.


de Kroon C.D.,Leiden University
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society | Year: 2010

Radical hysterectomy with pelvic lymphadenectomy is considered to be the cornerstone in the treatment of early-stage cervical cancer. Although survival in early-stage cervical cancer is up to 95%, long-term morbidity with regard to bladder, bowel, and sexual function is considerable. Damage to the pelvic autonomic nerves may be the cause of these long-term complications following radical hysterectomy. Some authors have presented surgical techniques to preserve the autonomic nerves (ie, the hypogastric nerves and the splanchnic nerves) without compromising radicality. Safety, efficacy, and the surgical techniques of nerve-sparing radical hysterectomy are presented, and data confirm that whenever the decision is made to perform a radical hysterectomy, nerve-sparing techniques should be considered.


Mutants with a defective non-homologous-end-joining (NHEJ) pathway have boosted functional genomics in filamentous fungi as they are very efficient recipient strains for gene-targeting approaches, achieving homologous recombination frequencies up to 100%. For example, deletion of the ku70 homologous gene kusA in Aspergillus niger resulted in a recipient strain in which deletions of essential or non-essential genes can efficiently be obtained. To verify that the mutant phenotype observed is the result of a gene deletion, a complementation approach has to be performed. Here, an intact copy of the gene is transformed back to the mutant, where it should integrate ectopically into the genome. However, ectopic complementation is difficult in NHEJ-deficient strains, and the gene will preferably integrate via homologous recombination at its endogenous locus. To circumvent that problem, we have constructed autonomously replicating vectors useful for many filamentous fungi which contain either the pyrG allele or a hygromycin resistance gene as selectable markers. Under selective conditions, the plasmids are maintained, allowing complementation analyses; once the selective pressure is removed, the plasmid becomes lost and the mutant phenotype prevails. Another disadvantage of NHEJ-defective strains is their increased sensitivity towards DNA damaging conditions such as radiation. Thus, mutant analyses in these genetic backgrounds are limited and can even be obscured by pleiotropic effects. The use of sexual crossings for the restoration of the NHEJ pathway is, however, impossible in imperfect filamentous fungi such as A. niger. We have therefore established a transiently disrupted kusA strain as recipient strain for gene-targeting approaches.


Timp J.F.,Leiden University
Blood | Year: 2013

Cancer-associated venous thrombosis is a common condition, although the reported incidence varies widely between studies depending on patient population, start and duration of follow-up, and the method of detecting and reporting thrombotic events. Furthermore, as cancer is a heterogeneous disease, the risk of venous thrombosis depends on cancer types and stages, treatment measures, and patient-related factors. In general, cancer patients with venous thrombosis do not fare well and have an increased mortality compared with cancer patients without. This may be explained by the more aggressive type of malignancies associated with this condition. It is hypothesized that thromboprophylaxis in cancer patients might improve prognosis and quality of life by preventing thrombotic events. However, anticoagulant treatment leads to increased bleeding, particularly in this patient group, so in case of proven benefit of thromboprophylaxis, only patients with a high risk of venous thrombosis should be considered. This review describes the literature on incidence of and risk factors for cancer-associated venous thrombosis, with the aim to provide a basis for identification of high-risk patients and for further development and refinement of prediction models. Furthermore, knowledge on risk factors for cancer-related venous thrombosis may enhance the understanding of the pathophysiology of thrombosis in these patients.


Huisman M.V.,Leiden University
Blood | Year: 2013

The clinical diagnosis of acute pulmonary embolism (PE) is frequently considered in patients presenting to the emergency department or when hospitalized. Since symptoms are a-specific and the consequences of anticoagulant treatment are considerable, objective tests to either establish or refute the diagnosis have become a standard of care. Computed tomographic pulmonary angiography (CTPA), which has replaced pulmonary angiography as first-line imaging test, is associated with radiation exposure, several complications resulting from contrast dye administration, and over diagnosis. Importantly, CTPA can be avoided in 20% to 30% of patients who present with a first or recurrent episode of clinically suspected acute PE by using a standardized algorithm. This algorithm should always include a clinical decision rule to assess the likelihood that PE is present, followed by a D-dimer blood test and/or CTPA. The aim of this review is to provide clinicians this practical diagnostic management approach using evidence from the literature.


Nijboer F.,Leiden University
Annals of Physical and Rehabilitation Medicine | Year: 2015

This paper provides an analysis of perspectives from different stakeholders on the state-of-the-art of BCI. Three barriers for technology transfer of BCIs as access technologies are identified. First, BCIs are developed with a narrow focus on creating a reliable technology, while a broader focus on creating a usable technology is needed. Second, the potential target group, which could benefit from BCIs as access technologies is expected to be very small. Development costs are therefore high, while reimbursements are expected to be low, which challenges the commercial viability. Third, potential target users should be much more included in the design process of BCIs to ensure that the end-products meet technical, ethical, legal and social requirements. These three issues need to be urgently addressed so that target users may benefit from this promising technology. © 2015 Elsevier Masson SAS.


van Hoof D.,Leiden University
Cold Spring Harbor perspectives in biology | Year: 2012

Genomics methodologies have advanced to the extent that it is now possible to interrogate the gene expression in a single cell but proteomics has traditionally lagged behind and required much greater cellular input and was not quantitative. Coupling protein with gene expression data is essential for understanding how cell behavior is regulated. Advances primarily in mass spectrometry have, however, greatly improved the sensitivity of proteomics methods over the last decade and the outcome of proteomic analyses can now also be quantified. Nevertheless, it is still difficult to obtain sufficient tissue from staged mammalian embryos to combine proteomic and genomic analyses. Recent developments in pluripotent stem cell biology have in part addressed this issue by providing surrogate scalable cell systems in which early developmental events can be modeled. Here we present an overview of current proteomics methodologies and the kind of information this can provide on the biology of human and mouse pluripotent stem cells.


Roep B.O.,Leiden University | Peakman M.,Kings College London
Cold Spring Harbor Perspectives in Medicine | Year: 2012

Type 1 diabetes is characterized by recognition of one or more β-cell proteins by the immune system. The list of target antigens in this disease is ever increasing and it is conceivable that additional islet autoantigens, possibly including pivotal β-cell targets, remain to be discovered. Many knowledge gaps remain with respect to the disorder's pathogenesis, including the cause of loss of tolerance to islet autoantigens and an explanation as to why targeting of proteins with a distribution of expression beyond β cells may result in selective β-cell destruction and type 1 diabetes. Yet, our knowledge of β-cell autoantigens has already led to translation into tissue-specific immune intervention strategies that are currently being assessed in clinical trials for their efficacy to halt or delay disease progression to type 1 diabetes, as well as to reverse type 1 diabetes. Here we will discuss recently gained insights into the identity, biology, structure, and presentation of islet antigens in relation to disease heterogeneity and β-cell destruction. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.


Jacobs W.,Leiden University
Cochrane database of systematic reviews (Online) | Year: 2011

The number of surgical techniques for decompression and solid interbody fusion as treatment for cervical spondylosis has increased rapidly, but the rationale for the choice between different techniques remains unclear. To determine which technique of anterior interbody fusion gives the best clinical and radiological outcomes in patients with single- or double-level degenerative disc disease of the cervical spine. We searched CENTRAL (The Cochrane Library 2009, issue 1), MEDLINE (1966 to May 2009), EMBASE (1980 to May 2009), BIOSIS (2004 to May 2009), and references of selected articles. Randomised comparative studies that compared anterior cervical decompression and interbody fusion techniques for participants with chronic degenerative disc disease. Two review authors independently assessed risk of bias using the Cochrane Back Review Group criteria. Data on demographics, intervention details and outcome measures were extracted onto a pre-tested data extraction form. Thirty-three small studies ( 2267 patients) compared different fusion techniques. The major treatments were discectomy alone, addition of an interbody fusion procedure (autograft, allograft, cement, or cage), and addition of anterior plates. Eight studies had a low risk of bias. Few studies reported on pain, therefore, at best, there was very low quality evidence of little or no difference in pain relief between the different techniques. We found moderate quality evidence for these secondary outcomes: no statistically significant difference in Odom's criteria between iliac crest autograft and a metal cage (6 studies, RR 1.11 (95% CI 0.99 to1.24)); bone graft produced more effective fusion than discectomy alone (5 studies, RR 0.22 (95% CI 0.17 to 0.48)); no statistically significant difference in complication rates between discectomy alone and iliac crest autograft (7 studies, RR 1.56 (95% CI 0.71 to 3.43)); and low quality evidence that iliac crest autograft results in better fusion than a cage (5 studies, RR 1.87 (95% CI 1.10 to 3.17)); but more complications (7 studies, RR 0.33 (95% CI 0.12 to 0.92)). When the working mechanism for pain relief and functional improvement is fusion of the motion segment, there is low quality evidence that iliac crest autograft appears to be the better technique. When ignoring fusion rates and looking at complication rates, a cage has a weak evidence base over iliac crest autograft, but not over discectomy alone. Future research should compare additional instrumentation such as screws, plates, and cages against discectomy with or without autograft.


Emery P.,University of Leeds | Emery P.,NIHR Leeds Musculoskeletal Biomedical Research Unit | Sebba A.,University of South Florida | Huizinga T.W.J.,Leiden University
Annals of the Rheumatic Diseases | Year: 2013

Clinical evidence demonstrates coadministration of tumour necrosis factor inhibitor (TNFi) agents and methotrexate (MTX) is more efficacious than administration of TNFi agents alone in patients with rheumatoid arthritis, leading to the perception that coadministration of MTX with all biologic agents or oral disease-modifying antirheumatic drugs is necessary for maximum efficacy. Real-life registry data reveal approximately one-third of patients taking biologic agents use them as monotherapy. Additionally, an analysis of healthcare claims data showed that when MTX was prescribed in conjunction with a biologic agent, as many as 58% of patients did not collect the MTX prescription. Given this discrepancy between perception and real life, we conducted a review of the peer-reviewed literature and rheumatology medical congress abstracts to determine whether data support biologic monotherapy as a treatment option for patients with rheumatoid arthritis. Our analysis suggests only for tocilizumab is there evidence that the efficacy of biologic monotherapy is comparable with combination therapy with MTX.


de Jager S.C.,Leiden University
Thrombosis and haemostasis | Year: 2011

The treatment of atherosclerosis is currently based on lipid lowering in combination with anti-inflammatory therapies that slow the progression of atherosclerosis. Still, we are not able to fully inhibit the formation or progression of atherosclerotic lesions. A very effective strategy in other disease pathologies is vaccination, in which the body is challenged with the culprit protein or micro-organism in order to create a highly specific humoral immune-response. Immunisation can typically be divided into active or passive immunisation. Active immunisation occurs naturally when the body is exposed to certain microbes or antigens, but also artificially in the case of vaccination. Exposure to a microbe or antigen will result in the production of (antigen specific) antibodies. Passive immunisation is defined as the transfer of humoral immunity (as a result of antibody transfer). Another mechanism to ensure immune-protection is tolerance induction. Immune tolerance occurs naturally to prevent immune responses to 'self-antigens', but can also be induced to non-self antigens. Acquired tolerance to foreign antigens is accompanied by suppression of cellular and/or humoral immune response to the introduced antigen. In its most effective way, vaccination can result in a lifelong protection against the targeted pathology, and therefore the development of an atherosclerosis-specific vaccination is of high importance in the future prevention of atherosclerosis. One of the difficulties in developing effective vaccination strategies for atherosclerosis is the selection of a specific antigen to target. So far vaccination strategies have been based on targeting of lipid-antigens, inflammation-derived antigens, and recently cell-based vaccination strategies have been employed; but also the cardiovascular 'side-effects' of infection-based vaccines are worthy of our attention. This review describes the current status-quo on classical antibody associated vaccination strategies but also includes promising immune-modulation approaches that may lead to a clinical application.


Ghaly M.,Leiden University
Medicine, Health Care and Philosophy | Year: 2012

This article analyzes the religio-ethical discussions of Muslim religious scholars, which took place in Europe specifically in the UK and the Netherlands, on organ donation. After introductory notes on fatwas (Islamic religious guidelines) relevant to biomedical ethics and the socio-political context in which discussions on organ donation took place, the article studies three specific fatwas issued in Europe whose analysis has escaped the attention of modern academic researchers. In 2000 the European Council for Fatwa and Research (ECFR) issued a fatwa on organ donation. Besides this "European" fatwa, two other fatwas were issued respectively in the UK by the Muslim Law (Shariah) Council in 1995 and in the Netherlands by the Moroccan religious scholar Mus{dot below}t{dot below}afā Ben H{dot below}amza during a conference on "Islam and Organ Donation" held in March 2006. The three fatwas show that a great number of Muslim religious scholars permit organ donation and this holds true for donating organs to non-Muslims as well. Further, they demonstrate that transnationalism is one of the main characteristics of contemporary Islamic bioethics. In a bid to develop their own standpoints towards organ donation, Muslims living in the West rely heavily on fatwas imported from the Muslim world. © 2011 The Author(s).


Maljaars J.,Leiden University
Current Opinion in Gastroenterology | Year: 2013

Purpose of review: As the prevalence of overweight and obesity increases, there is a growing need to develop effective treatment strategies in addition to bariatric surgery. Research has focused on understanding the pathophysiologic mechanisms that contribute to the occurrence and maintenance of obesity and overweight, and on how bariatric surgery is able to overcome these obstacles. In this review, new insights in the gastrointestinal regulatory mechanisms in obesity and bariatric surgery will be discussed. RECENT FINDINGS: Diet-induced obesity (DIO) leads to changes in gut peptide secretion and other gastrointestinal responses to nutrients. These changes reduce satiety signaling and therefore complicate loss of body weight. Weight loss by dietary restriction does not restore gastrointestinal responses to nutrients to normal, but alters these responses to further complicate weight loss. Only bariatric surgery is able to overcome these changes by mechanisms that are hitherto unclear but may involve altered gut peptide secretion or changes in bile acid metabolism. SUMMARY: DIO alters nutrient-induced gastrointestinal signaling in a way that facilitates further weight gain and complicates weight loss. A better understanding of these mechanisms and the way bariatric surgery can overcome these changes is crucial in developing effective treatment strategies. Copyright © Lippincott Williams & Wilkins.


Melief C.J.M.,Leiden University
Journal of Immunotherapy | Year: 2012

Here, we review a novel vaccine modality, characterized by the administration of long (23 to 45 amino acids) synthetic peptides in incomplete Freund's adjuvant (mineral oil based, Montanide ISA-51), delivered subcutaneously. Such vaccines were first demonstrated to be much more potent in preclinical T-cell response induction and tumor therapy experiments than were short major histocompatibility complex class I-binding peptides. Nevertheless, a recent study has shown the clinical efficacy of an anchor-modified short gp100 peptide in melanoma patients. We now review the evidence and mode of action of a long peptide vaccine consisting of 13 overlapping peptides, together covering the entire length of the 2 oncogenic proteins E6 and E7 of high-risk human papilloma virus type 16 (HPV16), causing complete regression of all lesions and eradicating virus in 9 of 20 women with high-grade vulvar intraepithelial neoplasia. The nature and strength of the vaccine-induced T-cell response correlated significantly with the clinical response. This vaccine promises to be of use not only in patients with premalignant lesions caused by high-risk HPV16 but also in malignant tumors caused by this virus, including HPV16-positive cervical cancer, vulvar cancer, anal cancer, and head and neck cancer. © 2012 by Lippincott Williams & Wilkins.


Fontein D.B.,Leiden University
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.


Wimmer M.,Leiden University
ACM Transactions on Mathematical Software | Year: 2012

Computing the Pfaffian of a skew-symmetric matrix is a problem that arises in various fields of physics. Both computing the Pfaffian and a related problem, computing the canonical form of a skew-symmetric matrix under unitary congruence, can be solved easily once the skew-symmetric matrix has been reduced to skew-symmetric tridiagonal form. We develop efficient numerical methods for computing this tridiagonal form based on Gaussian elimination, using a skew-symmetric, blocked form of the Parlett-Reid algorithm, or based on unitary transformations, using block Householder transformations and Givens rotations, that are applicable to dense and banded matrices, respectively. We also give a complete and fully optimized implementation of these algorithms in Fortran (including a C interface), and also provide Python, Matlab and Mathematica implementations for convenience. Finally, we apply these methods to compute the topological charge of a class D nanowire, and show numerically the equivalence of definitions based on the Hamiltonian and the scattering matrix. © 2012 ACM.


In the last two or three decades, many countries have used various market instruments to steer and manage their academic research sector. Proponents of a market approach claim greater efficiency and sharper incentives while critics point to the peculiarity of the university sector that is likely to cause an inefficient stratification amongst universities. This paper applies a market convergence model to empirically test the hypothesis that competition leads to a more concentrated research industry. The results from Australia show that less research-intensive universities improve their research performance relatively faster, particularly in the early years of the policy reform. However, the lower performing universities have not been 'catching up' with the top performers but maximizing their individual potential, given their unique productivity constraints. We cannot confirm a 'winner-takes-all' process but there are signs of an increasing gap between universities, most likely due to accumulating advantages in the academic research sector.


Waltman L.,Leiden University
Journal of Informetrics | Year: 2012

There are different ways in which the authors of a scientific publication can determine the order in which their names are listed. Sometimes author names are simply listed alphabetically. In other cases, authorship order is determined based on the contribution authors have made to a publication. Contribution-based authorship can facilitate proper credit assignment, for instance by giving most credits to the first author. In the case of alphabetical authorship, nothing can be inferred about the relative contribution made by the different authors of a publication.In this paper, we present an empirical analysis of the use of alphabetical authorship in scientific publishing. Our analysis covers all fields of science. We find that the use of alphabetical authorship is declining over time. In 2011, the authors of less than 4% of all publications intentionally chose to list their names alphabetically. The use of alphabetical authorship is most common in mathematics, economics (including finance), and high energy physics. Also, the use of alphabetical authorship is relatively more common in the case of publications with either a small or a large number of authors. © 2012 Elsevier Ltd.


