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Groningen, Netherlands

The University of Groningen , located in the city of Groningen, was founded in 1614. It is one of the oldest universities in the Netherlands as well as one of its largest. Since its inception more than 200,000 students have graduated. It is a member of the distinguished international Coimbra Group of European universities.In April 2013, according to the results of the International Student Barometer, the University of Groningen, for the third time in a row, has been voted the best University of the Netherlands. In 2014 the university celebrates its 400th anniversary and has planned various activities in and around the city of Groningen. For one month, from 15 May till 15 June, Groningen is immersed in a festive program RUG400 around the theme "For Infinity" .The University of Groningen has ten faculties, nine graduate schools, 27 research centres and institutes, and more than 175 degree programmes. Wikipedia.


Connolly M.P.,University of Groningen | Hoorens S.,RAND Europe | Chambers G.M.,University of New South Wales
Human Reproduction Update | Year: 2010

Background: Despite the growing use of assisted reproductive technologies (ART) worldwide, there is only a limited understanding of the economics of ART to inform policy about effective, safe and equitable financing of ART treatment. Methods: A review was undertaken of key studies regarding the costs and consequences of ART treatment, specifically examining the direct and indirect costs of treatment, economic drivers of utilization and clinical practice and broader economic consequences of ART-conceived children. Results: The direct costs of ART treatment vary substantially between countries, with the USA standing out as the most expensive. The direct costs generally reflect the costliness of the underlying healthcare system. If unsubsidized, direct costs represent a significant economic burden to patients. The level of affordability of ART treatment is an important driver of utilization, treatment choices, embryo transfer practices and ultimately multiple birth rates. The costs associated with caring for multiple-birth ART infants and their mothers are substantial, reflecting the underlying morbidity associated with such pregnancies. Investment analysis of ART treatment and ART-conceived children indicates that appropriate funding of ART services appears to represent sound fiscal policy. Conclusions: The complex interaction between the cost of ART treatment and how treatments are subsidized in different healthcare settings and for different patient groups has far-reaching consequences for ART utilization, clinical practice and infant outcomes. A greater understanding of the economics of ART is needed to inform policy decisions and to ensure the best possible outcomes from ART treatment. © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


De Vos P.,University of Groningen
Advances in Experimental Medicine and Biology | Year: 2010

Cell encapsulation has been proposed for the treatment of a wide variety of diseases since it allows for transplantation of cells in the absence of undesired immunosuppression. The technology has been proposed to be a solution for the treatment of diabetes since it potentially allows a mandatory minute-to-minute regulation of glucose levels without side-effects. Encapsulation is based on the principle that transplanted tissue is protected for the host immune system by a semipermeable capsule. Many different concepts of capsules have been tested. During the past two decades three major approaches of encapsulation have been studied. These include (i) intravascular macrocapsules, which are anastomosed to the vascular system as AV shunt, (ii) extravascular macrocapsules, which are mostly diffusion chambers transplanted at different sites and (iii) extravascular microcapsules transplanted in the peritoneal cavity. The advantages and pitfalls of the three approaches are discussed and compared in view of applicability in clinical islet transplantation. © 2010 Landes Bioscience and Springer Science+Business Media.


Tamiola K.,University of Groningen | Mulder F.A.A.,University of Aarhus
Biochemical Society Transactions | Year: 2012

NMR spectroscopy offers the unique possibility to relate the structural propensities of disordered proteins and loop segments of folded peptides to biological function and aggregation behaviour. Backbone chemical shifts are ideally suited for this task, provided that appropriate reference data are available and idiosyncratic sensitivity of backbone chemical shifts to structural information is treated in a sensible manner. In the present paper, we describe methods to detect structural protein changes from chemical shifts, and present an online tool [ncSPC (neighbour-corrected Structural Propensity Calculator)], which unites aspects of several current approaches. Examples of structural propensity calculations are given for two well-characterized systems, namely the binding of α-synuclein to micelles and light activation of photoactive yellow protein. These examples spotlight the great power of NMR chemical shift analysis for the quantitative assessment of protein disorder at the atomic level, and further our understanding of biologically important problems. ©The Authors Journal compilation ©2012 Biochemical Society.


BACKGROUND: Cases reported in the literature suggest that in some individuals sexual dysfunction associated with selective serotonin reuptake inhibitors (SSRIS) may persist following the discontinuation of SSRIS. AIM: To find out how many reports of persistent sexual dysfunction associated with the use of SSRIS were received by the Netherlands Pharmacovigilance Centre, Lareb. METHOD: The database of the Netherlands Pharmacovigilance Centre Lareb was searched for reports of sexual dysfunction in patients who had been using SSRIS and whose sexual functioning had not returned to normal at the time of notification. RESULTS: The database of the Netherlands Pharmacovigilance Centre Lareb contained 19 reports of persistent sexual dysfunction in patients who had stopped using SSRIS for two months up to three years and who had not regained normal sexual functioning. The sexual disorders that were reported most frequently were reduced libido, erectile dysfunction and delayed orgasm. It seems likely that these disorders were caused not only by pharmacological effects of SSRIS but also by psychological factors. CONCLUSION: Although it has previously been assumed that patients always regain normal sexual functioning shortly after discontinuation of SSRIS, emerging evidence suggests that this may not be the case.


Recent advances in nano-biotechnology have made it possible to realize a great variety of enzyme electrodes suitable for sensing and energy applications. In coating miniaturized electrodes with enzymes, there is no doubt that most of the available deposition processes suffer from the difficulty in depositing uniform and reproducible coatings of the active enzyme on the miniature transducer element. This mini-review highlights the promising prospects of two techniques, electrochemical deposition (ECD) and electrophoretic deposition (EPD), in enzyme immobilization onto miniaturized electrodes and their use as biosensors and biofuel cells. The main differences between ECD and EPD are described and highlighted in the sense to make it clear to the reader that both techniques employ electric fields to deposit enzyme but the conditions from which each process is achieved and hence the mechanisms are quite different. Many aspects dealing with deposition of enzyme under ECD and EPD are considered including surface charge of enzyme, its migration under the applied electric field and its precipitation on the electrode. Still all issues discussed in this mini-review are generic and need to be followed in the future by extensive theoretical and experimental research analysis. Finally, the advantages of ECD and EPD in fabrication of miniature biosensor and biofuel cell electrodes are described and discussed. © 2014 Elsevier B.V.


A climate response function is introduced that consists of six exponential (low-pass) filters with weights depending as a power law on their e-folding times. The response of this two-parameter function to the combined forcings of solar irradiance, greenhouse gases, and SO2-related aerosols is fitted simultaneously to reconstructed temperatures of the past millennium, the response to solar cycles, the response to the 1991 Pinatubo volcanic eruption, and the modern 1850-2010 temperature trend. Assuming strong long-term modulation of solar irradiance, the quite adequate fit produces a climate response function with a millennium-scale response to doubled CO2 concentration of 2.0 ± 0.3 °C (mean ± standard error), of which about 50 % is realized with e-folding times of 0.5 and 2 years, about 30 % with e-folding times of 8 and 32 years, and about 20 % with e-folding times of 128 and 512 years. The transient climate response (response after 70 years of 1 % yearly rise of CO2 concentration) is 1.5 ± 0.2 °C. The temperature rise from 1820 to 1950 can be attributed for about 70 % to increased solar irradiance, while the temperature changes after 1950 are almost completely produced by the interplay of anthropogenic greenhouse gases and aerosols. The SO2-related forcing produces a small temperature drop in the years 1950-1970 and an inflection of the temperature curve around the year 2000. Fitting with a tenfold smaller modulation of solar irradiance produces a less adequate fit with millennium-scale and transient climate responses of 2.5 ± 0.4 and 1.9 ± 0.3 °C, respectively. © 2012 The Author(s).


Harder S.,University of Groningen | Spielmann J.,Universitatsstrasse 5
Chemical Communications | Year: 2011

Reaction of DIPPnacnacAlH2 with DIPPNH2BH3 did not give the anticipated deprotonation but nucleophilic substitution at B was observed instead. The product DIPPnacnacAl(BH4)2 was isolated and structurally characterized. Nucleophilic displacement at B might play a role in mechanistic pathways related to metal amidoborane complexes. © 2011 The Royal Society of Chemistry.


Kazemi S.,University of Groningen | Yatawatta S.,ASTRON
Monthly Notices of the Royal Astronomical Society | Year: 2013

A major stage of radio interferometric data processing is calibration or the estimation of systematic errors in the data and the correction for such errors. A stochastic error (noise) model is assumed, and in most cases, this underlying model is assumed to be Gaussian. However, outliers in the data due to interference or due to errors in the sky model would have adverse effects on processing based on a Gaussian noise model. Most of the shortcomings of calibration such as the loss in flux or coherence, and the appearance of spurious sources, could be attributed to the deviations of the underlying noise model. In this paper, we propose to improve the robustness of calibration by using a noise model based on Student's t-distribution. Student's t-noise is a special case of Gaussian noise when the variance is unknown. Unlike Gaussian-noise-model-based calibration, traditional least-squares minimization would not directly extend to a case when we have a Student's t-noise model. Therefore, we use a variant of the expectation-maximization algorithm, called the expectation-conditional maximization either algorithm, when we have a Student's t-noise model and use the Levenberg-Marquardt algorithm in the maximization step. We give simulation results to show the robustness of the proposed calibration method as opposed to traditional Gaussian-noise-model-based calibration, especially in preserving the flux of weaker sources that are not included in the calibration model. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.


Jonker J.W.,University of Groningen | Liddle C.,University of Sydney | Downes M.,Salk Institute for Biological Studies
Journal of Steroid Biochemistry and Molecular Biology | Year: 2012

Cholestatic liver disorders encompass hepatobiliary diseases of diverse etiologies characterized by the accumulation of bile acids, bilirubin and cholesterol as the result of impaired secretion of bile. Members of the nuclear receptor (NR) family of ligand-modulated transcription factors are implicated in the adaptive response to cholestasis. NRs coordinately regulate bile acid and phospholipid transporter genes required for hepatobiliary transport, as well as the phases I and II metabolizing enzymes involved in processing of their substrates. In this review we will focus on FXR and PXR, two members of the NR family whose activities are regulated by bile acids. In addition, we also discuss the potential of pharmacological modulators of these receptors as novel therapies for cholestatic disorders. © 2011 Elsevier Ltd. All rights reserved.


Chen M.,Peking University | Kallenberg C.G.M.,University of Groningen
Nature Reviews Rheumatology | Year: 2010

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) include Wegener granulomatosis, microscopic polyangiitis, Churgĝ€ "Strauss syndrome and renal-limited vasculitis. This Review highlights the progress that has been made in our understanding of AAV pathogenesis and discusses new developments in the treatment of these diseases. Evidence from clinical studies, and both in vitro and in vivo experiments, supports a pathogenic role for ANCAs in the development of AAV; evidence is stronger for myeloperoxidase-ANCAs than for proteinase-3-ANCAs. Neutrophils, complement and effector T cells are also involved in AAV pathogenesis. With respect to treatment of AAV, glucocorticoids, cyclophosphamide and other conventional therapies are commonly used to induce remission in generalized disease. Pulse intravenous cyclophosphamide is equivalent in efficacy to oral cyclophosphamide but seems to be associated with less adverse effects. Nevertheless, alternatives to cyclophosphamide therapy have been investigated, such as the use of methotrexate as a less-toxic alternative to cyclophosphamide to induce remission in non-organ-threatening or non-life-threatening AAV. Furthermore, rituximab is equally as effective as cyclophosphamide for induction of remission in AAV and might become the standard of therapy in the near future. Controlled trials in which specific immune effector cells and molecules are being therapeutically targeted have been initiated or are currently being planned. © 2010 AJA, SIMM & SJTU All rights reserved.


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

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


Jonkers I.,University of Groningen | Lis J.T.,Cornell University
Nature Reviews Molecular Cell Biology | Year: 2015

Recent advances in sequencing techniques that measure nascent transcripts and that reveal the positioning of RNA polymerase II (Pol II) have shown that the pausing of Pol II in promoter-proximal regions and its release to initiate a phase of productive elongation are key steps in transcription regulation. Moreover, after the release of Pol II from the promoter-proximal region, elongation rates are highly dynamic throughout the transcription of a gene, and vary on a gene-by-gene basis. Interestingly, Pol II elongation rates affect co-transcriptional processes such as splicing, termination and genome stability. Increasing numbers of factors and regulatory mechanisms have been associated with the steps of transcription elongation by Pol II, revealing that elongation is a highly complex process. Elongation is thus now recognized as a key phase in the regulation of transcription by Pol II. © 2015 Macmillan Publishers Limited.


Schwander T.,University of Groningen
Current biology : CB | Year: 2012

An unusual reproductive system was discovered in desert ants, in which daughter queens are produced asexually via parthenogenesis, whereas workers develop from hybrid crosses between genetically divergent lineages. The system appears to be doomed to extinction. Copyright © 2012 Elsevier Ltd. All rights reserved.


With the increased international focus on personalized health care and preventive medicine, next-generation sequencing (NGS) has substantially expanded the options for carrier screening of serious, recessively inherited diseases. NGS screening tests not only offer reproductive options not previously available to couples, but they may also ultimately reduce the number of children born with devastating disorders. To date, preconception carrier screening (PCS) has largely targeted single diseases such as cystic fibrosis, but NGS allows the testing of many genes or diseases simultaneously. We have developed an expanded NGS PCS test for couples; simultaneously it covers 50 very serious, early-onset, autosomal recessive diseases that are untreatable. This is the first, noncommercial, population-based, expanded PCS test to be offered prospectively to couples in a health-care setting in Europe. So far, little is known about how potential users view such a PCS test. We therefore performed an online survey in 2014 among 500 people from the target population in the Netherlands. We enquired about their intention to take an expanded PCS test if one was offered, and through which provider they would like to see it offered. One-third of the respondents said they would take such a test were it to be offered. The majority (44%) preferred the test to be offered via their general practitioner (GP) and 58% would be willing to pay for the test, with a median cost of [euro ]75. Our next step is to perform an implementation study in which this PCS test will be provided via selected GPs in the Northern Netherlands.European Journal of Human Genetics advance online publication, 11 May 2016; doi:10.1038/ejhg.2016.43. © 2016 Macmillan Publishers Limited


Kuivenhoven J.A.,University of Groningen | Hegele R.A.,Robarts Research Institute
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2014

Mining of the genome for lipid genes has since the early 1970s helped to shape our understanding of how triglycerides are packaged (in chylomicrons), repackaged (in very low density lipoproteins; VLDL), and hydrolyzed, and also how remnant and low-density lipoproteins (LDL) are cleared from the circulation. Gene discoveries have also provided insights into high-density lipoprotein (HDL) biogenesis and remodeling. Interestingly, at least half of these key molecular genetic studies were initiated with the benefit of prior knowledge of relevant proteins. In addition, multiple important findings originated from studies in mouse, and from other types of non-genetic approaches. Although it appears by now that the main lipid pathways have been uncovered, and that only modulators or adaptor proteins such as those encoded by LDLRAP1, APOA5, ANGPLT3/4, and PCSK9 are currently being discovered, genome wide association studies (GWAS) in particular have implicated many new loci based on statistical analyses; these may prove to have equally large impacts on lipoprotein traits as gene products that are already known. On the other hand, since 2004 - and particularly since 2010 when massively parallel sequencing has become de rigeur - no major new insights into genes governing lipid metabolism have been reported. This is probably because the etiologies of true Mendelian lipid disorders with overt clinical complications have been largely resolved. In the meantime, it has become clear that proving the importance of new candidate genes is challenging. This could be due to very low frequencies of large impact variants in the population. It must further be emphasized that functional genetic studies, while necessary, are often difficult to accomplish, making it hazardous to upgrade a variant that is simply associated to being definitively causative. Also, it is clear that applying a monogenic approach to dissect complex lipid traits that are mostly of polygenic origin is the wrong way to proceed. The hope is that large-scale data acquisition combined with sophisticated computerized analyses will help to prioritize and select the most promising candidate genes for future research. We suggest that at this point in time, investment in sequence technology driven candidate gene discovery could be recalibrated by refocusing efforts on direct functional analysis of the genes that have already been discovered. This article is part of a Special Issue entitled: From Genome to Function. © 2014 Elsevier B.V.


Matrix-valued functions in the Wiener class on the imaginary line are considered in this note. This class of functions is large enough to be suitable for many applications in systems and control of infinite-dimensional systems. For this class of functions three kinds of factorization are discussed: (right-)standard factorization, canonical factorization, and J-spectral factorization. In particular, we focus on an algorithmic procedure to find a (right-)standard factorization and a J-spectral factorization for matrix-valued functions in the Wiener class under the assumption that such factorizations exists. In practice, the J-spectral factors for irrational functions are usually calculated using rational approximations. We show that approximation using rational functions may be achieved in the Wiener norm. © 2015 Elsevier Ltd.


Ozkan M.,University of Groningen | Pang Y.,Texas A&M University
Classical and Quantum Gravity | Year: 2014

We provide a succinct way to construct the supersymmetric completion of Rn (n ≥ 3) in components using the superconformal formulation of old minimal supergravity. As a consequence, we obtain the polynomial f(R) supergravity extending the supersymmetric Starobinsky model to any higher power of R. The supersymmetric vacua in polynomial f(R) supergravity are studied. We also present the Rn extended minimal Volkov-Akulov-Starobinsky model. © 2014 IOP Publishing Ltd.


Boer D.,University of Groningen
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

The possibility of a node in the x dependence of the Sivers and Qiu-Sterman functions is discussed in light of its importance for the experimental check of the overall sign change of the Sivers effect between semi-inclusive DIS and the Drell-Yan process. An x-dependent version of the Ehrnsperger-Schäfer-Greiner-Mankiewicz relation between the Qiu-Sterman function and a twist-3 part of g2 is presented, which naturally suggests a node in the Qiu-Sterman function. This relation could be checked experimentally as well and could provide qualitative information on the gluonic field strength inside the proton. Satisfying the Burkardt sum rule by means of a node is briefly discussed and the importance of modelling the Sivers function including its full Wilson line is pointed out. © 2011 Elsevier B.V.


Abbott D.W.,Agriculture and Agri Food Canada | van Bueren A.L.,University of Groningen
Current Opinion in Structural Biology | Year: 2014

Generally, non-catalytic carbohydrate binding module (CBM) specificity has been shown to parallel the catalytic activity of the carbohydrate active enzyme (CAZyme) module it is appended to. With the rapid expansion in metagenomic sequence space for the potential discovery of new CBMs in addition to the recent emergence of several new CBM families that display diverse binding profiles and novel functions, elucidating the function of these protein modules has become a much more challenging task. This review summarizes several approaches that have been reported for using primary structure to inform CBM specificity and streamlining their biophysical characterization. In addition we discuss general trends in binding site architecture and several newly identified functions for CBMs. Streams of investigation that will facilitate the development and refinement of sequence-based prediction tools are suggested. © 2014.


van Vliet M.J.,University of Groningen
PLoS pathogens | Year: 2010

Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis.


In this paper block circulant and block Toeplitz long strings of MIMO systems with finite length are compared with their corresponding infinite-dimensional spatially invariant systems. The focus is on the convergence of the sequence of solutions to the control Riccati equations and the convergence of the sequence of growth bounds of the closed-loop generators. We show that block circulant approximants of infinite-dimensional spatially invariant systems reflect well the LQR behavior of the infinite-dimensional systems. An example of an exponentially stabilizable and exponentially detectable infinite-dimensional system is also considered in this paper. This example shows that the growth bounds of the Toeplitz approximants, as the length of the string increases, and the growth bound of the corresponding infinite-dimensional model, can be significantly different. On the positive side, we give sufficient conditions for the convergence of the growth bounds. © 2012 Elsevier Ltd. All rights reserved.


Kallenberg C.G.M.,University of Groningen
Annals of the Rheumatic Diseases | Year: 2011

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides are characterised by necrotising inflammation of small vessels in conjunction with ANCA directed to either proteinase 3 (PR3) or myeloperoxidase (MPO). The aetiopathogenesis of these disorders is still not fully elucidated but clinical as well as in vitro and in vivo experimental data strongly suggest a role for the autoimmune responses to PR3 and MPO in disease development. Clinically, PR3-ANCA are strongly associated with granulomatous vasculitis as in Wegener's granulomatosis, and MPO-ANCA with necrotising small vessel vasculitis as in microscopic polyangiitis. Levels of PR3-ANCA and MPO-ANCA do, however, not fully reflect disease activity. In vitro, ANCA activate primed neutrophils to release lytic enzymes and reactive oxygen species, a process reinforced by the alternative pathway of complement. In the context of endothelial cells, this process leads to endothelial detachment and lysis. In vivo experimental studies have clearly demonstrated the pathogenic potential of MPO-ANCA for necrotising glomerulonephritis and pulmonary capillaritis. For PR3-ANCA-associated granulomatous vasculitis, an animal model is lacking. Here, effector T cells, in particular Th17 cells, appear to have a major pathogenic role in addition to ANCA. Finally, microbial factors, derived in particular from S aureus and Gram-negative bacteria, could play a part in disease induction and expression. These new insights into the pathogenesis of ANCA-associated vasculitides have opened new ways for targeted treatment.


ter Horst G.J.,University of Groningen
Vitamins and hormones | Year: 2010

Estrogens are a group of steroid hormones that function as the primary female sex hormone. Estrogens not only have an important role in the regulation of the estrous or menstrual cycle but also control, for example, bone formation, the cardiovascular system, and cognitive functions. Estradiol (E2), the main representative of the group, is highly lipophylic and can easily pass the blood-brain barrier to modulate neuronal activity. Particularly the limbic system, a group of tightly interconnected forebrain areas controlling mood and emotion, is rich in estrogen receptors. To date two cytoplasmatic and/or nuclear estrogen receptors named ER-alpha (ERalpha) and ER-beta (ERbeta) have been identified. In the brain, ERalpha plays a critical role in regulating reproductive neuroendocrine behavior and function. ERbeta appears to play an important role in nonreproductive behaviors, such as learning and memory, anxiety, and mood. Five splice variants of ERbeta, named Erb1, Erb2, Erb1d3, Erb2d3, and Erb1d4, have been identified with possibly different biological activities. There is evidence of a thus far not definitely characterized membrane-linked ER receptor named mER-X. In this review, the anatomy of the limbic system and the distribution of estrogen receptors (ERs) are described in relation to coping with stress and the higher prevalence of stress-related psychiatric disorders in women. Effects of cyclic estrogen administration and chronic stress on recovery and neuronal plasticity are illustrated with own results. Copyright 2010 Elsevier Inc. All rights reserved.


Rao S.,University of Groningen
IEEE Transactions on Automatic Control | Year: 2012

In this paper, behaviors with equal input and output cardinalities and with lossless positive real transfer functions corresponding to certain input-output partitions are considered. Based on Cauer synthesis method, an algorithm to obtain a minimal state map of such behaviors starting from an observable image representation is given. This algorithm makes use of polynomial algebraic methods to arrive at a minimal state map. It is shown that the algorithm has application in synthesis and analysis of lossless electrical networks. © 2012 IEEE.


This paper posits that corporate and technological diversification of firms and their relatedness in terms of products and technologies will impact their propensity to form technological alliances. It argues that both higher levels of diversification and greater relatedness signal superior capabilities and available resources to prospective partners that will facilitate exploration and exploitation of technological assets in an alliance. These theoretical conjectures are tested using a dataset of all tire producers worldwide between 1985 and 1996 that combines detailed firm data on establishment, patenting, and alliance activities. The results indicate that complementarity in terms of corporate and technological diversification strategies, as well as partner characteristics (e.g., size, age, and technological capabilities) drive exploitation alliances. Moreover, firms with similar product portfolios are more likely to engage in exploitative interactions. In contrast, exploration alliances exhibit strong partner similarity across all firm characteristics. Both corporate and technological diversification have positive effects on firms' propensity to engage in exploration, while technological distance has a negative nonlinear one. © 2015 Elsevier B.V. All rights reserved.


Van Haastert P.J.M.,University of Groningen
Biophysical Journal | Year: 2010

Many amoeboid cells move by extending pseudopods. Here I present a new stochastic model for chemotaxis that is based on pseudopod extensions by Dictyostelium cells. In the absence of external cues, pseudopod extension is highly ordered with two types of pseudopods: de novo formation of a pseudopod at the cell body in random directions, and alternating right/left splitting of an existing pseudopod that leads to a persistent zig-zag trajectory. We measured the directional probabilities of the extension of splitting and de novo pseudopods in chemoattractant gradients with different steepness. Very shallow cAMP gradients can bias the direction of splitting pseudopods, but the bias is not perfect. Orientation of de novo pseudopods require much steeper cAMP gradients and can be more precise. These measured probabilities of pseudopod directions were used to obtain an analytical model for chemotaxis of cell populations. Measured chemotaxis of wild-type cells and mutants with specific defects in these stochastic pseudopod properties are similar to predictions of the model. These results show that combining splitting and de novo pseudopods is a very effective way for cells to obtain very high sensitivity to stable gradient and still be responsive to changes in the direction of the gradient. © 2010 by the Biophysical Society.


This paper discusses the archaeozoological evidence from Neolithic Ulucak Höyük (İzmir, ca. 7000-5700 cal. BC) in light of current debates on early dairy technologies. The paper aims to add new dimension to the current understanding of the role western Anatolia played in the evolution of early animal husbandry systems towards wider applications of dairy technologies. The evidence from Ulucak can potentially shed important new information on how these technologies were exchanged across the European-Anatolian frontier. To explore the appearance and evolution of milk use at Ulucak, the paper evaluates two main lines of archaeozoological data: mortality profiles - the most tangible archaeozoological evidence to detect the ways in which domestic animals were exploited (Payne 1973; Vigne and Helmer 2007), and diachronic changes in the contribution of cattle to subsistence economy, with reference to Evershed et al. (2008)s proposal about a cattle-dairy link in northwestern Turkey. Results from Neolithic Ulucak are assessed in the context of relevant evidence from neighbouring sites in western Anatolia. © Publications Scientifiques du Muséum national d'Histoire naturelle.


Lambers Heerspink H.J.,University of Groningen
Contributions to nephrology | Year: 2013

Blood pressure is a strong risk factor for ischemic and atherosclerotic events such as stroke. Blood pressure is often elevated in patients with chronic kidney disease. Consequently, chronic kidney disease patients are at high risk of developing cardiovascular and cerebrovascular damage. Blood pressure reduction by means of inhibiting the renin-angiotensin-aldosterone system (RAAS) reduces the risk of stroke. There is evidence available in the primary and secondary prevention of stroke that RAAS blockade exerts cerebrovascular protective effects independent of blood pressure lowering. This chapter discusses the role of RAAS blockade for the prevention and treatment of stroke in chronic kidney disease. The role of dual RAAS blockade will be reviewed and alternative strategies to enhance the effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers will be provided. Copyright © 2013 S. Karger AG, Basel.


Kampen K.R.,University of Groningen
Leukemia Research | Year: 2012

The early history of leukemia reaches back 200 years. In 1811, Peter Cullen defined a case of splenitis acutus with unexplainable milky blood. Alfred Velpeau defined the leukemia associated symptoms, and observed pus in the blood vessels (1825). Alfred Donné detected a maturation arrest of the white blood cells (1844). John Bennett named the disease leucocythemia, based on the microscopic accumulation of purulent leucocytes (1845). That same year, Rudolf Virchow defined a reversed white and red blood cell balance. He introduced the disease as leukämie in 1847. Henry Fuller performed the first microscopic diagnose of a leukemic patient during life (1846). This gradual process brought us towards our current understanding of this complex disease. © 2011 Elsevier Ltd.


Verhulst E.C.,Wageningen University | Van de zande L.,University of Groningen
Briefings in Functional Genomics | Year: 2015

In recent years, our knowledge of the conserved master-switch gene doublesex (dsx) and its function in regulating the development of dimorphic traits in insects has deepened considerably. Here, a comprehensive overview is given on the properties of the male- and female-specific dsx transcripts yielding DSXF and DSXM proteins in Drosophila melanogaster, and the many downstream targets that they regulate. As insects have cell-autonomous sex determination, it was assumed that dsx would be expressed in every somatic cell, but recent research showed that dsx is expressed only when a cell is required to show its sexual identity through function or morphology. This spatiotemporal regulation of dsx expression has not only been established in D. melanogaster but in all insect species studied. Gradually, it has been appreciated that dsx could no longer be viewed as the master-switch gene orchestrating sexual development and behaviour in each cell, but instead should be viewed as the interpreter for the sexual identity of the cell, expressing this identity only on request, making dsx the central nexus of insect sex determination. © The Author 2015. Published by Oxford University Press.