Van Zuuren E.J.,Leiden University | Fedorowicz Z.,Bahrain Branch
British Journal of Dermatology | Year: 2015

Rosacea is a common chronic facial dermatosis. This update of our Cochrane review on interventions for rosacea summarizes the evidence, including Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group assessments, of the effects of the currently available treatments. Searches included the following: Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE, EMBASE, LILACS and the Science Citation Index, and ongoing trials registries (July 2014). We included 106 randomized controlled trials (RCTs) with 13 631 participants, a more than 80% increase since the last update in 2011. Pooling of data was feasible for a few outcomes, for topical metronidazole and azelaic acid and both appeared to be more effective than placebo (moderate and high-quality evidence, respectively). Topical ivermectin was more effective than placebo based on two studies (high-quality evidence), and slightly more effective than metronidazole in one study. Brimonidine was more effective than vehicle in reducing erythema in rosacea (high-quality evidence). Ciclosporin ophthalmic emulsion was effective for ocular rosacea (low-quality evidence). For oral treatments there was moderate-quality evidence for the effectiveness of tetracycline based on two old studies, and high-quality evidence for doxycycline 40 mg compared with placebo according to physician assessments. One study at high risk of bias demonstrated equivalent effectiveness for azithromycin and doxycycline 100 mg. Minocycline 45 mg may be effective for papulopustular rosacea (low-quality evidence). Low-dose isotretinoin appeared to be slightly more effective than doxycycline 50-100 mg (high-quality evidence). Laser and light-based therapies for erythema in rosacea were effective (low-quality evidence). Further RCTs are required for ocular rosacea. What's already known about this topic? Rosacea is a chronic debilitating facial dermatosis. Previously we reported that topical metronidazole, azelaic acid and oral doxycycline 40 mg were effective as was topical ciclosporin 0·05% for ocular rosacea. What does this study add? Detailed Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group assessment of the effects of various treatments. High-quality evidence for brimonidine for erythema, and for topical ivermectin and oral isotretinoin in papulopustular rosacea. Low-quality evidence for low-dose minocycline, laser and light-based therapies. © 2015 British Association of Dermatologists.


Breedveld F.,Leiden University
Clinical Rheumatology | Year: 2011

Rheumatoid arthritis (RA) is associated with progressive joint destruction, with functional status influenced by both disease activity and radiographic progression. The case for early aggressive treatment of RA is based on large amounts of good data in many countries. Studies with conventional disease-modifying anti-rheumatic drugs in early RA have shown improved outcomes compared with later treatment, especially if an aggressive approach with combinations of drugs is used. Early intervention with tumour necrosis factor (TNF) inhibitors has been shown to improve clinical outcomes, induce remission and prevent radiographic progression. It also improves patients' functional status, health-related quality of life, and reduces fatigue. Patients with RA have reduced productivity, an increased number of lost work days and retire early; enabling patients to work should be at the core of a therapy's cost-effectiveness. Introduction of anti-TNF therapy early in RA has been shown to decrease job loss and reduce the amount of working time missed. Although the drug costs of initial treatment with combination therapy including a TNF inhibitor are high, these may be compensated by the reduction in lost productivity, making such a strategy cost-effective overall. In addition, some patients who respond well to combination therapy may be able to stop the TNF inhibitor. It is important to assess the benefits of any intervention not just to healthcare costs but to society as a whole, and physicians should be advocates for optimal access to effective therapies for their patients. © 2011 Clinical Rheumatology.


Beenakker C.W.J.,Leiden University
Reviews of Modern Physics | Year: 2015

The theory of random matrices originated half a century ago as a universal description of the spectral statistics of atoms and nuclei, dependent only on the presence or absence of fundamental symmetries. Applications to quantum dots (artificial atoms) followed, stimulated by developments in the field of quantum chaos, as well as applications to Andreev billiards - quantum dots with induced superconductivity. Superconductors with topologically protected subgap states, Majorana zero modes, and Majorana edge modes, provide a new arena for applications of random-matrix theory. These recent developments are reviewed, with an emphasis on electrical and thermal transport properties that can probe the Majorana fermions. © 2015 American Physical Society. © 2015 American Physical Society.


Giomi L.,Leiden University
Physical Review X | Year: 2015

The problem of low Reynolds number turbulence in active nematic fluids is theoretically addressed. Using numerical simulations, I demonstrate that an incompressible turbulent flow, in two-dimensional active nematics, consists of an ensemble of vortices whose areas are exponentially distributed within a range of scales. Building on this evidence, I construct a mean-field theory of active turbulence by which several measurable quantities, including the spectral densities and the correlation functions, can be analytically calculated. Because of the profound connection between the flow geometry and the topological properties of the nematic director, the theory sheds light on the mechanisms leading to the proliferation of topological defects in active nematics and provides a number of testable predictions. A hypothesis, inspired by Onsager's statistical hydrodynamics, is finally introduced to account for the equilibrium probability distribution of the vortex sizes.


Vertegaal A.C.O.,Leiden University
Nature Reviews Molecular Cell Biology | Year: 2016

Small ubiquitin-like modifiers (SUMOs) are essential for the regulation of several cellular processes and are potential therapeutic targets owing to their involvement in diseases such as cancer and Alzheimer disease. In the past decade, we have witnessed a rapid expansion of proteomic approaches for identifying sumoylated proteins, with recent advances in detecting site-specific sumoylation. In this Analysis, we combined all human SUMO proteomics data currently available into one cohesive database. We provide proteomic evidence for sumoylation of 3,617 proteins at 7,327 sumoylation sites, and insight into SUMO group modification by clustering the sumoylated proteins into functional networks. The data support sumoylation being a frequent protein modification (on par with other major protein modifications) with multiple nuclear functions, including in transcription, mRNA processing, DNA replication and the DNA-damage response. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Breedveld F.,Leiden University
Molecular Medicine | Year: 2014

Rheumatoid arthritis (RA) is an autoimmune disease resulting from a largely unknown interaction between genetically determined and environmental factors. Progress in the understanding of this chronic inflammation in the synovial lining of joints has led to the insight that one cytokine, tumor necrosis factor (TNF), has an important role. This insight started the development of a series of targeted and highly effective therapeutics for RA and a range of other autoinflammatory diseases. RA has changed from a severely debilitating disease into a disease where progression can be stopped in most of the patients. © 2014 Molecular Medicine All rights received.


Rabe K.F.,University of Kiel | Rabe K.F.,Leiden University | Wedzicha J.A.,University College London
The Lancet | Year: 2011

Chronic obstructive pulmonary disease (COPD) is a chronic disorder with substantial comorbidity and major effects attributable to the high morbidity and mortality rates. Despite an increasing evidence base, some important controversies in COPD management still exist. The classic way to define COPD has been based on spirometric criteria, but more relevant diagnostic methods are needed that can be used to describe COPD severity and comorbidity. Initiation of interventions earlier in the natural history of the disease to slow disease progression is debatable, there are many controversies about the role of inhaled corticosteroids in the management of COPD, and long-term antibiotics for prevention of exacerbation have had a resurgence in interest. Novel therapeutic drugs are urgently needed for optimum management of the acute COPD exacerbation. COPD is a complex disease and consists of several clinically relevant phenotypes that in future will guide its management. © 2011 Elsevier Ltd.


Van Ingen J.,Radboud University Nijmegen | Kuijper E.J.,Leiden University
Future Microbiology | Year: 2014

Diseases caused by nontuberculous mycobacteria are emerging in many settings. With an increased number of patients needing treatment, the role of drug susceptibility testing is again in the spotlight. This articles covers the history and methodology of drug susceptibility tests for nontuberculous mycobacteria, but focuses on the correlations between in vitro drug susceptibility, pharmacokinetics and in vivo outcomes of treatment. Among slow-growing nontuberculous mycobacteria, clear correlations have been established for macrolides and amikacin (Mycobacterium avium complex) and for rifampicin (Mycobacterium kansasii). Among rapid-growing mycobacteria, correlations have been established in extrapulmonary disease for aminoglycosides, cefoxitin and co-trimoxazole. In pulmonary disease, correlations are less clear and outcomes of treatment are generally poor, especially for Mycobacterium abscessus. The clinical significance of inducible resistance to macrolides among rapid growers is an important topic. The true role of drug susceptibility testing for nontuberculous mycobacteria still needs to be addressed, preferably within clinical trials. © 2014 Future Medicine Ltd.


Pearce E.J.,University of Washington | Everts B.,Leiden University
Nature Reviews Immunology | Year: 2015

The past 15 years have seen enormous advances in our understanding of the receptor and signalling systems that allow dendritic cells (DCs) to respond to pathogens or other danger signals and initiate innate and adaptive immune responses. We are now beginning to appreciate that many of these pathways not only stimulate changes in the expression of genes that control DC immune functions, but also affect metabolic pathways, thereby integrating the cellular requirements of the activation process. In this Review, we focus on this relatively new area of research and attempt to describe an integrated view of DC immunometabolism. © 2015 Macmillan Publishers Limited. All rights reserved.


Bor A.S.E.,University Utrecht | Rinkel G.J.E.,University Utrecht | van Norden J.,University Utrecht | Wermer M.J.H.,Leiden University
The Lancet Neurology | Year: 2014

Background: Individuals with two or more first-degree relatives who have had aneurysmal subarachnoid haemorrhage (aSAH) have an increased risk of aneurysms and aSAH. We investigated the yield of long-term serial screening for intracranial aneurysms in these individuals. Methods: In a cohort study, we reviewed the results of screening of individuals with a positive family history of aSAH (two or more first-degree relatives who had had aSAH or unruptured intracranial aneurysms) done at the University Medical Centre Utrecht (Utrecht, Netherlands) between April 1, 1993, and April 1, 2013. Magnetic resonance angiography or CT angiography was done from age 16-18 years to 65-70 years. After a negative screen, we advised individuals to contact us after 5 years, but did not actively call them for repeated screening. We recorded familial history of ruptured and unruptured intracranial aneurysms, smoking history, hypertension, previous aneurysms, screening dates, and screening results. We identified risk factors for positive initial and follow-up screens with univariable and multivariable regression analysis. Findings: We identified aneurysms in 51 (11%, 95% CI 9-14) of 458 individuals at first screening, in 21 (8%, 5-12) of 261 at second screening, in seven (5%, 2-11) of 128 at third screening, and three (5%, 1-14) of 63 at fourth screening. Five (3%, 95% CI 1-6) of 188 individuals without a history of aneurysms and with two negative screens had a de-novo aneurysm in a follow-up screen. Smoking (odds ratio 2·7, 95% CI 1·2-5·9), history of previous aneurysms (3·9, 1·2-12·7), and familial history of aneurysms (3·5, 1·6-8·1) were significant risk factors for aneurysms at first screening in the multivariable analysis. History of previous aneurysms was the only significant risk factor for aneurysms at follow-up screening (hazard ratio 4·5, 1·1-18·7). Aneurysms were identified in six (5%, 95% CI 2-10) of 129 individuals who were screened before age 30 years. One patient developed a de-novo aneurysm that ruptured 3 years after the last negative screen. Interpretation: In individuals with a family history of aSAH, the yield of long-term screening is substantial even after more than 10 years of follow-up and two initial negative screens. We advocate long-term serial screening in these individuals, although the risk of aSAH within screening intervals is not eliminated. Funding: The Dutch Heart Foundation. © 2014 Elsevier Ltd.


Koper M.T.M.,Leiden University | Koper M.T.M.,Hokkaido University
Physical Chemistry Chemical Physics | Year: 2013

A theory for the calculation of potential energy surfaces of electrochemical proton-coupled electron transfer is considered and parameterized on the basis of thermodynamic relations. The paper discusses the qualitatively different potential energy surfaces predicted by the theory, and their relation to the existence of sequential and concerted proton-electron transfer pathways. The concomitant activation energies for sequential and concerted PET are calculated. The applied overpotential may change the qualitative shape of the PES and therefore the mechanism of the proton-coupled electron transfer reaction. © 2013 the Owner Societies.


The induction of adaptive immunity and prevention of tolerance is a critical component of vaccination and immunotherapy in order to prevent pathogen-related diseases and to eradicate malignant cells. Although many acute infections can be controlled by vaccination, the development of prophylactic and therapeutic vaccines against persistent viruses and tumors remains challenging. The diverse immune evasion strategies used by persistent DNA viruses such as herpesviruses contribute directly to their persistence and escape from immune control. Intriguingly, many tumors have also developed escape mechanisms to dismantle similar aspects of the host's immune system. Analogous targets of immune evasion mechanisms comprise suppression of antigen presentation and T cell costimulatory pathways, induction of immunosuppressive cytokines, and obstruction of interferon and chemokine functions, which emphasizes them not only as critical elements of T cell activation pathways but also as the potential " Achilles' heels" of the host immune system. The insight that immune evasion by viruses and tumors targets analogous host immune pathways might lead to cross-pollination of the viral and tumor immunology research fields, which could lead to new perspectives and appreciation of the intricacies and subtleties that arise from the merging of these fields. Accordingly, a rational and combinatorial manipulation of immune evasion pathways and their targets should aid in the development of safer and more effective vaccine strategies and immunotherapies for a wide range of infections and malignancies. © 2012 Elsevier Inc..


van Schellen M.,University Utrecht | Apel R.,Rutgers University | Nieuwbeerta P.,Leiden University
Journal of Quantitative Criminology | Year: 2012

Objectives: This study is an analysis of the relationship between marriage and crime in a high-risk sample of Dutch men and women. Marriages are classified as to whether the spouse had been convicted of a crime prior to the marriage, in order to ascertain if one's criminal career after marriage unfolds differently depending on the criminal history of one's spouse. Methods: Data are from the Criminal Career and Life-Course Study, a random sample of all individuals convicted of a criminal offense in the Netherlands in 1977 (N = 4,615). Lifetime criminal histories for all subjects are constructed from age 12 to calendar year 2003. Official marriage records are also consulted, and the criminal history of all spouses are similarly constructed. Fixed-effects Poisson models are estimated to quantify the relationship between marriage, spousal criminality, and conviction frequency, controlling for age, parenthood, prior conviction, and prior incarceration. Results: Among men, marriage reduces the frequency of criminal conviction, but only if the marriage is to a non-convicted spouse. Marriage to a convicted spouse, on the other hand, is indistinguishable from singlehood-it neither discourages nor promotes criminal behavior. Among women, marriage has a crime-reducing effect, regardless of the criminal history of the spouse. A set of preliminary follow-up analyses suggests further that men with more extensive criminal histories, and with more stable marriages, benefit in a more pronounced way from marriage to a non-convicted spouse. However, even unstable marriages to non-convicted spouses appear to reduce conviction frequency while they last. Conclusions: Marriage is indeed a salient transition in the criminal career, but there are important differences depending on the characteristics of the offender (gender, criminal history), the characteristics of the spouse (criminal history), and the characteristics of the marriage (duration). The authors conclude that while marriage matters, it does not necessarily mean the end of a criminal career, and that processes of both partner selection and partner influence deserve close attention by marriage-crime researchers. Qualifications of the study's findings include the use of conviction data from official sources, the use of a sample of men and women who were all convicted of a crime at some point in their lives, the study of legal marriage in the Netherlands, and the inability to measure potential mechanisms for the observed marriage effects. © 2012 Springer Science+Business Media, LLC.


Webb A.,Leiden University
Analytical Chemistry | Year: 2012

Nuclear magnetic resonance and magnetic resonance imaging are two of the most important techniques in analytical chemistry and noninvasive medical imaging, respectively. They share a common physical basis, one aspect of which is a low intrinsic sensitivity relative to complementary techniques. Encouragingly, recent advances in physics, chemistry, engineering, and data processing have enabled significant increases in sensitivity, as measured by both increased signal-to-noise and reduced data acquisition times, allowing previously unattainable data to be acquired and also new types of experiments to be designed. © 2011 American Chemical Society.


ten Cate C.,Leiden University | Okanoya K.,University of Tokyo
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2012

The domain of syntax is seen as the core of the language faculty and as the most critical difference between animal vocalizations and language.We review evidence from spontaneously produced vocalizations as well as from perceptual experiments using artificial grammars to analyse animal syntactic abilities, i.e. abilities to produce and perceive patterns following abstract rules. Animal vocalizations consist of vocal units (elements) that are combined in a species-specific way to create higher order strings that in turn can be produced in different patterns. While these patterns differ between species, they have in common that they are no more complex than a probabilistic finite-state grammar. Experiments on the perception of artificial grammars confirm that animals can generalize and categorize vocal strings based on phonetic features. They also demonstrate that animals can learn about the co-occurrence of elements or learn simple 'rules' like attending to reduplications of units. However, these experiments do not provide strong evidence for an ability to detect abstract rules or rules beyond finite-state grammars. Nevertheless, considering the rather limited number of experiments and the difficulty to design experiments that unequivocally demonstrate more complex rule learning, the question of what animals are able to do remains open. © 2012 The Royal Society.


Field M.H.,Leiden University
Quaternary International | Year: 2012

Archaeological artefact-bearing Pleistocene fluvial sediments, which form part of the Cromer Forest-bed Formation, below the modern beach just south-east of Happisburgh, Norfolk, UK (Happisburgh Site 1), yielded a diverse plant macrofossil assemblage that included a seed fragment of Actinidia faveolata C.Reid and E.M.Reid - an extinct relative of the modern Kiwi fruit (Actinidia deliciosa (A.Chev.) C.F.Liang and A.R.Ferguson, Actinidiaceae family). This is the first record of this taxon in the British Isles. Previously, this extinct species has been found in Upper Oligocene sediments from West Siberia and from Miocene, Pliocene and Early Pleistocene sediments in Europe. The stratigraphical and palaeoenvironmental setting of this find is briefly considered followed by a detailed description of the fossil with a comparison of specimens from the type area. The archaeological and biostratigraphical implications of this record are also discussed. © 2012.