Allersma T.,University of Groningen
The Cochrane database of systematic reviews | Year: 2013

Subfertility affects 15% to 20% of couples trying to conceive. In vitro fertilisation (IVF) is one of the assisted reproduction techniques developed to improve chances of achieving pregnancy. In the standard IVF method with controlled ovarian hyperstimulation (COH), growth and development of multiple follicles are stimulated by using gonadotrophins, often combined with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist. Although it is an established method of conception for subfertile couples, the treatment is expensive and has a high risk of adverse effects. Studies have shown that IVF in a natural cycle (NC) or a modified natural cycle (MNC) might be a promising low risk and low cost alternative to the standard stimulated IVF treatment since the available dominant follicle of each cycle is used. In this review, we included available randomised controlled studies comparing natural cycle IVF (NC and MNC) with standard IVF. To compare the efficacy and safety of natural cycle IVF (including both NC-IVF and MNC-IVF) with controlled ovarian hyperstimulation IVF (COH-IVF) in subfertile couples. An extended search including of the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ClinicalTrials.gov, conference abstracts in the Web of Knowledge, the World Health Organization International Trials Registry Platform search portal, LILACS database, PubMed and the OpenSIGLE database was conducted according to Cochrane guidelines. The last search was on 31st July 2013. All randomised controlled trials (RCTs) comparing either natural cycle IVF or modified natural cycle IVF versus standard IVF in subfertile couples were included. Data selection and extraction and risk of bias assessment were carried out independently by two authors (TA and AC). The primary outcome measures were live birth rate and ovarian hyperstimulation syndrome (OHSS) rate per randomised woman. We calculated Mantel-Haenszel odds ratios for each dichotomous outcome and either the mean difference or the standardised mean difference (SMD) for continuous outcomes, with 95% confidence intervals (CIs). A fixed effect model was used unless there was substantial heterogeneity, in which case a random effects model was used. Six randomised controlled trials with a total of 788 women were included. The largest of these trials included 396 women eligible for this review.No evidence of a statistically significant difference was found between natural cycle and standard IVF in live birth rates (OR 0.68, 95% CI 0.46 to 1.01, two studies, 425 women, I(2)= 0%, moderate quality evidence). The evidence suggests that for a woman with a 53% chance of live birth using standard IVF, the chance using natural cycle IVF would range from 34% to 53%. There was no evidence of a statistically significant difference between natural cycle and standard IVF in rates of OHSS (OR 0.19, 95% CI 0.01 to 4.06, one study, 60 women, very low quality evidence), clinical pregnancy (OR 0.52 95% CI 0.17 to 1.61, 4 studies, 351 women, I(2)=63%, low quality evidence), ongoing pregnancy (OR 0.72, 95% CI 0.50 to 1.05, three studies, 485 women, I(2)=0%, moderate quality evidence), multiple pregnancy (OR 0.76, 95% CI 0.25 to 2.31, 2 studies, 527 women, I(2)=0%, very low quality evidence), gestational abnormalities (OR 0.44 95% CI 0.03 to 5.93, 1 study, 18 women, very low quality evidence) or cycle cancellations (OR 8.98, 95% CI 0.20 to 393.66, 2 studies, 159 women, I(2)=83%, very low quality evidence). One trial reported that the oocyte retrieval rate was significantly lower in the natural cycle group (MD -4.40, 95% CI -7.87 to -0.93, 60 women, very low quality evidence). There were insufficient data to draw any conclusions about rates of treatment cancellation. Findings on treatment costs were inconsistent and more data are awaited. The evidence was limited by imprecision. Findings for pregnancy rate and for cycle cancellation were sensitive to the choice of statistical model: for these outcomes, use of a fixed effect model suggested a benefit for the standard IVF group. Moreover the largest trial has not yet completed follow up, though data have been reported for over 95% of women. Further evidence from well conducted large trials is awaited on natural cycle IVF treatment. Future trials should compare natural cycle IVF with standard IVF. Outcomes should include cumulative live birth and pregnancy rates, the number of treatment cycles necessary to reach live birth, treatment costs and adverse effects.


van der Molena T.,University of Groningen
Primary Care Respiratory Journal | Year: 2010

Introduction: In the Western world, chronic obstructive pulmonary disease (COPD) is predominantly caused by long-term smoking, which results in pulmonary inflammation that is often associated with systemic inflammation. A number of co-morbid conditions, such as cardiovascular disease, muscle wasting, type 2 diabetes and asthma, may coexist with COPD; these and other co-morbidities not directly related to COPD are major causes of excess morbidity and mortality. Aim: This review sets out to explore the most frequent co-morbidities in COPD and their implications for treatment. Method: Review of the literature on co-morbidities of COPD. Results: Co-morbidities are frequent, but often remain undiagnosed in the COPD patient. In order to provide the best possible care for people with COPD, the physician should be aware of all potential co-morbidities that may arise, and the critical role that effective management of these co-morbidities can play in improving patient outcomes. Conclusions: Increased awareness of the potential co-morbidities of COPD, although potentially adding to the general practitioner's work burden, may provide insights into this difficult disease state and possibly improve each individual's prospects for effective management. © 2010 Primary Care Respiratory Society UK. All rights reserved.


To carry out a systematic review of randomized controlled trials (RCTs) to investigate in patients with arthralgia of the temporomandibular joint (TMJ) the effectiveness of TMJ lavage compared to nonsurgical treatment with regard to pain intensity and mandibular range of motion. The electronic databases Cochrane Controlled Trials Register (1960-2012), PubMed÷Medline (1966-2012), and Embase (1966-2012) were systematically searched for relevant RCTs. References of relevant articles were searched for additional studies, as well as citing reports. Two authors independently performed data extraction by using predefined quality indicators. Relevant outcome data included reduction in pain, as assessed by a visual analog scale (VAS) or a pain score, and maximal mouth opening (MMO) before and 6 months after treatment. Included trials were combined using fixed and random effects meta-analysis. Three RCTs (222 patients) were included for meta-analysis. The statistically significant overall standardized mean difference (SMD) (P < .001) with regard to pain intensity was -1.07 (95% CI = -1.38, - 0.76) in favor of TMJ lavage. The MMO did not change significantly (P > .05, SMD = .05 [95% CI = -0.33, 0.23]). The results suggest that lavage of the TMJ may be slightly more effective than nonsurgical treatment for pain reduction. However, this difference is not likely to be clinically relevant.


OBJECTIVES: To update cost effectiveness estimates for the four dose (3+1) schedule of the seven valent pneumococcal conjugated vaccine (PCV-7) in the Netherlands and to explore the impact on cost effectiveness of reduced dose schedules and implementation of 10 valent and 13 valent pneumococcal vaccines (PCV-10 and PCV-13). DESIGN: Economic evaluation comparing PCV-7, PCV-10, and PCV-13 with no vaccination using a decision tree analytic model built from data in previous studies. SETTING: The Netherlands. Population A cohort of 180,000 newborns followed until 5 years of age. MAIN OUTCOME MEASURES: Costs; gains in life years and quality adjusted life years (QALYs); and incremental cost effectiveness ratios. RESULTS: Under base case assumptions-that is, assuming a five year protective period of the vaccine and no assumed net indirect effects (herd protection minus serotype replacement) among children aged over 5 years-vaccination with PVC-7 in a four dose (3+1) schedule was estimated to prevent 71 and 5778 cases of invasive and non-invasive pneumococcal disease, respectively, in children aged up to 5 years. This corresponds with a total net gain of 173 life years or 277 QALYs. The incremental cost effectiveness ratio of PCV-7 was estimated at euro113,891 ( pound98,300; $145,000) per QALY, well over the ratio of euro50,000 per QALY required for PCV-7 to be regarded as potentially cost effective. A three dose (2+1) schedule of PCV-7 reduced the incremental cost effectiveness ratio to euro82,975 per QALY. For various assumptions and including 10% of the maximum net indirect effects among individuals aged 5 years and over, PCV-10 and PCV-13 had incremental cost effectiveness ratios ranging from euro31,250 to euro52,947 per QALY. CONCLUSIONS: The current Dutch infant vaccination programme of four doses of PCV-7 is not cost effective because of increases in invasive disease caused by non-vaccine serotypes, which reduces the overall direct effects of vaccination and offsets potential positive herd protection benefits in unvaccinated individuals. The 10 valent and 13 valent pneumococcal vaccines could have better net health benefits than PCV-7 through less replacement disease and increased herd protection. Both these effects could substantially reduce the incremental cost effectiveness ratio to possibly acceptable levels, if total programme costs can be lowered by reduced schedules, reductions in vaccine prices, or both.


Kemp D.,University of Queensland | Vanclay F.,University of Groningen
Impact Assessment and Project Appraisal | Year: 2013

Historically, impact assessment practice has not explicitly considered human rights. That human rights are relevant to business has been confirmed through the United Nations Human Rights Council's endorsement of the 'Guiding Principles on Business and Human Rights'. Special Representative to the Secretary-General on business and human rights, Professor John Ruggie, advocated awareness of 'rights-holders' and 'duty-bearers' and a shift from third parties "naming and shaming" companies as a way of addressing human rights harms to companies also "knowing and showing" how they are taking responsibility for their human rights impacts and managing their human rights risks. Consideration of human rights should therefore be central to impact assessment for private sector projects, especially those affecting livelihoods, environment, health, safety and security, land and property, culture and gender dynamics. We provide an introduction to the business and human rights debate, discuss the relevance of human rights to the field of impact assessment, and examine a range of challenges associated with integrating the fields of human rights and social impact assessment. © 2013 Copyright IAIA.


Filatov M.,University of Groningen
Physical Chemistry Chemical Physics | Year: 2011

The ground state electronic structure of the high-temperature (HT) and the low-temperature (LT) phases of (EDO-TTF)2PF6 is investigated using the embedded cluster approach in combination with the density functional method designed to describe the strong non-dynamic electron correlation. It is found that, in the HT phase, the unpaired electron spins located on pairs of neighbouring EDO-TTF molecules are antiferromagnetically coupled along the stacking direction with the Heisenberg exchange integral J = -655 cm-1. In the LT phase, the unpaired spins located on the cationic EDO-TTF molecules are coupled antiferromagnetically with J values strongly alternating along the stacking axis of the crystal thus rendering it diamagnetic. The parameters of the extended Hubbard model are evaluated and the conductance properties of the two phases are estimated using these parameters. It is suggested to investigate the charge and spin excitations in the two phases of (EDO-TTF)2PF6 with the use of angle-resolved photoemission spectroscopy. © 2011 the Owner Societies.


Schmidt A.,TU Munich | Casini A.,University of Groningen | Kuhn F.E.,TU Munich
Coordination Chemistry Reviews | Year: 2014

Metal-mediated self-assemblies of the general formula MxLy (M=metal ion, L=ligand) have emerged as a promising research area of supramolecular chemistry because of their applicability in various fields such as molecular recognition, catalysis and drug delivery. The focus of this review is on discrete coordination cages of the type M2L4 using square-planar, square-pyramidal or octahedral coordinated metal ions (e.g. Pd, Pt, Co, Cu, Ni or Zn) and bis(monodentate) N-ligands. The synthesis and characterization of these metallocages is discussed, and special attention is given to the molecular structures with well-defined internal cavities and the molecular recognition properties. The self-assembled M2L4 cages are capable to encapsulate anionic, neutral or cationic guest molecules within their cavity. Therefore, some of these M2L4 host-guest systems are certainly promising for application in medical diagnostic, drug delivery, catalytic reactions, environmental analytics, material science and chemosensing. © 2014 Elsevier B.V.


De Jong B.,University of Groningen
Journal of Head Trauma Rehabilitation | Year: 2013

The demonstration by Monti et al. (2010) of willful modulation of brain activity in persistent vegetative state implies the exceptional condition of a complete motor locked-in syndrome. As a consequence, the contradictory character of the diagnosis minimally conscious state should be recognized because behaviorally observed minimal cognitive responsiveness does not exclude a higher level of well-differentiated self-consciousness. Introduction of the descriptive entities complete motor locked-in syndrome and minimal cognitive responsiveness is therefore advocated in the service of diagnostic precision. Copyright © 2013 Lippincott Williams & Wilkins.


One of the central aims of autism research is to identify specific neurodevelopmental mechanisms that cause and explain the visible autistic signs and symptoms. In this short paper, I argue that the persistent search for autism-specific pathophysiologies has two fundamental difficulties. The first regards the growing gap between basic autism science and clinical practice. The second regards the difficulties with demarcating autism as a psychiatric condition. Instead of the unremitting search for the neurobiological basis of autism, I suggest that basic autism research should focus on experiences of impairment and distress, and on how these experiences relate to particular (autistic) behaviors in particular circumstances, regardless of whether we are dealing with an autism diagnosis or not. © 2015, Springer Science+Business Media Dordrecht.


Verhoeff B.,University of Groningen
History of Psychiatry | Year: 2013

In this paper, I argue that a new relation between past and present - a supposed historical continuity in the meaning of autism - is created by the histories written by the discipline itself. In histories of autism written by 'practitioner-historians', a sense of scientific progress and an essentialist understanding of autism legitimize and reinforce current understandings and research directions in the field of autism. Conceptual discontinuities and earlier complexities and disputes concerning classifying and delineating autism are usually left out of the positivist narrative of autism. In an alternative history of the concept of autism, I demonstrate that there have been major shifts in the type of symptoms, signs and impairments that were - and are - thought to be essential and specific for autism. © The Author(s) 2013.


Franks D.M.,University of Queensland | Vanclay F.,University of Groningen
Environmental Impact Assessment Review | Year: 2013

Social Impact Assessment (SIA) has traditionally been practiced as a predictive study for the regulatory approval of major projects, however, in recent years the drivers and domain of focus for SIA have shifted. This paper details the emergence of Social Impact Management Plans (SIMPs) and undertakes an analysis of innovations in corporate and public policy that have put in place ongoing processes - assessment, management and monitoring - to better identify the nature and scope of the social impacts that might occur during implementation and to proactively respond to change across the lifecycle of developments. Four leading practice examples are analyzed. The International Finance Corporation (IFC) Performance Standards require the preparation of Environmental and Social Management Plans for all projects financed by the IFC identified as having significant environmental and social risks. Anglo American, a major resources company, has introduced a Socio-Economic Assessment Toolbox, which requires mine sites to undertake regular assessments and link these assessments with their internal management systems, monitoring activities and a Social Management Plan. In South Africa, Social and Labour Plans are submitted with an application for a mining or production right. In Queensland, Australia, Social Impact Management Plans were developed as part of an Environmental Impact Statement, which included assessment of social impacts. Collectively these initiatives, and others, are a practical realization of theoretical conceptions of SIA that include management and monitoring as core components of SIA. The paper concludes with an analysis of the implications for the practice of impact assessment including a summary of key criteria for the design and implementation of effective SIMPs. © 2013 Elsevier Inc.


Bystrykh L.V.,University of Groningen
PLoS ONE | Year: 2012

The diversity and scope of multiplex parallel sequencing applications is steadily increasing. Critically, multiplex parallel sequencing applications methods rely on the use of barcoded primers for sample identification, and the quality of the barcodes directly impacts the quality of the resulting sequence data. Inspection of the recent publications reveals a surprisingly variable quality of the barcodes employed. Some barcodes are made in a semi empirical fashion, without quantitative consideration of error correction or minimal distance properties. After systematic comparison of published barcode sets, including commercially distributed barcoded primers from Illumina and Epicentre, methods for improved, Hamming code-based sequences are suggested and illustrated. Hamming barcodes can be employed for DNA tag designs in many different ways while preserving minimal distance and error-correcting properties. In addition, Hamming barcodes remain flexible with regard to essential biological parameters such as sequence redundancy and GC content. Wider adoption of improved Hamming barcodes is encouraged in multiplex parallel sequencing applications. © 2012 Leonid V. Bystrykh.


Verhoeff B.,University of Groningen
Philosophy, Ethics, and Humanities in Medicine | Year: 2013

Although clinicians and researchers working in the field of autism are generally not concerned with philosophical categories of kinds, a model for understanding the nature of autism is important for guiding research and clinical practice. Contemporary research in the field of autism is guided by the depiction of autism as a scientific object that can be identified with systematic neuroscientific investigation. This image of autism is compatible with a permissive account of natural kinds: the mechanistic property cluster (MPC) account of natural kinds, recently proposed as the model for understanding psychiatric disorders. Despite the heterogeneity, multicausality and fuzzy boundaries that complicate autism research, a permissive account of natural kinds (MPC kinds) provides prescriptive guidance for the investigation of objective causal mechanisms that should inform nosologists in their attempt to carve autism's boundaries at its natural joints. However, this essay will argue that a mechanistic model of autism is limited since it disregards the way in which autism relates to ideas about what kind of behavior is abnormal. As historical studies and definitions of autism show, normative issues concerning disability, impairment and societal needs have been and still are inextricably linked to how we recognize and understand autism. The current search for autism's unity in neurobiological mechanisms ignores the values, social norms and various perspectives on mental pathology that play a significant role in 'the thing called autism'. Autism research needs to engage with these issues in order to achieve more success in the effort to become clinically valuable. © 2013 Verhoeff; licensee BioMed Central Ltd.


Roest D.,University of Groningen
Journal of Cosmology and Astroparticle Physics | Year: 2014

We investigate all single-field, slow-roll inflationary models whose slow-roll parameters scale as 1/N in the limit of a large number of e-folds N. We proof that all such models belong to two universality classes, characterised by a single parameter. One class contains small field models like hilltop inflation, while the other class consists of large field models like chaotic inflation. We give the leading expressions for the spectral index and tensor-to-scalar ratio r, which are universal for each class, plus subleading corrections for a number of models. This predicts r either to be unobservably small, r < 0.01, or close to the present observational limit, r 0.07. © 2014 IOP Publishing Ltd and Sissa Medialab srl.


Engqvist L.,University of Groningen | Engqvist L.,Bielefeld University
American Naturalist | Year: 2012

Sperm competition has been found to have a strong influence on the evolution of many male and female reproductive traits. Theoretical models have shown that, with increasing levels of sperm competition, males are predicted to increase ejaculate investment, and there is ample empirical evidence supporting this prediction. However, most theoretical models concern sperm number, and although the predictions are likely to apply to other sperm traits that will affect the sperm competitive ability of males, substantiated predictions are difficult unless the evolution of specific traits is explicitly modeled. Here I present a novel theoretical model aiming at predicting evolutionarily stable sperm viability in relation to female mating frequency in a mating system with internal fertilization. At odds with verbal arguments, this model demonstrates that sperm viability is expected to decrease with increasing female remating rates and thus to decrease with increasing levels of sperm competition. The major reason for this is that, with increasing female remating rates, the prospects of future fertilization success will decrease, which acts to reduce the benefit of long-lived viable sperm. An additional interesting result is that, as the cost of sperm viability increases, the overall energy investment in ejaculates will decrease. These novel results should have a strong impact on future sperm competition studies and will also have implications for our understanding of the evolution of female polyandry. © 2012 by The University of Chicago.


The vascular endothelial growth factor (VEGF) family has been proposed to be the most important signaling protein family in vessel formation and maturation. VEGF receptor-2 (VEGFR-2) plays an abundant role in the most common forms of cancer. The localization of VEGFR-2 expression is important in cancer pathogenesis; however, so far, little attention has been paid to this phenomenon. Induced cytoplasmic VEGFR-2 transition from the nucleus is associated with poor prognostic cancer stages. Current VEGFR-2-targeted therapy approaches are effective in inhibiting or arresting tumor growth. Moreover, VEGFR-2-targeted therapy was demonstrated to restore the abnormal vasculature in tumors, enhancing their susceptibility toward conventional therapy. Most effects can be found when VEGFR-2-targeted therapy inhibits not only the induced angiogenesis but also the cancer cells that sometimes overexpress VEGFR-2. Nevertheless, we still have little knowledge about the mechanisms that regulate VEGFR-2 expression and how its localization is exactly involved in cancer prognosis. Further research and evaluation of VEGFR-2 regulation and its nuclear transition is necessary to develop more accurate therapeutic strategies to improve the patients' quality of life and their survival. © 2012 Lippincott Williams & Wilkins, Inc.


Etienne R.S.,University of Groningen | Haegeman B.,French Institute for Research in Computer Science and Automation
American Naturalist | Year: 2012

In this article we propose a new framework for studying adaptive radiations in the context of diversity-dependent diversification. Diversity dependence causes diversification to decelerate at the end of an adaptive radiation but also plays a key role in the initial pulse of diversification. In particular, key innovations (which in our definition include novel traits as well as new environments) may cause decoupling of the diversity-dependent dynamics of the innovative clade from the diversity-dependent dynamics of its ancestral clade. We present a likelihood-based inference method to test for decoupling of diversity dependence using molecular phylogenies. The method, which can handle incomplete phylogenies, identifies when the decoupling took place and which diversification parameters are affected. We illustrate our approach by applying it to the molecular phylogeny of the North American clade of the legume tribe Psoraleeae (47 extant species, of which 4 are missing). Two diversification rate shifts were previously identified for this clade; our analysis shows that the first, positive shift can be associated with decoupling of two Pediomelum subgenera from the other Psoraleeae lineages, while we argue that the second, negative shift can be attributed to speciation being protracted. The latter explanation yields nonzero extinction rates, in contrast to previous findings. Our framework offers a new perspective on macroevolution: new environments and novel traits (ecological opportunity) and diversity dependence (ecological limits) cannot be considered separately. © 2012 by The University of Chicago.


Schwander T.,University of Groningen | Leimar O.,University of Stockholm
Trends in Ecology and Evolution | Year: 2011

A major question for the study of phenotypic evolution is whether intra- and interspecific diversity originates directly from genetic variation, or instead, as plastic responses to environmental influences initially, followed later by genetic change. In species with discrete alternative phenotypes, evolutionary sequences can be inferred from transitions between environmental and genetic phenotype control, and from losses of phenotypic alternatives. From the available evidence, sequences appear equally probable to start with genetic polymorphism as with polyphenism, with a possible dominance of one or the other for specific trait types. We argue in this review that to evaluate the prevalence of each route, an investigation of both genetic and environmental cues for phenotype determination in several related rather than in isolated species is required. © 2011 Elsevier Ltd.


Koornstra J.J.,University of Groningen
Best Practice and Research: Clinical Gastroenterology | Year: 2012

Patients with familial adenomatous polyposis (FAP) and patients with Lynch syndrome have an increased risk of developing small intestinal neoplasia. In both conditions, the lifetime risk to develop small bowel cancer is estimated to be around 5%. In FAP, this risk is associated with the degree of duodenal polyposis, classically assessed by the Spigelman classification. For this reason, gastroduodenal surveillance with forward-viewing and side-viewing endoscopy is generally recommended. Studies using video capsule endoscopy and balloon-assisted enteroscopy in FAP patients have revealed that jejunal and ileal polyps occur frequently in FAP, especially in those with extensive duodenal polyposis. Nevertheless, the clinical relevance of small bowel polyps beyond the duodenum appears to be limited. Compared to FAP, little is known about the prevalence and natural history of small bowel neoplasia in Lynch syndrome. Surveillance of the small bowel is not recommended in Lynch syndrome, although recent data using capsule endoscopy provided promising results. © 2012 Elsevier Ltd. All rights reserved.


Bergshoeff E.A.,University of Groningen | Riccioni F.,University of Rome La Sapienza
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

We show that the branes of ten-dimensional IIA/IIB string theory must satisfy, upon toroidal compactification, specific wrapping rules in order to reproduce the number of supersymmetric branes that follows from a supergravity analysis. The realization of these wrapping rules suggests that IIA/IIB string theory contains a whole class of generalized Kaluza-Klein monopoles. © 2011 Elsevier B.V.


van Winkelhoff A.J.,University of Groningen
European journal of oral implantology | Year: 2012

To review and discuss current literature on the use of systemically administered or locally delivered antibiotics in the treatment of peri-implantitis. A literature search was conducted using MEDLINE through the PubMed database of the US National Library of Medicine using studies up to 2011. Studies on the microbiology of peri-implantitis lesions were hand selected. Two studies on the use of systemically administered antibiotics in the treatment of peri-implantitis were identified. Both studies involved a case series without controls. Five studies on locally delivered antibiotics were found. In all cases, local antibiotics were used in conjunction with mechanical debridement and chemical disinfection with antimicrobial agents such as chlorhexidine digluconate or hydrogen peroxide. The additional effects of local antibiotics were noted in all studies but were in general moderate. This may in part be due to the selection of patients with advanced deep pockets and advanced bone loss. The current available scientific information on the use of locally or systemically administered antibiotics is insufficient to allow any firm specific recommendations for the use of these drugs. Local application of minocycline or doxycycline as an adjunct to mechanical debridement and irrigation with an antimicrobial agent may be effective in moderately deep lesions. Surgical access by full-thickness flap surgery in deeper lesions is probably necessary to halt the progression of bone loss. No sound scientific basis is available for the use of systemic antibiotics. There is an urgent need for randomised clinical trials on the use of antibiotics in the treatment of peri-implantitis. Proper periodontal infection control in dentate patients before implants are installed and frequent supportive implant care represent effective measures to reduce the risk of future infections and their complications around oral implants.


Buiter H.D.,University of Groningen
Archives of disease in childhood. Fetal and neonatal edition | Year: 2013

Fetal echogenic bowel (FEB) is a soft marker found on second trimester sonography. Our main aim was to determine the outcome of infants who presented with FEB and secondarily to identify additional sonographic findings that might have clinical relevance for the prognosis. We reviewed all pregnancies in which the diagnosis FEB was made in our Fetal Medicine Unit during 2009-2010 (N=121). We divided all cases into five groups according to additional sonographic findings. Group 1 consisted of cases of isolated FEB, group 2 of FEB associated with dilated bowels, group 3 of FEB with one or two other soft markers, group 4 of FEB with major congenital anomalies or three or more other soft markers, and group 5 consisted of FEB with isolated intrauterine growth restriction (IUGR). Of 121 cases, five were lost to follow-up. Of the remaining 116 cases, 48 (41.4%) were assigned to group 1, 15 (12.9%) to group 2, 15 (12.9%) to group 3, 27 (23.2%) to group 4, and 11 (9.5%) to group 5. The outcome for group 1 was uneventful. In group 2 and 3, two anomalies, anorectal malformation and cystic fibrosis, were detected postnatally (6.7%). In group 4, mortality and morbidity were high (78% resp. 22%). Group 5 also had high mortality (82%) and major morbidity (18%). If FEB occurs in isolation, it is a benign condition carrying a favourable prognosis. If multiple additional anomalies or early IUGR are observed, the prognosis tends to be less favourable to extremely poor.


Oxidative stress has been suggested to play a key role in the development of cardiovascular disease (CVD). The aim of our study was to investigate the associations of serum peroxiredoxin 4 (Prx4), a hydrogen peroxide-degrading peroxidase, with incident CVD and all-cause mortality. We subsequently examined the incremental value of Prx4 for the risk prediction of CVD compared with the Framingham risk score (FRS). We performed Cox regression analyses in 8141 participants without history of CVD (aged 28 to 75 years; women 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, The Netherlands. Serum Prx4 was measured by an immunoluminometric assay in baseline samples. Main outcomes were: (1) incident CVD events or CVD mortality and (2) all-cause mortality during a median follow-up of 10.5 years. In total, 708 participants (7.8%) developed CVD events or CVD mortality, and 517 participants (6.3%) died. Baseline serum Prx4 levels were significantly higher in participants with incident CVD events or CVD mortality and in those who died than in participants who remained free of outcomes (both P<0.001). In multivariable models with adjustment for Framingham risk factors, hazard ratios were 1.16 (95% CI 1.06 to 1.27, P<0.001) for incident CVD events or CVD mortality and 1.17 (95% CI 1.06 to 1.29, P=0.003) for all-cause mortality per doubling of Prx4 levels. After the addition of Prx4 to the FRS, the net reclassification improvement was 2.7% (P=0.01) using 10-year risk categories of CVD. Elevated serum Prx4 levels are associated with a significantly higher risk of incident CVD events or CVD mortality and all-cause mortality after adjustment for clinical risk factors. The addition of Prx4 to the FRS marginally improved risk prediction of future CVD.