Pollen analysis of the infill of an Eemian basin in Germany near the town of Halle revealed a history of the vegetation in and around this pool. The sediments of Neumark-Nord 2 cover a major part of the Eemian, although there is a hiatus in the record, beginning in the Carpinus phase and ending in de last Pinus phase. During most of the Eemian the landscape was covered by deciduous forests. The analysis shows high percentages of herbaceous taxa during the early part of the interglacial, which could suggest that the forest was relatively open. Alternatively, the high herbaceous taxa might have resulted from the inwash of herb-rich herbivore dung into the pool. In this study, I use non-pollen palynomorphs (NPPs) to show that it is unlikely that herbivore dung was a major source of herbaceous pollen, as the record shows only low numbers of coprophilous NPPs. According to malacological and sedimentological evidence, the former pool was apt to dry out and be filled with brackish water during most of its existence. The continuous presence of NPP Spirogyra however suggests that fresh water must have been present too, and that water quality may have fluctuated between slightly brackish and fresh. The study shows that NPPs can contribute to a better interpretation of a pollen record and the history of a pool. © 2012 Elsevier B.V.


Schall P.,University of Amsterdam | Van Hecke M.,Leiden University
Annual Review of Fluid Mechanics | Year: 2010

Shear bands, localized regions where shear flows concentrate, form in many complex fluids under a wide range of circumstances. In this review, we outline the main mechanisms that cause shear banding in complex fluids with granularity: foams, emulsions, colloidal suspensions, and granular matter. Apart from shear bands caused by continuum-scale mechanisms such as stress inhomogeneities and flow instabilities, we discuss a range of shear-banding phenomena for which the particle scale plays a crucial role. Copyright © 2010 by Annual Reviews. All rights reserved.


Wang L.,CAS National Astronomical Observatories | Weinmann S.M.,Leiden University | Neistein E.,Max Planck Institute for Extraterrestrial Physics
Monthly Notices of the Royal Astronomical Society | Year: 2012

In order to reproduce the low-mass end of the stellar mass function, most current models of galaxy evolution invoke very efficient supernova feedback. This solution seems to suffer from several shortcomings however, like predicting too little star formation (SF) in low-mass galaxies at z= 0. In this work, we explore modifications to the SF law as an alternative solution to achieve a match to the stellar mass function. This is done by applying semi-analytic models based on De Lucia & Blaizot, but with varying SF laws, to the Millennium and Millennium-II simulations, within the formalism developed by Neistein & Weinmann. Our best model includes lower SF efficiencies than predicted by the Kennicutt-Schmidt law at low stellar masses, no sharp threshold of cold gas mass for SF and an SF law that is independent of cosmic time. These simple modifications result in a model that is more successful than current standard models in reproducing various properties of galaxies less massive than 10 10M ⊙. The improvements include a good match to the observed autocorrelation function of galaxies, an evolution of the stellar mass function from z= 3 to z= 0 similar to observations and better agreement with observed specific SF rates. However, our modifications also lead to a dramatic overprediction of the cold mass content of galaxies. This shows that finding a successful model may require fine-tuning of both SF and supernova feedback, as well as improvements on gas cooling, or perhaps the inclusion of a yet unknown process which efficiently heats or expels gas at high redshifts. © 2012 The Authors Monthly Notices of the Royal Astronomical Society © 2012 RAS.


Moss-Racusin C.A.,Skidmore College | Van Der Toorn J.,Leiden University | Dovidio J.F.,Yale University | Brescoll V.L.,Yale University | And 2 more authors.
Science | Year: 2014

Fair treatment of other scientists is an essential aspect of scientific integrity, warranting diversity interventions.


Wit J.M.,Leiden University
Hormone Research in Paediatrics | Year: 2011

Although various expert and consensus meetings have been held, there remains uncertainty about the definition of idiopathic short stature (ISS) and its subgroups. In this short review, the hypothetical pathophysiology, diagnosis and subcategorization of ISS are discussed. ISS in childhood may be the result of a combination of variants of three groups of genes: (1) single genes (or combinations of a few single genes) of which mutations, deletions or duplications are associated with a relatively large negative effect on height; (2) genes of which relatively frequently occurring polymorphisms are associated with a small negative effect on height; and (3) genes associated with delayed maturation of the epiphyseal plate. Differentiation between ISS and short children born small for gestational age and those with dysmorphic syndromes, systemic diseases or growth hormone deficiency and resistance can be difficult. Subcategorization based on distance to target height and onset of puberty is arbitrary, but useful. Copyright © 2011 S. Karger AG, Basel.


Toyang N.J.,Virgin Botanicals and Biotech Inc. | Toyang N.J.,University of Maryland Baltimore County | Verpoorte R.,Leiden University
Journal of Ethnopharmacology | Year: 2013

Ethnopharmacological relevance: The Vernonia genus has about one thousand species and members of the genus are widely used as food and medicine. The aim of this review is to analyze published data on the ethnomedicinal, ethnoveterinary and zoopharmacognostic uses of plants of the Vernonia genus. This will help to identify the state of ethnopharmacological knowledge in regard to this genus and to propose future research priorities. Materials and methods: The major scientific databases including SciFinder, Sciencedirect, Medline and Google Scholar were queried for information on Vernonia genus using various keyword combinations. The International Plant Name Index was also used to verify the names of species and authors. Results: A total of 109 Vernonia species were reported in the literature to have medicinal properties. One hundred and five (105) plants were linked to the treatment or management of 44 human diseases or health conditions. Plants of the genus also feature in ethnoveterinary and zoopharmacognostic practices. A total of 12 vernonia species were identified to be used in ethnoveterinary medicine while 2 species are used in self medication practices by chimpanzees and gorillas. In vitro and in vivo research studies reporting the validation of the medicinal properties of some species were also reviewed. One hundred and three bioactive compounds isolated from various Vernonia species were also identified. Vernonia amygdalina was identified as the most frequently used member of the Vernonia genus. The Vernolides, a class of sesquiterpene lactone were identified as the most studied compounds from the genus and show interesting bioactivity in antiplasmodial, antileishmanial, antischistosomial, cytotoxicity, antimicrobial and anti-inflammatory assays. Conclusion: On the basis of results from a combination of in vitro and in vivo efficacy and toxicity studies reported, Vernonia amygdalina holds the most promise for development into a nutraceutical against diabetes and malaria while Vernonia cinerea has potential against cancer and inflammatory conditions. Vernolide A is so far the most promising single agent from a Vernonia species that has potential for development into an anticancer agent. The other Vernonia species and isolated compounds require further studies to ascertain their medicinal potentials. © 2013 Elsevier Ireland Ltd.


Cohen A.F.,Leiden University | Cohen A.F.,Center for Human Drug Research
Nature Reviews Drug Discovery | Year: 2010

New medicines are designed to bind to receptors or enzymes and are tested in animal cells, tissues and whole organisms in a highly scientific process. Subsequently they are often administered to human subjects with tolerability as the primary objective. The process of development is considered to be linear and consecutive and passes through the famous four phases of development (Phase I- Phase IV). This is efficient for those projects for which the uncertainty about the development is low. There is, however, an increasing number of new prototypical compounds resulting from the increased biological knowledge with a high level of uncertainty. For these prototypical drugs development has to proceed in a much more adaptive manner, using tailor-made objectives, the development of special methodology and a cyclical rather than a linear type of project management. © 2010 Macmillan Publishers Limited. All rights reserved.


Eekhof J.A.,Leiden University
Cochrane database of systematic reviews (Online) | Year: 2012

Ingrowing toenails are a common problem in which part of the nail penetrates the skinfold alongside the nail, creating a painful area. Different non-surgical and surgical interventions for ingrowing toenails are available, but there is no consensus about a standard first-choice treatment. To evaluate the effects of non-surgical and surgical interventions in a medical setting for ingrowing toenails, with the aim of relieving symptoms and preventing regrowth of the nail edge or recurrence of the ingrowing toenail. We updated our searches of the following databases to January 2010: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE, and EMBASE. We also updated our searches of CINAHL, WEB of SCIENCE, ongoing trials databases, and reference lists of articles. Randomised controlled trials of non-surgical and surgical interventions for ingrowing toenails, which are also known by the terms 'unguis incarnatus' and 'onychocryptosis', and those comparing postoperative treatment options. Studies must have had a follow-up period of at least one month. Two authors independently selected studies, assessed methodological quality, and extracted data from selected studies. We analysed outcomes as risk ratios (RR) with 95% confidence intervals (CI). This is an update of the Cochrane review 'Surgical treatments for ingrowing toenails'. In this update we included 24 studies, with a total of 2826 participants (of which 7 were also included in the previous review). Five studies were on non-surgical interventions, and 19 were on surgical interventions.The risk of bias of each included study was assessed; this is a measure of the methodological quality of several characteristics in these studies. It was found to be unclear for several items, due to incomplete reporting. Participants were not blinded to the treatment they received because of the nature of the interventions, e.g. surgery or wearing a brace on the toe. Outcome assessors were reported to be blinded in only 9 of the 24 studies.None of the included studies addressed our primary outcomes of 'relief of symptoms' or 'regrowth', but 16 did address 'recurrence'. Not all of the included studies addressed all of our secondary outcomes (healing time, postoperative complications - infection and haemorrhage, pain of operation/postoperative pain, participant satisfaction), and two studies did not address any of the secondary outcomes.Surgical interventions were better at preventing recurrence than non-surgical interventions with gutter treatment (or gutter removal), and they were probably better than non-surgical treatments with orthonyxia (brace treatment).In 4 of the 12 studies in which a surgical intervention with chemical ablation (e.g. phenol) was compared with a surgical intervention without chemical ablation, a significant reduction of recurrence was found. The surgical interventions on both sides in these comparisons were not equal, so it is not clear if the reduction was caused by the addition of the chemical ablation.In only one study, a comparison was made of a surgical intervention known as partial nail avulsion with matrix excision compared to the same surgical intervention with phenol. In this study of 117 participants, the surgical intervention with phenol was significantly more effective in preventing recurrence than the surgical intervention alone (14% compared to 41% respectively, RR 0.34, 95% CI 0.17 to 0.69).None of the postoperative interventions described, such as the use of antibiotics or manuka honey; povidone-iodine with paraffin; hydrogel with paraffin; or paraffin gauze, showed any significant difference when looking at infection rates, pain, or healing time. Surgical interventions are more effective than non-surgical interventions in preventing the recurrence of an ingrowing toenail.In the studies comparing a surgical intervention to a surgical intervention with the application of phenol, the addition of phenol is probably more effective in preventing recurrence and regrowth of the ingrowing toenail. Because there is only one study in which the surgical interventions in both study arms were equal, more studies have to be done to confirm these outcomes.Postoperative interventions do not decrease the risk of postoperative infection, postoperative pain, or healing time.


Pijl H.,Leiden University
Physiology and Behavior | Year: 2012

Restriction of food intake by 10-50% of ad libitum on a per unit of weight or energy content basis can extend the lifespan of a wide variety of species and prevent or delay age-related disease. This review first briefly summarizes the data delineating mortality trajectories of various species' populations maintained on restricted diets to provide insight into the effects of nutrient deprivation on distinct components of the aging process. Next, I discuss a number of important studies that have addressed the question whether it is the lack of calories and/or specific nutrients that determines the longevity response to dietary restriction. Finally, I review the evidence for hormesis as a proximate mechanism underpinning the impact of dietary restriction on lifespan. In aggregate, the currently available demographic data suggest that dietary restriction can both slow the age-related progressive accumulation of cellular damage and also enhance the ability of organisms to cope with irreversible injury. Restriction of essential nutrients as well as calories may affect life expectancy, perhaps in a species specific fashion. Hormesis, i.e. an evolutionary conserved stress response routine providing protection against a wide variety of (other) hazards in response to low levels of stress, is very likely to contribute to the beneficial health effects of dietary restriction. © 2011 Elsevier Inc.


Boyarsky A.,Leiden University | Frohlich J.,ETH Zurich | Ruchayskiy O.,Ecole Polytechnique Federale de Lausanne
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

We study the dynamics of a plasma of charged relativistic fermions at very high temperature T蠑m, where m is the fermion mass, coupled to the electromagnetic field. In particular, we derive a magnetohydrodynamical description of the evolution of such a plasma. We show that, compared to conventional magnetohydronamics (MHD) for a plasma of nonrelativistic particles, the hydrodynamical description of the relativistic plasma involves new degrees of freedom described by a pseudoscalar field originating in a local asymmetry in the densities of left-handed and right-handed fermions. This field can be interpreted as an effective axion field. Taking into account the chiral anomaly we present dynamical equations for the evolution of this field, as well as of other fields appearing in the MHD description of the plasma. Due to its nonlinear coupling to helical magnetic fields, the axion field significantly affects the dynamics of a magnetized plasma and can give rise to a novel type of inverse cascade. © 2015 American Physical Society.


Leja J.,Yale University | Van Dokkum P.,Yale University | Franx M.,Leiden University
Astrophysical Journal | Year: 2013

A central challenge in observational studies of galaxy formation is how to associate progenitor galaxies with their descendants at lower redshifts. One promising approach is to link galaxies at fixed number density rather than fixed luminosity or mass. This method is effective if stellar mass rank order is broadly conserved through cosmic time. In this paper, we use the Guo et al. semi-analytical model to analyze under what circumstances this assumption is valid in the context of a cosmological simulation. Specifically, we select progenitor galaxies at a constant number density and compare the stellar mass evolution of their descendants to the evolution at a constant number density. The median stellar mass of the descendants increases by a factor of four (0.6 dex) from z = 3 to z = 0. Constant number density selection reproduces this to within 40% (0.15 dex) over a wide range of number densities. We show that the discrepancy primarily results from scatter in the stellar mass growth rates and merging. After applying simple, observationally based corrections for these processes, the discrepancy is reduced to 12% (0.05 dex). We conclude that number density selection can be used to predict the median descendant mass of high-redshift progenitor galaxies. The main uncertainty in this study is that semi-analytical models do not reproduce the observed mass evolution of galaxies, which makes the quantitative aggregate effects of star formation, merging, and quenching on the rank order of galaxies somewhat uncertain. © 2013. The American Astronomical Society. All rights reserved.


Waaijer C.J.F.,Leiden University
Scientometrics | Year: 2013

This study analyzes the editorials in Science and Nature published between 2000 and 2012 about careers in science. Of the total body of documents, 8.8 % dealt with science careers. The editorials were manually classified by topics and then mapped using the VOSviewer. This revealed six easily distinguishable clusters: career conditions in science, the attractiveness of science as a career, merit-based career policies, the effect of research funding on careers, specific groups underrepresented in science, and mobility of scientists. The paper summarizes the main thrust of the arguments in these editorials. There is strong agreement about the problems in scientific careers, but less consensus on the solutions to these problems. The paper also explores whether mapping on the basis of automatically identified terms could have provided adequate results, but concludes that manual classification is needed. © 2013 Akadémiai Kiadó, Budapest, Hungary.


Knevel R.,University Hospitals Geneva Medical Center | Knevel R.,Hasselt University | Knevel R.,University of Zurich | Knevel R.,Leiden University
Annals of the rheumatic diseases | Year: 2014

METHODS: We performed a genome-wide association study on the radiological progression rate in 384 autoantibody-positive patients with RA. In stage-II 1557 X-rays of 301 Dutch autoantibody-positive patients with RA were studied and in stage-III 861 X-rays of 742 North American autoantibody-positive patients with RA. Sperm-Associated Antigen 16 (SPAG16) expression in RA synovium and fibroblast-like synoviocytes (FLS) was examined using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry. FLS secrete metalloproteinases that degrade cartilage and bone. SPAG16 genotypes were related to matrix metalloproteinase (MMP)-3 and MMP-1 expression by FLS in vitro and MMP-3 production ex vivo.RESULTS: A cluster of single nucleotide polymorphisms (SNPs) at 2q34, located at SPAG16, associated with the radiological progression rate; rs7607479 reached genome-wide significance. A protective role of rs7607479 was replicated in European and North American patients with RA. Per minor allele, patients had a 0.78-fold (95% CI 0.67 to 0.91) progression rate over 7 years. mRNA and protein expression of SPAG16 in RA synovium and FLS was verified. FLS carrying the minor allele secreted less MMP-3 (p=1.60×10(-2)). Furthermore, patients with RA carrying the minor allele had lower serum levels of MMP-3 (p=4.28×10(-2)). In a multivariate analysis on rs7607479 and MMP-3, only MMP-3 associated with progression (p=2.77×10(-4)), suggesting that the association between SPAG16-rs7607479 and joint damage is mediated via an effect on MMP-3 secretion.CONCLUSIONS: Genetic and functional analyses indicate that SPAG16 influences MMP-3 regulation and protects against joint destruction in autoantibody-positive RA. These findings could enhance risk stratification in autoantibody-positive RA.BACKGROUND: Joint destruction is a hallmark of autoantibody-positive rheumatoid arthritis (RA), though the severity is highly variable between patients. The processes underlying these interindividual differences are incompletely understood. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.


Vlieland T.P.M.V.,Leiden University | Van Den Ende C.H.,Sint Maartenskliniek
Current Opinion in Rheumatology | Year: 2011

Purpose of Review: To summarize recent literature on nonpharmacological and nonsurgical interventions in patients with rheumatoid arthritis (RA). Recent Findings: Recent systematic reviews and individual studies substantiate the effectiveness of aerobic and strength exercise programmes in RA. The evidence for the promotion of physical activity according to public health recommendations is scarce, and implementation research found that the reach and maintenance of exercise or physical activity programmes in RA patients are suboptimal. For self-management interventions, characteristics that increase their effectiveness were identified, including the use of cognitive behavioural approaches and approaches derived from the self-regulation theory. A limited number of recent individual trials substantiate the effectiveness of comprehensive occupational therapy, foot orthoses, finger splints and wrist working splints, but not of wrist resting splints. Overall, the evidence for the effectiveness of assistive devices and dietary interventions is scanty. Summary: For exercise and physical activity programmes and self-management interventions in RA, research is increasingly directed towards the optimization of their content, intensity, frequency, duration and mode of delivery and effective implementation strategies. A number of studies substantiate the effectiveness of comprehensive occupational therapy, wrist working splints and finger splints. More research into the effectiveness of assistive devices, foot orthoses and dietary interventions is needed. © 2011 Wolters Kluwer Health | Lippincott Williams and Wilkins.