Schepers J.P.,Center for Transport and Navigation | Heinen E.,University of Groningen
Accident Analysis and Prevention | Year: 2013

Governments aim to promote a shift from car to bicycle, but concerns about road safety seem to represent an important argument against this encouragement. This study examines the road safety impact of a modal shift from short car trips to cycling in Dutch municipalities. The road safety effect is estimated using Accident Prediction Models (APMs) that account for the non-linearity of risk. APMs are developed utilizing Negative Binomial regression. This study is the first to develop APMs using crash and mobility data from municipalities, and utilizing these models to estimate the effects of changing modal splits of current car and bicycle use to modal splits that actually exist in these municipalities. The results suggest that, under conditions such as in Dutch municipalities, transferring short trips made by cars to bicycles does not change the number of fatalities, but increases the number of serious road injuries. The neutral effect on fatalities, despite the high fatality risk for cyclists, can be explained by there being fewer cars on the road to pose a risk to others, the shorter length of bicycle trips compared to the car trips they replace, and the "safety in numbers" phenomenon. The rise in the number of serious road injuries is due wholly to the high number of cycling crashes with no other vehicle involved. The effect of a modal shift is dependent on the age of the population in which the shift is concentrated, and can be influenced by measures affecting cyclists' injury risk. © 2012 Elsevier Ltd.


Giordani P.,University of Rome La Sapienza | Kiers H.A.L.,University of Groningen | Del Ferraro M.A.,University of Rome La Sapienza
Journal of Statistical Software | Year: 2014

The R package ThreeWay is presented and its main features are illustrated. The aim of ThreeWay is to offer a suit of functions for handling three-way arrays. In particular, the most relevant available functions are T3 and CP, which implement, respectively, the Tucker3 and Candecomp/Parafac methods. They are the two most popular tools for summarizing three-way arrays in terms of components. After briefly recalling both techniques from a theoretical point of view, the functions T3 and CP are described by considering three real life examples.


Harder S.,University of Groningen
Coordination Chemistry Reviews | Year: 2011

This review summarizes the rapid developments in the chemistry of phosphonium-stabilized group 1 and 2 methandiides, i.e. that of alkali and alkaline-earth metal bis(iminophosphorane)methandiide and bis(thiophosphorane)methandiide complexes. Apart from syntheses, structures and reactivities, also a critical discussion on bonding is given. The group 2 complexes of this type can truly be seen as polar metal carbene compounds with a formally polar double metal-carbon bond. © 2010 Elsevier B.V.


van Haastert P.J.M.,University of Groningen
PLoS Computational Biology | Year: 2010

Cell migration in the absence of external cues is well described by a correlated random walk. Most single cells move by extending protrusions called pseudopodia. To deduce how cells walk, we have analyzed the formation of pseudopodia by Dictyostelium cells. We have observed that the formation of pseudopodia is highly ordered with two types of pseudopodia: First, de novo formation of pseudopodia at random positions on the cell body, and therefore in random directions. Second, pseudopod splitting near the tip of the current pseudopod in alternating right/left directions, leading to a persistent zig-zag trajectory. Here we analyzed the probability frequency distributions of the angles between pseudopodia and used this information to design a stochastic model for cell movement. Monte Carlo simulations show that the critical elements are the ratio of persistent splitting pseudopodia relative to random de novo pseudopodia, the Left/Right alternation, the angle between pseudopodia and the variance of this angle. Experiments confirm predictions of the model, showing reduced persistence in mutants that are defective in pseudopod splitting and in mutants with an irregular cell surface. © 2010 Peter J. M. Van Haastert.


Garcia R.,Northeastern University | Jager W.,University of Groningen
Journal of Product Innovation Management | Year: 2011

Agent-based modeling (ABM), a tool for capturing micro-level individuals' underlying decision processes and mimicking dynamic social effects observed at the macro level in the marketplace, is studied. The value of agent-based simulation models for practitioners and for management science depends on their capacity to contribute to the understanding and management of real markets. Studies are devoted towards combining multiple theories from innovation economics and economic sociology in a single modeling framework (SKIN) to capture the relevant processes of knowledge diffusion in industry networks. Data from a conjoint analysis is used to parameterize consumer agents in conjunction with data from an engineering-based design model to parameterize manufacturer agents. ABMs are being designed for testing managerial strategies that influence the degree and speed of diffusion processes is not currently available.


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

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


Barta K.,University of Groningen | Ford P.C.,University of California at Santa Barbara
Accounts of Chemical Research | Year: 2014

ConspectusThis Account outlines recent efforts in our laboratories addressing a fundamental challenge of sustainability chemistry, the effective utilization of biomass for production of chemicals and fuels. Efficient methods for converting renewable biomass solids to chemicals and liquid fuels would reduce society's dependence on nonrenewable petroleum resources while easing the atmospheric carbon dioxide burden. The major nonfood component of biomass is lignocellulose, a matrix of the biopolymers cellulose, hemicellulose, and lignin. New approaches are needed to effect facile conversion of lignocellulose solids to liquid fuels and to other chemical precursors without the formation of intractable side products and with sufficient specificity to give economically sustainable product streams.We have devised a novel catalytic system whereby the renewable feedstocks cellulose, organosolv lignin, and even lignocellulose composites such as sawdust are transformed into organic liquids. The reaction medium is supercritical methanol (sc-MeOH), while the catalyst is a copper-doped porous metal oxide (PMO) prepared from inexpensive, Earth-abundant starting materials. This transformation occurs in a single stage reactor operating at 300-320°C and 160-220 bar. The reducing equivalents for these transformations are derived by the reforming of MeOH (to H2 and CO), which thereby serves as a "liquid syngas" in the present case. Water generated by deoxygenation processes is quickly removed by the water-gas shift reaction. The Cu-doped PMO serves multiple purposes, catalyzing substrate hydrogenolysis and hydrogenation as well as the methanol reforming and shift reactions. This one-pot "UCSB process" is quantitative, giving little or no biochar residual.Provided is an overview of these catalysis studies beginning with reactions of the model compound dihydrobenzofuran that help define the key processes occurring. The initial step is phenyl-ether bond hydrogenolysis, and this is followed by aromatic ring hydrogenation. The complete catalytic disassembly of the more complex organosolv lignin to monomeric units, largely propyl-cyclohexanol derivatives is then described. Operational indices based on 1H NMR analysis are also presented that facilitate holistic evaluation of these product streams that within several hours consist largely of propyl-cyclohexanol derivatives. Lastly, we describe the application of this methodology with several types of wood (pine sawdust, etc.) and with cellulose fibers. The product distribution, albeit still complex, displays unprecedented selectivity toward the production of aliphatic alcohols and methylated derivatives thereof. These observations clearly indicate that the Cu-doped solid metal oxide catalyst combined with sc-MeOH is capable of breaking down the complex biomass derived substrates to markedly deoxygenated monomeric units with increased hydrogen content. Possible implementations of this promising system on a larger scale are discussed. © 2014 American Chemical Society.


Van De Vliert E.,University of Groningen | Van De Vliert E.,University of Bergen
Behavioral and Brain Sciences | Year: 2013

This paper examines why fundamental freedoms are so unevenly distributed across the earth. Climato-economic theorizing proposes that humans adapt needs, stresses, and choices of goals, means, and outcomes to the livability of their habitat. The evolutionary process at work is one of collectively meeting climatic demands of cold winters or hot summers by using monetary resources. Freedom is expected to be lowest in poor populations threatened by demanding thermal climates, intermediate in populations comforted by undemanding temperate climates irrespective of income per head, and highest in rich populations challenged by demanding thermal climates. This core hypothesis is supported with new survey data across 85 countries and 15 Chinese provinces and with a reinterpretative review of results of prior studies comprising 174 countries and the 50 states in the United States. Empirical support covers freedom from want, freedom from fear, freedom of expression and participation, freedom from discrimination, and freedom to develop and realize one's human potential. Applying the theory to projections of temperature and income for 104 countries by 2112 forecasts that (a) poor populations in Asia, perhaps except Afghans and Pakistanis, will move up the international ladder of freedom, (b) poor populations in Africa will lose, rather than gain, relative levels of freedom unless climate protection and poverty reduction prevent this from happening, and (c) several rich populations will be challenged to defend current levels of freedom against worsening climato-economic livability. Copyright © 2013 Cambridge University Press.


The effect of urban expansion on transportation in growing megacities has become a key issue in the context of global climate change as motorized mobility is a major source of domestic greenhouse gas emissions. The management of forms of urban development on the city fringe in order to encourage a sustainable transport system is usually overlooked in China, although it is increasingly attracting attention in developed countries. Examining the case of Beijing, this paper aims to reveal the policy implications of urban growth management for sustainable transportation in China's megacities. The analysis shows that in the rapid urban expansion process there has been obvious urban sprawl on the fringe of Beijing, characterized by low density and dispersed development in its physical aspect and a low degree of local mixed land use in its functional aspect. Trip distance and car use for travel on the city fringe have increased greatly due to urban sprawl. The results of the analysis suggest that urban growth management designed to curb urban sprawl would contribute to containing the growth in vehicle miles travelled in the suburbs. In addition, since urban sprawl has been greatly fuelled by increasing local government autonomy and fiscal responsibility, the negative effects of sprawling development on transportation certainly reflect the government's failure to manage growth in the current transformation process. To achieve sustainable urban expansion, stronger metropolitan development management measures should be enforced to control local development on the city fringe and promote sustainable transportation. © 2009 Elsevier Ltd. All rights reserved.


Georgiadis J.R.,University of Groningen | Kringelbach M.L.,University of Oxford | Kringelbach M.L.,University of Aarhus
Progress in Neurobiology | Year: 2012

Sexual behavior is critical to species survival, yet comparatively little is known about the neural mechanisms in the human brain. Here we systematically review the existing human brain imaging literature on sexual behavior and show that the functional neuroanatomy of sexual behavior is comparable to that involved in processing other rewarding stimuli. Sexual behavior clearly follows the established principles and phases for wanting, liking and satiety involved in the pleasure cycle of other rewards. The studies have uncovered the brain networks involved in sexual wanting or motivation/anticipation, as well as sexual liking or arousal/consummation, while there is very little data on sexual satiety or post-orgasmic refractory period. Human sexual behavior also interacts with other pleasures, most notably social interaction and high arousal states. We discuss the changes in the underlying brain networks supporting sexual behavior in the context of the pleasure cycle, the changes to this cycle over the individual's life-time and the interactions between them. Overall, it is clear from the data that the functional neuroanatomy of sex is very similar to that of other pleasures and that it is unlikely that there is anything special about the brain mechanisms and networks underlying sex. © 2012 Elsevier Ltd.


Buschmann T.,Carl Gustav Carus Institute | Bystrykh L.V.,University of Groningen
BMC Bioinformatics | Year: 2013

Background: High-throughput sequencing technologies are improving in quality, capacity and costs, providing versatile applications in DNA and RNA research. For small genomes or fraction of larger genomes, DNA samples can be mixed and loaded together on the same sequencing track. This so-called multiplexing approach relies on a specific DNA tag or barcode that is attached to the sequencing or amplification primer and hence appears at the beginning of the sequence in every read. After sequencing, each sample read is identified on the basis of the respective barcode sequence.Alterations of DNA barcodes during synthesis, primer ligation, DNA amplification, or sequencing may lead to incorrect sample identification unless the error is revealed and corrected. This can be accomplished by implementing error correcting algorithms and codes. This barcoding strategy increases the total number of correctly identified samples, thus improving overall sequencing efficiency. Two popular sets of error-correcting codes are Hamming codes and Levenshtein codes.Result: Levenshtein codes operate only on words of known length. Since a DNA sequence with an embedded barcode is essentially one continuous long word, application of the classical Levenshtein algorithm is problematic. In this paper we demonstrate the decreased error correction capability of Levenshtein codes in a DNA context and suggest an adaptation of Levenshtein codes that is proven of efficiently correcting nucleotide errors in DNA sequences. In our adaption we take the DNA context into account and redefine the word length whenever an insertion or deletion is revealed. In simulations we show the superior error correction capability of the new method compared to traditional Levenshtein and Hamming based codes in the presence of multiple errors.Conclusion: We present an adaptation of Levenshtein codes to DNA contexts capable of correction of a pre-defined number of insertion, deletion, and substitution mutations. Our improved method is additionally capable of recovering the new length of the corrupted codeword and of correcting on average more random mutations than traditional Levenshtein or Hamming codes.As part of this work we prepared software for the flexible generation of DNA codes based on our new approach. To adapt codes to specific experimental conditions, the user can customize sequence filtering, the number of correctable mutations and barcode length for highest performance. © 2013 Buschmann and Bystrykh; licensee BioMed Central Ltd.


Aleman A.,University of Groningen
Clinical Psychopharmacology and Neuroscience | Year: 2013

The potential of noninvasive neurostimulation by repetitive transcranial magnetic stimulation (rTMS) for improving psychiatric disorders has been studied increasingly over the past two decades. This is especially the case for major depression and for auditory-verbal hallucinations in schizophrenia. The present review briefly describes the background of this novel treatment modality and summarizes evidence from clinical trials into the efficacy of rTMS for depression and hallucinations. Evidence for efficacy in depression is stronger than for hallucinations, although a number of studies have reported clinically relevant improvements for hallucinations too. Different stimulation parameters (frequency, duration, location of stimulation) are discussed. There is a paucity of research into other psychiatric disorders, but initial evidence suggests that rTMS may also hold promise for the treatment of negative symptoms in schizophrenia, obsessive compulsive disorder and post-traumatic stress disorder. It can be concluded that rTMS induces alterations in neural networks relevant for psychiatric disorders and that more research is needed to elucidate efficacy and underlying mechanisms of action. Copyright © 2013, Korean College of Neuropsychopharmacology.


Dijk C.,University of Amsterdam | de Jong P.J.,University of Groningen
Behaviour Research and Therapy | Year: 2012

It has been proposed that blushing-fearful individuals overestimate both the probability and the interpersonal costs of blushing. To study these judgmental biases, we presented a treatment-seeking sample of blushing-fearful individuals a series of vignettes describing social events and tested whether this clinical sample would overestimate the costs and probability of blushing compared to non-fearful controls. To test if blushing-fearfuls overestimate and/or low-fearful individuals underestimate the cost of displaying a blush, a second experiment examined the effects of blushing in these situations on observers' judgments. Experiment 1 showed that blushing-fearfuls indeed have judgmental biases for the probability and costs of blushing. Experiment 2 showed that the observers' judgments were very similar to the judgments anticipated by the low-fear group in Experiment 1. Thus the judgmental biases that were evident in the high-fearfuls can be best interpreted as an overestimation of the social costs of displaying a blush. These findings help improving our understanding of the mechanisms that may drive blushing phobia and also point to the clinical implication that it might be worthwhile to challenge blushing-fearfuls' judgmental biases. © 2011 Elsevier Ltd.


Sidorenkov G.,University of Groningen
PloS one | Year: 2013

Landmark clinical trials have led to optimal treatment recommendations for patients with diabetes. Whether optimal treatment is actually delivered in practice is even more important than the efficacy of the drugs tested in trials. To this end, treatment quality indicators have been developed and tested against intermediate outcomes. No studies have tested whether these treatment quality indicators also predict hard patient outcomes. A cohort study was conducted using data collected from >10.000 diabetes patients in the Groningen Initiative to Analyze Type 2 Treatment (GIANTT) database and Dutch Hospital Data register. Included quality indicators measured glucose-, lipid-, blood pressure- and albuminuria-lowering treatment status and treatment intensification. Hard patient outcome was the composite of cardiovascular events and all-cause death. Associations were tested using Cox regression adjusting for confounding, reporting hazard ratios (HR) with 95% confidence intervals. Lipid and albuminuria treatment status, but not blood pressure lowering treatment status, were associated with the composite outcome (HR = 0.77, 0.67-0.88; HR = 0.75, 0.59-0.94). Glucose lowering treatment status was associated with the composite outcome only in patients with an elevated HbA1c level (HR = 0.72, 0.56-0.93). Treatment intensification with glucose-lowering but not with lipid-, blood pressure- and albuminuria-lowering drugs was associated with the outcome (HR = 0.73, 0.60-0.89). Treatment quality indicators measuring lipid- and albuminuria-lowering treatment status are valid quality measures, since they predict a lower risk of cardiovascular events and mortality in patients with diabetes. The quality indicators for glucose-lowering treatment should only be used for restricted populations with elevated HbA1c levels. Intriguingly, the tested indicators for blood pressure-lowering treatment did not predict patient outcomes. These results question whether all treatment indicators are valid measures to judge quality of health care and its economics.


Beckel J.M.,University of Pennsylvania | Holstege G.,University of Groningen
Handbook of Experimental Pharmacology | Year: 2011

The lower urinary tract (LUT) has two functions: (1) the storage of waste products in the form of urine and (2) the elimination of those wastes through micturition. The LUT operates in a simple "on-off" fashion, either storing urine or releasing it during voiding. While this activity may seem simple, micturition is controlled by a complex set of peripheral neurons that are, in turn, coordinated by cell groups in the spinal cord, brainstem, and brain. When this careful coordination is interrupted, the control of the bladder is lost, resulting in incontinence or retention of urine. The purpose of this chapter is to review how the neural systems coordinating the activity of the lower urinary tract form neural circuits that are responsible for either maintaining continence (the storage reflex) or inducing micturition (the voiding reflex). We will also discuss the brain centers that enable higher organisms to voluntarily choose the time and place for voiding. Finally, we will discuss how defects in the pathways controlling micturition can lead to urinary incontinence and which treatments may normalize LUT function. © 2011 Springer-Verlag Berlin Heidelberg.


Beckel J.M.,University of Pennsylvania | Holstege G.,University of Groningen
Handbook of Experimental Pharmacology | Year: 2011

The lower urinary tract (LUT), which consists of the urinary bladder and its outlet, the urethra, is responsible for the storage and periodic elimination of bodily waste in the form of urine. The LUT is controlled by a complex set of peripheral autonomic and somatic nerves, which in turn are controlled through neural pathways in the spinal cord and brain. This influence of the central nervous system allows for the conscious control of the bladder, allowing the individual to choose an appropriate place to urinate. Defects in the CNS pathways that control the LUT can lead to incontinence, an embarrassing condition that affects over 200 million people worldwide. As a first step in understanding the neural control of the bladder, we will discuss the neuroanatomy of the LUT, focusing first on the peripheral neural pathways, including the sensory pathways that transmit information on bladder filling and the motoneurons that control LUT muscle contractility. We will also discuss the organization of the central pathways in the spinal cord and brainstem that are responsible for coordinating bladder activity, promoting continuous storage of urine except for a few short minutes per day when micturition takes place. To conclude, we will discuss current studies underway that aim to elucidate the higher areas of the brain that control the voluntary nature of micturition in higher organisms. © 2011 Springer-Verlag Berlin Heidelberg.


Vedder H.,University of Groningen
Journal of Environmental Law | Year: 2010

This contribution analyses the effects of the entry into force of the Treaty of Lisbon for European environmental law and policy. The central conclusion is that, apart from the new numbering and some new names for procedures and institutions, this does not entail any major changes. The new Energy Title, it is submitted, does not go beyond confirming the status quo. One potentially interesting innovation is the special treaty infringement procedure for noncommunication of implementing measures. Similarly, a new paragraph on standing to challenge the legality of European acts (Article 230 EC) may result in wider access to justice also in environmental matters. © The Author [2010]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.


Hoedeman R.,University of Groningen
Cochrane database of systematic reviews (Online) | Year: 2010

In primary care between 10% and 35% of all visits concern patients with medically unexplained physical symptoms (MUPS). MUPS are associated with high medical consumption, significant disabilities and psychiatric morbidity. To assess the effectiveness of consultation letters (CLs) to assist primary care physicians or occupational health physicians in the treatment of patients with MUPS and diagnostic subgroups. We searched for randomized controlled trials (RCTs) on the Cochrane Collaboration Depression, Anxiety and Neurosis Group Controlled Trials Registers, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2009), MEDLINE  (1966-2009), MEDLINE In Process (2009-08-17), EMBASE (1974-2009), PSYCINFO (1980-2009) and CINAHL (1982-2009). We screened the references lists of selected studies and consulted experts in the field to identify any additional, eligible RCTs. RCTs of CLs for patients with MUPS being treated in primary care settings. Two authors independently screened the abstracts of the studies identified through the searches and independently assessed the risk of bias of the included studies. We resolved any disagreement by discussion with a third review author. We assessed heterogeneity and, where a number of studies reported the same outcomes, pooled results in a meta-analysis. We included six RCTs, with a total of 449 patients. In four studies (267 patients) the CL intervention resulted in reduced medical costs (in two studies the outcomes could be pooled: MD -352.55 US Dollars (95% CI -522.32 to -182.78)) and improved physical functioning (three studies, MD 5.71 (95% CI 4.11 to 7.31)). In two studies (182 patients) the intervention was a joint consultation with a psychiatrist in presence of the physician, and resulted in reduced severity of somatization symptoms, reduced medical consumption and improved social functioning. There is limited evidence that a CL is effective in terms of medical costs and improvement of physical functioning for patients with MUPS in primary care. The results are even less pronounced in patients with clinically less severe, but more meaningful, forms of MUPS and the results vary for other patient-related outcomes. All studies, except one, were performed in the United States and therefore the results can not be generalized directly to countries with other healthcare systems. Furthermore all studies were small and of only moderate quality. There is very limited evidence that a joint consultation with the patient by a psychiatrist in the presence of the physician, together with the provision of a CL, reduces severity of somatization symptoms and medical consumption.


Mazo Jr. M.,University of Groningen | Tabuada P.,University of California at Los Angeles
Systems and Control Letters | Year: 2011

There is an increasing demand for controller design techniques capable of addressing the complex requirements of today's embedded applications. This demand has sparked the interest in symbolic control where lower complexity models of control systems are used to cater for complex specifications given by temporal logics, regular languages, or automata. These specification mechanisms can be regarded as qualitative since they divide the trajectories of the plant into bad trajectories (those that need to be avoided) and good trajectories. However, many applications require also the optimization of quantitative measures of the trajectories retained by the controller, as specified by a cost or utility function. As a first step towards the synthesis of controllers reconciling both qualitative and quantitative specifications, we investigate in this paper the use of symbolic models for time-optimal controller synthesis. We consider systems related by approximate (alternating) simulation relations and show how such relations enable the transfer of time-optimality information between the systems. We then use this insight to synthesize approximately time-optimal controllers for a control system by working with a lower complexity symbolic model. The resulting approximately time-optimal controllers are equipped with upper and lower bounds for the time to reach a target, describing the quality of the controller. The results described in this paper were implemented in the Matlab Toolbox Pessoa (Mazo et al., 2009 [12]) which we used to workout several illustrative examples reported in this paper. © 2011 Elsevier B.V. All rights reserved.


Johnson C.,University of North Carolina at Greensboro | Boersma T.,University of Groningen
Energy Policy | Year: 2013

The large scale extraction of natural gas from shale rock layers in North America using hydraulic fracturing, or "fracking", has prompted geologists, economists and politicians in various parts of the world to ask whether there are new reserves of this precious resource to be found under their soils. It has also raised a host of questions about the potential environmental impacts of extracting it. Drawing on research on both sides of the Atlantic, this paper assesses the most pressing issues for research and policy makers related to shale gas extraction. The paper first provides a survey of environmental and economic issues related to shale gas. It then turns to a case study of Poland, whose policy makers have been among the most fervent proponents of shale gas development in the European Union. We examine the status of shale gas extraction in that country and what the barriers are to overcome before commercial extraction can in fact take place, if at all. © 2012 Elsevier Ltd.


Caputi K.I.,University of Groningen
International Journal of Modern Physics D | Year: 2014

The remarkable progress made in infrared (IR) astronomical instruments over the last 10-15 years has radically changed our vision of the extragalactic IR sky, and overall understanding of galaxy evolution. In particular, this has been the case for the study of active galactic nuclei (AGN), for which IR observations provide a wealth of complementary information that cannot be derived from data in other wavelength regimes. In this review, I summarize the unique contribution that IR astronomy has recently made to our understanding of AGN and their role in galaxy evolution, including both physical studies of AGN at IR wavelengths, and the search for AGN among IR galaxies in general. Finally, I identify and discuss key open issues that should be possible to address with forthcoming IR telescopes. © 2014 World Scientific Publishing Company.


Schwander T.,University of Groningen
Proceedings. Biological sciences / The Royal Society | Year: 2013

Environmental shifts and lifestyle changes may result in formerly adaptive traits becoming non-functional or maladaptive. The subsequent decay of such traits highlights the importance of natural selection for adaptations, yet its causes have rarely been investigated. To study the fate of formerly adaptive traits after lifestyle changes, we evaluated sexual traits in five independently derived asexual lineages, including traits that are specific to males and therefore not exposed to selection. At least four of the asexual lineages retained the capacity to produce males that display normal courtship behaviours and are able to fertilize eggs of females from related sexual species. The maintenance of male traits may stem from pleiotropy, or from these traits only regressing via drift, which may require millions of years to generate phenotypic effects. By contrast, we found parallel decay of sexual traits in females. Asexual females produced altered airborne and contact signals, had modified sperm storage organs, and lost the ability to fertilize their eggs, impeding reversals to sexual reproduction. Female sexual traits were decayed even in recently derived asexuals, suggesting that trait changes following the evolution of asexuality, when they occur, proceed rapidly and are driven by selective processes rather than drift.


The Best Interest of the Child-Questionnaire (BIC-Q) has been designed as an instrument for screening the quality of the rearing situation of children with behavioural problems or delinquency. It is intended to aid legal decisions in juvenile and family law. The aim of the study was to establish the reliability and validation of the BIC-Q. Records of 83 children in detention or secure treatment centres and 58 children with no delinquent behaviours were rated by trained researchers. Interrater reliability was tested with a sub-sample of 31 of the former. Content validity was evaluated across the whole group, using Cronbach's alpha to check internal consistency, Spearman's rho to examine correlations and explorative principal component analysis (PCA) to test the extent to which variance in the 14 underlying conditions could be accounted for by a single factor 'quality of rearing'. Interrater reliability was good (r = 0.89). The PCA lent support to the content validity of the questionnaire with four factors, which together explained 66% of the variance in child rearing: (1) attachment and bonding; (2) rules and provisions; (3) health care and physical care in the family context; and (4) care and models provided for in the societal environment. The BIC-Q is a reliable and valid measure of the overall quality of child rearing. Preliminary results indicate that the BIC-Q may be applied to support court decisions on where the child should live after detention or secure treatment. Copyright © 2011 John Wiley & Sons, Ltd.


Fingleton B.,University of Cambridge | Garretsen H.,University of Groningen | Martin R.,University of Cambridge
Journal of Regional Science | Year: 2012

We analyze the resilience of U.K. regions to employment shocks. Two basic notions of resilience are distinguished. With engineering resilience, there is an underlying stable growth path to which a regional economy rebounds following a shock. With ecological resilience, shocks can permanently affect the growth path of the regional economy. Our data set consists of quarterly employment series for 12 U.K. regions (NUTS I) for the period 1971-2010. Using a seemingly unrelated regression (SUR) model specification, we test for the relevance of (engineering) resilience of U.K. regional employment to the four recessionary shocks in our sample. It turns out that U.K. regions do indeed differ in their resilience, but that these differences mainly concern the initial resistance to these shocks and not so much the recovery stage. The SUR model does not allow shocks to have permanent effects and it also does not take the possibility of time differentiated shock spillovers between the 12 regions into account. To this end, we also estimate a vector error-correction model (VECM) specification where employment shocks can have permanent effects and where also interregional employment linkages are included. We find that employment shocks typically have permanent effects when it concerns the own-region effects. Permanent effects can also be found for the impact on other regions but the interregional effects are typically only significant for nearby regions. © 2012, Wiley Periodicals, Inc.


Koolhaas J.M.,University of Groningen
Journal of visualized experiments : JoVE | Year: 2013

This video publication explains in detail the experimental protocol of the resident-intruder paradigm in rats. This test is a standardized method to measure offensive aggression and defensive behavior in a semi natural setting. The most important behavioral elements performed by the resident and the intruder are demonstrated in the video and illustrated using artistic drawings. The use of the resident intruder paradigm for acute and chronic social stress experiments is explained as well. Finally, some brief tests and criteria are presented to distinguish aggression from its more violent and pathological forms.


Brenninkmeijer J.,University of Groningen
History of the Human Sciences | Year: 2010

The increasing attention to the brain in science and the media, and people's continuing quest for a better life, have resulted in a successful self-help industry for brain enhancement. Apart from brain books, foods and games, there are several devices on the market that people can use to stimulate their brains and become happier, healthier or more successful. People can, for example, switch their brain state into relaxation or concentration with a light-and-sound machine, they can train their brainwaves to cure their Attention Deficit Hyperactivity Disorder (ADHD) or solve their sleeping problems with a neurofeedback device, or they can influence the firing of their neurons with electric or magnetic stimulation to overcome their depression and anxieties. Working on your self with a brain device can be seen as a contemporary form of Michel Foucault's 'technologies of the self'. Foucault described how since antiquity people had used techniques such as reading manuscripts, listening to teachers, or saying prayers to 'act on their selves' and control their own thoughts and behaviours. Different techniques, Foucault stated, are based on different precepts and constitute different selves. I follow Foucault by stating that using a brain device for self-improvement indeed constitutes a new self. Drawing on interviews with users of brain devices and observations of the practices in brain clinics, I analyse how a new self takes shape in the use of brain devices; not a monistic (neuroscientific) self, but a 'layered' self of all kinds of entities that exchange and control each other continuously. © The Author(s), 2010.


Massy Z.A.,Charles University | De Zeeuw D.,University of Groningen
Kidney International | Year: 2013

In the majority of patients with chronic kidney disease (CKD) the total and low-density lipoprotein (LDL) cholesterol are usually normal, with the exception of patients with nephrotic-range proteinuria and in peritoneal dialysis patients. Moreover, epidemiological evidence shows that the link between serum total cholesterol or LDL cholesterol and cardiovascular disease (CVD) in CKD is not as straightforward as in the general population. In addition, atherosclerosis-related events are responsible for only ∼30% of CVD in these patients. Nevertheless, intervention trials, particularly the Study of Heart and Renal Protection, and meta-analyses showed a proportional reduction of cardiovascular risk associated with the absolute reduction in LDL cholesterol in patients with CKD similar to the general population, with apparent attenuation of this relationship in end-stage kidney disease. Therefore, the use of cholesterol-lowering agents appears to be indicated in early CKD stages to prevent atherosclerosis-related risk. However, uncertainty persists as to the optimal management of this risk in end-stage kidney disease patients. In the present review, we discuss these issues and end up with a practical plan aimed to help the nephrologist in managing atherosclerosis- related risk using cholesterol-lowering therapies in CKD patients. © 2013 International Society of Nephrology.


Advanced glycation end products (AGEs) are increased in patients with heart failure (HF). We studied the predictive value of plasma AGEs N(ε)-(carboxymethyl)lysine (CML), pentosidine, and the soluble form of its receptor (sRAGE) in a large HF population. In 580 patients hospitalized with HF, plasma AGEs were measured before discharge when patients were clinically stable. Patients were followed for a period of 18 months. Primary end point was a composite of death and HF admissions. CML was determined by liquid chromatography mass spectrometry, pentosidine by high-performance liquid chromatography and sRAGE by sequential sandwich immunoassay. Mean age was 71 ± 11 years, 62% were men, and mean left ventricular ejection fraction was 0.32 ± 0.14. At baseline, mean CML level was 2.16 ± 0.73 μmol/L, median pentosidine was 0.043 (0.030-0.074) μmol/L, and median sRAGE level was 2.92 (1.90-4.59) ng/mL. CML and pentosidine levels were independently related to the composite end-point (HR, 1.20 per SD; 95% CI,1.05-1.37; P = .01 and HR, 1.15 per SD; 95% CI, 1.00-1.31; P = .045, respectively) and HF hospitalization (HR, 1.27 per SD; 95% CI, 1.10-1.48; P = .001 and HR, 1.27 per SD; 95% CI, 1.10-1.47; P = .001, respectively). Furthermore, CML levels were independently related to increased mortality (P = .006). Whereas sRAGE levels were univariately predictive for outcome, in multivariate models sRAGE did not reach statistical significance. In HF patients, both CML and pentosidine predict HF hospitalization and the combined primary end-point (mortality or HF-hospitalization), whereas sRAGE did not predict events. In addition, CML was significantly and independently associated with a higher risk for mortality. Copyright © 2012 Mosby, Inc. All rights reserved.


Stavenga D.G.,University of Groningen
Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology | Year: 2010

The absorbance spectra of visual pigments can be approximated with mathematical expressions using as single parameter the absorbance peak wavelength. A comparison of the formulae of Stavenga et al. in Vision Res 33:1011-1017 (1993) and Govardovskii et al. in Vis Neurosci 17:509-528 (2000) applied to a number of invertebrate rhodopsins reveals that both templates well describe the normalized α-band of rhodopsins with peak wavelength > 400 nm; the template spectra are virtually indistinguishable in an absorbance range of about three log units. The template formulae of Govardovskii et al. in Vis Neurosci 17:509-528 (2000) describe the rhodopsin spectra better for absorbances below 10-3. The template predicted spectra deviate in the ultraviolet wavelength range from each other as well as from measured spectra, preventing a definite conclusion about the spectral shape in the wavelength range <400 nm. The metarhodopsin spectra of blowfly and fruitfly R1-6 photoreceptors derived from measured data appear to be virtually identical. The established templates describe the spectral shape of fly metarhodopsin reasonably well. However, the best fitting template spectrum slightly deviates from the experimental spectra near the peak and in the long-wavelength tail. Improved formulae for fitting the fly metarhodopsin spectra are proposed. © 2010 The Author(s).


Rottier B.L.,University of Groningen | Rubin B.K.,Virginia Commonwealth University
Paediatric Respiratory Reviews | Year: 2013

Asthma is usually treated with inhaled corticosteroids (ICS) and bronchodilators generated from pressurized metered dose inhalers (pMDI), dry powder inhalers (DPI), or nebulizers. The target areas for ICS and beta 2-agonists in the treatment of asthma are explained. Drug deposition not only depends on particle size, but also on inhalation manoeuvre. Myths regarding inhalation treatments lead to less than optimal use of these delivery systems. We discuss the origin of many of these myths and provide the background and evidence for rejecting them. © 2013.


Willems D.L.,University of Amsterdam | Verhagen A.A.,University of Groningen | van Wijlick E.,Royal Dutch Medical Association
Pediatrics | Year: 2014

BACKGROUND AND OBJECTIVES: Pediatric bioethics presumes that decisions should be taken in the child's best interest. If it's ambiguous whether a decision is in the child's interest, we defer to parents. Should parents be permitted to consider their own interests in making decisions for their child? In the Netherlands, where neonatal euthanasia is legal, such questions sometimes arise in deciding whether to hasten the death of a critically ill, suffering child. We describe the recommendations of a national Dutch committee. Our objectives were to analyze the role of competing child and family interests and to provide guidance on end-of-life decisions for doctors caring for severely ill newborns.METHODS: We undertook literature review, 7 consensus meetings in a multidisciplinary expert commission, and invited comments on draft report by specialists' associations.RESULTS: Initial treatment is mandatory for most ill newborns, to clarify the prognosis. Continuation of treatment is conditional on further diagnostic and prognostic data. Muscle relaxants can sometimes be continued after withdrawal of artificial respiration without aiming to shorten the child's life. When gasping causes suffering, or protracted dying is unbearable for the parents, muscle relaxants may be used to end a newborn's life. Whenever muscle relaxants are used, cases should be reported to the national review committee.CONCLUSIONS: New national recommendations in the Netherlands for end-of-life decisions in newborns suggest that treatment should generally be seen as conditional. If treatment fails, it should be abandoned. In those cases, palliative care should be directed at both infant and parental suffering. Sometimes, this may permit interventions that hasten death. Copyright © 2014 by the American Academy of Pediatrics.


Koster L.J.A.,Zernike Institute for Advanced Materials | Shaheen S.E.,University of Denver | Hummelen J.C.,Zernike Institute for Advanced Materials | Hummelen J.C.,University of Groningen
Advanced Energy Materials | Year: 2012

Three different theoretical approaches are presented to identify pathways to organic solar cells with power conversion effi ciencies in excess of 20%. A radiation limit for organic solar cells is introduced that elucidates the role of charge-transfer (CT) state absorption. Provided this CT action is suffi ciently weak, organic solar cells can be as effi cient as their inorganic counterparts. Next, a model based on Marcus theory of electronic transfer that also considers exciton generation in both the electron donor and electron acceptor is used to show how reduction of the reorganization energies can lead to substantial effi ciency gains. Finally, the dielectric constant is introduced as a central parameter for effi cient solar cells. By using a drift-diffusion model, it is found that effi ciencies of more than 20% are within reach. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Pasmooij A.M.,University of Groningen
Discovery medicine | Year: 2012

Revertant mosaicism (RM) refers to the co-existence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous event. It has been discovered in an increasing number of heritable skin diseases: ichthyosis with confetti and different subtypes of epidermolysis bullosa. This "natural gene therapy" phenomenon manifests as normal appearing skin areas surrounded by affected skin. Although initially thought to be rare, RM is now considered relatively common in genetic skin diseases. To address the issues relevant to RM, we here discuss the following questions: 1) What is the incidence of RM in heritable skin diseases? 2) What are the repair mechanisms in RM? 3) When do the revertant mutations occur? 4) How do you recognize revertant skin? 5) Do the areas of RM change in size? The answers to these questions allow us to acquire knowledge on these reverted cells, the mechanisms of RM, and utility of the reverted cells to the advantage of the patient. The revertant skin could potentially be used to treat the patient's own affected skin.


Tiessen A.H.,University of Groningen
BMC family practice | Year: 2012

Lower social economic status (SES) is related to an elevated cardiovascular (CV) risk. A pro-active primary prevention CV screening approach in general practice (GP) might be effective in a region with a low mean SES. This approach, supported by a regional GP laboratory, was investigated on feasibility, attendance rate and proportion of persons identified with an elevated risk. In a region with a low mean SES, men and women aged ≥ 50/55 years, respectively, were invited for cardiovascular risk profiling, based on SCORE 10-year risk of fatal cardiovascular disease and additional risk factors (family history, weight and end organ damage). Screening was performed by laboratory personnel, at the GP practice. Treatment advice was based on Dutch GP guidelines for cardiovascular risk management. Response rates were compared to those in five other practices, using the same screening method. 521 persons received invitations, 354 (68%) were interested, 33 did not attend and 43 were not further analysed because of already known diabetes/cardiovascular disease. Eventually 278 risk profiles were analysed, of which 60% had a low cardiovascular risk (SCORE-risk <5%). From the 40% participants with a SCORE-risk ≥ 5%, 60% did not receive medication yet for hypertension/hypercholesterolemia. In the other five GPs response rates were comparable to the currently described GP. Screening in GP in a low SES area, performed by a laboratory service, was feasible, resulted in high attendance, and identification and treatment advice of many new persons at risk for cardiovascular disease.


Jansonius N.M.,University of Groningen
Journal of the Optical Society of America A: Optics and Image Science, and Vision | Year: 2010

Wave-front analysis data from the human eye are commonly presented using the aberration coefficient c40 (primary spherical aberration) together with an overall measure of all higher-order aberrations. If groups of subjects are compared, however, the relevance of an observed difference cannot easily be assessed from these summary aberration measures. A method was developed for estimating various optical variables relevant to visual perception from summary wave-front analysis data. These variables were the myopic shift (the difference in the optimal focus between high and low spatial frequencies, a threat to the simultaneous in-focus viewing of fine and coarse patterns), the depth-of-focus (at 8 cpd), and the modulation transfer at high (16 cpd; reading small print) and low (4 cpd; edge detection) spatial frequencies. The depth-of-focus was defined in two ways: using a relative measure (the full width at half-height of the through-focus curve) and an absolute measure (the range where the through-focus curve exceeds a predefined modulation transfer value). The method was shown to be accurate by using previously published contrast sensitivity data and wave-front analysis data. The applicability of the method was illustrated by applying the method to wave-front analysis measurements performed in pseudophakic patients with aspheric and spherical intraocular lenses. © 2010 Optical Society of America.


Objectives: There is no robust proof that the efficacy of lithium in the prevention of manic and depressive episodes in bipolar disorder depends on its plasma level. This analysis aimed to compare the effect of lithium within the presumed therapeutic range of 0.6-1.2mEq/L and below 0.6mEq/L with that of placebo. Methods: We carried out a post hoc analysis of a double-blind trial in which patients aged ≥18years with bipolar I disorder (DSM-IV) who had achieved stabilization from a manic, depressive, or mixed episode during open-label treatment with quetiapine were randomized to continue quetiapine or to switch to lithium or placebo for up to 104weeks. Of patients randomized to lithium, 201 obtained median lithium levels between 0.6 and 1.2mEq/L, and 137 obtained median lithium levels <0.6mEq/L. Their outcomes were compared with those of patients receiving placebo (n=404). The primary outcome was time to recurrence of any mood event; additional outcomes included time to recurrence of a manic or depressive event. Results: Times to recurrence of any mood event as well as a manic or depressive event were significantly longer for the lithium 0.6-1.2mEq/L group versus placebo and versus lithium <0.6mEq/L, with no differences between lithium <0.6mEq/L and placebo. Conclusions: The results support and expand previous findings that lithium should be dosed high enough to achieve plasma levels ≥0.6mEq/L in order to achieve an effect in the prevention of both manic and depressive recurrences of bipolar I disorder. A major limitation is that the composition of the two lithium groups was not based on randomization. © 2012 John Wiley and Sons A/S.


Ozgo M.,Pomeranian University | Schilthuizen M.,Netherlands Center for Biodiversity Naturalis | Schilthuizen M.,University of Groningen
Global Change Biology | Year: 2012

We compared shell colour forms in the land snail Cepaea nemoralis at 16 sites in a 7 × 8 km section of the Province of Groningen, the Netherlands, between 1967 and 2010. To do so, we used stored samples in a natural history collection and resampled the exact collection localities. We found that almost all populations had experienced considerable evolutionary change in various phenotypes, possibly due to population bottlenecks and habitat change after repeated land consolidation schemes in the area. More importantly, we found a consistent increase in yellow effectively unbanded snails at the expense of brown snails. This is one of the expected adaptations to climate change (this area of the Netherlands has warmed by 1.5-2.0 °C over the time period spanned by the two sampling years), and the first clear demonstration of this in C. nemoralis. © 2011 Blackwell Publishing Ltd.


Tangerman A.,University of Groningen
Journal of breath research | Year: 2010

Halitosis can be subdivided into intra-oral and extra-oral halitosis, depending on the place where it originates. Most reports now agree that the most frequent sources of halitosis exist within the oral cavity and include bacterial reservoirs such as the dorsum of the tongue, saliva and periodontal pockets, where anaerobic bacteria degrade sulfur-containing amino acids to produce the foul smelling volatile sulfur compounds (VSCs), especially hydrogen sulfide (H(2)S) and methyl mercaptan (CH(3)SH). Tongue coating is considered to be the most important source of VSCs. Oral malodor can now be treated effectively. Special attention in this overview is given to extra-oral halitosis. Extra-oral halitosis can be subdivided into non-blood-borne halitosis, such as halitosis from the upper respiratory tract including the nose and from the lower respiratory tract, and blood-borne halitosis. The majority of patients with extra-oral halitosis have blood-borne halitosis. Blood-borne halitosis is also frequently caused by odorous VSCs, in particular dimethyl sulfide (CH3SCH3). Extra-oral halitosis, covering about 5-10% of all cases of halitosis, might be a manifestation of a serious disease for which treatment is much more complicated than for intra-oral halitosis. It is therefore of utmost importance to differentiate between intra-oral and extra-oral halitosis. Differences between intra-oral and extra-oral halitosis are discussed extensively. The importance of applying odor characterization of various odorants in halitosis research is also highlighted in this article. The use of the odor index, odor threshold values and simulation of bad breath samples is explained.


Lewis-Evans B.,University of Groningen
Journal of Safety Research | Year: 2010

Introduction: The New Zealand Graduated Driver Licensing System (GDLS) is designed to allow novice drivers to gain driving experience under conditions of reduced risk. Method: To examine the effectiveness of the GDLS, an analysis of how the crash involvement of novice drivers changes as drivers move through the GDLS was undertaken. Crash profiles were created by data matching the New Zealand license and crash databases, covering a time period from 1999-2006. Results: The crash profiles show that the initial learner period of the GDLS is relatively safe and the time at which novice drivers have the highest rate of crash involvement is during the first few months of solo driving. Analysis using logistic regression also showed an effect of age and gender, with higher crash involvement associated with younger drivers and males. In addition, individuals who gained a full license within 12-18 months of holding a restricted license, due to completion of a time-discount associated educational program, had a higher level of involvement in crashes than individuals who gained a full license after 18 months. Conclusions: The crash profiles provide an insight into the crash risk associated with different phases of the New Zealand GDLS. Impact on Industry: Increasing the age at which drivers first begin to solo drive and the removal of the time-discount associated with completion of an educational program should be considered. © 2010 Elsevier Ltd.


van Rijn H.,University of Groningen
Current Opinion in Behavioral Sciences | Year: 2016

Interval timing tasks can only be performed efficiently when the output of a clock system can be stored over a longer period of time, and be retrieved and reused during later trials. Although the importance of temporal reference memory for accurate timing has been acknowledged since the earliest theoretical work on interval timing, formal accounts of the role of memory in interval timing are fairly recent. An short overview is given of the first formal models in which memory effects were accounted for, followed by a review of the current theoretical approaches, which can be categorized on the basis of whether they assume a dynamic or static memory system. © 2016 Elsevier Ltd.


Polyuga R.V.,ABM AMRO N.V. Bank | Van Der Schaft A.,University of Groningen
IEEE Transactions on Automatic Control | Year: 2011

Structure preserving model reduction of single-input single-output port-Hamiltonian systems is considered by employing the rational Krylov methods. The rational Arnoldi method is shown to preserve (for the reduced order model) not only a specific number of the moments at an arbitrary point in the complex plane but also the port-Hamiltonian structure. Furthermore, it is shown how the rational Lanczos method applied to a subclass of port-Hamiltonian systems, characterized by an algebraic condition, preserves the port-Hamiltonian structure. In fact, for the same subclass of port-Hamiltonian systems the rational Arnoldi method and the rational Lanczos method turn out to be equivalent in the sense of producing reduced order port-Hamiltonian models with the same transfer function. © 2006 IEEE.


Wilhelm M.M.,University of Groningen
Journal of Operations Management | Year: 2011

A growing research stream has expanded the level of analysis beyond single buyer-supplier relations to the network, including supplier-supplier relations. These supplier-supplier relations may constitute a missing link between the traditional analysis of the dyadic and the network level of analysis that are often treated separately. This paper explores the interplay of the supplier-supplier and network of analysis by focusing on the inherent tension between cooperation and competition, using a multiple case study design in the Japanese and German automobile industries. It is argued that the buyer is able to exert influence not only on the coopetition level, so within "horizontal supply chain relations," but that the coopetitive tension in the overall network can in fact be managed through the active establishment and maintenance of such relations. © 2011 Elsevier B.V. All rights reserved.


Trentelman H.L.,University of Groningen
Systems and Control Letters | Year: 2011

In passivity preserving and bounded realness preserving model reduction by balanced truncation, an important role is played by the so-called positive real (PR) and bounded real (BR) characteristic values. Both for the positive real as well as the bounded real case, these values are defined in terms of the extremal solutions of the algebraic Riccati associated with the system, more precisely as the square roots of the eigenvalues of the product matrix obtained by multiplying the smallest solution with the inverse of the largest solution of the Riccati equation. In this paper we will establish a representation free characterization of these values in terms of the behavior of the system. We will consider positive realness and bounded realness as special cases of half line dissipativity of the behavior. We will then show that both for the PR and the BR case, the characteristic values coincide with the singular values of the linear operator that assigns to each past trajectory in the inputoutput behavior its unique maximal supply extracting future continuation. We will explain that the term 'singular values' should be interpreted here in a generalized sense, since in our setup the future behavior is only an indefinite inner product space. © 2010 Elsevier B.V. All rights reserved.


Both C.,Netherlands Institute of Ecology | Both C.,University of Groningen
Current Biology | Year: 2010

During the past decades, phenology of many organisms has advanced in response to climate change [1]. Earlier arrival of long-distance migrants has been reported frequently [2, 3], but advancements of arrival and breeding were not always sufficient to match phenology at other trophic levels [4]. This has led to increased selection for early breeding [5] and severe population declines [6, 7]. This inadequate response has been explained by an inflexible start of migration, governed by cues unrelated to climate change, such as photoperiod [8]. It has been suggested that evolution at the genetic level is required for a change in photoresponsiveness [9]. Recently, such an evolutionary change in migration timing was suggested [10]. Here I show that timing of spring migration of pied flycatchers (Ficedula hypoleuca) has responded flexibly to climate change. Recovery dates during spring migration in Northern Africa advanced by ten days between 1980 and 2002, which was explained by improving Sahel rainfall and a phenotypic effect of birth date. The lack of advance on the breeding grounds most likely was due to environmental constraints during migration. Adjustment of arrival date in migrants to climate change could thus be rapid, but only if circumstances favorably change for the whole journey. © 2010 Elsevier Ltd. All rights reserved.


Verhoeff B.,University of Groningen
Studies in History and Philosophy of Science Part C :Studies in History and Philosophy of Biological and Biomedical Sciences | Year: 2014

Using the conceptual tools of philosopher of science Ludwik Fleck, I argue that the reframing of autism as a neurodevelopmental spectrum disorder is constrained by two governing 'styles of thought' of contemporary psychiatry. The first is the historically conditioned 'readiness for directed perception' of, and thinking in terms of, ontologically distinct diseases. The clinical gaze of mental health professionals, the bureaucratic needs of health administration, the clinical and scientific utility of disease categories, and the practices of autism-oriented advocacy groups all imply a bias toward thinking about autism and related disorders as ontologically distinct psychiatric and scientific entities. Second, within the 'neuromolecular style of thought', mental disorders are more and more located at the neurobiological levels of the brain. In autism research, one of the biggest challenges is the identification of autism's neurobiological singularity. However, at a moment when biological and categorical approaches toward autism face serious empirical difficulties, a balance is established that holds together these two styles of thought. With a need to account for some of the most persistent uncertainties and conflicts in autism research, namely ubiquitous heterogeneity and a failure to identify disease specific biomarkers, the reframing of autism as a neurodevelopmental spectrum disorder satisfies the scientific, institutional and socio-political needs for stability and homogenization. © 2014 Elsevier Ltd.


Siissalo S.,University of Groningen | Heikkinen A.T.,Hoffmann-La Roche
Current Drug Metabolism | Year: 2013

This review provides an overview of the in vitro methods currently used in studies of intestinal drug metabolism and active efflux with a special emphasis on the efflux-metabolism interplay. These methods include e.g. expressed enzymes or efflux transporters, fractionated intestinal cells, cell lines, primary cells, intestinal segments and other tissue preparations. Pharmacokinetics of effluxmetabolism interplay is often very complicated, possibly involving saturation, stimulation and/or inhibition of one or both of these mechanisms. Parent drug and/or metabolite(s) can be substrates for several enzymes and/or efflux proteins. These detoxifying proteins may alter the exposure of drugs to each other and, consequently, their contributions to the overall drug elimination. Depending on the complexity of the in vitro system used, different kinds of information can be extracted from the results. Simple methods concentrating on single mechanisms provide easily interpretable information, but neglect the interplay between various mechanisms influencing the kinetics in a whole organism. More complex experimental systems mimic the mechanistic complexity of in vivo setting better, but at the same time the interpretation and utilization of the results becomes more challenging. Advantages and limitations of various in vitro systems are addressed and consideration is given to the physiological relevance of the results obtained and there is discussion of approaches for in vitro - in vivo translation of the data. © 2013 Bentham Science Publishers.


Rokstad A.M.A.,Norwegian University of Science and Technology | Lacik I.,Slovak Academy of Sciences | de Vos P.,University of Groningen | Strand B.L.,Norwegian University of Science and Technology
Advanced Drug Delivery Reviews | Year: 2014

Cell encapsulation has already shown its high potential and holds the promise for future cell therapies to enter the clinics as a large scale treatment option for various types of diseases. The advancement in cell biology towards this goal has to be complemented with functional biomaterials suitable for cell encapsulation. This cannot be achieved without understanding the close correlation between cell performance and properties of microspheres. The ongoing challenges in the field of cell encapsulation require a critical view on techniques and approaches currently utilized to characterize microspheres. This review deals with both principal subjects of microspheres characterization in the cell encapsulation field: physico-chemical characterization and biocompatibility. The up-to-day knowledge is summarized and discussed with the focus to identify missing knowledge and uncertainties, and to propose the mandatory next steps in characterization of microspheres for cell encapsulation. The primary conclusion of this review is that further success in development of microspheres for cell therapies cannot be accomplished without careful selection of characterization techniques, which are employed in conjunction with biological tests. © 2013 Elsevier B.V.


Cao M.,University of Groningen | Morse A.S.,Yale University
Systems and Control Letters | Year: 2010

Dwell-time switching is a logic for orchestrating the switching between controllers in a family of candidate controllers in order to control a process with a highly uncertain model. An analysis is given of dwell-time switching which is appropriate to a variety of control problems in which the class of candidate controllers is either a finite set or a continuum of linear controllers. An example is given to illustrate the use of the paper's main technical result. © 2009 Elsevier B.V. All rights reserved.


Novaes C.D.,University of Groningen
Behavioral and Brain Sciences | Year: 2011

Elqayam & Evans' (E&E's) critique of normativism is related to an inherently philosophical question: Is thinking a normative affair? Should thinking be held accountable towards certain norms? I present the historical and philosophical origins of the view that thinking belongs to the realm of normativity and has a tight connection with logic, stressing the pivotal role of Kant in these developments. © 2011 Cambridge University Press.


Meijer M.F.,University of Groningen
Clinical orthopaedics and related research | Year: 2014

Computer-assisted surgery (CAS) has been developed to enhance prosthetic alignment during primary TKAs. Imageless CAS improves coronal and sagittal alignment compared with conventional TKA. However, the effect of imageless CAS on rotational alignment remains unclear. We conducted a systematic and qualitative review of the current literature regarding the effectiveness of imageless CAS during TKA on (1) rotational alignment of the femoral and tibial components and tibiofemoral mismatch in terms of deviation from neutral rotation, and (2) the number of femoral and tibial rotational outliers. Data sources included PubMed, MEDLINE, and EMBASE. Study selection, data extraction, and methodologic quality assessment were conducted independently by two reviewers. Standardized mean difference with 95% CI was calculated for continuous variables (rotational alignment of the femoral or tibial component and tibiofemoral mismatch). To compare the number of outliers for femoral and tibial component rotation, the odds ratio and 95% CI were calculated. The literature search produced 657 potentially relevant studies, 17 of which met the inclusion criteria. One study was considered as having high methodologic quality, 15 studies had medium, and one study had low quality. Conflicting evidence was found for all outcome measures except for tibiofemoral mismatch. Moderate evidence was found that imageless CAS had no influence on postoperative tibiofemoral mismatch. The measurement protocol for measuring tibial rotation varied among the studies and in only one of the studies was the sample size calculation based on one of the outcome measures used in our systematic review. More studies of high methodologic quality and with a sample size calculation based on the outcome measures will be helpful to assess whether an imageless CAS TKA improves femoral and tibial rotational alignment and tibiofemoral mismatch or decreases the number of femoral and tibial rotational outliers. To statistically analyze the results of different studies, the same measurement protocol should be used among the studies.