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.


Jakimowicz D.,Wroclaw University | Jakimowicz D.,Institute of Immunology and Experimental Therapy | Van Wezel G.P.,Leiden University
Molecular Microbiology | Year: 2012

Streptomycetes are antibiotic-producing filamentous microorganisms that have a mycelial life style. In many ways streptomycetes are the odd ones out in terms of cell division. While the basic components of the cell division machinery are similar to those found in rod-shaped bacteria such as Escherichia coli and Bacillus subtilis, many aspects of the control of cell division and its co-ordination with chromosome segregation are remarkably different. The rather astonishing fact that cell division is not essential for growth makes these bacteria unique. The fundamental difference between the cross-walls produced during normal growth and sporulation septa formed in aerial hyphae, and the role of the divisome in their formation are discussed. We then take a closer look at the way septum site localization is regulated in the long and multinucleoid Streptomyces hyphae, with particular focus on actinomycete-specific proteins and the role of nucleoid segregation and condensation. © 2012 Blackwell Publishing Ltd.


Bender A.,Leiden University
Methods in molecular biology (Clifton, N.J.) | Year: 2011

The Naïve Bayesian Classifier, as well as related classification and regression approaches based on Bayes' theorem, has experienced increased attention in the cheminformatics world in recent years. In this contribution, we first review the mathematical framework on which Bayes' methods are built, and then continue to discuss implications of this framework as well as practical experience under which conditions Bayes' methods give the best performance in virtual screening settings. Finally, we present an overview of applications of Bayes' methods to both virtual screening and the chemical biology arena, where applications range from bridging phenotypic and mechanistic space of drug action to the prediction of ligand-target interactions.


Hagenaars M.A.,Leiden University | Arntz A.,Maastricht University
Journal of Behavior Therapy and Experimental Psychiatry | Year: 2012

Background and objectives: Contemporary theories predict PTSD development after trauma if trauma information is not adequately processed or negatively appraised. Mental imagery and emotional processing seem to be strongly related and evidence-based treatment strategies such as imaginal exposure and EMDR indeed include imagery as a main component. Moreover, imagery rescripting of traumatic memories is an effective treatment for PTSD. Methods: The present study combined these lines of research and investigated the impact of early imagery rescripting on intrusion development after an aversive film. Seventy-six participants were randomly allocated to one of three conditions: imagery rescripting (IRS), imagery reexperiencing (IRE) and positive imagery (PI). All participants watched an aversive film, had a 30-min break and then received a 9-min intervention (IRS, IRE or PI). They indicated subjective distress during the intervention, recorded intrusive memories of the film for 1 week and completed the Posttraumatic Cognitions Inventory (PTCI) and a cued recall test one week later. Results: The IRS group developed fewer intrusive memories relative to the IRE and PI groups, and less negative cognitions than the IRE group, while cued recall was enhanced in IRS and IRE groups compared to the PI group. IRS and PI groups experienced less distress during the intervention than the IRE group. Limitations: This is an analogue design and results should be replicated in clinical samples. Conclusions: The results suggest that IRS might be an adequate technique to change memory consolidation at an early stage and therefore a powerful and non-distressing strategy to prevent PTSD symptoms. © 2011 Elsevier Ltd. All rights reserved.


Pijl H.,Leiden University
Netherlands Journal of Medicine | Year: 2011

This paper delineates the evolutionary background of the unprecedented epidemic of obesity that has evolved over the last century. Some two million years ago, a change of climate in the habitat of our primate ancestors triggered dietary adaptations which allowed our brain to grow. A shift from principally carbohydrate-based to fish- and meat-based eating habits provided sufficient fuel and building blocks to facilitate encephalisation. Insulin resistance may have evolved simultaneously as a means to avert the danger of hypoglycaemia to the brain (in view of the reduction of carbohydrate intake). Ensuing cognitive capacities enabled the control of fire and the manufacturing of tools, which increased energy yield from food even further and eased the defence against predators. The latter development relieved the selective pressure to maintain an upper level of bodyweight (driven by predation of overweight individuals). Since then, random mutations allowing bodyweight to increase spread in the human gene pool by genetic drift. Also, (seasonal) food insecurity in hunter-gatherer societies spurred the evolution of thrifty genes to maximise nutrient intake and energy storage when food was available. The agricultural and industrial revolutions rapidly changed our habitat: virtually unlimited stocks of (refined) foodstuffs and mechanical substitutes of physical efforts push up energy balance, particularly in those of us who are still adapted to former environmental conditions: i.e. who carry thrifty genes and lack (genetic) protection against weight gain. Intrauterine epigenetic mechanisms potentially reinforce the impact of these genes on the propensity to grow obese. © Van Zuiden Communications B.V. All rights reserved.


Furuya K.,Kobe University | Furuya K.,Leiden University | Aikawa Y.,Kobe University
Astrophysical Journal | Year: 2014

We study the influence of the turbulent transport on ice chemistry in protoplanetary disks, focusing on carbon- and nitrogen-bearing molecules. Chemical rate equations are solved with the diffusion term, mimicking the turbulent mixing in the vertical direction. Turbulence can bring ice-coated dust grains from the midplane to the warm irradiated disk surface, and the ice mantles are reprocessed by photoreactions, thermal desorption, and surface reactions. The upward transport decreases the abundance of methanol and ammonia ices at r ≲ 30 AU because warm dust temperature prohibits their reformation on grain surfaces. This reprocessing could explain the smaller abundances of carbon and nitrogen bearing molecules in cometary coma than those in low-mass protostellar envelopes. We also show the effect of mixing on the synthesis of complex organic molecules (COMs) in two ways: (1) transport of ices from the midplane to the disk surface and (2) transport of atomic hydrogen from the surface to the midplane. The former enhances the COMs formation in the disk surface, while the latter suppresses it in the midplane. Then, when mixing is strong, COMs are predominantly formed in the disk surface, while their parent molecules are (re)formed in the midplane. This cycle expands the COMs distribution both vertically and radially outward compared with that in the non-turbulent model. We derive the timescale of the sink mechanism by which CO and N2 are converted to less volatile molecules to be depleted from the gas phase and find that the vertical mixing suppresses this mechanism in the inner disks. © 2014. The American Astronomical Society. All rights reserved.


Waltman L.,Leiden University
Journal of Informetrics | Year: 2016

Citation impact indicators nowadays play an important role in research evaluation, and consequently these indicators have received a lot of attention in the bibliometric and scientometric literature. This paper provides an in-depth review of the literature on citation impact indicators. First, an overview is given of the literature on bibliographic databases that can be used to calculate citation impact indicators (Web of Science, Scopus, and Google Scholar). Next, selected topics in the literature on citation impact indicators are reviewed in detail. The first topic is the selection of publications and citations to be included in the calculation of citation impact indicators. The second topic is the normalization of citation impact indicators, in particular normalization for field differences. Counting methods for dealing with co-authored publications are the third topic, and citation impact indicators for journals are the last topic. The paper concludes by offering some recommendations for future research. © 2016 Elsevier Ltd.


Marinskis G.,Vilnius University | Van Erven L.,Leiden University
Europace | Year: 2010

This survey assesses the current opinion on and practice of the management of terminally ill patients with implanted cardioverter-defibrillators (ICDs) in 47 large European centres. The principal findings of this survey were that most physicians (62) from European centres who responded to this survey would consider deactivating ICDs at the patient's endoflife. In these circumstances, multiple appropriate ICD shocks may be an indication to deactivate an ICD (83 positive answers). Remote deactivation by a remote monitoring system is not considered appropriate by 68. Practices of deactivating procedure differ and approach to standardized clinical scenarios is inhomogeneous. Patients are provided with surprisingly little information on the possibility of deactivation of ICDs since this subject is only actively discussed in 4 of centres. Published on behalf of the European Society of Cardiology. © The Author 2010.


Malessy M.J.,Leiden University
The Journal of bone and joint surgery. American volume | Year: 2014

BACKGROUND: Nerve reconstruction strategies for restoration of elbow flexion and shoulder function in patients with neonatal brachial plexus palsy with neurotmesis of C5 and avulsion of C6 are not well defined and the outcomes are unclear.METHODS: From 1990 to 2008, nerve surgery was performed in 421 patients with neonatal brachial plexus palsy. This study focused on thirty-four infants who had a neurotmetic lesion of C5 and avulsion or intraforaminal neurotmesis of C6, irrespective of C7. The C8 and T1 functions were intact. Intraplexal transfer of C6 to C5 with direct coaptation was preferred for restoration of elbow flexion. The suprascapular nerve was reconnected either by extra-intraplexal transfer of the accessory nerve or by grafting from C5 to restore shoulder function. Additional grafts were attached from C5 to the C5 contribution of the posterior division of the superior trunk when technically possible.RESULTS: Transfer of either the C6 anterior root filaments or the entire C6 nerve to C5 was performed in seventeen patients (group A) with direct coaptation in fifteen of them. Grafting from C5 to the anterior division of the superior trunk was performed in the remaining seventeen infants (group B). An accessory-to-suprascapular nerve transfer was applied in twenty-nine infants. The suprascapular nerve was reconnected in five patients by grafting from C5. It was possible to attach one, two, or three additional grafts from C5 to the posterior division of the superior trunk in twenty-one patients. All infants had biceps muscle recovery to a Medical Research Council (MRC) grade of ≥4, twenty-two (65%) of the thirty-four patients obtained Mallet grade-IV abduction, and eleven (32%) of the thirty-four obtained Mallet grade-IV external rotation.CONCLUSIONS: In patients with neonatal brachial plexus palsy who have neurotmesis of C5 and avulsion of C6, elbow flexion can be successfully restored with supraclavicular intraplexal reconstruction with use of C5 as the proximal outlet. However, shoulder function recovery following suprascapular nerve reinnervation and additional grafting from C5 to the posterior division of the superior trunk is less successful.LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.


Ottenhoff T.H.M.,Leiden University | Kaufmann S.H.E.,Max Planck Institute for Infection Biology
PLoS Pathogens | Year: 2012

In this review we discuss recent progress in the development, testing, and clinical evaluation of new vaccines against tuberculosis (TB). Over the last 20 years, tremendous progress has been made in TB vaccine research and development: from a pipeline virtually empty of new TB candidate vaccines in the early 1990s, to an era in which a dozen novel TB vaccine candidates have been and are being evaluated in human clinical trials. In addition, innovative approaches are being pursued to further improve existing vaccines, as well as discover new ones. Thus, there is good reason for optimism in the field of TB vaccines that it will be possible to develop better vaccines than BCG, which is still the only vaccine available against TB. © 2012 Ottenhoff, Kaufmann.


de Wit F.R.,Leiden University
Psychophysiology | Year: 2012

This study examined how the outcomes of joint decision making relate to cardiovascular reactions when group members disagree about the decision to be taken. A conflict was experimentally induced during a joint decision-making task, while cardiovascular markers of challenge/threat motivational states were assessed following the biopsychosocial model of challenge and threat (BPSM; J. Blascovich, 2008). Results show that individuals were less likely to adjust their initially preferred decision alternative the more they exhibited a cardiovascular pattern indicative of threat (i.e., relatively high total peripheral resistance and low cardiac output) compared to challenge. This finding extends the BPSM by showing a link between threat and rigidity, and emphasizes the importance of psychophysiological processes for studying intragroup conflict and decision making. Copyright © 2012 Society for Psychophysiological Research.


Verkuil B.,Leiden University
Psychology & health | Year: 2012

Somatic health complaints are extremely common and are responsible for a large part of human suffering and healthcare costs. It has been recognised that psychosocial stress can affect somatic health. According to the 'perseverative cognition hypothesis', stressful events affect somatic health because people keep on worrying about them. Worry would prolong stress-related physiological activity that can ultimately lead to health problems. In this ambulatory study we tested whether stressful events and worry predict daily somatic complaints, and whether worry mediates the effects of stressful events. In addition, it was tested whether these effects were independent from negative affect. Using electronic diaries, 69 teachers (age 21-60 years) from Dutch primary and secondary schools reported daily stressful events, worry episodes, negative affect and somatic complaints for a period of 6 days. Results showed that worry intensity predicted the number of somatic complaints and mediated the effect of stressful events on somatic complaints. Furthermore, these results were independent from biobehavioural variables and daily negative affect. These findings support the perseverative cognition hypothesis proposing that the negative somatic health effects of stressful events are largely due to the worry; that is, to the prolonged cognitive representation of stressors.


Reedeker W.,Leiden University
Psychosomatics | Year: 2012

This study investigates the presence and course of formal psychiatric disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) in 142 Huntington's disease (HD) mutation carriers in a two-year follow-up design. Of the 142 mutation carriers, 106 (75%) participated in the second measurement of an ongoing cohort study on psychopathology in HD. Presence of psychiatric disorders was assessed using the Composite International Diagnostic Interview. Of the 91 patients without a formal psychiatric disorder at baseline, 14 (15%) had a psychiatric disorder after 2 years, mostly a major depressive disorder (MDD) (64%). The baseline characteristics of lower education, having no children, a lower level of global daily functioning, a lifetime psychiatric diagnosis, and the use of psychotropic medication were predictive of incident psychiatric disorders after 2 years. Of the 15 patients with a psychiatric diagnosis at baseline, eight (53%) no longer had a psychiatric disorder at follow-up. All seven patients (47%) with a persistent psychiatric disorder were female and their most prevalent diagnosis was generalized anxiety disorder. This cohort study confirms that psychiatric disorders, in particular MDD, frequently occur in patients with HD. Professionals working with HD patients should therefore be aware of the high risk of psychopathology in HD because early diagnosis and treatment of psychiatric disorders may improve the quality of life of patients and their caregivers. Copyright © 2012 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.


The Tup1-Cyc8 (Ssn6) complex is a well characterized and conserved general transcriptional repressor complex in eukaryotic cells. Here, we report the identification of the Tup1 (TupA) homolog in the filamentous fungus Aspergillus niger in a genetic screen for mutants with a constitutive expression of the agsA gene. The agsA gene encodes a putative alpha-glucan synthase, which is induced in response to cell wall stress in A. niger. Apart from the constitutive expression of agsA, the selected mutant was also found to produce an unknown pigment at high temperatures. Complementation analysis with a genomic library showed that the tupA gene could complement the phenotypes of the mutant. Screening of a collection of 240 mutants with constitutive expression of agsA identified sixteen additional pigment-secreting mutants, which were all mutated in the tupA gene. The phenotypes of the tupA mutants were very similar to the phenotypes of a tupA deletion strain. Further analysis of the tupA-17 mutant and the ΔtupA mutant revealed that TupA is also required for normal growth and morphogenesis. The production of the pigment at 37°C is nitrogen source-dependent and repressed by ammonium. Genome-wide expression analysis of the tupA mutant during exponential growth revealed derepression of a large group of diverse genes, including genes related to development and cell wall biosynthesis, and also protease-encoding genes that are normally repressed by ammonium. Comparison of the transcriptome of up-regulated genes in the tupA mutant showed limited overlap with the transcriptome of caspofungin-induced cell wall stress-related genes, suggesting that TupA is not a general suppressor of cell wall stress-induced genes. We propose that TupA is an important repressor of genes related to development and nitrogen metabolism.


Spectroscopy forms the bridge between theory and experiment in the analysis of structure, properties, and reactivity of functional molecules and molecular aggregates. Our knowledge on the basic working principles of systems such as photosynthetic units strongly relies on spectroscopic information, which is interpreted in terms of molecular or submolecular building blocks. To choose such entities as the essential ingredients in a quantum chemical framework is thus a promising route to the theoretical spectroscopy of complex systems.This work describes developments of chromophore-specific quantum chemical methods, which focus on relevant substructures without sacrificing the view on the entire system. A subsystem density-functional theory approach is analyzed that employs a real-space partitioning of the electron density for the description of complex aggregates in terms of simple fragments. This approach can be used as a chromophore-specific embedding method and allows for efficient and accurate analyses of environmental effects. However, it fails for phenomena caused by a collective response of an aggregate of molecules. The limitations of this embedding scheme can be overcome by a general subsystem approach to time-dependent density functional theory, which easily relates to phenomenological theories such as excitonic coupling models.Resonance Raman spectroscopy can be used to probe local excited states in larger molecules and is thus intrinsically chromophore-specific. It is shown that well-known approximations for resonance Raman calculations can efficiently be used with time-dependent density-functional theory methods to study photochemical and photophysical processes in large molecules such as artificial photosynthetic systems. Intensity-driven approaches to resonance Raman calculations can exploit the selectivity observed in experiments for an iterative determination of high-intensity spectral features. Applications of such schemes to biochemical building blocks are discussed. © 2009 Elsevier B.V.


Anguelova G.V.,Leiden University
Developmental medicine and child neurology | Year: 2013

Sensory function is assumed to recover almost completely in obstetric brachial plexus lesion (OBPL), and is reported to recover much better than motor function. However, there is no obvious physiological reason why this should be so. Any persistent problems with sensory innervation might contribute to disability, therefore we aimed to assess sensory dysfunction in adults resulting from OBPL. Adults with conservatively treated OBPL (n=17; 12 females, five males; median age 38y; lesion levels: C5-C6, n=7; C5-C7, n=7; C5-C8, n=2; C5-Th1, n=1) and 19 healthy comparison persons (10 females, nine males; median age 23y) were investigated. Sensory function was measured using Semmes-Weinstein monofilaments, two-point discrimination, object recognition, and a locognosia test. Scores of the Semmes-Weinstein monofilaments and two-point discrimination, but not object recognition or locognosia, were significantly worse in those with OBPL than in those without OBPL. There may be systematic abnormalities in sensory function in adults with conservatively treated OBPL. The existence of these impairments and their contribution to functional impairment needs to be acknowledged. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.