Subramanian H.H.,University of Leeds | Holstege G.,University of Groningen
Journal of Neurophysiology | Year: 2011

Studies on brain stem respiratory neurons suggest that eupnea consists of three phases: inspiration, postinspiration, and expiration. However, it is not well understood how postinspiration is organized in the diaphragm, i.e., whether postinspiration differs in the crural and costal segments of the diaphragm and what the influence is of postinspiratory neurons on diaphragm function during eupnea. In this in vivo study we investigated the postinspiratory activity of the two diaphragm segments during eupnea and the changes in diaphragm function following modulation of eupnea. Postinspiratory neurons in the medulla were stereotaxically localized extracellularly and neurochemically stimulated. We used three types of preparations: precollicularly decerebrated unanesthetized cats and rats and anesthetized rats. In all preparations, during eupnea, postinspiratory activity was found in the crural but not in the costal diaphragm. When eupnea was discontinued in decerebrate cats in which stimulation in the nucleus retroambiguus induced activation of laryngeal or abdominal muscles, all postinspiratory activity in the crural diaphragm was abolished. In decerebrate rats, stimulation of the midbrain periaqueductal gray abolished postinspiration in the crural diaphragm but induced activation in the costal diaphragm. In anesthetized rats, stimulation of medullary postinspiratory neurons abolished the postinspiratory activity of the crural diaphragm. Vagal nerve stimulation in these rats increased the intensity of postinspiratory neuronal discharge in the solitary nucleus, leading to decreased activity of the crural diaphragm. These data demonstrate that three-phase breathing in the crural diaphragm during eupnea exists in vivo and that postinspiratory neurons have an inhibitory effect on crural diaphragm function. © 2011 the American Physiological Society.


Bergshoeffa E.A.,University of Groningen | Riccionib F.,Kings College London
Journal of High Energy Physics | Year: 2011

We construct for arbitrary dimensions a universal T-duality covariant expression for the Wess-Zumino terms of supersymmetric String Solitons in toroidally compactified string theories with 32 supercharges. The worldvolume fields occurring in the effective action of these String Solitons form either a vector or a tensor multiplet with 16 supercharges. We determine the dimensions of the conjugacy classes under T-duality to which these String Solitons belong. We do this in two steps. First, we determine the T-duality representations of the p-forms of maximal supergravities that contain the potentials that couple to these String Solitons. We find that these are p-forms, with D - 4 ≤ p ≤ 6 if D ≥ 6 and with D - 4 ≤ p ≤ D if D < 6, transforming in the antisymmetric representation of rank m = p + 4 - D ≤ 4 of the T-duality symmetry SO(10 - D, 10 - D). All branes support vector multiplets except when m = 10 - D. In that case the T-duality representation splits, for D < 10, into a selfdual and anti-selfdual part, corresponding to 5- branes supporting either a vector or a tensor multiplet. In a second step we show that only certain well-defined lightlike directions in the anti-symmetric tensor representations of the T-duality group correspond to supersymmetric String Solitons. These lightlike directions define the conjugacy classes. As a by-product we show how by a straightforward procedure all solitonic fields of maximal supergravity are derived using the Kac-Moody algebra E11. © SISSA 2011.


Boer D.,University of Groningen | Den Dunnen W.J.,University of Tubingen | Pisano C.,University of Cagliari | Schlegel M.,University of Tubingen
Physical Review Letters | Year: 2013

We calculate the diphoton distribution in the decay of arbitrary spin-0 and spin-2 bosons produced from gluon fusion, taking into account the fact that gluons inside an unpolarized proton are generally linearly polarized. The gluon polarization brings about a difference in the transverse momentum distribution of positive and negative parity states. At the same time, it causes the azimuthal distribution of the photon pair to be nonisotropic for several spin-2 coupling hypotheses, allowing one to distinguish these from the isotropic scalar and pseudoscalar distributions. © 2013 American Physical Society.


Brenninkmeijer J.,University of Groningen
BioSocieties | Year: 2013

Many psychologists and other practitioners have started to use neurofeedback, a biofeedback system that is designed to help people adapt to their brain waves, usually either as a treatment for disorders like ADHD, depression, or as a form of enhancement to achieve 'peak performance'. Although scientific approval of this therapy is lacking, commercial neurofeedback clinics are proliferating across Europe and the United States. In this article, ethnographic material gathered through interviews with practitioners and clients and observations during neurofeedback sessions provides the groundwork for a theoretical analysis of neurofeedback. This account demonstrates that although at first glance neurofeedback appears as a straightforward engagement between the two agents - practitioner and client - and a computer, it is in fact a complex entanglement of collaborating and competing actors. Human and non-human actors together perform a process in which it is unclear which actor is directing the 'treatment'. While it remains unclear if and how the client is cured, restored or enhanced, this article demonstrates that through the process of neurofeedback, a new kind of self - one that is extended with all kind of entities that have emerged during the process - has clearly been brought into being. © 2013 Macmillan Publishers Ltd.


Ongoing growth in health care expenditures and changing patterns in the demand for health care challenge societies worldwide. The Chronic Care Model (CCM), combined with classification for care needs based on Kaiser Permanente (KP) Triangle, may offer a suitable framework for change. The aim of the present study is to investigate the effectiveness of Embrace, a population-based model for integrated elderly care, regarding patient outcomes, service use, costs, and quality of care. The CCM and the KP Triangle were translated to the Dutch setting and adapted to the full elderly population living in the community. A randomized controlled trial with balanced allocation was designed to test the effectiveness of Embrace. Eligible elderly persons are 75 years and older and enrolled with one of the participating general practitioner practices. Based on scores on the INTERMED-Elderly Self-Assessment and Groningen Frailty Indicator, participants will be stratified into one of three strata: (A) robust; (B) frail; and (C) complex care needs. Next, participants will be randomized per stratum to Embrace or care as usual. Embrace encompasses an Elderly Care Team per general practitioner practice, an Electronic Elderly Record System, decision support instruments, and a self-management support and prevention program - combined with care and support intensity levels increasing from stratum A to stratum C. Primary outcome variables are patient outcomes, service use, costs, and quality of care. Data will be collected at baseline, twelve months after starting date, and during the intervention period. This study could provide evidence for the effectiveness of Embrace. The Netherlands National Trial Register NTR3039.


Heinemann M.,ETH Zurich | Heinemann M.,University of Groningen | Zenobi R.,ETH Zurich
Current Opinion in Biotechnology | Year: 2011

Recent discoveries suggest that cells of a clonal population often display multiple metabolic phenotypes at the same time. Motivated by the success of mass spectrometry (MS) in the investigation of population-level metabolomics, the analytical community has initiated efforts towards MS-based single cell metabolomics to investigate metabolic phenomena that are buried under the population average. Here, we review the current approaches and illustrate their advantages and disadvantages. Because of significant advances in the field, different technologies are now at the verge of generating data that are useful for exploring and investigating metabolic heterogeneity. © 2010 Elsevier Ltd.


Roest A.M.,University of Tilburg | Martens E.J.,University of Tilburg | de Jonge P.,University of Tilburg | de Jonge P.,University of Groningen | Denollet J.,University of Tilburg
Journal of the American College of Cardiology | Year: 2010

Objectives: The purpose of this study was to assess the association between anxiety and risk of coronary heart disease (CHD). Background: Less research has focused on the association of anxiety with incident CHD in contrast to other negative emotions, such as depression. Methods: A meta-analysis of references derived from PubMed, EMBASE, and PsycINFO (1980 to May 2009) was performed without language restrictions. End points were cardiac death, myocardial infarction (MI), and cardiac events. The authors selected prospective studies of (nonpsychiatric) cohorts of initially healthy persons in which anxiety was assessed at baseline. Results: Twenty studies reporting on incident CHD comprised 249,846 persons with a mean follow-up period of 11.2 years. Anxious persons were at risk of CHD (hazard ratio [HR] random: 1.26; 95% confidence interval [CI]: 1.15 to 1.38; p < 0.0001) and cardiac death (HR: 1.48; 95% CI: 1.14 to 1.92; p = 0.003), independent of demographic variables, biological risk factors, and health behaviors. There was a nonsignificant trend for an association between anxiety and nonfatal MI (HR: 1.43; 95% CI: 0.85 to 2.40; p = 0.180). Subgroup analyses did not show any significant differences regarding study characteristics, with significant associations for different types of anxiety, short- and long-term follow-up, and both men and women. Conclusions: Anxiety seemed to be an independent risk factor for incident CHD and cardiac mortality. Future research should examine the association between anxiety and CHD with valid and reliable anxiety measures and focus on the mechanisms through which anxiety might affect CHD. © 2010 American College of Cardiology Foundation.


Voss T.,TU Eindhoven | Scherpen J.M.A.,University of Groningen
Automatica | Year: 2011

In this paper we show how to perform stabilization and shape control for a finite dimensional model that recasts the dynamics of an inflatable space reflector in port-Hamiltonian (pH) form. We show how to derive a decentralized passivity-based controller which can be used to stabilize a 1D piezoelectric Timoshenko beam around a desired shape. Furthermore, we present simulation results obtained for the proposed decentralized control approach. © 2011 Elsevier Ltd. All rights reserved.


Bu S.-C.,University of Groningen
Retina | Year: 2014

BACKGROUND:: Idiopathic epiretinal membrane (iERM) is a fibrocellular membrane that proliferates on the inner surface of the retina at the macular area. Membrane contraction is an important sight-threatening event and is due to fibrotic remodeling.METHODS:: Analysis of the current literature regarding the epidemiology, clinical features, and pathogenesis of iERM and fibrotic tissue contraction.RESULTS:: Epidemiologic studies report a relationship between iERM prevalence, increasing age, and posterior vitreous detachment. Clinically, iERM progresses through different stages characterized by an increased thickness and wrinkling of the membrane. Pathophysiologically, iERM formation is a fibrotic process in which myofibroblast formation and the deposition of newly formed collagens play key roles. Anomalous posterior vitreous detachment may be a key event initiating the formation of iERM. The age-related accumulation of advanced glycation end products may contribute to anomalous posterior vitreous detachment formation and may also influence the mechanical properties of the iERM.CONCLUSION:: Remodeling of the extracellular matrix at the vitreoretinal interface by aging and fibrotic changes, plays a significant role in the pathogenesis of iERM. A better understanding of molecular mechanisms underlying this process may eventually lead to the development of effective and nonsurgical approaches to treat and prevent vitreoretinal fibrotic diseases. © 2014 by Ophthalmic Communications Society, Inc.


de Laat P.B.,University of Groningen
Ethics and Information Technology | Year: 2010

Open-source communities that focus on content rely squarely on the contributions of invisible strangers in cyberspace. How do such communities handle the problem of trusting that strangers have good intentions and adequate competence? This question is explored in relation to communities in which such trust is a vital issue: peer production of software (FreeBSD and Mozilla in particular) and encyclopaedia entries (Wikipedia in particular). In the context of open-source software, it is argued that trust was inferred from an underlying 'hacker ethic', which already existed. The Wikipedian project, by contrast, had to create an appropriate ethic along the way. In the interim, the assumption simply had to be that potential contributors were trustworthy; they were granted 'substantial trust'. Subsequently, projects from both communities introduced rules and regulations which partly substituted for the need to perceive contributors as trustworthy. They faced a design choice in the continuum between a high-discretion design (granting a large amount of trust to contributors) and a low-discretion design (leaving only a small amount of trust to contributors). It is found that open-source designs for software and encyclopaedias are likely to converge in the future towards a mid-level of discretion. In such a design the anonymous user is no longer invested with unquestioning trust. © 2010 The Author(s).


Gamerdinger M.,Johannes Gutenberg University Mainz | Carra S.,University of Groningen | Behl C.,Johannes Gutenberg University Mainz
Journal of Molecular Medicine | Year: 2011

Macroautophagy is a catabolic process by which the cell degrades cytoplasmic components through the lysosomal machinery. While initially acknowledged as a rather unspecific bulk degradation process, growing lines of evidence indicate the selectivity of macroautophagy pathways in the removal of misfolded or aggregated proteins. How such substrates are recognized and specifically targeted to the macroautophagy machinery has become a hotspot of investigation, and recent evidence suggests that here molecular chaperones and co-chaperones play a central role. One emerging pathway is mediated by the co-chaperone protein Bcl-2-associated athanogene 3 (BAG 3) which seems to utilize the specificity of molecular chaperones (heat-shock proteins) towards non-native proteins as basis for targeted macroautophagic degradation. In this short review, we focus on the molecular interplay between the macroautophagy system and molecular chaperones and highlight the relevance of the pathway mediated by BAG3 to aging and age-associated protein-misfolding diseases. © 2011 Springer-Verlag.


Koning R.H.,University of Groningen
Journal of Sports Sciences | Year: 2011

Home advantage is a pervasive phenomenon in sport. It has been established in team sports such as basketball, baseball, American football, and European soccer. Attention to home advantage in individual sports has so far been limited. The aim of this study was to examine home advantage in professional tennis. Match-level data are used to measure home advantage. The test used is based on logit models, and consistent specification is addressed explicitly. Depending on the interpretation of home advantage, restrictions on the specification of the model need to be imposed. We find that although significant home advantage exists for men, the performance of women tennis players appears to be unaffected by home advantage. © 2011 Taylor & Francis.


van Imhoff D.E.,University of Groningen
Archives of disease in childhood. Fetal and neonatal edition | Year: 2013

To evaluate phototherapy practices by measuring the irradiance levels of phototherapy (PT) devices. Prospective study. Tertiary neonatal intensive care units. None. Irradiance levels of PT devices used in the 10 Dutch Neonatal Intensive Care Units (NICUs) were measured according to the local PT practice patterns. The irradiance levels of all overhead and fibre-optic PT devices were measured with a radiometer using an infant silhouette model. Eight different PT devices were used in the 10 NICUs; five were overhead devices and three fibre-optic pads. The median (range) irradiance level for overhead PT devices was 9.7 (4.3-32.6) μW/cm(2)/nm and for fibre-optic pads 6.8 (0.8-15.6) μW/cm(2)/nm. Approximately 50% of PT devices failed to meet the minimal recommended irradiance level of 10 μW/cm(2)/nm. Maximal irradiance levels for overhead PT spot lights were inversely related to the distance between device and infant model (R2=0.33). The distances ranged from 37 cm to 65 cm. PT devices in the Dutch NICUs show considerable variability with often too low irradiance levels. These results indicate that suboptimal PT is frequently applied and may even be ineffective towards reducing total serum bilirubin levels. These results underline the need for greater awareness among all healthcare workers towards the requirements for effective PT including measurements of irradiance and distance.


Pieper P.G.,University of Groningen
Netherlands Heart Journal | Year: 2011

Pregnant women with heart disease often have an increased risk of maternal cardiovascular and offspring complications. The magnitude of these risks varies depending on the type and severity of the underlying disease. Therefore risk assessment should be performed before pregnancy. This can be accomplished by taking into account predictors and risk scores that have been developed in large populations of pregnant women with heart disease, as well as by consulting disease-specific pregnancy literature. A system that integrates all available knowledge about the risk of pregnancy is the adapted World Health Organisation risk classification. The safety of pregnancy for women with heart disease can be enhanced by adequate risk assessment and counselling. © The Author(s) 2011.


Brookhuis K.A.,University of Groningen
Transportation Research Part F: Traffic Psychology and Behaviour | Year: 2014

After the definite breakthrough of the awakening to the negative effects of alcohol on traffic safety, some 50 years ago in the sixties of the past century (see Borkenstein et al.; 1974), authorities began to worry about drugs, initially medicinal drugs. After World War II, the prescription and administration of medicinal drugs expanded enormously. Pharmaceutical research was booming, for instance leading to the extremely successful introduction of Benzodiazepines, a group of depressing drugs administered for various symptoms. Laboratory studies gave strong indications that at least some medicinal drugs were likely to affect traffic safety. However, contrary to alcohol, no unambiguous effect with respect to traffic safety could be assessed easily by standard methodology, i.e. epidemiological research. Thereupon a new line of experimental research was developed, in the field itself, by means of instrumented vehicles. People were administered medicinal drugs, and placebo in double-blind within-subjects cross-over designs, driving on closed circuits or in some countries even out on the public road under strict surveillance. Several performance measures were registered, of which "swerving" or "weaving", i.e. the control over lateral position as measured by the standard deviation of lateral position (SDLP) came forth as the most promising. To date SDLP proved itself as the most valid and reliable indicator of performance deterioration, and is at the basis of recently developed categorization systems of (medicinal) drugs. © 2013 Elsevier Ltd. All rights reserved.


Roenneberg T.,Ludwig Maximilians University of Munich | Allebrandt K.V.,Ludwig Maximilians University of Munich | Merrow M.,University of Groningen | Vetter C.,Ludwig Maximilians University of Munich
Current Biology | Year: 2012

Obesity has reached crisis proportions in industrialized societies [1]. Many factors converge to yield increased body mass index (BMI). Among these is sleep duration [2-10]. The circadian clock controls sleep timing through the process of entrainment. Chronotype describes individual differences in sleep timing, and it is determined by genetic background, age, sex, and environment (e.g., light exposure) [11-14]. Social jetlag quantifies the discrepancy that often arises between circadian and social clocks, which results in chronic sleep loss [11, 15]. The circadian clock also regulates energy homeostasis [16], and its disruption - as with social jetlag - may contribute to weight-related pathologies [17-19]. Here, we report the results from a large-scale epidemiological study, showing that, beyond sleep duration, social jetlag is associated with increased BMI. Our results demonstrate that living "against the clock" may be a factor contributing to the epidemic of obesity. This is of key importance in pending discussions on the implementation of Daylight Saving Time and on work or school times, which all contribute to the amount of social jetlag accrued by an individual. Our data suggest that improving the correspondence between biological and social clocks will contribute to the management of obesity. Video Abstract: © 2012 Elsevier Ltd.


Rosindell J.,University of Leeds | Cornell S.J.,University of Leeds | Hubbell S.P.,University of California at Los Angeles | Etienne R.S.,University of Groningen
Ecology Letters | Year: 2010

Understanding the maintenance and origin of biodiversity is a formidable task, yet many ubiquitous ecological patterns are predicted by a surprisingly simple and widely studied neutral model that ignores functional differences between species. However, this model assumes that new species arise instantaneously as singletons and consequently makes unrealistic predictions about species lifetimes, speciation rates and number of rare species. Here, we resolve these anomalies - without compromising any of the original model's existing achievements and retaining computational and analytical tractability - by modelling speciation as a gradual, protracted, process rather than an instantaneous event. Our model also makes new predictions about the diversity of 'incipient' species and rare species in the metacommunity. We show that it is both necessary and straightforward to incorporate protracted speciation in future studies of neutral models, and argue that non-neutral models should also model speciation as a gradual process rather than an instantaneous one. © 2010 Blackwell Publishing Ltd/CNRS.


Schutte E.,University of Groningen
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2016

OBJECTIVE—: Skin autofluorescence (SAF), a measure of advanced glycation end product accumulation, is associated with kidney function. We investigated the association of SAF with rate of kidney function decline in a cohort of patients with peripheral artery disease. APPROACH AND RESULTS—: We performed a post hoc analysis of an observational longitudinal cohort study. We included 471 patients with peripheral artery disease, and SAF was measured at baseline. Primary end point was rate of estimated glomerular filtration rate (eGFR) decline. Secondary end points were incidence of eGFR <60 and <45 mL/min/1.73 m and rapid eGFR decline, defined as a decrease in eGFR of >5 mL/min/1.73 m/y. During a median follow-up of 3 years, the mean change in eGFR per year was −1.8±4.4 mL/min/1.73 m/y. No significant difference in rate of eGFR decline was observed per 1 arbitrary unit increase in SAF (−0.1 mL/min/1.73 m/y; 95% confidence interval, −0.7 to 0.5; P=0.8). Analyses of the secondary end points showed that there was an association of SAF with incidence of eGFR <60 and <45 mL/min/1.73 m (hazard ratio, 1.54; 95% confidence interval, 1.13–2.10; P=0.006 and hazard ratio, 1.76; 95% confidence interval, 1.20–2.59; P=0.004, respectively), but after adjustment for age and sex, significance was lost. There was no association of SAF with rapid eGFR decline. CONCLUSIONS—: In conclusion, in this cohort of patients with peripheral artery disease, elevated SAF was associated with lower baseline eGFR. Although SAF has previously been established as a predictor for cardiovascular disease and mortality, it did not predict the rate of kidney function decline during follow-up in this study. © 2016 American Heart Association, Inc.


Walton K.E.,St. Johns University | Ormel J.,University of Groningen | Krueger R.F.,University of Minnesota
Journal of Abnormal Child Psychology | Year: 2011

Researchers have recognized the importance of developing an accurate classification system for externalizing disorders, though much of this work has been framed by a priori preferences for categorical vs. dimensional constructs. Newer statistical technologies now allow categorical and dimensional models of psychopathology to be compared empirically. In this study, we directly compared the fit of categorical and dimensional models of externalizing behaviors in a large and representative community sample of adolescents at two time points separated by nearly 2.5 years (N=2027; mean age at Time 1=11.09 years; 50.8% female). Delinquent and aggressive behaviors were assessed with child and parent Child Behavior Checklist reports. Latent trait, latent class, and factor mixture models were fit to the data, and at both time points, the latent trait model provided the best fit to the data. The item parameters were inspected and interpreted, and it was determined that the items were differentially sensitive across all regions of the dimension. We conclude that classification models can be based on empirical evidence rather than a priori preferences, and while current classification systems conceptualize externalizing problems in terms of discrete groups, they can be better conceptualized as dimensions. © 2010 Springer Science+Business Media, LLC.


Eduard Verhagen A.A.,University of Groningen
Journal of Medical Ethics | Year: 2013

In The Netherlands, neonatal euthanasia has become a legal option and the Groningen Protocol contains an approach to identify situations in which neonatal euthanasia might be appropriate. In the 5 years following the publication of the protocol, neither the prediction that this would be the first step on a slippery slope, nor the prediction of complete transparency and legal control became true. Instead, we experienced a transformation of the healthcare system after antenatal screening policy became a part of antenatal care. This resulted in increased terminations of pregnancy and less euthanasia.


Kallenberg C.G.M.,University of Groningen
Clinical and Experimental Rheumatology | Year: 2015

Recent studies have increased our insight into the pathogenesis of ANCA-associated vasculitis (AAV). Although many data from in vitro and in vivo experimental studies support the pathogenic role of the autoantibodies, cellular immunity seems involved as well. Besides, an amplification loop via the alternative pathway of complement is apparent. These new insights make a more targeted therapeutic approach possible. In particular, the B-cell depleting antibody rituximab has been shown non-inferior to cyclophosphamide for induction of remission, and even superior in patients with relapsing disease being positive for PR3-ANCA. Rituximab is also superior to cyclophosphamide for maintaining remission. Blocking the C5a-receptor seems promising as well as an alternative for high dose corticosteroids during induction of remission. © Clinical and Experimental Rheumatology 2015.


Serrano M.,University of Barcelona | Dietzenbacher E.,University of Groningen
Ecological Economics | Year: 2010

This paper compares two concepts to evaluate the international responsibility of a country with respect to its emissions. Using a multi-regional input-output model, we show that the trade emission balance and the responsibility emission balance yield the same result. In practical work, however, a lack of data availability implies that the same technology assumption has been commonly adopted. In that case, also a third alternative exists, which simply evaluates the emissions embodied in the trade balance of the country. This third alternative yields the same results as the other two approaches at the aggregate level. At the level of individual products, however, the results are clearly different and it turns out that the third alternative answers a different question. That is, it is appropriate for measuring the emission content of the products that cross the border. In our empirical application, we consider Spain in 1995 and 2000, distinguishing nine different gases: CO2, CH4, N2O, SF6, HFCs, PFCs, SO2, NOx, and NH3. © 2010 Elsevier B.V.


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

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


OBJECTIVE:: The aim of the present study was to describe different presentations, diagnostic tools, and available treatments for melanoma metastasized to the intestines. BACKGROUND:: The intestine is a frequent site of metastases in melanoma patients. In the current era, with long-term survival after systemic treatment, there is a need for a timely diagnosis and optimal treatment of intestinal metastases. METHODS:: Patients diagnosed between 2011 and 2015 with intestinal metastases of melanoma were included. Diagnostic procedures, treatment strategies, and their outcome were analyzed for all patients. RESULTS:: A total of 22 patients were included. Twenty patients received systemic therapy for widely disseminated disease. Fourteen of these twenty patients received local treatment for symptomatic intestinal metastases. Median overall survival after detection of intestinal metastasis in patients receiving systemic treatment was 22 months. On the basis of this cohort, a treatment algorithm for treatment of patients with symptomatic intestinal melanoma metastases was constructed. CONCLUSIONS:: The treatment of intestinal melanoma metastases has changed due to the introduction of novel systemic treatments that can result in long-term survival of patients with widely metastatic melanoma. Surgeons and other clinicians should be aware of these changes in clinical practice as well as the diverse presentation of intestinal melanoma metastases and the diagnostic and therapeutic dilemmas involved. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Molleman L.,University of Groningen
Proceedings. Biological sciences / The Royal Society | Year: 2013

There is ample evidence that human cooperative behaviour towards other individuals is often conditioned on information about previous interactions. This information derives both from personal experience (direct reciprocity) and from experience of others (i.e. reputation; indirect reciprocity). Direct and indirect reciprocity have been studied separately, but humans often have access to both types of information. Here, we experimentally investigate information use in a repeated helping game. When acting as donor, subjects can condition their decisions to help recipients with both types of information at a small cost to access such information. We find that information from direct interactions weighs more heavily in decisions to help, and participants tend to react less forgivingly to negative personal experience than to negative reputation. Moreover, effects of personal experience and reputation interact in decisions to help. If a recipient's reputation is positive, the personal experience of the donor has a weak effect on the decision to help, and vice versa. Yet if the two types of information indicate conflicting signatures of helpfulness, most decisions to help follow personal experience. To understand the roles of direct and indirect reciprocity in human cooperation, they should be studied in concert, not in isolation.


Bile acids (BAs) are essential for fat absorption and appear to modulate glucose and energy metabolism. Colesevelam, a BA sequestrant, improves glycemic control in type 2 diabetes mellitus (T2DM). We aimed to characterize the alterations in BA metabolism associated with T2DM and colesevelam treatment and to establish whether metabolic consequences of T2DM and colesevelam are related to changes in BA metabolism. Male subjects with T2DM (n = 16) and controls (n = 12) were matched for age and body mass index. BA pool sizes and synthesis/input rates were determined before and after 2 and 8 weeks of colesevelam treatment. T2DM subjects had higher cholic acid (CA) synthesis rate, higher deoxycholic acid (DCA) input rate, and enlarged DCA pool size. Colesevelam resulted in a preferential increase in CA synthesis in both groups. CA pool size was increased whereas chenodeoxycholic acid and DCA pool sizes were decreased upon treatment. Fasting and postprandial fibroblast growth factor 19 (FGF19) levels did not differ between controls and diabetics, but were decreased by treatment in both groups. Colesevelam treatment reduced hemoglobin A1C by 0.7% (P < 0.01) in diabetics. Yet, no relationships between BA kinetic parameters and changes in glucose metabolism were found in T2DM or with colesevelam treatment. CONCLUSION: Our results reveal significant changes in BA metabolism in T2DM, particularly affecting CA and DCA. Colesevelam treatment reduced FGF19 signaling associated with increased BA synthesis, particularly of CA, and resulted in a more hydrophilic BA pool without altering total BA pool size. However, these changes could not be related to the improved glycemic control in T2DM.


Mulder F.A.A.,University of Groningen | Filatov M.,Zernike Institute for Advanced Materials
Chemical Society Reviews | Year: 2010

In this tutorial review, we discuss the utilization of chemical shift information as well as ab initio calculations of nuclear shieldings for protein structure determination. Both the empirical and computational aspects of the chemical shift are reviewed and the role of molecular dynamics and the accuracy of different computational methods are discussed. It is anticipated that incorporating theoretical information on chemical shifts will increase the accuracy of protein structures, in the solid and liquid state alike, and extend the applicability of NMR spectroscopy to ever larger systems. © 2010 The Royal Society of Chemistry.


Riezebos J.,University of Groningen
International Journal of Production Research | Year: 2010

POLCA is a material control system designed for make-to-order or engineer-to-order companies. These firms have to cope with a high variety of customised products, and strong pressure to provide short throughput times. POLCA constrains the amount of work in progress on the shop floor in order to achieve a short average shop floor throughput time. Earlier work has shown that the POLCA system has the capability to reduce both the average shop floor throughput time and the average total throughput time, but it is only effective if the POLCA system has been appropriately designed. The design of the POLCA system is therefore being investigated and discussed in this paper. We give an extensive literature review and give attention to the authorisation mechanisms of POLCA, the design of control loops, the route-specific capacity signals (POLCA cards), and specific facilities needed to use the POLCA system in practice. Finally, we report on the design of a POLCA system in practice, the first complete implementation of POLCA in The Netherlands, and present the quick scan that was used in the design of the POLCA system for this SME.