Hollmann T.J.,Harvard University | Bovee J.V.M.G.,Leiden University | Fletcher C.D.M.,Harvard University
American Journal of Surgical Pathology | Year: 2012

Digital fibromyxoma (first described by Fetsch and colleagues as superficial acral fibromyxoma) is a distinctive soft tissue tumor with a predilection for the subungual or periungual region of the hands and feet. This report details the histologic, immunophenotypic, and clinical findings in 124 cases of digital fibromyxoma. The study group included 70 male and 54 female patients (1.3:1, M:F), ranging in age from 4 to 86 years (mean, 48 y; median, 49 y). Mean tumor size was 1.7 cm (range, 0.5 to 5 cm; median, 1.5 cm). Nearly half of the patients (41%) presented with a painful mass. Tumors arose on the hands (52%) or feet (45%), with rare tumors arising on the ankle or leg. Most tumors occurred on the digits (94% of hand tumors, 82% of foot tumors), with the majority growing in close proximity to the nail (97% on fingers, 96% on toes). Histologically, 80% of cases were poorly marginated; 70% infiltrated the dermal collagen, 27% infiltrated fat, and 3% invaded bone. In cases in which imaging studies were available, bone involvement by an erosive or lytic lesion was more frequent (9/25, 36%). All tumors were composed of spindle-shaped or stellate-shaped cells with palely eosinophilic cytoplasm and a random or loosely fascicular growth pattern. The tumor cells were separated by dense hyaline collagen alternating with myxoid stroma. Most (86%) of the tumors showed alternating areas of fibrous and myxoid stroma, 11% showed predominantly fibrous stroma, and 3% had predominantly myxoid stroma. Increased mast cells were noted in 88% of tumors. All tumors comprised cells with minimal atypia, occasionally showing scattered larger cells with so-called "degenerative change." Mitotic figures were infrequent, and all tumors lacked necrosis, pleomorphism, or neural/perineural infiltration. Multinucleate stromal cells were occasionally seen. Tumor cells were reactive for CD34 in 42/61 cases (69%), with rare tumors showing focal reactivity for EMA (3/40, 7.5%), smooth muscle actin (5/42, 12%), and desmin (1/18, 6%). All tumors were negative for S100 (0/66), MUC4 (0/11), GFAP (0/10), AE1/AE3 (0/4), Cam5.2 (0/2), PanK (0/2), Claudin (0/4), and NFP (0/3). Follow-up in 47 cases ranged from 1 to 252 months (mean, 35 mo). Ten tumors (24%) recurred locally (all near the nail unit of the fingers or toes) after a mean interval of 27 months. One tumor recurred twice. All recurrent tumors had positive margins on initial biopsy or subsequent excision and no other clinical or pathologic features correlated with recurrence/persistence. To date, no tumor has metastasized. Finally, sequencing of 8 digital fibromyxomas failed to reveal mutations in exon 8 or 9 of GNAS1, in contrast to intramuscular or cellular myxoma. © 2012 by Lippincott Williams & Wilkins.


van Raan A.F.J.,Leiden University
Scientometrics | Year: 2012

In this paper we present a compilation of journal impact properties in relation to other bibliometric indicators as found in our earlier studies together with new results. We argue that journal impact, even calculated in a sufficiently advanced way, becomes important in evaluation practices based on bibliometric analysis only at an aggregate level. In the relation between average journal impact and actual citation impact of groups, the influence of research performance is substantial. Top-performance as well as lower performance groups publish in more or less the same range of journal impact values, but top-performance groups are, on average, more successful in the entire range of journal impact. We find that for the high field citation-density groups a larger size implies a lower average journal impact. For groups in the low field citation-density regions however a larger size implies a considerably higher average journal impact. Finally, we found that top-performance groups have relatively less self-citations than the lower performance groups and this fraction is decreasing with journal impact. © 2012 The Author(s).


Cox F.M.,Leiden University
Rheumatology (Oxford, England) | Year: 2011

To analyse whether MRI of upper and lower extremity muscles in a large patient group with sporadic IBM (sIBM) is of additional value in the diagnostic work-up of sIBM. Thirty-two sIBM patients were included. Magnetic resonance (MR) parameters evaluated in 68 muscles of upper and lower extremity were muscle atrophy, fatty infiltration and inflammation. These findings were correlated with disease duration, weakness and serum creatine kinase (sCK) levels. Fatty infiltration was far more common than inflammation. Muscles most frequently infiltrated with fat were the flexor digitorum profundus (FDP), anterior muscles of the upper leg and all muscles of the lower leg, preferentially the medial part of the gastrocnemius. The rectus femoris was relatively spared compared with other quadriceps muscles as well as the adductors of the upper leg. Inflammation was common in general, but individually sparse, present in 78% of the patients with a median of two inflamed muscles per patient. A statistically significant correlation was found between the amount of fatty infiltration and disease severity, disease duration and sCK. We provide a detailed description of the MRI in sIBM and show a distinct pattern of muscle involvement. Relatively severe affliction of the medial compartment of the gastrocnemius, combined with relative sparing of the rectus femoris or involvement of the FDP can be indicative of sIBM. MRI can contribute to the diagnosis in selected patients with clear clinical suspicion, but lacking the mandatory set of muscle biopsy features.


van Heemst D.,Leiden University
Aging and Disease | Year: 2010

It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. Likewise, substantial increases in lifespan are associated with mutations that reduce insulin/IGF-1 signaling in the fruit fly Drosophila melanogaster. In invertebrates, multiple insulin-like ligands exist that bind to a common single insulin/IGF-1 like receptor. In contrast, in mammals, different receptors exist that bind insulin, IGF-1 and IGF-2 with different affinities. In several mouse models, mutations that are associated with decreased GH/IGF-1 signaling or decreased insulin signaling have been associated with enhanced lifespan. However, the increased complexity of the mammalian insulin/IGF-1 system has made it difficult to separate the roles of insulin, GH and IGF-1 in mammalian longevity. Likewise, the relevance of reduced insulin and IGF-1 signaling in human longevity remains controversial. However, studies on the genetic and metabolic characteristics that are associated with healthy longevity and old age survival suggest that the conserved ancient IIS pathway may also play a role in human longevity.


Ament L.J.P.,Leiden University | Van Veenendaal M.,Argonne National Laboratory | Van Veenendaal M.,Northern Illinois University | Devereaux T.P.,SLAC | And 2 more authors.
Reviews of Modern Physics | Year: 2011

In the past decade, resonant inelastic x-ray scattering (RIXS) has made remarkable progress as a spectroscopic technique. This is a direct result of the availability of high-brilliance synchrotron x-ray radiation sources and of advanced photon detection instrumentation. The technique's unique capability to probe elementary excitations in complex materials by measuring their energy, momentum, and polarization dependence has brought RIXS to the forefront of experimental photon science. Both the experimental and theoretical RIXS investigations of the past decade are reviewed, focusing on those determining the low-energy charge, spin, orbital, and lattice excitations of solids. The fundamentals of RIXS as an experimental method are presented and then the theoretical state of affairs, its recent developments, and the different (approximate) methods to compute the dynamical RIXS response are reviewed. The last decade's body of experimental RIXS data and its interpretation is surveyed, with an emphasis on RIXS studies of correlated electron systems, especially transition-metal compounds. Finally, the promise that RIXS holds for the near future is discussed, particularly in view of the advent of x-ray laser photon sources. © 2011 American Physical Society.


Koper M.T.M.,Leiden University | Koper M.T.M.,Hokkaido University
Journal of Solid State Electrochemistry | Year: 2013

This paper discusses the concepts of rate-determining step and potential-determining step in the context of electrocatalytic reaction schemes, illustrates how the simpler concept of potential-determining step often captures the essence of a bottleneck in a reaction scheme, and thereby provides straightforward hints for developing better catalysts. © 2012 Springer-Verlag Berlin Heidelberg.


Daha M.R.,Leiden University
Critical Reviews in Immunology | Year: 2010

The complement system is a major player in our innate defense and constitutes one of the key effector mechanisms of antibody-dependent and-independent immunity. The complement system is composed of a large number of proteins found in the circulation, in other body fluids, and in tissues in a biologically inactive state. Biological activity of the complement system is generated following activation of the complement system via three initiating pathways, which ultimately lead to the activation of C3, the central component of complement, and the generation of a large number of biological functions such as anaphylaxis, chemotaxis, and phagocytosis. The crucial role of C3 activation is evidenced by the susceptibility of individuals with C3 deficiency to infections with various types of microorganisms and the inability to properly handle immune complexes, self-debris, etc. This review will focus on the protective role of the lectin pathway of complement and the alternative pathway in bacterial defense. © 2010 by Begell House, Inc.


Van Der Helm-Van Mil A.H.M.,Leiden University
Nature Reviews Rheumatology | Year: 2014

The prognosis for patients with rheumatoid arthritis (RA) who were diagnosed in the years since 2010 is much better than for individuals who were diagnosed with the disease 20 years ago. This improvement in the long-term outcome of disease is the result of earlier initiation of therapy, disease-activity-guided modification of treatment and the availability of new, and effective, drugs. Nonetheless, current treatment strategies remain population-based, rather than individualized. Decision-making processes relevant to the provision of individualized treatment require appropriate prognostication with regard to a number of variables. Here, the methods available to evaluate the performance of predictive models are discussed. In addition, I highlight the advances in risk estimation that have been made concerning three treatment decisions relevant to the management of RA that are made daily in the clinic: when to initiate treatment with DMARDs in patients in the early stages of arthritis; the ideal intensity of initial treatment; and the likely responsiveness of the patient to a particular therapy. Apart from a model predicting the development of RA, the majority of prognostic tools derived in arthritis and RA are not accurate or not validated. Hence, personalized treatment decisions in arthritis and RA are still far from bedside. © 2014 Macmillan Publishers Limited.


Tijssen R.J.W.,Leiden University
Journal of the American Society for Information Science and Technology | Year: 2010

This paper introduces a comprehensive system for classifying scholarly journals according to their degree of 'application orientation.' The method extends earlier models and journal classification systems that were designed to tackle the crude duality between 'basic research' and 'applied research.'This metrics-based system rests on a 'Knowledge Utilization Triangle' typology, which distinguishes three types of coexisting knowledge application domains: 'clinical,' 'industrial,' and 'civic.' The empirical data relate to the institutional origin of authors who publish their research papers in the scientific journal literature. The case study applies indicators of 'clinical relevance' and 'industrial relevance' to 11,000 journals indexed by the Web of Science (WoS) database. The resulting multidimensional classification system of journals comprises six Journal Application Domain (JAD) categories. Macro-level trend analysis of the WoS-indexed research publication output by JAD category reveals redistributions within global science during the years 1999-2008, with a slight increase of output published in 'industrially relevant' journals. © 2010 ASIS&T.


Tollenaar L.S.A.,Leiden University
Fetal Diagnosis and Therapy | Year: 2016

Objective: To determine the color intensity difference between the 2 placental shares in monochorionic placentas with twin anemia-polycythemia sequence (TAPS). Methods: We evaluated all digital pictures of TAPS placentas examined at our center and compared them to a control group of uncomplicated monochorionic placentas. We determined the color intensity of individual placental share on the maternal side of each monochorionic placenta using an image processing program and calculated the color difference ratio (CDR). Results: Digital pictures of 19 TAPS and 19 uncomplicated monochorionic placentas were included in this study. The TAPS group consisted of 12 spontaneous TAPS placentas (63%) and 7 post-laser TAPS placentas (37%). The median CDR in the group with TAPS was significantly higher than in the control group, 2.73 (range 1.73-6.36) versus 1.09 (range 1.00-1.35), respectively (p < 0.01). We found a positive correlation between CDR and inter-twin hemoglobin (Hb) difference in the TAPS group (R = 0.66, p < 0.01) but not in the control group (R = 0.04, p = 0.87). Conclusion: TAPS placentas have a significantly higher CDR compared to uncomplicated monochorionic twin placentas. Large inter-twin Hb differences in TAPS are associated with higher CDR. © 2016 S. Karger AG, Basel Copyright © 2016, S. Karger AG. All rights reserved.


Loenen W.A.M.,Leiden University | Dryden D.T.F.,University of Edinburgh | Raleigh E.A.,New England Biolabs | Wilson G.G.,New England Biolabs
Nucleic Acids Research | Year: 2014

Type I restriction enzymes (REases) are large pentameric proteins with separate restriction (R), methylation (M) and DNA sequence-recognition (S) subunits. They were the first REases to be discovered and purified, but unlike the enormously useful Type II REases, they have yet to find a place in the enzymatic toolbox of molecular biologists. Type I enzymes have been difficult to characterize, but this is changing as genome analysis reveals their genes, and methylome analysis reveals their recognition sequences. Several Type I REases have been studied in detail and what has been learned about them invites greater attention. In this article, we discuss aspects of the biochemistry, biology and regulation of Type I REases, and of the mechanisms that bacteriophages and plasmids have evolved to evade them. Type I REases have a remarkable ability to change sequence specificity by domain shuffling and rearrangements. We summarize the classic experiments and observations that led to this discovery, and we discuss how this ability depends on the modular organizations of the enzymes and of their S subunits. Finally, we describe examples of Type II restriction-modification systems that have features in common with Type I enzymes, with emphasis on the varied Type IIG enzymes. © The Author(s) 2013. Published by Oxford University Press.


Bruggemans E.F.,Leiden University
Netherlands Heart Journal | Year: 2013

Despite improvements in surgical techniques and the implementation of effective brain protection strategies, the incidence of brain injury after cardiac surgery has remained relatively constant over the years as patients have become older and sicker. Cognitive dysfunction is the most common clinical manifestation of brain injury after cardiac surgery. Its occurrence is related to a combination of three factors that are often associated with cardiopulmonary bypass (CPB): embolism, hypoperfusion, and the inflammatory response. However, such factors and their potential cerebral consequences are not exclusive to CPB. Postoperative cognitive dysfunction also afflicts patients who undergo cardiac surgery without CPB as well as nonsurgery patients who undergo transcatheter interventions. There is growing evidence that patient-related factors such as the presence of (cerebro)vascular risk factors play an important role in both early and late postoperative cognitive dysfunction. © Springer Media/Bohn Stafleu van Loghum 2012.


Swenne C.A.,Leiden University
Netherlands Heart Journal | Year: 2013

This article is a brief review of baroreflex physiology, the definition and functional meaning of baroreflex sensitivity, and the methods used to measure baroreflex sensitivity. The arterial baroreflex is important for haemodynamic stability and for cardioprotection, and it has convincingly been demonstrated that baroreflex sensitivity, even when assessed with different methods, has a strong prognostic value. Development of new baroreflex assessing procedures is still ongoing, with a focus on increased reliability in difficult measuring circumstances, e.g., in patients with a weak baroreflex and in patients with frequent arrhythmias. © Springer Media/Bohn Stafleu van Loghum 2012.


Luijsterburg M.S.,Karolinska Institutet | Van Attikum H.,Leiden University
Molecular Oncology | Year: 2011

The integrity of the human genome is constantly threatened by genotoxic agents that cause DNA damage. Inefficient or inaccurate repair of DNA lesions triggers genome instability and can lead to cancer development or even cell death. Cells counteract the adverse effects of DNA lesions by activating the DNA damage response (DDR), which entails a coordinated series of events that regulates cell cycle progression and repair of DNA lesions. Efficient DNA repair in living cells is complicated by the packaging of genomic DNA into a condensed, often inaccessible structure called chromatin. Cells utilize post-translational histone modifications and ATP-dependent chromatin remodeling to modulate chromatin structure and increase the accessibility of the repair machinery to lesions embedded in chromatin. Here we review and discuss our current knowledge and recent advances on DNA damage-induced chromatin changes and their implications for the mammalian DNA damage response, genome stability and carcinogenesis. Exploiting our improving understanding of how modulators of chromatin structure orchestrate the DDR may provide new avenues to improve cancer management. © 2011 Federation of European Biochemical Societies.


Rabe K.F.,Leiden University
Expert Review of Respiratory Medicine | Year: 2010

Roflumilast is a new phosphodiesterase 4 inhibitor that has recently completed Phase III trials for the treatment of chronic obstructive pulmonary disease (COPD). Preclinical studies have shown that roflumilast targets inflammatory processes in COPD, with beneficial effects on tobacco-induced lung inflammation, lung fibrosis and remodeling, mucociliary malfunction and oxidative stress. Two recent, 1-year Phase III trials in COPD have shown that roflumilast reduces exacerbations and improves lung function in patients with COPD who have symptoms of chronic bronchitis and a history of exacerbations. Two other 6-month Phase III trials have demonstrated the beneficial effects of roflumilast in patients already receiving treatment with the long-acting -agonist salmeterol or the long-acting muscarinic antagonist tiotropium. This article reviews the pharmacology, pharmacokinetics and preclinical pharmacology of roflumilast, the clinical studies supporting its use in COPD and its side-effect profile. © 2010 Expert Reviews Ltd.


Kroes G.-J.,Leiden University
Journal of Physical Chemistry Letters | Year: 2015

Being able to calculate reaction barrier heights to within chemical accuracy (errors < 1 kcal/mol) is crucial to the accurate modeling of chemical reactions. Although accurate databases exist that can help theorists with benchmarking new electronic structure theories on gas-phase chemical reactions, no such databases exist for reactions of molecules with metal surfaces. Nonetheless, most chemicals are made in heterogeneously catalyzed processes, of which many take place over metal particles. Presently, barrier heights for molecule-metal surface reactions have been determined with chemical accuracy for only two systems, that is, H2 + Cu(111) and H2 + Cu(100). This has been done with semiempirically determined density functionals, which were fitted through comparisons of dynamics results with molecular beam sticking probabilities. The prospects of extending the database with chemically accurate data for other molecule-metal reactions, either with the use of semiempirical density functional theory or with first-principles theory, are discussed. © 2015 American Chemical Society.