Lefrandt J.D.,University of Groningen
Current diabetes reviews | Year: 2010

In 1976, D.J. Ewing showed a clear survival disadvantage for diabetic patients that had 'diabetic autonomic neuropathy', as assessed by heart rate and blood pressure variations during a battery of bedside tests. However, these variations do not solely depend on autonomic nervous system function, but also and possibly to a more important extent on the integrity of cardiovascular autonomic reflex loops. Increased intima media thickness at the site of the baroreceptors, reduced vascular distensibility, endothelial dysfunction and impaired cardiac function contribute to the cardiovascular autonomic dysfunction. Interestingly, these abnormalities are closely associated with the presence of (micro-) albuminuria that is regarded as a reflection of endothelial dysfunction or vascular damage in diabetes mellitus. Modern techniques to assess cardiovascular autonomic, vascular and cardiac function have improved the ability to detect early abnormalities. Analysis of heart rate variability, baroreflex sensitivity, muscle sympathetic nervous activity, LNMAinfusions and advanced echocardiography have shown that it is the interplay between autonomic control and cardiac and vascular properties that determines cardiovascular autonomic function. Moreover, these modern techniques have improved power to predict survival in diabetic patients in comparison with the classical Ewing's bedside tests. In conclusion, cardiovascular damage may be more important in cardiovascular autonomic dysfunction than neural function.


Koppelman G.H.,University of Groningen | Sayers I.,University of Nottingham
Journal of Allergy and Clinical Immunology | Year: 2011

There has been great progress in identifying new asthma susceptibility genes. In asthmatic subjects there is variable airway remodeling that includes features such as smooth muscle hypertrophy/hyperplasia, basement membrane thickening, and increased extracellular matrix deposition. Does airway remodeling have a genetic contribution in asthma? Data from different murine strains suggest there is a genetic contribution to the development and progression of airway remodeling. In human subjects it is important to consider what surrogate markers of remodeling have been used in genetic studies. Baseline FEV1 and airway hyperresponsiveness are determined by a complex interplay of factors, including nonremodeling mechanisms; however, we consider a decline in FEV1 as a robust marker of remodeling. To date, single nucleotide polymorphisms spanning ADAM33, ESR1, PLAUR, and VEGF have been associated with an excess decline in lung function in asthmatic subjects carrying the rare alleles (FEV1, -13.0 to 55.2 mL/y excess). Interestingly these genes have overlapping functions in proteolytic pathways in the airways. There is accumulating evidence that genetic factors are important in the development of airway remodeling in asthmatic subjects, and further longitudinal studies with additional remodeling phenotypes and genome-wide association studies will identify novel susceptibility genes, leading to new approaches to target remodeling in asthmatic subjects. © 2011 American Academy of Allergy, Asthma & Immunology.


Nederhof E.,University of Groningen
Physiology & behavior | Year: 2012

This paper integrates the cumulative stress hypothesis with the mismatch hypothesis, taking into account individual differences in sensitivity to programming. According to the cumulative stress hypothesis, individuals are more likely to suffer from disease as adversity accumulates. According to the mismatch hypothesis, individuals are more likely to suffer from disease if a mismatch occurs between the early programming environment and the later adult environment. These seemingly contradicting hypotheses are integrated into a new model proposing that the cumulative stress hypothesis applies to individuals who were not or only to a small extent programmed by their early environment, while the mismatch hypothesis applies to individuals who experienced strong programming effects. Evidence for the main effects of adversity as well as evidence for the interaction between adversity in early and later life is presented from human observational studies and animal models. Next, convincing evidence for individual differences in sensitivity to programming is presented. We extensively discuss how our integrated model can be tested empirically in animal models and human studies, inviting researchers to test this model. Furthermore, this integrated model should tempt clinicians and other intervenors to interpret symptoms as possible adaptations from an evolutionary biology perspective. Copyright © 2011 Elsevier Inc. All rights reserved.


Efstathiou K.,University of Groningen | Sadovskii D.A.,University of the Littoral Opal Coast
Reviews of Modern Physics | Year: 2010

The hydrogen atom perturbed by sufficiently small homogeneous static electric and magnetic fields of arbitrary mutual alignment is a specific perturbation of the Kepler system with three degrees of freedom and three parameters. Normalization of the Keplerian symmetry reveals that the parameter space is stratified into resonant zones of systems, each zone with an internal dynamical stratification of its own (Efstathiou, Sadovskií, and Zhilinskií, 2007, Proc. R. Soc. London, Ser. A 463, 177110.1098/rspa. 2007.1843). Based on the fully integrable approximation, the bundle of invariant tori of individual systems within zones is characterized globally and the qualitative dynamical stratification is uncovered. The techniques involved in this analysis are illustrated with the example of the 1:1 resonance zone (near orthogonal fields) whose structure is known at present. Applications in the corresponding quantum system are also described. © 2010 The American Physical Society.


Maan M.E.,University of Groningen | Sefc K.M.,University of Graz
Seminars in Cell and Developmental Biology | Year: 2013

Cichlid fishes constitute one of the most species-rich families of vertebrates. In addition to complex social behaviour and morphological versatility, they are characterised by extensive diversity in colouration, both within and between species. Here, we review the cellular and molecular mechanisms underlying colour variation in this group and the selective pressures responsible for the observed variation. We specifically address the evidence for the hypothesis that divergence in colouration is associated with the evolution of reproductive isolation between lineages. While we conclude that cichlid colours are excellent models for understanding the role of animal communication in species divergence, we also identify taxonomic and methodological biases in the current research effort. We suggest that the integration of genomic approaches with ecological and behavioural studies, across the entire cichlid family and beyond it, will contribute to the utility of the cichlid model system for understanding the evolution of biological diversity. © 2013 The Authors.


Hunt R.A.R.,University of Cambridge | Otto S.,University of Groningen
Chemical Communications | Year: 2011

Combinatorial chemistry is a tool for selecting molecules with special properties. Dynamic combinatorial chemistry started off aiming to be just that. However, unlike ordinary combinatorial chemistry, the interconnectedness of dynamic libraries gives them an extra dimension. An understanding of these molecular networks at systems level is essential for their use as a selection tool and creates exciting new opportunities in systems chemistry. In this feature article we discuss selected examples and considerations related to the advanced exploitation of dynamic combinatorial libraries for their originally conceived purpose of identifying strong binding interactions. Also reviewed are examples illustrating a trend towards increasing complexity in terms of network behaviour and reversible chemistry. Finally, new applications of dynamic combinatorial chemistry in self-assembly, transport and self-replication are discussed.


van de Meeberg E.K.,University of Groningen
European Journal of Emergency Medicine | Year: 2016

OBJECTIVE: To evaluate the effect of routine use of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) on the diagnosis rate of delirium in elderly Emergency Department (ED) patients and the validity of the CAM-ICU in the ED setting. METHODS: This was a prospective observational study in a tertiary care academic ED. We compared the diagnosis rate of delirium before implementation of the CAM-ICU, without routine use of a screening tool, with the diagnosis rate after implementation of the CAM-ICU. All consecutive patients aged 70 years or older were enrolled. The diagnosis rate before implementation was based on chart review and after implementation on a positive CAM-ICU score. In a subsample, the presence of delirium was evaluated independently according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) criteria to assess the validity of the CAM-ICU. RESULTS: The total study population included 968 patients: 490 before and 478 after implementation of the CAM-ICU. The two groups were not significantly different in patient characteristics. Before implementation of the CAM-ICU, delirium was diagnosed in 14 patients (3%) and after implementation in 48 patients (10%) (P<0.001). The sensitivity of the CAM-ICU for delirium in the ED setting was 100%, specificity was 98%, positive predictive value was 92%, and negative predictive value was 100%. CONCLUSION: The diagnosis rate of delirium after implementation of the CAM-ICU was three-fold higher than before. The CAM-ICU is a reliable screening tool in the ED, with high sensitivity, specificity, and positive and negative predictive value. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Henry L.,University of Oxford | Schwander T.,University of Groningen | Crespi B.J.,Simon Fraser University
Molecular Biology and Evolution | Year: 2012

Sexual reproduction is extremely widespread in spite of its presumed costs relative to asexual reproduction, indicating that it must provide significant advantages. One postulated benefit of sex and recombination is that they facilitate the purging of mildly deleterious mutations, which would accumulate in asexual lineages and contribute to their short evolutionary life span. To test this prediction, we estimated the accumulation rate of coding (nonsynonymous) mutations, which are expected to be deleterious, in parts of one mitochondrial (COI) and two nuclear (Actin and Hsp70) genes in six independently derived asexual lineages and related sexual species of Timema stick insects. We found signatures of increased coding mutation accumulation in all six asexual Timema and for each of the three analyzed genes, with 3.6- to 13.4-fold higher rates in the asexuals as compared with the sexuals. In addition, because coding mutations in the asexuals often resulted in considerable hydrophobicity changes at the concerned amino acid positions, coding mutations in the asexuals are likely associated with more strongly deleterious effects than in the sexuals. Our results demonstrate that deleterious mutation accumulation can differentially affect sexual and asexual lineages and support the idea that deleterious mutation accumulation plays an important role in limiting the long-Term persistence of all-female lineages. © The Author 2011.


Chaiyen P.,Mahidol University | Fraaije M.W.,University of Groningen | Mattevi A.,University of Pavia
Trends in Biochemical Sciences | Year: 2012

The reaction of flavoenzymes with oxygen remains a fascinating area of research because of its relevance for reactive oxygen species (ROS) generation. Several exciting recent studies provide consistent mechanistic clues about the specific functional and structural properties of the oxidase and monooxygenase flavoenzymatic systems. Specifically, the spatial arrangement of the reacting oxygen that is in direct contact with the flavin group is emerging as a crucial factor that differentiates between oxidase and monooxygenase enzymes. A challenge for the future will be to use these emerging concepts to rationally engineer flavoenzymes, paving the way to new research avenues with far-reaching implications for oxidative biocatalysis and metabolic engineering. © 2012 Elsevier Ltd.


Rupak G.,Mississippi State University | Higa R.,University of Groningen
Physical Review Letters | Year: 2011

The radiative neutron capture on lithium-7 is calculated model independently using a low-energy halo effective field theory. The cross section is expressed in terms of scattering parameters directly related to the S-matrix elements. It depends on the poorly known p-wave effective range parameter r 1. This constitutes the largest uncertainty in traditional model calculations. It is explicitly demonstrated by comparing with potential model calculations. A single parameter fit describes the low-energy data extremely well and yields r1≈1.47fm-1. © 2011 American Physical Society.


Dashty M.,University of Groningen
Clinical Biochemistry | Year: 2013

In mammals, there are different metabolic pathways in cells that break down fuel molecules to transfer their energy into high energy compounds such as adenosine-5'-triphosphate (ATP), guanosine-5'-triphosphate (GTP), reduced nicotinamide adenine dinucleotide (NADH2), reduced flavin adenine dinucleotide (FADH2) and reduced nicotinamide adenine dinucleotide phosphate (NADPH2). This process is called cellular respiration. In carbohydrate metabolism, the breakdown starts from digestion of food in the gastrointestinal tract and is followed by absorption of carbohydrate components by the enterocytes in the form of monosaccharides. Monosaccharides are transferred to cells for aerobic and anaerobic respiration via glycolysis, citric acid cycle and pentose phosphate pathway to be used in the starvation state. In the normal state, the skeletal muscle and liver cells store monosaccharides in the form of glycogen. In the obesity state, the extra glucose is converted to triglycerides via lipogenesis and is stored in the lipid droplets of adipocytes. In the lipotoxicity state, the lipid droplets of other tissues such as the liver, skeletal muscle and pancreatic beta cells also accumulate triacylglycerol. This event is the axis of the pathogenesis of metabolic dysregulation in insulin resistance, metabolic syndrome and type 2 diabetes. In this paper a summary of the metabolism of carbohydrates is presented in a way that researchers can follow the biochemical processes easily. © 2013 The Canadian Society of Clinical Chemists.


Vakis A.I.,University of Groningen
Journal of Applied Mechanics, Transactions ASME | Year: 2014

A method is proposed to account for asperity interaction and bulk substrate deformation in models that utilize statistical summation of asperity forces to characterize contact between rough surfaces. Interaction deformations of noncontacting asperities are calculated based on the probability that they have taller neighbors in their vicinity, whose deformation upon contact, in turn, induces local substrate deformations. The effect of the order of interaction on the total contact force is explored and a limit is proposed based on asperity density. The updated contact force accounting for asperity interaction is found to tend to a constant fraction of the nominal contact force at the mathematical limit of asperity contact independent of the order of interaction, roughness, or material properties. For contact in the vicinity of zero mean plane separation, rough surfaces are found to exhibit greater asperity interaction resulting in reduced contact forces. A simplified curve-fitted expression is introduced that can be used to account for asperity interaction by adjusting the nominal contact force predicted by other models. © 2014 by ASME.


Stevanovic J.,University of Groningen
European journal of preventive cardiology | Year: 2012

Long-term trials on the effectiveness of pharmacological treatment for primary cardiovascular disease prevention are scant. For that reason risk prediction models are used as a tool to project changes in cardiovascular disease incidence due to changes in risk factor levels observed in short-term randomized clinical trials. In this article, we summarize the literature on the application of these risk models in pharmacoeconomic studies for primary cardiovascular disease prevention interventions in high-income countries. We systematically reviewed the available literature on the application of cardiovascular disease risk models in pharmacoeconomic studies and assessed the quality of incorporation of risk models in these studies. Quality assessment indicated the distance between the characteristics of populations of the risk model and the studies reviewed, the frequent disagreement between risk model and study time horizons and the lack of proper consideration of the uncertainty surrounding risk predictions. Given that utilizing a risk model to project the effect of a pharmacological intervention to cardiovascular events provides an estimate of the intervention's clinical and economical impact, consideration should be paid to the agreement between the study and risk model populations as well as the level of uncertainty that these predictions add to the outcome of a decision-analytic model. In the absence of hard endpoint trials, the value of risk models to model pharmacological efficacy in primary cardiovascular disease prevention remains high, although their limitations should beacknowledged


Kallosh R.,Stanford University | Linde A.,Stanford University | Roest D.,University of Groningen
Journal of High Energy Physics | Year: 2014

Abstract: We consider a broad class of inflationary models that arise naturally in super-gravity. They are defined in terms of a parameter α that determines the curvature and cutoff of these models. As a function of this parameter, we exhibit that the inflationary predictions generically interpolate between two attractor points. At small cutoff α, the resulting inflationary model is of plateau-type with ns = 1 − 2/N and r = 12α/N2. For α = 1, these predictions coincide with predictions of the Starobinsky model and Higgs inflation. In contrast, for large cutoff α, the theory asymptotes to quadratic inflation, with ns = 1 − 2/N, r = 8/N. Both universal predictions can be attributed to a stretching of the moduli space. For intermediate values of α, the predictions interpolate between these two critical points, thus covering the sweet spots of both Planck and BICEP2. © 2014, The Author(s).


Hoendermis E.S.,University of Groningen
Netherlands Heart Journal | Year: 2011

Pulmonary arterial hypertension (PAH), defined as group 1 of the World Heart Organisation (WHO) classification of pulmonary hypertension, is an uncommon disorder of the pulmonary vascular system. It is characterised by an increased pulmonary artery pressure, increased pulmonary vascular resistance and specific histological changes. It is a progressive disease finally resulting in right heart failure and premature death. Typical symptoms are dyspnoea at exercise, chest pain and syncope; furthermore clinical signs of right heart failure develop with disease progression. Echocardiography is the key investigation when pulmonary hypertension is suspected, but a reliable diagnosis of PAH and associated conditions requires an intense work-up including invasive measurement by right heart catheterisation. Treatment includes general measures and drugs targeting the pulmonary artery tone and vascular remodelling. This advanced medical therapy has significantly improved morbidity and mortality in patients with PAH in the last decade. Combinations of these drugs are indicated when treatment goals of disease stabilisation are not met. In patients refractory to medical therapy lung transplantation should be considered an option. © The Author(s) 2011.


Medema M.H.,University of Groningen
Bioengineered bugs | Year: 2011

Natural products derived from the secondary metabolism of microbes constitute a cornerstone of modern medicine. Engineering bugs to produce these products in high quantities is a major challenge for biotechnology, which has usually been tackled by either one of two strategies: iterative random mutagenesis or rational design. Recently, we analyzed the transcriptome of a Streptomyces clavuligerus strain optimized for production of the β-lactamase inhibitor clavulanic acid by multiple rounds of mutagenesis and selection, and discovered that the observed changes matched surprisingly well with simple changes that have been introduced into these strains by rational engineering. Here, we discuss how in the new field of synthetic biology, random mutagenesis and rational engineering can be implemented complementarily in ways which may enable one to go beyond the status quo that has now been reached by each method independently.


Groothuis T.G.,University of Groningen | Trillmich F.,Bielefeld University
Developmental Psychobiology | Year: 2011

We aim to stimulate an ontogenetic approach to personalities. We explain the importance of studying development for understanding proximate and ultimate aspects of personality and critically discuss, partly by perhaps provocative statements, our current lack of knowledge and potential approaches to the study of personality development. We first clarify some terminology and argue for a difference between behavioral profiles (BP; at the descriptive level) and personality (at the explanatory level). We then focus on the issue of temporal stability of personality, arguing that based on evolutionary theory, neurophysiological knowledge, and recent findings, personality is probably less stable than often thought. Next we consider the potential influence of genes, discussing gene by environment correlations and interactions and argue that developmental changes in the regulation of DNA expression are probably more relevant than individual differences in DNA sequence. We end by suggesting perspectives for future research. © 2011 Wiley Periodicals, Inc.


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

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


Minh B.Q.,University of Vienna | Nguyen M.A.T.,University of Groningen | Von Haeseler A.,University of Vienna
Molecular Biology and Evolution | Year: 2013

Nonparametric bootstrap has been a widely used tool in phylogenetic analysis to assess the clade support of phylogenetic trees. However, with the rapidly growing amount of data, this task remains a computational bottleneck. Recently, approximation methods such as the RAxML rapid bootstrap (RBS) and the Shimodaira-Hasegawa-like approximate likelihood ratio test have been introduced to speed up the bootstrap. Here, we suggest an ultrafast bootstrap approximation approach (UFBoot) to compute the support of phylogenetic groups in maximum likelihood (ML) based trees. To achieve this, we combine the resampling estimated log-likelihood method with a simple but effective collection scheme of candidate trees. We also propose a stopping rule that assesses the convergence of branch support values to automatically determine when to stop collecting candidate trees. UFBoot achieves a median speed up of 3.1 (range: 0.66-33.3) to 10.2 (range: 1.32-41.4) compared with RAxML RBS for real DNA and amino acid alignments, respectively. Moreover, our extensive simulations show that UFBoot is robust against moderate model violations and the support values obtained appear to be relatively unbiased compared with the conservative standard bootstrap. This provides a more direct interpretation of the bootstrap support. We offer an efficient and easy-to-use software (available at http://www.cibiv.at/software/iqtree) to perform the UFBoot analysis with ML tree inference. © 2013 The Author.


Sival D.,University of Groningen
European Journal of Human Genetics | Year: 2016

CHD7 variants are a well-established cause of CHARGE syndrome, a disabling multi-system malformation disorder that is often associated with deafness, visual impairment and intellectual disability. Less severe forms of CHD7-related disease are known to exist, but the full spectrum of phenotypes remains uncertain. We identified a de novo missense variant in CHD7 in a family presenting with musculoskeletal abnormalities as the main manifestation of CHD7-related disease, representing a new phenotype. The proband presented with prominent scapulae, mild shoulder girdle weakness and only subtle dysmorphic features. Investigation revealed hypoplasia of the trapezius and sternocleidomastoid muscles and semicircular canal defects, but he did not fulfill diagnostic criteria for CHARGE syndrome. Although the shoulders are often sloping and anteverted in CHARGE syndrome, the underlying neuromuscular cause has never been investigated. This report expands the phenotypes associated with CHD7 mutations to include a musculoskeletal presentation, with hypoplasia of the shoulder and neck muscles. CHD7 should be considered in patients presenting in childhood with stable scapular winging, particularly if accompanied by dysmorphic features and balance difficulties.European Journal of Human Genetics advance online publication, 27 January 2016; doi:10.1038/ejhg.2015.276. © 2016 Macmillan Publishers Limited


Gosens R.,University of Groningen | Grainge C.,Hunter Medical Research Institute
Chest | Year: 2015

Recent work has demonstrated that mechanical forces occurring in the airway as a consequence of bronchoconstriction are sufficient to not only induce symptoms but also influence airway biology. Animal and human in vitro and in vivo work demonstrates that the airways are structurally and functionally altered by mechanical stress induced by bronchoconstriction. Compression of the airway epithelium and mechanosensing by the airway smooth muscle trigger the activation and release of growth factors, causing cell proliferation, extracellular matrix protein accumulation, and goblet cell differentiation. These effects of bronchoconstriction are of major importance to asthma pathophysiology and appear sufficient to induce remodeling independent of the inflammatory response. We review these findings in detail and discuss previous studies in light of this new evidence regarding the influence of mechanical forces in the airways. Furthermore, we highlight potential impacts of therapies influencing mechanical forces on airway structure and function in asthma. © 2015 American College of Chest Physicians.


Lundin K.E.A.,University of Oslo | Wijmenga C.,University of Groningen
Nature Reviews Gastroenterology and Hepatology | Year: 2015

Coeliac disease is a treatable, gluten-induced disease that often occurs concurrently with other autoimmune diseases. In genetic studies since 2007, a partial genetic overlap between these diseases has been revealed and further insights into the pathophysiology of coeliac disease and autoimmunity have been gained. However, genetic screening is not sensitive and specific enough to accurately predict disease development. The current method to diagnose individuals with coeliac disease is serological testing for the presence of autoantibodies whilst the patient is on a regular, gluten-containing diet, followed by gastroduodenoscopy with duodenal biopsy. Serological test results can also predict the probability of coeliac disease development, even if asymptomatic. In patients with autoimmune diseases known to occur alongside coeliac disease (particularly type 1 diabetes mellitus or thyroid disorders), disease screening - and subsequent treatment if coeliac disease is detected - could have beneficial effects on progression or potential complications of both diseases, owing to the effectiveness of gluten-free dietary interventions in coeliac disease. However, whether diagnosis of coeliac disease and subsequent dietary treatment can prevent autoimmune diseases is debated. In this Review, the genetic and immunological features of coeliac disease, overlap with other autoimmune diseases and implications for current screening strategies will be discussed. © 2015 Macmillan Publishers Limited. All rights reserved.


Geerligs L.,University of Groningen
Psychophysiology | Year: 2012

Temporal integration was examined using a missing element task, in which task performance depends on the ability to integrate brief successive stimulus displays. Previous studies have suggested that temporal integration is under endogenous control and that integration is more likely when stimuli match the observer's temporal expectancies. Beta oscillations have previously been related to such cognitive (and attentional) control, as well as to audiovisual integration. We thus hypothesized that prestimulus power in the beta frequency band might reflect "integration readiness" and distinguish trials in which stimuli were successfully integrated from unsuccessful ones. The results showed increased upper beta power (21-30 Hz) prior to successful integration over central and parietal electrodes. This finding supported the idea that increased prestimulus beta power might reflect general control processes that can facilitate integration. Copyright © 2012 Society for Psychophysiological Research.


Botero C.A.,North Carolina State University | Botero C.A.,Washington University in St. Louis | Weissing F.J.,University of Groningen | Wright J.,Norwegian University of Science and Technology | Rubenstein D.R.,Columbia University
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

In an era of rapid climate change, there is a pressing need to understand how organisms will cope with faster and less predictable variation in environmental conditions. Here we develop a unifying model that predicts evolutionary responses to environmentally driven fluctuating selection and use this theoretical framework to explore the potential consequences of altered environmental cycles. We first show that the parameter space determined by different combinations of predictability and timescale of environmental variation is partitioned into distinct regions where a single mode of response (reversible phenotypic plasticity, irreversible phenotypic plasticity, bet-hedging, or adaptive tracking) has a clear selective advantage over all others. We then demonstrate that, although significant environmental changes within these regions can be accommodated by evolution, most changes that involve transitions between regions result in rapid population collapse and often extinction. Thus, the boundaries between response mode regions in our model correspond to evolutionary tipping points, where even minor changes in environmental parameters can have dramatic and disproportionate consequences on population viability. Finally, we discuss how different life histories and genetic architectures may influence the location of tipping points in parameter space and the likelihood of extinction during such transitions. These insights can help identify and address some of the cryptic threats to natural populations that are likely to result from any natural or human-induced change in environmental conditions. They also demonstrate the potential value of evolutionary thinking in the study of global climate change. © 2015, National Academy of Sciences. All rights reserved.


Batstra L.,University of Groningen | Frances A.,Duke University
Journal of Nervous and Mental Disease | Year: 2012

There have been a striking diagnostic inflation and a corresponding increase in the use of psychotropic drugs during the past 30 years. DSM-5, scheduled to appear in May 2013, proposes another grand expansion of mental illness. In this article, we will review the causes of diagnostic exuberance and associated medical treatment. We will then suggest a method of stepped care combined with stepped diagnosis, which may reduce overdiagnosis without risking undertreatment of those who really need help. The goal is to control diagnostic inflation, to reduce the harms and costs of unnecessary treatment, and to save psychiatry from overdiagnosis and ridicule. Copyright © 2012 by Lippincott Williams & Wilkins.


van den Heuvel W.J.A.,University of Groningen
European Journal of Ageing | Year: 2011

This study analyses the experienced age discrimination of old European citizens and the factors related to this discrimination. Differences in experienced discrimination between old citizens of different European countries are explored. Data from the 2008 ESS survey are used. Old age is defined as being 62 years or older. The survey data come from 28 European countries and 14,364 old-age citizens. Their average age is 72 years. Factor analysis is used to construct the core variable 'experienced discrimination'. The influence of the independent variables on experienced discrimination is analysed using linear regression analysis. About one-quarter of old European citizens sometimes or frequently experience discrimination because of their age. Gender, education, income and belonging to a minority are related to experienced age discrimination. Satisfaction with life and subjective health are strongly associated with experienced age discrimination, as is trust in other people and the seriousness of age discrimination in the country. Large, significant differences in experienced discrimination due to old age exist between European countries. A north-west versus south-east European gradient is found in experienced discrimination due to old age. The socio-cultural context is important in explaining experienced age discrimination in old European citizens. Old-age discrimination is experienced less frequently in countries with social security arrangements. Further research is needed to understand the variation in (old) age discrimination between European countries. Measures recommended include increasing public awareness about the value of ageing for communities and changing public attitudes towards the old in a positive way. © 2011 The Author(s).


Van Haastert P.J.M.,University of Groningen
Science Signaling | Year: 2011

Pseudopods are cell extensions used for movement. The direction and trajectory of cell movement depend on how cells extend pseudopods. Experimental data show that new pseudopods are frequently formed by the splitting of an existing pseudopod, often as a series of left-right extensions. Here, these data on pseudopod extensions are discussed in the context of a theoretical model for pseudopod splitting.


Papadodimas K.,University of Groningen | Papadodimas K.,CERN | Raju S.,Tata Institute of Fundamental Research
Physical Review Letters | Year: 2015

In the AdS/CFT correspondence, states obtained by Hamiltonian evolution of the thermofield doubled state are also dual to an eternal black-hole geometry, which is glued to the boundary with a time shift generated by a large diffeomorphism. We describe gauge-invariant relational observables that probe the black hole interior in these states and constrain their properties using effective field theory. By adapting recent versions of the information paradox we show that these observables are necessarily described by state-dependent bulk-boundary maps, which we construct explicitly. © 2015 authors. Published by the American Physical Society. Published by the American Physical Society under the terms of the «http://creativecommons.org/licenses/by/3.0/» Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.


Kiedrowski G.V.,Ruhr University Bochum | Otto S.,University of Groningen | Herdewijn P.,Catholic University of Leuven
Journal of Systems Chemistry | Year: 2013

It is our utmost pleasure to launch the Journal of Systems Chemistry. What systems chemistry exactly is will be known in a few years from now when one is able to sketch the scope and vision of the field also based on upcoming contributions to our journal. How systems chemistry came up is more easy to tell. In this editorial we therefore focus predominantly on how the term "Systems Chemistry" came into being and how its scope evolved over recent years. It is perhaps not surprising that the term emerged within the communities researching the origin and synthesis of life, as this is probably the most challenging question in Systems Chemistry. The field however encompasses much more than just this subject - it offers a plethora of new opportunities for the discovery of lifelike dynamic signatures in all areas in chemistry © 2010 von Kiedrowski et al.


Koopmans K.P.,Martini Hospital | Glaudemans A.W.J.M.,University of Groningen
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2012

Nuclear medicine techniques are becoming more important in imaging oncological and infectious diseases. For metabolic imaging of these diseases, antibody and peptide imaging are currently used. In recent years peptide imaging has become important, therefore the rationale for the use of peptide imaging is described in this article. Criteria for a successful peptide tracer are a high target specificity, a high binding affinity, a long metabolic stability and a high target-to-background ratio. Tracer internalization is also beneficial. For oncological imaging, many tracers are available, most originating from regulatory peptides, but penetrating peptides are also being developed. Peptides for imaging inflammatory and infectious diseases include regulatory peptides, antimicrobial peptides and others. In conclusion, for the imaging of oncological, imflammatory and infectious diseases, many promising peptides are being developed. The ideal peptide probe is characterized by rapid and specific target localization and binding with a high tumour-to-background ratio. © 2012 Springer-Verlag.


Yu W.,City University of Hong Kong | Yu W.,Nanjing Southeast University | Chen G.,City University of Hong Kong | Cao M.,University of Groningen
Automatica | Year: 2010

This paper studies some necessary and sufficient conditions for second-order consensus in multi-agent dynamical systems. First, basic theoretical analysis is carried out for the case where for each agent the second-order dynamics are governed by the position and velocity terms and the asymptotic velocity is constant. A necessary and sufficient condition is given to ensure second-order consensus and it is found that both the real and imaginary parts of the eigenvalues of the Laplacian matrix of the corresponding network play key roles in reaching consensus. Based on this result, a second-order consensus algorithm is derived for the multi-agent system facing communication delays. A necessary and sufficient condition is provided, which shows that consensus can be achieved in a multi-agent system whose network topology contains a directed spanning tree if and only if the time delay is less than a critical value. Finally, simulation examples are given to verify the theoretical analysis. © 2010 Elsevier Ltd. All rights reserved.


Van't Hof B.,VORtech BV | Veldman A.E.P.,University of Groningen
Journal of Computational Physics | Year: 2012

The paper explains a method by which discretizations of the continuity and momentum equations can be designed, such that they can be combined with an equation of state into a discrete energy equation. The resulting 'MaMEC' discretizations conserve mass, momentum as well as energy, although no explicit conservation law for the total energy is present. Essential ingredients are (i) discrete convection that leaves the discrete energy invariant, and (ii) discrete consistency between the thermodynamic terms. Of particular relevance is the way in which finite volume fluxes are related to nodal values. The method is an extension of existing methods based on skew-symmetry of discrete operators, because it allows arbitrary equations of state and a larger class of grids than earlier methods.The method is first illustrated with a one-dimensional example on a highly stretched staggered grid, in which the MaMEC method calculates qualitatively correct results and a non-skew-symmetric finite volume method becomes unstable. A further example is a two-dimensional shallow water calculation on a rectilinear grid as well as on an unstructured grid. The conservation of mass, momentum and energy is checked, and losses are found negligible up to machine accuracy. © 2012 Elsevier Inc.


Korf J.,University of Groningen
Neuroscientist | Year: 2015

This article examines the possible relevance of physical-mathematical multidimensional or quantum concepts aiming at understanding the (human) mind in a neurobiological context. Some typical features of the quantum and multidimensional concepts are briefly introduced, including entanglement, superposition, holonomic, and quantum field theories. Next, we consider neurobiological principles, such as the brain and its emerging (physical) mind, evolutionary and ontological origins, entropy, syntropy/neg-entropy, causation, and brain energy metabolism. In many biological processes, including biochemical conversions, protein folding, and sensory perception, the ubiquitous involvement of quantum mechanisms is well recognized. Quantum and multidimensional approaches might be expected to help describe and model both brain and mental processes, but an understanding of their direct involvement in mental activity, that is, without mediation by molecular processes, remains elusive. More work has to be done to bridge the gap between current neurobiological and physical-mathematical concepts with their associated quantum-mind theories. © The Author(s) 2014.


Etienne R.S.,University of Groningen | Rosindell J.,University of Leeds
PLoS ONE | Year: 2011

The unified neutral theory of biodiversity and biogeography is increasingly accepted as an informative null model of community composition and dynamics. It has successfully produced macro-ecological patterns such as species-area relationships and species abundance distributions. However, the models employed make many unrealistic auxiliary assumptions. For example, the popular spatially implicit version assumes a local plot exchanging migrants with a large panmictic regional source pool. This simple structure allows rigorous testing of its fit to data. In contrast, spatially explicit models assume that offspring disperse only limited distances from their parents, but one cannot as yet test the significance of their fit to data. Here we compare the spatially explicit and the spatially implicit model, fitting the most-used implicit model (with two levels, local and regional) to data simulated by the most-used spatially explicit model (where offspring are distributed about their parent on a grid according to either a radially symmetric Gaussian or a 'fat-tailed' distribution). Based on these fits, we express spatially implicit parameters in terms of spatially explicit parameters. This suggests how we may obtain estimates of spatially explicit parameters from spatially implicit ones. The relationship between these parameters, however, makes no intuitive sense. Furthermore, the spatially implicit model usually fits observed species-abundance distributions better than those calculated from the spatially explicit model's simulated data. Current spatially explicit neutral models therefore have limited descriptive power. However, our results suggest that a fatter tail of the dispersal kernel seems to improve the fit, suggesting that dispersal kernels with even fatter tails should be studied in future. We conclude that more advanced spatially explicit models and tools to analyze them need to be developed. © 2011 Etienne, Rosindell.


Karliczek A.,University of Groningen
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland | Year: 2010

Anastomotic leakage is associated with increased morbidity and mortality. However, there is no accurate tool to predict its occurrence. We evaluated the predictive value of visible light spectroscopy (VLS), a novel method to measure tissue oxygenation [saturated O(2) (StO(2) )], for anastomotic leakage of the colon and the rectum. Oxygen saturation in the bowel was measured in 77 colorectal resections. The anastomosis was between 2 and 30 cm (mean 13 cm) from the anal verge. The oxygen saturation was measured in the colon and rectum before and after anastomosis construction. This was compared with a reference measurement in the caecum. Data on postoperative complications were prospectively collected. Anastomotic leakage occurred in 14 (18%) patients. When compared with a leaking anastomosis, normal anastomoses showed rising O(2) values during the operation (mean StO(2) 72.1 ± 9.0-76.7 ± 8.0 vs 73.9 ± 7.9-73.1 ± 7.4) (P ≤ 0.05). There were also higher StO(2) values in the caecum compared with those which ultimately leaked (73.6 ± 5.7 normal anastomoses, 69.6 ± 5.6 anastomotic leaks) (P ≤ 0.05). Both StO(2) values were predictive of anastomotic leakage. Tissue oxygenation O(2) appears to be a potentially useful means of predicting anastomotic leakage after colorectal anastomosis. © 2010 The Authors. Colorectal Disease © 2010 The Association of Coloproctology of Great Britain and Ireland.


Elhorst J.P.,University of Groningen
Spatial Economic Analysis | Year: 2010

This paper places the key issues and implications of the new 'introductory' book on spatial econometrics by James LeSage & Kelley Pace (2009) in a broader perspective: the argument in favour of the spatial Durbin model, the use of indirect effects as a more valid basis for testing whether spatial spillovers are significant, the use of Bayesian posterior model probabilities to determine which spatial weights matrix best describes the data, and the book's contribution to the literature on spatiotemporal models. The main conclusion is that the state of the art of applied spatial econometrics has taken a step change with the publication of this book. © 2010 Regional Studies Association.


Dickinson P.J.C.,University of Groningen
Journal of Global Optimization | Year: 2014

During the last 40 years, simplicial partitioning has been shown to be highly useful, including in the field of nonlinear optimization, specifically global optimization. In this article, we consider results on the exhaustivity of simplicial partitioning schemes. We consider conjectures on this exhaustivity which seem at first glance to be true (two of which have been stated as true in published articles). However, we will provide counter-examples to these conjectures. We also provide a new simplicial partitioning scheme, which provides a lot of freedom, whilst guaranteeing exhaustivity. © 2013 Springer Science+Business Media New York.


De Boer R.A.,University of Groningen | Daniels L.B.,University of California at San Diego | Daniels L.B.,Veterans Affairs San Diego Medical Center | Maisel A.S.,University of California at San Diego | Januzzi J.L.,Harvard University
European Journal of Heart Failure | Year: 2015

Since natriuretic peptides were successfully integrated into the clinical practice of heart failure (HF), the possibility of using new biomarkers to advance the management of affected patients has been explored. While a huge number of candidate HF biomarkers have been described recently, very few have made the difficult translation from initial promise to clinical application. These markers mirror the complex pathophysiology of heart failure at various levels: cell loss (troponin), fibrosis (ST2 and galectin-3), infection (procalcitonin), and renal disease (several renal markers). In this review, we examine the best emerging candidates for clinical assessment and management of patients with HF. © 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.


Paganetti H.,Harvard University | Van Luijk P.,University of Groningen
Seminars in Radiation Oncology | Year: 2013

Owing to the limited availability of data on the outcome of proton therapy, treatments are generally optimized based on broadly available data on photon-based treatments. However, the microscopic pattern of energy deposition of protons differs from that of photons, leading to a different biological effect. Consequently, proton therapy needs a correction factor (relative biological effectiveness) to relate proton doses to photon doses, and currently, a generic value is used. Moreover, the macroscopic distribution of dose in proton therapy differs compared with photon treatments. Although this may offer new opportunities to reduce dose to normal tissues, it raises the question whether data obtained from photon-based treatments offer sufficient information on dose-volume effects to optimally use unique features of protons. In addition, there are potential differences in late effects due to low doses of secondary radiation outside the volume irradiated by the primary beam. This article discusses the controversies associated with these 3 issues when comparing proton and photon therapy. © 2013 Elsevier Inc.


Samanta A.,University of Munster | Stuart M.C.A.,University of Groningen | Ravoo B.J.,University of Munster
Journal of the American Chemical Society | Year: 2012

The development of triggered release systems for delivery of peptides and proteins is critical to the success of biological drug therapies. In this paper we describe a dynamic supramolecular system able to capture and release proteins in response to light. The ternary system self-assembles in a dilute aqueous solution of three components: vesicles of amphiphilic cyclodextrin host, noncovalent cross-linkers with an azobenzene and a carbohydrate moiety, and lectins. The cross-linkers form inclusion complexes with the host vesicles, provided the azobenzene is in the trans state. The formation of a ternary complex with lectins requires a high density of cross-linkers on the surface of vesicles. The key innovation in this system is a photoinduced switch from a multivalent, high-affinity state that captures protein to a monovalent, low-affinity state that releases protein. By using isothermal titration calorimetry, dynamic light scattering, UV/vis spectroscopy, and cryogenic transmission electron microscopy, we demonstrate that photoinduced capture and release of lectins in dense multilamellar complexes is highly efficient, highly selective, and fully reversible. © 2012 American Chemical Society.


Crean A.J.,University of New South Wales | Kopps A.M.,University of New South Wales | Kopps A.M.,University of Groningen | Bonduriansky R.,University of New South Wales
Ecology Letters | Year: 2014

Newly discovered non-genetic mechanisms break the link between genes and inheritance, thereby also raising the possibility that previous mating partners could influence traits in offspring sired by subsequent males that mate with the same female ('telegony'). In the fly Telostylinus angusticollis, males transmit their environmentally acquired condition via paternal effects on offspring body size. We manipulated male condition, and mated females to two males in high or low condition in a fully crossed design. Although the second male sired a large majority of offspring, offspring body size was influenced by the condition of the first male. This effect was not observed when females were exposed to the first male without mating, implicating semen-mediated effects rather than female differential allocation based on pre-mating assessment of male quality. Our results reveal a novel type of transgenerational effect with potential implications for the evolution of reproductive strategies. © 2014 John Wiley & Sons Ltd/CNRS.


Fetchenhauer D.,University of Cologne | Fetchenhauer D.,University of Groningen | Dunning D.,Cornell University
Psychological Science | Year: 2010

People tend to grossly underestimate the trustworthiness of other people. We tested whether this cynicism grows out of an asymmetry in the feedback people receive when they decide to trust others. When people trust others, they painfully learn when other people prove to be untrustworthy; however, when people refrain from trusting others, they fail to learn of instances when the other person would have honored their trust. Participants saw short videos of other people and had to decide whether to trust each person in an economic game. Participants overall underestimated the trustworthiness of the people they viewed, regardless of whether they were given financial incentives to provide accurate estimates. However, people who received symmetric feedback about the trustworthiness of others (i.e., who received feedback regardless of their own decision to trust) exhibited reduced cynicism relative to those who received no feedback or asymmetric feedback (i.e., who received feedback only after they trusted the other person). © The Author(s) 2010.


Krajewska M.,University of Groningen
Oncogene | Year: 2014

Homologous recombination (HR) is required for faithful repair of double-strand DNA breaks. Defects in HR repair cause severe genomic instability and challenge cellular viability. Paradoxically, various cancers are HR defective and have apparently acquired characteristics to survive genomic instability. We aimed to identify these characteristics to uncover therapeutic targets for HR-deficient cancers. Cytogenetic analysis of 1143 ovarian cancers showed that the degree of genomic instability was correlated to amplification of replication checkpoint genes ataxia telangiectasia and Rad3-related kinase (ATR) and CHEK1. To test whether genomic instability leads to increased reliance on replication checkpoint signaling, we inactivated Rad51 to model HR-related genomic instability. Rad51 inactivation caused defective HR repair and induced aberrant replication dynamics. Notably, inhibition of Rad51 led to increased ATR/checkpoint kinase-1 (Chk1)-mediated replication stress signaling. Importantly, inhibition of ATR or Chk1 preferentially killed HR-deficient cancer cells. Combined, our data show that defective HR caused by Rad51 inhibition results in differential sensitivity for ATR and Chk1 inhibitors, implicating replication checkpoint kinases as potential drug targets for HR-defective cancers.Oncogene advance online publication, 1 September 2014; doi:10.1038/onc.2014.276.


Van Vugt M.A.T.M.,University of Groningen | Yaffe M.B.,Massachusetts Institute of Technology
Cell Cycle | Year: 2010

In order to maintain genetic integrity, cells are equipped with cell cycle checkpoints that detect DNA damage, orchestrate repair, and if necessary, eliminate severely damaged cells by inducing apoptotic cell death. The mitotic machinery is now emerging as an important determinant of the cellular responses to DNA damage where it functions as both the downstream target and the upstream regulator of the G2/M checkpoint. Cell cycle kinases and the DNA damage checkpoint kinases appear to reciprocally control each other. Specifically, cell cycle kinases control the inactivation of DNA damage checkpoint signaling. Termination of a DNA damage response by mitotic kinases appears to be an evolutionary conserved mechanism that allows resumption of cell cycle progression. Here we review recent reports in which molecular mechanisms underlying checkpoint silencing at the G2/M transition are elucidated. © 2010 Landes Bioscience.


Nijmeijer J.S.,University of Groningen
Journal of child psychology and psychiatry, and allied disciplines | Year: 2010

Symptoms of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) often co-occur. Given the previously found familiality of ASD symptoms in children with ADHD, addressing these symptoms may be useful for genetic association studies, especially for candidate gene findings that have not been consistently replicated for ADHD. We studied the association of the catechol O-methyltransferase (COMT) Val158Met polymorphism and the serotonin transporter (SLC6A4/SERT/5-HTT) 5-HTTLPR insertion/deletion polymorphism with ASD symptoms in children with ADHD, and whether these polymorphisms would interact with pre- and perinatal risk factors, i.e., maternal smoking during pregnancy and low birth weight. Analyses were performed using linear regression in 207 Dutch participants with combined type ADHD of the International Multicenter ADHD Genetics (IMAGE) study, and repeated in an independent ADHD sample (n=439) selected from the TRracking Adolescents' Individual Lives Survey (TRAILS). Dependent variables were the total and subscale scores of the Children's Social Behavior Questionnaire (CSBQ). No significant main effects of COMT Val158Met, 5-HTTLPR, maternal smoking during pregnancy and low birth weight on ASD symptoms were found. However, the COMT Val/Val genotype interacted with maternal smoking during pregnancy in increasing stereotyped behavior in the IMAGE sample (p=.008); this interaction reached significance in the TRAILS sample after correction for confounders (p=.02). In the IMAGE sample, the 5-HTTLPR S/S genotype interacted with maternal smoking during pregnancy, increasing problems in social interaction (p=.02), and also interacted with low birth weight, increasing rigid behavior (p=.03). Findings for 5-HTTLPR in the TRAILS sample were similar, albeit for related CSBQ subscales. These findings suggest gene-environment interaction effects on ASD symptoms in children with ADHD. © 2010 The Authors. Journal of Child Psychology and Psychiatry © 2010 Association for Child and Adolescent Mental Health.


Sabat A.J.,University of Groningen
Euro surveillance : bulletin européen sur les maladies transmissibles = European communicable disease bulletin | Year: 2013

Typing methods for discriminating different bacterial isolates of the same species are essential epidemiological tools in infection prevention and control. Traditional typing systems based on phenotypes, such as serotype, biotype, phage-type, or antibiogram, have been used for many years. However, more recent methods that examine the relatedness of isolates at a molecular level have revolutionised our ability to differentiate among bacterial types and subtypes. Importantly, the development of molecular methods has provided new tools for enhanced surveillance and outbreak detection. This has resulted in better implementation of rational infection control programmes and efficient allocation of resources across Europe. The emergence of benchtop sequencers using next generation sequencing technology makes bacterial whole genome sequencing (WGS) feasible even in small research and clinical laboratories. WGS has already been used for the characterisation of bacterial isolates in several large outbreaks in Europe and, in the near future, is likely to replace currently used typing methodologies due to its ultimate resolution. However, WGS is still too laborious and time-consuming to obtain useful data in routine surveillance. Also, a largely unresolved question is how genome sequences must be examined for epidemiological characterisation. In the coming years, the lessons learnt from currently used molecular methods will allow us to condense the WGS data into epidemiologically useful information. On this basis, we have reviewed current and new molecular typing methods for outbreak detection and epidemiological surveillance of bacterial pathogens in clinical practice, aiming to give an overview of their specific advantages and disadvantages.


de Laat P.B.,University of Groningen
Ethics and Information Technology | Year: 2012

In communities of user-generated content, systems for the management of content and/or their contributors are usually accepted without much protest. Not so, however, in the case of Wikipedia, in which the proposal to introduce a system of review for new edits (in order to counter vandalism) led to heated discussions. This debate is analysed, and arguments of both supporters and opponents (of English, German and French tongue) are extracted from Wikipedian archives. In order to better understand this division of the minds, an analogy is drawn with theories of bureaucracy as developed for real-life organizations. From these it transpires that bureaucratic rules may be perceived as springing from either a control logic or an enabling logic. In Wikipedia, then, both perceptions were at work, depending on the underlying views of participants. Wikipedians either rejected the proposed scheme (because it is antithetical to their conception of Wikipedia as a community) or endorsed it (because it is consonant with their conception of Wikipedia as an organization with clearly defined boundaries). Are other open-content communities susceptible to the same kind of 'essential contestation'?. © 2012 The Author(s).


Vos L.M.,University of Groningen
Journal of orofacial pain | Year: 2012

To determine the available evidence in the literature for whether hypoxia-reperfusion injury plays a role in the pathogenesis of joint diseases in general and of osteoarthritis (OA) of the temporomandibular joint (TMJ) in particular. The electronic databases CENTRAL, PubMed, and EMBASE were systematically searched. The search strategy combined thesaurus terms "reperfusion injury" and "joints" and excluded "tourniquet," which possibly induces iatrogenic reperfusion injury. Inclusion and exclusion criteria were applied, data were extracted, and quality was assessed. Four studies could be included, investigating four different aspects of the hypoxia-reperfusion mechanism in joints. All studies investigated several arthritides in the knee or shoulder joint and were observational studies, except for one section of one of the studies, which was a randomized controlled trial. These studies do not provide any evidence to support or reject the hypothesis that hypoxia reperfusion occurs in TMJ OA. Positive but weak evidence is provided to support the hypothesis that hypoxia-reperfusion injury occurs in OA of the knee joint. Furthermore, some results of the included studies suggest differences between OA and other types of arthritis in relation to the hypoxia-reperfusion mechanism. There is no evidence to support or reject the hypothesis that hypoxia reperfusion occurs in TMJ OA, and limited evidence is provided to support that hypoxia-reperfusion injury occurs in OA of the knee joint. Since the studies suggest differences between OA and other types of arthritis in relation to hypoxia-reperfusion mechanisms, further research in this field needs to distinguish OA from other types of arthritis.


Niesters H.G.,University of Groningen
Euro surveillance : bulletin européen sur les maladies transmissibles = European communicable disease bulletin | Year: 2013

Laboratory-based surveillance, one of the pillars of monitoring infectious disease trends, relies on data produced in clinical and/or public health laboratories. Currently, diagnostic laboratories worldwide submit strains or samples to a relatively small number of reference laboratories for characterisation and typing. However, with the introduction of molecular diagnostic methods and sequencing in most of the larger diagnostic and university hospital centres in high-income countries, the distinction between diagnostic and reference/public health laboratory functions has become less clear-cut. Given these developments, new ways of networking and data sharing are needed. Assuming that clinical and public health laboratories may be able to use the same data for their own purposes when sequence-based testing and typing are used, we explored ways to develop a collaborative approach and a jointly owned database (TYPENED) in the Netherlands. The rationale was that sequence data - whether produced to support clinical care or for surveillance -can be aggregated to meet both needs. Here we describe the development of the TYPENED approach and supporting infrastructure, and the implementation of a pilot laboratory network sharing enterovirus sequences and metadata.


Bastiaanse R.,University of Groningen
Clinical Linguistics and Phonetics | Year: 2013

Many studies have shown that verb inflections are difficult to produce for agrammatic aphasic speakers: they are frequently omitted and substituted. The present article gives an overview of our search to understanding why this is the case. The hypothesis is that grammatical morphology referring to the past is selectively impaired in agrammatic aphasia. That is, verb inflections for past tense and perfect aspect are hard to produce. Furthermore, verb clusters that refer to the past will be affected as well, even if the auxiliary is in present tense, as in he has been writing a letter. It will be argued that all these verb forms referring to the past require discourse linking [Zagona, K. (2003). Tense and anaphora: Is there a tense-specific theory of coreference. In A. Barrs (Ed.), Anaphora: A reference guide (pp. 140-171). Oxford: Blackwell Publishing] and discourse linking is affected in agrammatic aphasia [Avrutin, S. (2006). Weak syntax. In K. Amunts, & Y. Grodzinsky (Eds.), Broca's region (pp. 49-62). New York: Oxford Press]. This hypothesis has been coined the PAst DIscourse LInking Hypothesis (PADILIH) [Bastiaanse, R., Bamyaci, E., Hsu, C.-J., Lee, J., Yarbay Duman, T., & Thompson, C.K. (2011). Time reference in agrammatic aphasia: A cross-linguistic study. Journal of Neurolinguistics, 24, 652-673]. The PADILIH has been tested in several languages and populations that have hardly been studied before in aphasiology: languages such as Turkish, Swahili and Indonesian were included, as well as monolingual and bilingual populations. In all these populations, the same test has been used: the Test for Assessing Reference of Time [Bastiaanse, R., Jonkers, R., & Thompson, C.K. (2008). Test for assessing reference of time (TART). Groningen: University of Groningen] to enable reliable comparisons between the languages. The results show that the PADILIH predicts the performance of agrammatic speakers very well: discourse-linked grammatical morphemes expressing time reference to the past are hard to produce for agrammatic speakers, whereas non-discourse-linked verb inflections (for present and future) are relatively spared. In languages that use aspectual adverbs (free-standing and optional time reference markers), such as Chinese and Indonesian, time reference to all time frames is impaired, since all aspectual adverbs, regardless of the time frame they refer to, require discourse linking. Remarkably, the problems are not restricted to grammatical morphemes: the production of temporal lexical adverbs is impaired as well. © 2013 Informa UK Ltd.


Struik F.M.,University of Groningen
The Cochrane database of systematic reviews | Year: 2013

Non-invasive positive pressure ventilation (NIPPV) is effective in treating acute exacerbations of chronic obstructive pulmonary disease (COPD). Nocturnal non-invasive positive pressure ventilation (nocturnal-NIPPV) has been proposed as an intervention for stable hypercapnic patients with COPD. To assess the effects of nocturnal-NIPPV at home via nasal mask or face mask in people with COPD by using a meta-analysis based on individual patient data (IPD). We searched the Cochrane Airways Group Specialised Register. We performed the latest search in August 2012. Randomised controlled trials in people with stable COPD that compared nocturnal-NIPPV at home for at least five hours per night, for at least three consecutive weeks plus standard therapy with standard therapy alone. IPD were collected and two review authors assessed risk of bias independently. This update of the systematic review on nocturnal-NIPPV in COPD (Wijkstra 2002), has led to the inclusion of three new studies, leading to seven included studies on 245 people. We obtained IPD for all participants in all included studies. The 95% confidence interval (CI) of all outcomes included zero. These included partial pressure of CO2 and O2 in arterial blood, six-minute walking distance (6MWD), health-related quality of life (HRQoL), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), maximal inspiratory pressure (PImax) and sleep efficiency. The mean effect on 6MWD was small at 27.7 m and not statistically significant. Given the width of the 95% CI (-28.1 to 66.3 m), the real effect of NIPPV on 6MWD is uncertain and we cannot exclude an effect that is clinically significant (considering that the minimal clinically difference on 6MWD is around 26 m). Nocturnal-NIPPV at home for at least three months in hypercapnic patients with stable COPD had no consistent clinically or statistically significant effect on gas exchange, exercise tolerance, HRQoL, lung function, respiratory muscle strength or sleep efficiency. Meta-analysis of the two new long-term studies did not show significant improvements in blood gases, HRQoL or lung function after 12 months of NIPPV. However, the small sample sizes of these studies preclude a definite conclusion regarding the effects of NIPPV in COPD.


van der Molen T.,University of Groningen | Cazzola M.,University of Rome Tor Vergata
Primary Care Respiratory Journal | Year: 2012

Bronchodilators are central to the management of chronic obstructive pulmonary disease (COPD). Clinical studies combining different classes of bronchodilators, in particular a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA), have demonstrated greater improvements in lung function (forced expiratory volume in 1 second, FEV1) in patients with COPD than monotherapy. FEV1 has served as an important diagnostic measurement of COPD, and the majority of clinical studies of currently available pharmacotherapies grade effectiveness of treatment regimens based on improvements in FEV1. However, FEV1 alone may not adequately reflect the overall health status of the patient. Published evidence suggests that LABA/LAMA combination therapies demonstrate greater improvements in patient-centred outcomes such as dyspnoea, symptoms, rescue medication use, and quality of life than individual drugs used alone. Evaluating patient-centred outcomes associated with COPD is likely to play an important role in future research as a measure of overall treatment effectiveness. Raising awareness of the importance of outcomes beyond lung function alone, particularly in primary care where most patients initially present themselves for medical evaluation, should form a fundamental part of a more holistic approach to COPD management. © 2010 Primary Care Respiratory Society UK.