Van Der Helm-Van Mil A.H.,Leiden University
Current Opinion in Rheumatology | Year: 2010

Purpose of review: The incidence of acute rheumatic fever (ARF) in the United States and Western Europe is decreasing and postStreptococcal reactive arthritis (PSRA) is more prevalent. It is not clear whether PSRA is a forme fruste of ARF or a separate disease entity. Therefore, this review explores similarities and dissimilarities in initial symptoms and signs, disease course and underlying pathophysiologic mechanisms. Recent findings: ARF and PSRA present differently. PSRA patients are generally older, have a longer interval between group A streptococcus infection and symptom onset, and respond less dramatically to salicylates than ARF patients. The course of ARF may be complicated by carditis and valvular heart disease. Echocardiographic studies in Caucasian adults with PSRA have revealed no increase in valvular heart disease. The course of PSRA is characterized by arthritis that, in contrast to ARF, is additive, nonmigratory and is frequently chronic. Factors of the host, the Streptococcus and the immune response involved in the development of PSRA are scarcely explored, hampering comparisons with ARF. Summary: On the basis of the differences in clinical presentation and disease course, ARF and PSRA are separate disease entities. Development of validated diagnostic criteria for PSRA is mandatory to proceed with studies on pathophysiological mechanisms and treatment in PSRA. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Kruis A.L.,Leiden University
International journal of chronic obstructive pulmonary disease | Year: 2010

Chronic obstructive pulmonary disease (COPD) constitutes a growing health care problem worldwide. Integrated disease management (IDM) of mild to moderate COPD patients has been demonstrated to improve exercise capacity and health status after one year, but long-term results are currently lacking in primary care. Long-term data from the Bocholtz study, a controlled clinical trial comparing the effects of IDM versus usual care on health status in 106 primary care COPD patients during 24 months of follow-up, were analyzed using the Clinical COPD Questionnaire (CCQ). In addition, the Kroonluchter IDM implementation program has treated 216 primary care patients with mild to moderate COPD since 2006. Longitudinal six-minute walking distance (6MWD) results for patients reaching 24 months of follow-up were analyzed using paired-sample t-tests. In prespecified subgroup analyses, the differential effects of baseline CCQ score, Medical Research Council (MRC) dyspnea score, and 6MWD were investigated. In the Bocholtz study, subjects were of mean age 64 years, with an average postbronchodilator forced expiratory volume in one second (FEV(1)) of 63% predicted and an FEV(1)/forced vital capacity (FVC) ratio of 0.56. No significant differences existed between groups at baseline. CCQ improved significantly and in a clinically relevant manner by 0.4 points over 24 months; effect sizes were doubled in patients with CCQ > 1 at baseline and tripled in patients with MRC dyspnea score >2. In the Kroonluchter cohort, 56 subjects completed follow-up, were of mean age 69 years, with an FEV(1)/FVC ratio of 0.59, while their postbronchodilator FEV(1) of 65% predicted was somewhat lower than in the total group. 6MWD improved significantly and in a clinically relevant manner up to 93 m at 12 months and was sustained at 83 m over 24 months; this effect occurred faster in patients with MRC dyspnea score >2. In patients with baseline 6MWD < 400 m the improvement remained >100 m at 24 months. In this study, IDM improved and sustained health status and exercise capacity in primary care COPD patients during two years of follow-up. Improvements in health status are consistently higher in patients with CCQ > 1 at baseline, being strongest in patients with baseline MRC dyspnea score >2. Improvements in exercise capacity remain highest in patients with 6MWD < 400 m at baseline and seem to occur earlier in patients with MRC dyspnea score >2.


Van Wezel G.P.,Leiden University | McDowall K.J.,University of Leeds
Natural Product Reports | Year: 2011

Streptomycetes and other actinobacteria are renowned as a rich source of natural products of clinical, agricultural and biotechnological value. They are being mined with renewed vigour, supported by genome sequencing efforts, which have revealed a coding capacity for secondary metabolites in vast excess of expectations that were based on the detection of antibiotic activities under standard laboratory conditions. Here we review what is known about the control of production of so-called secondary metabolites in streptomycetes, with an emphasis on examples where details of the underlying regulatory mechanisms are known. Intriguing links between nutritional regulators, primary and secondary metabolism and morphological development are discussed, and new data are included on the carbon control of development and antibiotic production, and on aspects of the regulation of the biosynthesis of microbial hormones. Given the tide of antibiotic resistance emerging in pathogens, this review is peppered with approaches that may expand the screening of streptomycetes for new antibiotics by awakening expression of cryptic antibiotic biosynthetic genes. New technologies are also described that have potential to greatly further our understanding of gene regulation in what is an area fertile for discovery and exploitation. © 2011 The Royal Society of Chemistry.


Giles J.T.,Columbia University | Van Der Heijde D.M.,Leiden University | Bathon J.M.,Columbia University
Annals of the Rheumatic Diseases | Year: 2011

Background: Adipokines have inflammatory and immunomodulatory properties that may contribute to erosive joint damage. The association of serum adipokine levels with progression of radiographic joint damage in patients with rheumatoid arthritis (RA) was prospectively explored. Methods: Patients with RA underwent serum adipokine assessment (adiponectin, resistin, leptin) at three timepoints and hand/feet x-rays, scored using the Sharpvan der Heijde Score (SHS), at baseline and the third study visit, separated by an average of 39±4 months. The associations of baseline and average adipokine levels with change in SHS were explored, adjusting for pertinent confounders. Results: Of the 152 patients studied, 85 (56%) showed an increase in SHS (defined as >0 SHS units). Among the adipokines studied, only adiponectin was significantly associated with radiographic progression, with average adiponectin levels more strongly associated than baseline levels. After adjusting for average C reactive protein and baseline SHS, patients in the highest quartile of average adiponectin had a SHS progression rate more than double the lowest quartile (1.00 vs 0.48 units/year; p=0.008). Similarly, those in the highest quartile of adiponectin had a more than fivefold greater odds of any radiographic progression compared with the lowest quartile (OR 5.75; p=0.002). The magnitude of the association of average adiponectin levels with radiographic progression was greater in women, those with body mass index <30 kg/m2 and those receiving baseline biological disease-modifying antirheumatic drugs. Conclusions: These prospective data provide evidence of temporality and dose-response in the relationship between circulating adiponectin and erosive joint destruction in RA, and highlight subgroups of patients at highest risk for adiponectin-associated radiographic progression.


Engels C.C.,Leiden University
British Journal of Cancer | Year: 2016

Background:Predicting breast cancer outcome in older patients is challenging, as it has been shown that the available tools are not accurate in older patients. The PREDICT tool may serve as an alternative tool, as it was developed in a cohort that included almost 1800 women aged 65 years or over. The aim of this study was to assess the validity of the online PREDICT tool in a population-based cohort of unselected older patients with breast cancer.Methods:Patients were included from the population-based FOCUS-cohort. Observed 5- and 10-year overall survival were estimated using the Kaplan–Meier method, and compared with predicted outcomes. Calibration was tested by composing calibration plots and Poisson Regression. Discriminatory accuracy was assessed by composing receiver-operator-curves and corresponding c-indices.Results:In all 2012 included patients, observed and predicted overall survival differed by 1.7%, 95% confidence interval (CI)=−0.3–3.7, for 5-year overall survival, and 4.5%, 95% CI=2.3–6.6, for 10-year overall survival. Poisson regression showed that 5-year overall survival did not significantly differ from the ideal line (standardised mortality ratio (SMR)=1.07, 95% CI=0.98–1.16, P=0.133), but 10-year overall survival was significantly different from the perfect calibration (SMR=1.12, 95% CI=1.05–1.20, P=0.0004). The c-index for 5-year overall survival was 0.73, 95% CI=0.70–0.75, and 0.74, 95% CI=0.72–0.76, for 10-year overall survival.Conclusions:PREDICT can accurately predict 5-year overall survival in older patients with breast cancer. Ten-year predicted overall survival was, however, slightly overestimated.British Journal of Cancer advance online publication, 19 January 2016; doi:10.1038/bjc.2015.466 www.bjcancer.com. © 2016 Cancer Research UK


Rommel J.B.,University of Stuttgart | Goumans T.P.M.,Leiden University | Kastner J.,University of Stuttgart
Journal of Chemical Theory and Computation | Year: 2011

We implemented and compared four algorithms to locate instantons, i.e., the most likely tunneling paths at a given temperature. These allow to calculate reaction rates, including atom tunneling, down to very low temperature. An instanton is a first-order saddle point of the Euclidean action in the space of closed Feynman paths. We compared the Newton-Raphson method to the partitioned rational function optimization (P-RFO) algorithm, the dimer method, and a newly proposed mode-following algorithm, where the unstable mode is directly estimated from the instanton path. We tested the algorithms on three chemical systems, each including a hydrogen transfer, at different temperatures. Overall, the Newton-Raphson turned out to be the most promising method, with our newly proposed mode following, being the fall-back option. © 2011 American Chemical Society.


Bassnett S.,University of Washington | Shi Y.,University of Washington | Vrensen G.F.J.M.,Leiden University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

The purpose of the lens is to project a sharply focused, undistorted image of the visual surround onto the neural retina. The first pre-requisite, therefore, is that the tissue should be transparent. Despite the presence of remarkably high levels of protein, the lens cytosol remains transparent as a result of short-range-order interactions between the proteins. At a cellular level, the programmed elimination of nuclei and other light-scattering organelles from cells located within the pupillary space contributes directly to tissue transparency. Scattering at the cell borders is minimized by the close apposition of lens fibre cells facilitated by a plethora of adhesive proteins, some expressed only in the lens. Similarly, refractive index matching between lens membranes and cytosol is believed to minimize scatter. Refractive index matching between the cytoplasm of adjacent cells is achieved through the formation of cellular fusions that allow the intermingling of proteins. Together, these structural adaptations serve to minimize light scatter and enable this living, cellular structure to function as 'biological glass'. © 2011 The Royal Society.


Tambur A.R.,Northwestern University | Claas F.H.J.,Leiden University
American Journal of Transplantation | Year: 2015

The need for new approaches to define HLA antibodies, in the context of organ transplantation, is intensely debated among HLA professionals. In this review, we sought to provide background and perspective to current understanding of the immunogenicity of HLA mismatches with respect to the humoral alloimmune response and the definition of B cell epitopes. Initial data suggest that epitope matching not only assists in defining better matches for the current transplant, but also minimizes the risk of developing de novo HLA-donor-specific-antibodies posttransplant. In other words, other than lowering the risk of current graft rejection, epitope matching is likely to lower overall future sensitization levels and thus increases the likelihood of finding a compatible donor when the need for a retransplantation arises. More detailed knowledge of epitopes makes it possible to investigate what constitutes permissible versus non-permissible HLA mismatches. The currently available evidence suggest that epitope matching is the most rational way to decrease the risk of HLA-linked transplant rejection. This review is aimed at stimulating further and more intense collaborative effort in this field. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.


This article examines children's enactment of spirit possession idioms and witchcraft in Africa including the meanings such idioms provide and the local healing resources they mobilize. Idioms of haunting spirits in Northern Uganda and witch-children elsewhere in Africa can be interpreted as manifestations of social crises and mass traumatic stress. On the other hand, such idioms also allow children to articulate, reflect upon, and communicate the complex feelings resulting from their precarious positions within families and communities under duress. With the help of Dow's transactional model of symbolic healing, this article explores obstacles to the effectivity of the rich variety of symbolic healing available for haunting spirits in Uganda and points to the generational gap between children and their families and communities. Elsewhere, witchcraft idioms may act as a healing resource at the group level, but at the expense of the accused child. The idioms of evil spirits and witchcraft speak of these children's navigation of the moral universe of their postconflict communities. Given that children's appraisal of their experiences through these notions may also exacerbate their anxiety, interdisciplinary research examining the microprocesses that lead to children being haunted or accused, including emotional and physiological levels effects, is urgently needed. © The Author(s) 2013.


Windecker S.,University of Bern | Bax J.J.,Leiden University | Myat A.,Kings College London | Stone G.W.,Columbia University Medical Center | Marber M.S.,Kings College London
The Lancet | Year: 2013

Over the past five decades, management of acute ST-segment elevation myocardial infarction (STEMI) has evolved substantially. Current treatment encompasses a systematic chain of network activation, antithrombotic drugs, and rapid instigation of mechanical reperfusion, although pharmacoinvasive strategies remain relevant. Secondary prevention with drugs and lifestyle modifications completes the contemporary management package. Despite a tangible improvement in outcomes, STEMI remains a frequent cause of morbidity and mortality, justifying the quest to find new therapeutic avenues. Ways to reduce delays in doing coronary angioplasty after STEMI onset include early recognition of symptoms by patients and prehospital diagnosis by paramedics so that the emergency room can be bypassed in favour of direct admission to the catheterisation laboratory. Mechanical reperfusion can be optimised by improvements to stent design, whereas visualisation of infarct size has been improved by developments in cardiac MRI. Novel treatments to modulate the inflammatory component of atherosclerosis and the vulnerable plaque include use of bioresorbable vascular scaffolds and anti-proliferative drugs. Translational efforts to improve patients' outcomes after STEMI in relation to cardioprotection, cardiac remodelling, and regeneration are also being realised.


Blossey R.,Lille University of Science and Technology | Schiessel H.,Leiden University
FEBS Journal | Year: 2011

With nucleosomes being tightly associated with the majority of eukaryotic DNA, it is essential that mechanisms are in place that can move nucleosomes 'out of the way'. A focus of current research comprises chromatin remodeling complexes, which are ATP-consuming protein complexes that, for example, pull or push nucleosomes along DNA. The precise mechanisms used by those complexes are not yet understood. Hints for possible mechanisms might be found among the various spontaneous fluctuations that nucleosomes show in the absence of remodelers. Thermal fluctuations induce the partial unwrapping of DNA from the nucleosomes and introduce twist or loop defects in the wrapped DNA, leading to nucleosome sliding along DNA. In this minireview, we discuss nucleosome dynamics from two angles. First, we describe the dynamical modes of nucleosomes in the absence of remodelers that are experimentally fairly well characterized and theoretically understood. Then, we discuss remodelers and describe recent insights about the possible schemes that they might use. Nucleosomes are tightly associated with eukaryotic DNA. Mechanisms which can move nucleosomes 'out of the way' are required. Possible mechanisms might be found among the spontaneous fluctuations which nucleosomes undergo, that induces partial unwrapping of DNA and introduces twist or loop defects in the wrapped DNA. We further discuss remodelers and describe recent insights about schemes that they might use. © 2011 FEBS.


Valkenburg W.,Leiden University | Valkenburg W.,University of Heidelberg
General Relativity and Gravitation | Year: 2012

We present elliptic solutions to the background equations describing the Lemaître-Tolman-Bondi metric as well as the homogeneous Friedmann equation, in the presence of dust, curvature and a cosmological constant Λ. For none of the presented solutions any numerical integration has to be performed. All presented solutions are given for expanding and collapsing phases, preserving continuity in time and radius; both radial and angular scale functions are given. Hence, these solutions describe the complete spacetime of a collapsing spherical object in an expanding universe, as well as those of ever expanding objects. In the appendix we present for completeness a solution of the Friedmann equation in the additional presence of radiation, only valid for the Robertson-Walker metric. © 2012 The Author(s).


Pandit A.,VU University Amsterdam | De Groot H.J.M.,Leiden University
Photosynthesis Research | Year: 2012

This short review describes how solid-state NMR has provided a mechanistic and electronic picture of pigment-protein and pigment-pigment interactions in photosynthetic antenna complexes. NMR results on purple bacterial antenna complexes show how the packing of the protein and the pigments inside the light-harvesting oligomers induces mutual conformational stress. The protein scaffold produces deformation and electrostatic polarization of the BChl macrocycles and leads to a partial electronic charge transfer between the BChls and their coordinating histidines, which can tune the light-harvesting function. In chlorosome antennae assemblies, the NMR template structure reveals how the chromophores can direct their self-assembly into higher macrostructures which, in turn, tune the light-harvesting properties of the individual molecules by controlling their disorder, structural deformation, and electronic polarization without the need for a protein scaffold. These results pave the way for addressing the next challenge, which is to resolve the functional conformational dynamics of the lhc antennae of oxygenic species that allows them to switch between light-emitting and light-energy dissipating states. © 2011 The Author(s).


Huisman E.M.,Leiden University | Lubensky T.C.,University of Pennsylvania
Physical Review Letters | Year: 2011

We numerically investigate deformations and modes of networks of semiflexible biopolymers as a function of crosslink coordination number z and strength of bending and stretching energies. In equilibrium filaments are under internal stress, and the networks exhibit shear rigidity below the Maxwell isostatic point. In contrast to two-dimensional networks, ours exhibit nonaffine bending-dominated response in all rigid states, including those near the maximum of z=4 when bending energies are less than stretching ones. © 2011 American Physical Society.


Schilperoort M.,Leiden University
Current Opinion in Lipidology | Year: 2016

PURPOSE OF REVIEW: Brown adipose tissue (BAT) is an emerging target to combat cardiometabolic disorders as it can take up substantial amounts of glucose and lipids from the circulation for heat production. This review focuses on new concepts in BAT physiology and discusses the need for new techniques to determine BAT activity in humans. RECENT FINDINGS: Mouse studies showed that BAT activation selectively increases oxidation of lipids over glucose, by recruiting fatty acids from intracellular triglycerides. To replenish these intracellular lipid stores, brown adipocytes take up both glucose and triglyceride-derived fatty acids, resulting in attenuation of dyslipidaemia, insulin resistance and atherosclerosis. Clinical studies identified the involvement of the β3-adrenergic receptor in BAT activation and demonstrated that human BAT activation also selectively increases lipid oxidation. Notably, insulin resistance during ageing or weight gain reduces the capacity of BAT to internalize glucose, without reducing fatty acid uptake or oxidative metabolism. SUMMARY: Preclinical studies established BAT as an important target to combat cardiometabolic disorders and elucidated underlying mechanisms whereas clinical studies identified therapeutic handles. Development of novel lipid-based PET-CT tracers and identification of translational biomarkers of BAT activity are required as alternatives to [F]fluorodeoxyglucose PET-CT to accelerate clinical development of BAT-activating therapeutic strategies. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Dekkers K.F.,Leiden University
Current Opinion in Lipidology | Year: 2016

PURPOSE OF REVIEW: The interplay between lipids and epigenetic mechanisms has recently gained increased interest because of its relevance for common diseases and most notably atherosclerosis. This review discusses recent advances in unravelling this interplay with a particular focus on promising approaches and methods that will be able to establish causal relationships. RECENT FINDINGS: Complementary approaches uncovered close links between circulating lipids and epigenetic mechanisms at multiple levels. A characterization of lipid-associated genetic variants suggests that these variants exert their influence on lipid levels through epigenetic changes in the liver. Moreover, exposure of monocytes to lipids persistently alters their epigenetic makeup resulting in more proinflammatory cells. Hence, epigenetic changes can both impact on and be induced by lipids. SUMMARY: It is the combined application of technological advances to probe epigenetic modifications at a genome-wide scale and methodological advances aimed at causal inference (including Mendelian randomization and integrative genomics) that will elucidate the interplay between circulating lipids and epigenetics. Understanding its role in the development of atherosclerosis holds the promise of identifying a new category of therapeutic targets, since epigenetic changes are amenable to reversal. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Biesheuvel J.D.,Leiden University
Ear and Hearing | Year: 2016

OBJECTIVE:: The width of the spread of excitation (SOE) curve has been widely thought to represent an estimate of SOE. Therefore, correlates between psychophysical parameters, such as pitch discrimination and speech perception, and the width of SOE curves, have long been investigated. However, to date, no relationships between these objective and subjective measurements have yet been determined. In a departure from the current thinking, the authors now propose that the SOE curve, recorded with forward masking, is the equivalent of a convolution operation. As such, deconvolution would be expected to retrieve the excitation areas attributable to either masker or probe, potentially more closely revealing the actual neural SOE. This study aimed to develop a new analytical tool with which to derive SOE using this principle. DESIGN:: Intraoperative SOE curve measurements of 16 subjects, implanted with an Advanced Bionics implant, were analyzed. Evoked compound action potential (ECAP)-based SOE curves were recorded on electrodes 3 to 16, using the forward masker paradigm, with variable masker. The measured SOE curves were then compared with predicted SOE curves, built by the convolution of basic excitation density profiles (EDPs). Predicted SOE curves were fitted to the measured SOEs by iterative adjustment of the EDPs for the masker and the probe. RESULTS:: It was possible to generate a good fit between the predicted and measured SOE curves, inclusive of their asymmetry. The rectangular EDP was of least value in terms of its ability to generate a good fit; smoother SOE curves were modeled using the exponential or Gaussian EDPs. In most subjects, the EDP width (i.e., the size of the excitation area) gradually changed from wide at the apex of the electrode array, to narrow at the base. A comparison of EDP widths to SOE curve widths, as calculated in the literature, revealed that the EDPs now provide a measure of the SOE that is qualitatively distinct from that provided using conventional methods. CONCLUSIONS:: This study shows that an eCAP-based SOE curve, measured with forward masking, can be treated as a convolution of EDPs for masker and probe. The poor fit achieved for the measured and modeled data using the rectangular EDP, emphasizes the requirement for a sloping excitation area to mimic actual SOE recordings. Our deconvolution method provides an explanation for the frequently observed asymmetry of SOE curves measured along the electrode array, as this is a consequence of a wider excitation area in the apical part of the cochlea, in the absence of any asymmetry in the actual EDP. In addition, broader apical EDPs underlie the higher eCAP amplitudes found for apical stimulation. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Tighe B.P.,Leiden University
Physical Review Letters | Year: 2011

We determine the form of the complex shear modulus G* in soft sphere packings near jamming. Viscoelastic response at finite frequency is closely tied to a packing's intrinsic relaxational modes, which are distinct from the vibrational modes of undamped packings. We demonstrate and explain the appearance of an anomalous excess of slowly relaxing modes near jamming, reflected in a diverging relaxational density of states. From the density of states, we derive the dependence of G* on the frequency and distance to the jamming transition, which is confirmed by numerics. © 2011 American Physical Society.


Bezanson R.,Yale University | Van Dokkum P.,Yale University | Franx M.,Leiden University
Astrophysical Journal | Year: 2012

We measure stellar masses and structural parameters for 5500 quiescent and 20,000 star-forming galaxies at 0.3 < z ≤ 1.5 in the Newfirm Medium Band Survey COSMOS and UKIDSS UDS fields. We combine these measurements to infer velocity dispersions and determine how the number density of galaxies at fixed inferred dispersion, or the velocity dispersion function (VDF), evolves with time for each population. We show that the number of galaxies with high velocity dispersions appears to be surprisingly stable with time, regardless of their star formation history. Furthermore, the overall VDF for star-forming galaxies is constant with redshift, extending down to the lowest velocity dispersions probed by this study. The only galaxy population showing strong evolution are quiescent galaxies with low inferred dispersions, whose number density increases by a factor of ∼ 4 since z = 1.5. This buildup leads to an evolution in the quiescent fraction of galaxies such that the threshold dispersion above which quiescent galaxies dominate the counts moves to lower velocity dispersion with time. We show that our results are qualitatively consistent with a simple model in which star-forming galaxies quench and are added to the quiescent population. In order to compensate for the migration into the quiescent population, the velocity dispersions of star-forming galaxies must increase, with a rate that increases with dispersion. © 2012. The American Astronomical Society. All rights reserved.


Dooley S.,University of Heidelberg | Ten Dijke P.,Leiden University
Cell and Tissue Research | Year: 2012

Transforming growth factor-β (TGF-β) is a central regulator in chronic liver disease contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver-damage-induced levels of active TGF-β enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Being recognised as a major profibrogenic cytokine, the targeting of the TGF-β signalling pathway has been explored with respect to the inhibition of liver disease progression. Whereas interference with TGF-β signalling in various short-term animal models has provided promising results, liver disease progression in humans is a process of decades with different phases in which TGF-β or its targeting might have both beneficial and adverse outcomes. Based on recent literature, we summarise the cell-type-directed double-edged role of TGF-β in various liver disease stages. We emphasise that, in order to achieve therapeutic effects, we need to target TGF-β signalling in the right cell type at the right time. © The Author(s) 2011.


Loenen W.A.M.,Leiden University | Dryden D.T.F.,University of Edinburgh | Raleigh E.A.,New England Biolabs | Wilson G.G.,New England Biolabs
Nucleic Acids Research | Year: 2014

In the early 1950's, 'host-controlled variation in bacterial viruses' was reported as a non-hereditary phenomenon: one cycle of viral growth on certain bacterial hosts affected the ability of progeny virus to grow on other hosts by either restricting or enlarging their host range. Unlike mutation, this change was reversible, and one cycle of growth in the previous host returned the virus to its original form. These simple observations heralded the discovery of the endonuclease and methyltransferase activities of what are now termed Type I, II, III and IV DNA restriction-modification systems. The Type II restriction enzymes (e.g. EcoRI) gave rise to recombinant DNA technology that has transformed molecular biology and medicine. This review traces the discovery of restriction enzymes and their continuing impact on molecular biology and medicine. © The Author(s) 2013. Published by Oxford University Press.


Bhaseen M.J.,Kings College London | Doyon B.,Kings College London | Lucas A.,Harvard University | Schalm K.,Harvard University | Schalm K.,Leiden University
Nature Physics | Year: 2015

Characterizing the behaviour of strongly coupled quantum systems out of equilibrium is a cardinal challenge for both theory and experiment. With diverse applications ranging from the dynamics of the quark-gluon plasma to transport in novel states of quantum matter, establishing universal results and organizing principles out of equilibrium is crucial. We present a universal description of energy transport between quantum critical heat baths in arbitrary dimension. The current-carrying non-equilibrium steady state (NESS) is a Lorentz-boosted thermal state. In the context of gauge/gravity duality this reveals an intimate correspondence between far-from-equilibrium transport and black hole uniqueness theorems. We provide analytical expressions for the energy current and the generating function of energy current fluctuations, together with predictions for experiment. © 2015 Macmillan Publishers Limited. All rights reserved.


Beenakker C.W.J.,Leiden University
Physical Review Letters | Year: 2014

The single-particle excitations of a superconductor are coherent superpositions of electrons and holes near the Fermi level, called Bogoliubov quasiparticles. They are Majorana fermions, meaning that pairs of quasiparticles can annihilate. We calculate the annihilation probability at a beam splitter for chiral quantum Hall edge states, obtaining a 1±cos dependence on the phase difference of the superconductors from which the excitations originated (with the ± sign distinguishing singlet and triplet pairing). This provides for a nonlocal measurement of the superconducting phase in the absence of any supercurrent. © 2014 American Physical Society.


Andersen P.K.,Copenhagen University | Geskus R.B.,Academic Medical Center and Public Health Service Amsterdam | De witte T.,Radboud University Nijmegen | Putter H.,Leiden University
International Journal of Epidemiology | Year: 2012

Background In studies of all-cause mortality, the fundamental epidemiological concepts of rate and risk are connected through a well-defined one-to-one relation. An important consequence of this relation is that regression models such as the proportional hazards model that are defined through the hazard (the rate) immediately dictate how the covariates relate to the survival function (the risk).Methods This introductory paper reviews the concepts of rate and risk and their one-to-one relation in all-cause mortality studies and introduces the analogous concepts of rate and risk in the context of competing risks, the cause-specific hazard and the cause-specific cumulative incidence function. Results The key feature of competing risks is that the one-to-one correspondence between cause-specific hazard and cumulative incidence, between rate and risk, is lost. This fact has two important implications. First, the naïve Kaplan-Meier that takes the competing events as censored observations, is biased. Secondly, the way in which covariates are associated with the cause-specific hazards may not coincide with the way these covariates are associated with the cumulative incidence. An example with relapse and non-relapse mortality as competing risks in a stem cell transplantation study is used for illustration. Conclusion The two implications of the loss of one-to-one correspondence between cause-specific hazard and cumulative incidence should be kept in mind when deciding on how to make inference in a competing risks situation. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012.


Deconvolution of protein film voltammetric data by fitting multiple components (sigmoids, derivative peaks) often is ambiguous when features are partially overlapping, due to exchangeability between the width and the number of components. Here, a new method is presented to obtain the width of the components. This is based on the equivalence between the sigmoidal catalytic response as function of electrode potential, and the classical saturation curve obtained for the enzyme activity as function of the soluble substrate concentration, which is also sigmoidal when plotted versus log[S]. Thus, analysis of the catalytic voltammogram with Lineweaver-Burk, Eadie-Hofstee, and Hanes-Woolf plots is feasible. This provides a very sensitive measure of the cooperativity number (Hill coefficient), which for electrons equals the apparent (fractional) number of electrons that determine the width, and thereby the number of components (kinetic phases). This analysis is applied to the electrocatalytic oxygen reduction by Paracoccus denitrificans cytochrome aa3 (cytochrome c oxidase). Four partially overlapping kinetic phases are observed that (stepwise) increase the catalytic efficiency with increasingly reductive potential. Translated to cell biology, the activity of the terminal oxidase stepwise adapts to metabolic demand for oxidative phosphorylation. © 2011 Elsevier B.V.


Hagenaars M.A.,Leiden University | Van Minnen A.,Overwaal Clinic of Anxiety Disorders
Journal of Traumatic Stress | Year: 2010

This study aims to increase our understanding of trauma positive outcomes by (a) exploring associations between posttraumatic growth and posttraumatic stress disorder (PTSD), and (b) investigating posttraumatic growth course and its impact on exposure treatment. In 80 mixed trauma PTSD patients, growth was negatively related to PTSD symptoms, especially emotional numbing. Sixty-five PTSD patients also completed Prolonged Exposure therapy with pretreatment and posttreatment assessments. Posttraumatic growth-New Possibilities and Personal Strength-increased during exposure therapy, and these increases were associated to decreases of PTSD symptoms. Pretreatment posttraumatic growth, more specifically the Appreciation of Life subscale, predicted better treatment outcome after controlling for pretreatment PTSD. The results indicate that posttraumatic growth may be a valuable new concept in trauma therapy. Copyright © 2010 International Society for Traumatic Stress Studies.


Mullenders L.,Leiden University
DNA Repair | Year: 2015

The disturbance of DNA helix conformation by bulky DNA damage poses hindrance to transcription elongating due to stalling of RNA polymerase at transcription blocking lesions. Stalling of RNA polymerase provokes the formation of R-loops, i.e. the formation of a DNA-RNA hybrid and a displaced single stranded DNA strand as well as displacement of spliceosomes. R-loops are processed into DNA single and double strand breaks by NER factors depending on TC-NER factors leading to genome instability. Moreover, stalling of RNA polymerase induces a strong signal for cell cycle arrest and apoptosis. These toxic and mutagenic effects are counteracted by a rapid recruitment of DNA repair proteins to perform transcription coupled nucleotide excision repair (TC-NER) to remove the blocking DNA lesions and to restore transcription. Recent studies have highlighted the role of backtracking of RNA polymerase to facilitate TC-NER and identified novel factors that play key roles in TC-NER and in restoration of transcription. On the molecular level these factors facilitate stability of the repair complex by promotion and regulation of various post-translational modifications of NER factors and chromatin substrate. In addition, the continuous flow of new factors that emerge from screening assays hints to several regulatory levels to safeguard the integrity of transcription elongation after disturbance by DNA damage that have yet to be explored. © 2015 Elsevier B.V.


Yusuf E.,Leiden University
Arthritis Research and Therapy | Year: 2012

Obesity is an important risk factor for the development and progression of osteoarthritis (OA). Recently, the paradigm that obesity predisposes people to OA because of extra-mechanical loading only has shifted to the paradigm that metabolic factors (adipokines) are also involved in the pathophysiology of OA. In a cross-sectional study in the previous issue of Arthritis Research & Therapy, Massengale and colleagues investigated the association between one of the adipokines - leptin - and hand OA. Hand joints are an ideal target to investigate the role of adipokines since they are not weight-bearing. Interestingly, no association with OA was found, bringing into question a metabolic, rather than a mechanical, explanation for the association between obesity and OA. © 2012 BioMed Central Ltd.


Visser L.G.,Leiden University
Current Infectious Disease Reports | Year: 2011

Tumor necrosis factor (TNF) antagonists have proven to be very effective in the treatment of several autoimmune-mediated inflammatory diseases. The two classes of TNF antagonists-soluble TNF receptors and TNF monoclonal antibodies-have several important structural, pharmacokinetic, and functional differences. TNF antagonists interfere at different steps in the immune response to infections and vaccines. The immune response to pneumococcal polysaccharide vaccines is impaired in patients treated with methotrexate with some additional immunosuppressive effect of TNF antagonists. The secondary immune responses to inactivated and live attenuated vaccines, such as yellow fever vaccine, during treatment with TNF antagonists is mostly adequate despite significantly lower antibody levels. Little is known about the primary immune response to inactivated travel-related vaccines, but it is likely to be poor. Primary vaccination with live attenuated vaccines of patients receiving TNF antagonists should be avoided at all times. © 2011 Springer Science+Business Media, LLC.


Van Der Molen A.J.,Leiden University | Hovius M.C.,Onze Lieve Vrouwe Gasthuis
American Journal of Roentgenology | Year: 2012

OBJECTIVE. To present a problem-based algorithm in the work-up of patients with Hematuria. Since the 2010 Dutch Guideline on Hematuria was problem-based, this served as an illustration for such an approach.. CONCLUSION. The work-up of hematuria should be individualized and risk-based. Given the a priori low likelihood of cancer in hematuria, risk categories should be established and imaging algorithms should be tailored to populations at low-risk, medium-risk and high-risk for developing urothelial cancer. © American Roentgen Ray Society.


Hetterscheid D.G.H.,Leiden University | Reek J.N.H.,University of Amsterdam
European Journal of Inorganic Chemistry | Year: 2014

Treatment of Ir(OH)2 with sodium periodate in aqueous solution results in formation of dioxygen following the rate law v = k obs[Ir]0.65[IO4]0.5, with k obs = 1.5 × 10-3 {Ir(OH)2 = [IrCp(Me 2NHC)(OH)2], where Me2NHC = N-dimethylimidazolin-2-ylidene and Cp* = cyclopentadienyl}. In situ ESI-MS experiments in combination with DFT calculations show that [Ir III(IO3)]+ and [IrV(=O)(IO 3)]+ species are present in the reaction mixture. On the basis of the presence of these species, a mechanistic pathway was calculated illustrating that water is not necessarily the source of the oxygen. A low-lying pathway exists wherein O2 production proceeds via two consecutive O-atom-transfer reactions from periodate to the catalyst. The resulting iodite ligand is further oxidized to close the catalytic cycle. The rate-determining step in this process is formation of the O-O bond. For this transition a 21.8 kcal/mol barrier was found. This value fits very well with the observed turnover frequency of 0.27 s-1. Although it is difficult to prove that this is the dominant pathway, these data clearly illustrate that one has to be very careful with interpretation of catalytic results in periodate-driven water oxidation reactions. Treatment of water with periodate in the presence of [IrCp(Me2NHC)(OH)2] results in formation of O2. DFT calculations and in situ mass spectrometry experiments point to a mechanism involving one or two O-atom-transfer steps, rather than electron-transfer steps only. Results must thus be interpreted cautiously when periodate is used as an oxidant in the study of catalytic water oxidation. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Linmans A.J.M.,Leiden University
Scientometrics | Year: 2010

In this study an attempt is made to establish new bibliometric indicators for the assessment of research in the Humanities. Data from a Dutch Faculty of Humanities was used to provide the investigation a sound empirical basis. For several reasons (particularly related to coverage) the standard citation indicators, developed for the sciences, are unsatisfactory. Target expanded citation analysis and the use of oeuvre (lifetime) citation data, as well as the addition of library holdings and productivity indicators enable a more representative and fair assessment. Given the skew distribution of population data, individual rankings can best be determined based on log transformed data. For group rankings this is less urgent because of the central limit theorem. Lifetime citation data is corrected for professional age by means of exponential regression. © 2009 Akadémiai Kiadó, Budapest, Hungary.


van Houwelingen H.C.,Leiden University
Statistics in Medicine | Year: 2014

This paper is the written version of the President's invited lecture speaker at the International Society for Clinical Biostatistics conference in Munich in 2013. The paper takes the stand of clinician and patient who are in need of a reliable prognostic model for the planning of treatment and patient care during the follow-up after the initial treatment. The paper discusses (i) the need for grouping of data; (ii) the lack of robustness of the Cox model; (iii) the robust approach to repeated measures; and (iv) the robust handling of time-dependent covariates (biomarkers) in dynamic survival analysis. © 2014 John Wiley & Sons, Ltd.


Mill J.,University of Exeter | Mill J.,Kings College London | Heijmans B.T.,Leiden University
Nature Reviews Genetics | Year: 2013

The epigenome has been heralded as a key 'missing piece' of the aetiological puzzle for complex phenotypes across the biomedical sciences. The standard research approaches developed for genetic epidemiology, however, are not necessarily appropriate for epigenetic studies of common disease. Here, we discuss the optimal execution of population-based studies of epigenetic variation, which will contribute to the emerging field of 'epigenetic epidemiology' and emphasize the importance of establishing a causal role in pathology for disease-associated epigenetic changes. We propose that improved understanding of the molecular mechanisms underlying human health and disease are best achieved through carrying out studies of epigenetics in populations as a part of an integrated functional genomics strategy. © 2013 Macmillan Publishers Limited. All rights reserved.


de Vrij J.,Leiden University
Human gene therapy | Year: 2010

Prostate cancer is a leading cause of death among men in Western countries. Whereas the survival rate approaches 100% for patients with localized cancer, the results of treatment in patients with metastasized prostate cancer at diagnosis are much less successful. The patients are usually presented with a variety of treatment options, but therapeutic interventions in prostate cancer are associated with frequent adverse side effects. Gene therapy and oncolytic virus therapy may constitute new strategies. Already a wide variety of preclinical studies has demonstrated the therapeutic potential of such approaches, with oncolytic prostate-specific adenoviruses as the most prominent vector. The state of the art and future prospects of gene therapy in prostate cancer are reviewed, with a focus on adenoviral vectors. We summarize advances in adenovirus technology for prostate cancer treatment and highlight areas where further developments are necessary.


van Leeuwen T.,Leiden University
Scientometrics | Year: 2012

In this study the issue of the validity of the argument against the applied length of citation windows in Journal Impact Factors calculations is critically re-analyzed. While previous studies argued against the relatively short citation window of 1-2 years, this study shows that the relative short term citation impact measured in the window underlying the Journal Impact Factor is a good predictor of the citation impact of the journals in the next years to come. Possible exceptions to this observation relate to journals with relatively low numbers of publications, and the citation impact related to publications in the year of publication. The study focuses on five Journal Subject Categories from the science and social sciences, on normal articles published in these journals, in the 2 years 2000 and 2004. © 2012 The Author(s).


van den Berg R.,Leiden University
Polskie Archiwum Medycyny Wewnetrznej | Year: 2010

The Assessment of SpondyloArthritis International Society (ASAS) group has recently developed criteria to classify patients with axial SpA with or without radiographic sacroiliitis, and criteria to classify patients with peripheral SpA. The ASAS axial criteria consist of 2 arms and can be applied in patients with back pain (>3 months almost every day). In one arm, imaging (radiographs and magnetic resonance imaging [MRI]) has an important role, in the other arm--HLA-B27. MRI can detect active inflammation and structural damage associated with SpA. According to the ASAS axial SpA criteria, patients with chronic back pain aged less than 45 years at onset can be classified as having axial SpA if sacroiliitis on imaging (radiographs or MRI) plus 1 further SpA feature are present, or if HLA-B27 plus 2 further SpA features are present. The ASAS peripheral criteria can be applied in patients with peripheral arthritis (usually asymmetric arthritis predominantly involving the lower limbs), enthesitis, or dactylitis. Patients can be classified as having peripheral SpA if 1 of the following features is present: uveitis, HLA-B27, preceding genitourinary or gastrointestinal infection, psoriasis, inflammatory bowel disease, sacroiliitis on imaging (radiographs or MRI), or if 2 of the following features besides the entry feature are present: arthritis, enthesitis, dactylitis, inflammatory back pain, or a positive family history of SpA.


de Graaf B.,Leiden University
Studies in Conflict and Terrorism | Year: 2010

This article deals with the role of government in encouraging the decline of radical movements. The question posed is: "Which story can the government tell to encourage the decline of radical groups and the disengagement of their members?" The article makes use of the survey of factors promoting decline and disengagement drawn up by Demant, Slootman, Buijs (†) and Tillie in 2008, as well as the factor "official policy strategies" based on concepts taken from discourse analysis, adapted to counterterrorism and deradicalization strategies by De Graaf in 2009. The article will therefore not address the different practical measures in this field, but focus instead on the perception of these official measures by the radicals. It will illustrate this with two case studies: the deradicalization of South Moluccan youths in the 1970s and of jihadist radicals after 2001, both in the Netherlands. © Taylor & Francis Group, LLC.


Thevenaz C.,State of Vaud | Resodihardjo S.L.,Leiden University
International Journal of Production Economics | Year: 2010

Which conditions make it difficult to effectively respond to an emergency? The literature shows that even if emergency response plans are in place, the emergency response could still be hampered by a myriad of factors. What these factors are, however, remains unclear as authors provide different ideas on what can go wrong. Sometimes these ideas overlap, but sometimes they do not. In this article, we provide an overview of the factors impeding emergency response. We will illustrate each factor with examples drawn from the emergency responses in New Orleans following the Katrina hurricane and in Indonesia following the Tsunami. © 2009 Elsevier B.V. All rights reserved.


Kenworthy M.A.,Leiden University | Mamajek E.E.,University of Rochester
Astrophysical Journal | Year: 2015

The light curve of 1SWASP J140747.93-394542.6, a 16 Myr old star in the Sco-Cen OB association, underwent a complex series of deep eclipses that lasted 56 days, centered on 2007 April. This light curve is interpreted as the transit of a giant ring system that is filling up a fraction of the Hill sphere of an unseen secondary companion, J1407b. We fit the light curve with a model of an azimuthally symmetric ring system, including spatial scales down to the temporal limit set by the star's diameter and relative velocity. The best ring model has 37 rings and extends out to a radius of 0.6 AU (9 × 107 km), and the rings have an estimated total mass on the order of 100 M Moon. The ring system has one clearly defined gap at 0.4 AU (6.1 × 107 km), which, we hypothesize, is being cleared out by a <0.8 M ⊕ exosatellite orbiting around J1407b. This eclipse and model imply that we are seeing a circumplanetary disk undergoing a dynamic transition to an exosatellite-sculpted ring structure, which is one of the first seen outside our solar system. © 2015. The American Astronomical Society. All rights reserved.


Peijnenburg W.J.,Leiden University
Integrated environmental assessment and management | Year: 2014

"Dissolved" concentrations of contaminants in sediment porewater (Cfree ) provide a more relevant exposure metric for risk assessment than do total concentrations. Passive sampling methods (PSMs) for estimating Cfree offer the potential for cost-efficient and accurate in situ characterization of Cfree for inorganic sediment contaminants. In contrast to the PSMs validated and applied for organic contaminants, the various passive sampling devices developed for metals, metalloids, and some nonmetals (collectively termed "metals") have been exploited to a limited extent, despite recognized advantages that include low detection limits, detection of time-averaged trends, high spatial resolution, information about dissolved metal speciation, and the ability to capture episodic events and cyclic changes that may be missed by occasional grab sampling. We summarize the PSM approaches for assessing metal toxicity to, and bioaccumulation by, sediment-dwelling biota, including the recognized advantages and limitations of each approach, the need for standardization, and further work needed to facilitate broader acceptance and application of PSM-derived information by decision makers. © 2014 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of SETAC.


Bornmann L.,Max Planck Society | Waltman L.,Leiden University
Journal of Informetrics | Year: 2011

Spatial scientometrics has attracted a lot of attention in the very recent past. The visualization methods (density maps) presented in this paper allow for an analysis revealing regions of excellence around the world using computer programs that are freely available. Based on Scopus and Web of Science data, field-specific and field-overlapping scientific excellence can be identified in broader regions (worldwide or for a specific continent) where high quality papers (highly cited papers or papers published in Nature or Science) were published. We used a geographic information system to produce our density maps. We also briefly discuss the use of Google Earth. © 2011 Elsevier Ltd.


Cobanera E.,Leiden University | Ortiz G.,Indiana University Bloomington
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2014

Because of potential relevance to topological quantum information processing, we introduce and study the self-dual family of representations of the braid group. Self-dual representations are physically well motivated and provide a natural generalization of the Majorana and Gaussian representations, which appear as particular instances. To show that self-dual representations admit a particle interpretation, we introduce and describe in second quantization a family of particle species with p=2,3,â̄ exclusion and θ=2π/p exchange statistics. We call these anyons Fock parafermions, because they are the particles naturally associated to the parafermionic zero-energy modes, potentially realizable in mesoscopic arrays of fractional topological insulators. Josephson junctions modeled with Fock parafermions may display a 2πp periodic relation between the Josephson current and the phase difference across the junction. Self-dual representations can be realized in terms of local quadratic combinations of either parafermions or Fock parafermions, an important requisite for physical implementation of quantum logic gates. The second-quantization description of Fock parafermions entails the concept of Fock algebra, i.e., a Fock space endowed with a statistical multiplication that captures and logically correlates these anyons' exclusion and exchange statistics. As a consequence normal ordering continues to be a well-defined operation. © 2014 American Physical Society.


Panja D.,University of Amsterdam | Barkema G.T.,Leiden University
Journal of Chemical Physics | Year: 2010

We use the bond fluctuation model (BFM) to study the pore-blockade times of a translocating polymer of length N in two dimensions, in the absence of external forces on the polymer (i.e., unbiased translocation) and hydrodynamic interactions (i.e., the polymer is a Rouse polymer), through a narrow pore. Earlier studies using the BFM concluded that the pore-blockade time scales with polymer length as τd ∼ NΒ, with Β=1+2ν, whereas some recent studies using different polymer models produce results consistent with Β=2+ν, originally predicted by us. Here is the Flory exponent of the polymer ν=0.75 in 2D. In this paper we show that for the BFM if the simulations are extended to longer polymers, the purported scaling τd ∼ N1+2 ceases to hold. We characterize the finite-size effects, and study the mobility of individual monomers in the BFM. In particular, we find that in the BFM, in the vicinity of the pore the individual monomeric mobilities are heavily suppressed in the direction perpendicular to the membrane. After a modification of the BFM which counters this suppression (but possibly introduces other artifacts in the dynamics), the apparent exponent Β increases significantly. Our conclusion is that BFM simulations do not rule out our theoretical prediction for unbiased translocation, namely, Β=2+ν. © 2010 American Institute of Physics.


Kloppenburg M.,Leiden University
Nature Reviews Rheumatology | Year: 2014

Hand osteoarthritis (OA) is a prevalent disease with a high clinical burden. The number of clinical trials in hand OA is limited and, therefore, recommendations for the management of hand OA are mostly expert-based instead of evidence-based, and medication is often prescribed off-label. However, in the past 5 years, this 'forgotten' disease has attracted increasing attention and a number of high-quality clinical trials have now been performed, or are ongoing. The results from studies conducted to assess nonpharmacological treatment modalities indicate that educating patients about self-management, the provision of assistive devices and the application of splints for thumb base OA, are effective for pain and disability. For pharmacological management, more high-quality trials are needed, although evidence is available for short-term symptom alleviation of pain by topical and oral NSAIDs. The role of anti-inflammatory medication, such as corticosteroids and biologic agents, is controversial, and the same holds true for the efficacy of symptomatic slow acting drugs for OA. Disease modifying OA drugs (DMOADs) for hand OA are currently not available. The results from the ongoing pharmacological trials will increase our knowledge for evidence-based management of hand OA in the near future. © 2014 Macmillan Publishers Limited. All rights reserved.


Hiemstra P.S.,Leiden University
Annals of the American Thoracic Society | Year: 2013

The observation that macrophages are increased in chronic obstructive pulmonary disease (COPD) and are associated with COPD severity has led to a large number of studies on macrophage function in COPD. These studies have provided evidence that these cells contribute to tissue injury through the release of various mediators, including proteases such as matrix metalloprotease-12. In addition, it was found that macrophages in COPD have an impaired ability to clear respiratory pathogens and apoptotic cells. Macrophage phagocytic function in COPD can be restored at least in part, as shown by in vitro studies. In a search to further understand this altered function of macrophages in COPD, several studies have used a range ofmarkers to phenotypemacrophages in COPD. Macrophages constitute a heterogeneous cell population, and, currently, proin flammatory M1 and anti-inflammatory M2 and M2-like cells are considered to represent the extremes of a pattern of macrophage polarization. In COPD, there is no clear evidence for a predominance of one of these phenotypes, and an intermediate phenotype may be present. Future studies are needed to establish the nature of this apparent COPD-specific macrophage subset, and to link macrophage dysfunction to COPD phenotypes. Copyright © 2013 by the American Thoracic Society.


Bocanegra B.R.,Leiden University
Cognitive, Affective and Behavioral Neuroscience | Year: 2014

An account of affective modulations in perceptual speed and accuracy (ASAP: Affecting Speed and Accuracy in Perception) is proposed and tested. This account assumes an emotion-induced inhibitory interaction between parallel channels in the visual system that modulates the onset latencies and response durations of visual signals. By trading off speed and accuracy between channels, this mechanism achieves (a) fast visuo-motor responding to course-grained information, and (b) accurate visuo-attentional selection of fine-grained information. ASAP gives a functional account of previously counterintuitive findings, and may be useful for explaining affective influences in both featural-level single-stimulus tasks and object-level multistimulus tasks. © 2014, Psychonomic Society, Inc.


Huizinga T.W.J.,Leiden University
Journal of Internal Medicine | Year: 2015

The care of patients with rheumatoid arthritis (RA) has been revolutionized since the 1990s. Strict monitoring and disease control based on measurement of signs and symptoms towards a target of low disease activity have improved outcome of patients enormously. As a result of treatment strategies based upon individualized measurement of disease activity, the clinical view of RA has changed from a destructive autoimmune disease (with a median joint damage of >10 Sharp units per year) to a condition in which significant damage can be prevented in the majority of patients. Moreover, a large number of targeted therapies (tumour necrosis factor, IL6, CD80/CD86 and CD20 inhibitors) have become available to better treat the underlying disease process. However, identification of the underlying pathways that drive the disease process in an individual patient has been relatively unsuccessful, implying that no predictive factors have been identified to guide the choice of a specific treatment. Distinct subsets of RA patients have been identified, based on the presence or absence of anticitrullinated protein antibodies (ACPAs). These two subsets are associated with different environmental and genetic risk factors, histology and disease outcome (a more destructive disease course with more persistent joint inflammation is observed when ACPAs are present). Therefore, it is recommended that treatment should be guided towards a more consistently low level of disease activity in the presence of ACPAs than in the absence of the antibodies. © 2014 The Association for the Publication of the Journal of Internal Medicine.


Traumatic brain injury is a major public health concern and is characterised by both apoptotic and necrotic cell death in the lesion. Anatomical imaging is usually used to assess traumatic brain injuries and there is a need for imaging modalities that provide complementary cellular information. We sought to non-invasively image cell death in a mouse model of traumatic brain injury using a near-infrared fluorescent conjugate of a synthetic heat shock protein-90 alkylator, 4-(N-(S-glutathionylacetyl) amino) phenylarsonous acid (GSAO). GSAO labels both apoptotic and necrotic cells coincident with loss of plasma membrane integrity. The optical GSAO specifically labelled apoptotic and necrotic cells in culture and did not accumulate in healthy organs or tissues in the living mouse body. The conjugate is a very effective imager of cell death in brain lesions. The optical GSAO was detected by fluorescence intensity and GSAO bound to dying/dead cells was detected from prolongation of the fluorescence lifetime. An optimal signal-to-background ratio was achieved as early as 3 h after injection of the probe and the signal intensity positively correlated with both lesion size and probe concentration. This optical GSAO offers a convenient and robust means to non-invasively image apoptotic and necrotic cell death in brain and other lesions.


Ottenhoff T.H.M.,Leiden University
International Journal of Tuberculosis and Lung Disease | Year: 2012

In this review, we discuss the 'knowns' and 'unknowns' of host defence towards Mycobacterium tuberculosis. With regard to the 'knowns', both protective and immunopathogenic mechanisms are discussed, including recently discovered new pathways of host defence and inflammatory immunopathology. With regard to the 'unknowns', there will be emphasis on unanswered key questions, accompanied by a perspective on needs and priorities for future research. The role of the inflammatory response and its dysregulation in tuberculosis-related immune reconstitution inflammatory syndrome will also be discussed. © 2012 The Union.