Schoemaker M.M.,University of Groningen
Developmental medicine and child neurology | Year: 2012

The aim of this study was to investigate the validity and reliability of the Movement Assessment Battery for Children-2 Checklist (MABC-2). Teachers completed the Checklist for 383 children (age range 5-8y; mean age 6y 9mo; 190 males; 193 females) and the parents of 130 of these children completed the Developmental Disorder Coordination Questionnaire 2007 (DCDQ'07). All children were assessed with the MABC-2 Test. The internal consistency of the 30 items of the Checklist was determined to measure reliability. Construct validity was investigated using factor analysis and discriminative validity was assessed by comparing the scores of children with and without movement difficulties. Concurrent validity was measured by calculating correlations between the Checklist, Test, and the DCDQ'07. Incremental validity was assessed to determine whether the Checklist was a better predictor of motor impairment than the DCDQ'07. Sensitivity and specificity were investigated using the MABC-2 Test as reference standard (cut-off 15th centile). The Checklist items measure the same construct. Six factors were obtained after factor analysis. This implies that a broad range of functional activities can be assessed with the Checklist, which renders the Checklist useful for assessing criterion B of the diagnostic criteria for DCD. The mean Checklist scores for children with and without motor impairments significantly differed (p<0.001). The scores for the Checklist/Test and DCDQ'07 were significantly correlated (r(S) =-0.38 and p<0.001, and r(S) =-0.36 and p<0.001, respectively). The Checklist better predicted motor impairment than the DCDQ'07. Overall, the sensitivity was low (41%) and the specificity was acceptable (88%). The Checklist meets standards for validity and reliability. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.


Ripperger J.A.,University of Fribourg | Merrow M.,University of Groningen
FEBS Letters | Year: 2011

In mammals, higher order chromatin structures are critical for downsizing the genome (packaging) so that the nucleus can be small. The adjustable density of chromatin also regulates gene expression, thus this post-genetic molecular mechanism is one of the routes by which phenotype is shaped. Phenotypes that arise without a concomitant mutation of the underlying genome are termed epigenetic phenomena. Here we discuss epigenetic phenomena from histone and DNA modification as it pertains to the dynamic regulatory processes of the circadian clock. Epigenetic phenomena certainly explain some regulatory aspects of the mammalian circadian oscillator. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Ouzounis G.K.,European Commission - Joint Research Center Ispra | Wilkinson M.H.F.,University of Groningen
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2011

In this paper, we present a new method for attribute filtering, combining contrast and structural information. Using hyperconnectivity based on k-flat zones, we improve the ability of attribute filters to retain internal details in detected objects. Simultaneously, we improve the suppression of small, unwanted detail in the background. We extend the theory of attribute filters to hyperconnectivity and provide a fast algorithm to implement the new method. The new version is only marginally slower than the standard Max-Tree algorithm for connected attribute filters, and linear in the number of pixels or voxels. It is two orders of magnitude faster than anisotropic diffusion. The method is implemented in the form of a filtering rule suitable for handling both increasing (size) and nonincreasing (shape) attributes. We test this new framework on nonincreasing shape filters on both 2D images from astronomy, document processing, and microscopy, and 3D CT scans, and show increased robustness to noise while maintaining the advantages of previous methods. © 2011 IEEE.


De Jong Gierveld J.,University of Groningen
Canadian Journal on Aging | Year: 2015

Recently, rising numbers of mid-life and older adults are starting a living apart together (LAT) relationship following divorce or widowhood. LAT describes an intimate relationship wherein partners maintain separate households. This study investigated the characteristics of care arrangements in older long-term LAT couples and elicited personal comments about intra-couple care. We interviewed 25 LAT partners and a comparison group of 17 remarried older adults in the Netherlands in a side study of the Netherlands Kinship Panel Study. Results showed that about half of the LAT partners intended to exchange care if needed (partnership commitment); the other half had ambiguous feelings or intentions to refuse care (independence orientation). However, for those LAT partners already confronted with illness in their current relationship, all provided care to the partner in need. The minority of LAT partners who would not exchange care reciprocally are more likely to give as opposed to receive care. Copyright © Canadian Association on Gerontology 2015.


Bauch C.,Institute of Avian Research Vogelwarte Helgoland | Becker P.H.,Institute of Avian Research Vogelwarte Helgoland | Verhulst S.,University of Groningen
Molecular Ecology | Year: 2014

Telomeres, DNA-protein structures at chromosome ends, shorten with age, and telomere length has been linked to age-related diseases and survival. In vitro studies revealed that the shortest telomeres trigger cell senescence, but whether the shortest telomeres are also the best biomarker of ageing is not known. We measured telomeres in erythrocytes of wild common terns Sterna hirundo using terminal restriction fragment analysis. This yields a distribution of telomere lengths for each sample, and we investigated how different telomere subpopulations (percentiles) varied in their relation to age and fitness proxies. Longer telomeres within a genome lost more base pairs with age and were better predictors of survival than shorter telomeres. Likewise, fitness proxies such as arrival date at the breeding grounds and reproductive success were best predicted by telomere length at the higher percentiles. Our finding that longer telomeres within a genome predict fitness components better than the shorter telomeres indicates that they are a more informative ageing biomarker. This finding contrasts with the fact that cell senescence is triggered by the shortest telomeres. We suggest that this paradox arises, because longer telomeres lose more base pairs per unit time and thus better reflect the various forms of stress that accelerate telomere shortening, and that telomeres primarily function as biomarker because their shortening reflects cumulative effects of various stressors rather than reflecting telomere-induced cell senescence. © 2013 John Wiley & Sons Ltd.


Schreiber R.,Suadeo Drug Discovery Consulting LLC | Schreiber R.,University of Groningen | Newman-Tancredi A.,Neurolixis, Inc.
Neurobiology of Learning and Memory | Year: 2014

Atypical antipsychotics fail to substantially improve cognitive impairment associated with schizophrenia (CIAS) and one strategy to improve it is to stimulate adult neurogenesis in hippocampus, because this structure is part of an altered circuitry that underlies aspects of CIAS. Deficits in hippocampal adult neurogenesis may disrupt cognitive processes that are dependent on newborn neurons, such as pattern separation (the formation of distinct representations of similar inputs). Mechanisms by which hippocampal adult neurogenesis can be increased are therefore of therapeutic interest and a promising molecular target is the activation of serotonin 5-HT1A receptors because agonists at this site increase adult neuronal proliferation in the dentate gyrus. We hypothesize that use of antipsychotics possessing 5-HT1A receptor agonist properties may protect against or attenuate CIAS by a dual mechanism: a favorable influence on adult neurogenesis that develops upon sustained drug treatment, and an increase in dopamine levels in the prefrontal cortex that starts upon acute treatment. This hypothesis is consistent with the beneficial properties of 5-HT1A activation reported from pilot clinical studies using 5-HT1A agonists as adjunct to antipsychotic treatments. Recent antipsychotics, including clozapine and aripiprazole, exhibit different levels of 5-HT1A receptor partial agonism and may, therefore, differentially elicit hippocampal adult neurogenesis and increases in prefrontal cortex dopamine. We suggest that comparative studies should elucidate correlations between effects of antipsychotics on adult neurogenesis and prefrontal cortex dopamine with effects on performance in translational cognitive tasks known to involve new born neurons, such as tasks involving pattern separation, and working memory tasks sensitive to prefrontal cortex dopamine levels. © 2014 Elsevier Inc.


Van den Ouweland J.M.W.,Canisius Wilhelmina Hospital | Kema I.P.,University of Groningen
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2012

Liquid chromatography coupled to mass spectrometry (LC-MS/MS) is increasingly used as a routine methodology in clinical laboratories for the analysis of low molecular weight molecules. The high specificity in combination with high sensitivity and multi-analyte potential makes it an attractive complementary method to traditional methodology used for routine applications. Its strength and weaknesses in this context will be discussed and examples of successful clinical applications will be given. For LC-MS/MS to truly fulfil its promise in clinical diagnosis, the prerequisite steps being sample pre-treatment, chromatographic separation and detection by selected reaction monitoring must become more integrated as they are in conventional clinical analysers. The availability of ready-to-use reagents kits, eliminating efforts needed for method development and extensive validation, are likely to contribute to a wider acceptance of LC-MS/MS in clinical laboratories. Growing applicability of LC-MS/MS in the clinical laboratory field is expected from quantitative protein analysis. © 2011 Elsevier B.V..


Haydar D.,University of Groningen
Diversity and Distributions | Year: 2012

Aim Cryptogenic species may include those taxa that were historically introduced and are now falsely viewed as native. Investigated here is the scale of cryptogenesis in the North Atlantic Ocean by examining disjunct distributions, defined as temperate species occurring only on both sides of the North Atlantic. Disjunct distributions can be explained by four scenarios: glacial relicts, taxonomic artefacts, natural trans-oceanic dispersal and human-mediated introduction. Location North Atlantic Ocean. Methods Model taxa included ascidians, bivalves and hydrozoans. Biogeographic status (native, introduced or cryptogenic) was assigned to all species exhibiting a disjunct distribution, based upon multiple criteria. Results Of 1030 species, 60 have a strictly disjunct distribution. Of these disjunct species, for five species there is no reason to doubt their native status, and 55 species are cryptogenic or introduced. Groups with high relative dispersal capacities do not have disjunct distributions more often. Infaunal bivalves have the lowest relative number of disjunct species; none are cryptogenic or naturally disjunct. This supports the concept that glaciations are unlikely to cause disjunct distributions: there are no studies that provide conclusive evidence for the glacial relict model. Hydrozoa have the highest relative number of disjunct species, which, while historically explained by undocumented rafting, may more likely be the result of dispersal by ships, which travel relatively fast, are independent of currents and provide greater surface area. Main conclusions This reanalysis of the historical biogeography of the North Atlantic marine biota reveals that far more species may have been introduced than previously recognized, potentially significantly altering our fundamental understanding of community evolution and ecology. Species that have been present for centuries and can be important ecological engineers who have shaped contemporary communities are possibly falsely viewed as native: they may in fact be the unrecognized introductions of historical times. © 2011 Blackwell Publishing Ltd.


Dubinsky L.,Ben - Gurion University of the Negev | Krom B.P.,University of Groningen | Meijler M.M.,Ben - Gurion University of the Negev
Bioorganic and Medicinal Chemistry | Year: 2012

Diazirines are among the smallest photoreactive groups that form a reactive carbene upon light irradiation. This feature has been widely utilized in photoaffinity labeling to study ligand-receptor, ligand-enzyme and protein-protein interactions, and in the isolation and identification of unknown proteins. This review summarizes recent advances in the use of diazirines in photoaffinity labeling. © 2010 Elsevier Ltd. All rights reserved.


Casini A.,Ecole Polytechnique Federale de Lausanne | Casini A.,University of Groningen
Journal of Inorganic Biochemistry | Year: 2012

The peculiar chemical properties of metal-based drugs impart innovative pharmacological profiles to this class of therapeutic and diagnostic agents, most likely in relation to novel molecular mechanisms still poorly understood. However, inorganic drugs have been scarcely considered for medicinal applications with respect to classical organic compounds due to the prejudice of the relevant toxic effects evidenced in certain cases. Thus, the development of improved metallodrugs requires clearer understanding of their physiological processing and molecular basis of actions. Among the various issues in the area of medicinal inorganic chemistry, the possibility of target elucidation is essential for the identification of new therapeutic applications for metal compounds or as molecular biological tools. Here we present the results of our recent research in the field, which in our opinion constitute the basis of a systematic and interdisciplinary approach to address some of the critical issues in the study of the molecular mechanisms of metallodrugs' action via the implementation of high-resolution biophysical techniques coupled with more pharmacological methods. © 2011 Elsevier Inc. All rights reserved.


Lunsing R.J.,University of Groningen
Seminars in Perinatology | Year: 2014

Subtle bilirubin-induced neurological dysfunction (BIND) is defined as disturbances in sensory and sensorimotor integration, central auditory processing, coordination, and muscle tone in the absence of the classical findings of kernicterus. This review is restricted to the (sensori)motor signs of BIND associated with unconjugated hyperbilirubinemia in term and late preterm neonates. The diagnosis of BIND at follow-up requires validated, age-specific techniques that are designed to identify these disturbances in infancy and later childhood. The (sensori)motor signs of BIND are compatible with the pathological substrate of unconjugated hyperbilirubinemia and its known effects on the brain. © 2014 Elsevier Inc.


Kiel J.A.K.W.,University of Groningen
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Cells need a constant supply of precursors to enable the production of macromolecules to sustain growth and survival. Unlike metazoans, unicellular eukaryotes depend exclusively on the extracellular medium for this supply. When environmental nutrients become depleted, existing cytoplasmic components will be catabolized by (macro)autophagy in order to re-use building blocks and to support ATP production. In many cases, autophagy takes care of cellular housekeeping to sustain cellular viability. Autophagy encompasses a multitude of related and often highly specific processes that are implicated in both biogenetic and catabolic processes. Recent data indicate that in some unicellular eukaryotes that undergo profound differentiation during their life cycle (e.g. kinetoplastid parasites and amoebes), autophagy is essential for the developmental change that allows the cell to adapt to a new host or form spores. This review summarizes the knowledge on the molecular mechanisms of autophagy as well as the cytoplasm-to-vacuole-targeting pathway, pexophagy, mitophagy, ER-phagy, ribophagy and piecemeal microautophagy of the nucleus, all highly selective forms of autophagy that have first been uncovered in yeast species. Additionally, a detailed analysis will be presented on the state of knowledge on autophagy in non-yeast unicellular eukaryotes with emphasis on the role of this process in differentiation. © 2010 The Royal Society.


Sinkeler S.J.,University of Groningen
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | Year: 2011

Accurate glomerular filtration rate (GFR) measurement in normal to high range is important for epidemiological studies and workup for kidney donation. Creatinine-based equations perform poorly in this GFR range. Creatinine clearance (CrCl) provides a substitute, provided urine is collected accurately and tubular creatinine handling can be accounted for. The latter is poorly characterized in the normal GFR range. Therefore, we studied performance of CrCl, fractional creatinine excretion (FE(creat)) and its determinants in 226 potential kidney donors (47% males, mean 53 ± 10 years). GFR was assessed as (125)I-iothalamate clearance, simultaneously with 2-h CrCl and 24-h CrCl. Mean GFR was 101 ± 18, 2-h CrCl 110 ± 20 and 24-h CrCl 106 ± 29 mL/min/1.73 m(2). Mean bias of 24 h CrCl was 7.4 [inter-quartile range -6.7 to 20.0] mL/min/1.73 m(2), precision (R(2)) 0.39 and 30% accuracy 82%. Mean FE(creat) was 110 ± 11%. FE(creat) correlated with body mass index (BMI) (r = 0.34, P < 0.001). Consequently, bias of 24-h CrCl increased from 2.7 (inter-quartile range -6.5 to 16.7) to 8.6 (inter-quartile range -5.8 to 20.5) and 12.6 (inter-quartile range 7.0 to 25.4) mL/min in subjects with BMI <25, 25-30 and >30 kg/m(2), respectively (P < 0.05). On multivariate analysis, BMI and gender were predictors of FE(creat). CrCl systematically overestimates GFR in healthy subjects. The overestimation significantly correlates with BMI, with higher FE(creat) in subjects with higher BMI. The impact of BMI on tubular creatinine secretion can be accounted for, when using CrCl for GFR assessment in the normal to high range, by the following formula: GFR = 24-h CrCl - (22.75 + 0.76 × BMI - 0.29 × mean arterial pressure (-6.11 if female).


Dirksz D.A.,TU Eindhoven | Scherpen J.M.A.,University of Groningen
Automatica | Year: 2012

Power-based modeling was originally developed in the early sixties to describe a large class of nonlinear electrical RLC networks, in a special gradient form. Recently this idea has been extended for modeling and control of a larger class of physical systems. In this paper, first, coordinate transformations are introduced for systems described in this framework, such that the physical structure is preserved. Such a transformation can provide new insights for both analysis and control design. Second, power-based integral and adaptive control schemes are presented. Advantages of these schemes are shown by their application on standard mechanical systems. © 2012 Elsevier Ltd. All rights reserved.


Curtain R.F.,University of Groningen
Automatica | Year: 2012

Recently, the class of spatially invariant systems was introduced with motivating examples of partial differential equations on an infinite domain. For these it was shown that by taking Fourier transforms, one obtains infinitely many finite-dimensional systems with a scalar parameter. The idea is that, for the LQR controller design for these systems, one can solve the parameterized LQR-Riccati equation pointwise. While for simple first order systems like the heat equations this approach works, for second order systems like wave or beam equations it is easy to construct examples for which this approach fails. Here we give a correct formulation for second order partial differential systems including wave and beam type equations. © 2011 Elsevier Ltd. All rights reserved.


Schuurhuis J.M.,University of Groningen
British Journal of Cancer | Year: 2016

Background:Leukaemic patients receiving intensive chemotherapy and patients undergoing autologous stem-cell transplantation (ASCT) are routinely screened for oral foci of infection to reduce infectious complications that could occur during therapy. In this prospective study we assessed the effect of leaving chronic oral foci of infection untreated on the development of infectious complications in intensively treated haematological patients.Methods:We included and prospectively evaluated all intensively treated leukaemic patients and patients undergoing ASCT who were referred to our medical centre between September 2012 and May 2014, and who matched the inclusion/exclusion criteria. Acute oral foci of infection were removed before chemotherapy or ASCT, whereas chronic oral foci were left untreated.Results:In total 28 leukaemic and 35 ASCT patients were included. Acute oral foci of infection were found in 2 leukaemic (7%) and 2 ASCT patients (6%), and chronic oral foci of infection in 24 leukaemic (86%) and 22 ASCT patients (63%). Positive blood cultures with microorganisms potentially originating from the oral cavity occurred in 7 patients during treatment, but were uneventful on development of infectious complications.Conclusions:Our prospective study supports the hypothesis that chronic oral foci of infection can be left untreated as this does not increase infectious complications during intensive chemotherapy.British Journal of Cancer advance online publication, 22 March 2016; doi:10.1038/bjc.2016.60 www.bjcancer.com. © 2016 Cancer Research UK


Kahya N.,University of Groningen
Biochimica et Biophysica Acta - Biomembranes | Year: 2010

Giant Unilamellar Vesicles (GUVs) provide a key model membrane system to study lipid-lipid and lipid-protein interactions, which are relevant to vital cellular processes, by (single-molecule) optical microscopy. Here, we review the work on reconstitution techniques for membrane proteins and other preparation methods for developing GUVs towards most suitable close-to-native membrane systems. Next, we present a few applications of protein-containing GUVs to study domain assembly and protein partitioning into raft-like domains. © 2010 Elsevier B.V.


Mulder G.M.,University of Groningen
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | Year: 2012

Interstitial fibrosis and tubular atrophy (IF/TA) is an important cause of renal function loss and ischaemia-reperfusion (I/R) injury is considered to play an important role in its pathophysiology. The aim of the present study was to investigate the role of a disintegrin and metalloproteinase 17 (ADAM17) in human renal allograft disease and in experimental I/R injury of the kidney. We studied the expression of ADAM17 messenger RNA (mRNA) in IF/TA and control kidneys by reverse transcription-polymerase chain reaction and in situ hybridization. Moreover, we assessed ADAM17-mediated heparin-binding epidermal growth factor (HB-EGF) shedding in immortalized human cells. Finally, we studied the effect of pharmacological ADAM17 inhibition in a model of renal I/R injury in rats. ADAM17 mRNA was up-regulated in IF/TA when compared to control kidneys. In normal kidneys, ADAM17 mRNA was weakly expressed in proximal tubules, peritubular capillaries, glomerular endothelium and parietal epithelium. In IF/TA, tubular, capillary and glomerular ADAM17 expression was strongly enhanced with de novo expression in the mesangium. In interstitial fibrotic lesions, we observed co-localization of ADAM17 with HB-EGF protein. In vitro, inhibition of ADAM17 with TNF484 resulted in a dose-dependent reduction of HB-EGF shedding in phorbol 12-myrisate 13-acetate-stimulated cells and non-stimulated cells. In vivo, ADAM17 inhibition significantly reduced the number of glomerular and interstitial macrophages at Day 4 of reperfusion. In conclusion, HB-EGF co-expresses with ADAM17 in renal interstitial fibrosis, suggesting a potential interaction in IF/TA. Targeting ADAM17 to reduce epidermal growth factor receptor phosphorylation could be a promising way of intervention in human renal disease.


Mulder M.,University of Groningen
Energy Journal | Year: 2015

We assess the development of competition in the Dutch electricity wholesale market over 2006-2011. In this period domestic generation capacity, both centralized and decentralized, as well as the cross-border transmission capacity increased. Using hourly plant-level data of centralized units and engineering-costs estimates, we estimate the weighted average Lerner index. During super peak hours, the annual average value of this index decreased from 0.23 in 2006 to 0.03 in 2011, indicating more competition. We find indications that the increase in competition can be attributed to the extension of cross-border connections, a higher price elasticity of net demand and more Bertrand-like competition. Enhancing the role of decentralized generation as well as fostering integration of markets seem to be effective measures to promote competition. Copyright © 2015 by the IAEE. All rights reserved.


de Faria P.,University of Groningen | Sofka W.,University of Tilburg
Research Policy | Year: 2010

International knowledge spillovers, especially through multinational companies (MNCs), have recently been a major topic of discussion among academics and practitioners. Most research in this field focuses on knowledge sharing activities of MNC subsidiaries. Relatively little is known about their capabilities for protecting valuable knowledge from spilling over to host country competitors. We extend this stream of research by investigating both formal protection strategies (e.g. patenting) as well as strategic ones (secrecy, lead time, complex design). We conceptualize the breadth of firm's knowledge protection strategies and relate it to the particular situation of MNC subsidiaries. Moreover, we argue that their approaches differ with regard to host country challenges and opportunities. We address these issues empirically, based on a harmonized survey of innovation activities of more than 1800 firms located in Portugal and Germany. We find evidence that MNCs prefer broader sets of knowledge protection strategies in a host country with fewer opportunities for knowledge sourcing (Portugal). In Germany, though, they opt for narrower sets of knowledge protection strategies if they invest in innovation activities themselves. We deduce that these results are due to a need for reciprocity in knowledge exchanges to benefit fully from promising host country knowledge flows. © 2010 Elsevier B.V. All rights reserved.


Graham T.,University of Groningen
Journal of Information Technology and Politics | Year: 2012

Net-based public sphere researchers have examined online deliberation in numerous ways. However, most studies have focused exclusively on political discussion forums. This article moves beyond such spaces by analyzing political talk from an online forum dedicated to reality television. The purpose is to examine the democratic quality of political talk that emerges in this space in light of a set of normative criteria of the public sphere. The analysis also moved beyond an elite model of deliberation by investigating the use of expressives (humor, emotional comments, and acknowledgments). The findings reveal that participants engaged in political talk that was often deliberative. It was a space where the use of expressives played a significant role in enhancing such talk. © 2012 Copyright Taylor and Francis Group, LLC.


Harison E.,University of Groningen | Koski H.,The Research Institute of the Finnish economics ETLA
Research Policy | Year: 2010

Our study aims at shedding light on the innovative business strategies in the software sector and understanding better the economics that underlies the supply of Open Source Software (OSS). We use survey data collected from 170 Finnish software companies to investigate how different properties of software firms, such as size, age, intellectual capital, absorptive capacity, and ownership structure affect their decisions to base their business strategies on OSS supply or proprietary distribution of products and services. Our empirical findings indicate that the adoption of technologically advanced strategies requiring complex legal and managerial knowledge, such as the OSS supply strategy, demands relatively highly educated employees. The support for and development of an education system providing highly skilled people from different fields are essential for the firms' successful adoption of innovative business strategies. We also find that market entrants have largely driven the OSS adoption, but there are no significant age-related differences in the adoption behavior of incumbent software firms. © 2010 Elsevier B.V. All rights reserved.


In situations of serious uncertain risk, precautionary assessment, decision-making and control may be inevitable. In this paper, the long and wide-ranging debate about the precautionary principle (PP) is surveyed in comparison to parallel developments of classical risk analysis. The 'new risks' provoking precaution typically are complex, often extensive in space and time, socially diverse, supposedly unlikely but highly uncertain, and potentially catastrophic. Classical risk analysis falls short of grasping such ill-defined problems validly enough for effective policy support. Similarly, the 'prudent' PP is criticised for its vagueness, multiple meanings and lack of practical elaboration. Despite their differences, however, risk-analytic and precautionary-principled approaches seem to be converging. On the way towards a decision-theoretic exposition (see follow-up paper), an integrative circumscription of the PP is proposed, which comprises 10 key issues for further elaboration. Logically, the 'pessimistic' PP is contrasted with its 'optimistic' counterpart, the venture principle (VP), which may be equally rational and/or inevitable in particular uncertain decision situations. © 2010 Taylor & Francis.


Kocer A.,University of Groningen
Current Opinion in Chemical Biology | Year: 2015

Sensing and responding to mechanical stimuli is an ancient behavior and ubiquitous to all forms of life. One of its players 'mechanosensitive ion channels' are involved in processes from osmosensing in bacteria to pain in humans. However, the mechanism of mechanosensing is yet to be elucidated. This review describes recent developments in the understanding of a bacterial mechanosensitive channel. Force from the lipid principle of mechanosensation, new methods to understand protein-lipid interactions, the role of water in the gating, the use of engineered mechanosensitive channels in the understanding of the gating mechanism and application of the accumulated knowledge in the field of drug delivery, drug design and sensor technologies are discussed. © 2015 Elsevier Ltd.


Gerkema M.P.,University of Groningen
Proceedings. Biological sciences / The Royal Society | Year: 2013

In 1942, Walls described the concept of a 'nocturnal bottleneck' in placental mammals, where these species could survive only by avoiding daytime activity during times in which dinosaurs were the dominant taxon. Walls based this concept of a longer episode of nocturnality in early eutherian mammals by comparing the visual systems of reptiles, birds and all three extant taxa of the mammalian lineage, namely the monotremes, marsupials (now included in the metatherians) and placentals (included in the eutherians). This review describes the status of what has become known as the nocturnal bottleneck hypothesis, giving an overview of the chronobiological patterns of activity. We review the ecological plausibility that the activity patterns of (early) eutherian mammals were restricted to the night, based on arguments relating to endothermia, energy balance, foraging and predation, taking into account recent palaeontological information. We also assess genes, relating to light detection (visual and non-visual systems) and the photolyase DNA protection system that were lost in the eutherian mammalian lineage. Our conclusion presently is that arguments in favour of the nocturnal bottleneck hypothesis in eutherians prevail.


Hut R.A.,University of Groningen
Proceedings. Biological sciences / The Royal Society | Year: 2013

Properties of the circadian and annual timing systems are expected to vary systematically with latitude on the basis of different annual light and temperature patterns at higher latitudes, creating specific selection pressures. We review literature with respect to latitudinal clines in circadian phenotypes as well as in polymorphisms of circadian clock genes and their possible association with annual timing. The use of latitudinal (and altitudinal) clines in identifying selective forces acting on biological rhythms is discussed, and we evaluate how these studies can reveal novel molecular and physiological components of these rhythms.


Der Zee D.-J.V.,University of Groningen
Decision Support Systems | Year: 2011

Petri Nets have essential strengths in capturing a system's static structure and dynamics, its mathematical underpinning, and providing a graphical representation. However, visual simulation models of realistic systems based on Petri Nets are often perceived as too large and too complex to be easily understood. This constrains stakeholders in participating in such modeling and solution finding, and limits acceptance. We address this issue by considering a structured approach for guiding the analyst in creating more insightful models. Key elements are a domain-related reference architecture that supports conceptual modeling coupled with uniform rules for mapping high-level concepts onto low-level Petri Net components. The proposed approach is implemented and illustrated in the manufacturing domain. © 2010 Elsevier B.V. All rights reserved.


Bulmer A.C.,Griffith University | Verkade H.J.,University of Groningen | Wagner K.-H.,Griffith University | Wagner K.-H.,University of Vienna
Progress in Lipid Research | Year: 2013

Gilbert's syndrome (GS) is characterized by a benign, mildly elevated bilirubin concentration in the blood. Recent reports show clear protection from cardiovascular disease in this population. Protection of lipids, proteins and other macromolecules from oxidation by bilirubin represents the most commonly accepted mechanism contributing to protection in this group. However, a recent meta-analysis estimated that bilirubin only accounts for ∼34% of the cardioprotective effects within analysed studies. To reveal the additional contributing variables we have explored circulating cholesterol and triacylglycerol concentrations, which appear to be decreased in hyperbilirubinemic individuals/animals, and are accompanied by lower body mass index in highly powered studies. These results suggest that bilirubin could be responsible for the development of a lean and hypolipidemic state in GS. Here we also discuss the possible contributing mechanisms that might reduce circulating cholesterol and triacylglycerol concentrations in individuals with syndromes affecting bilirubin metabolism/excretion, which we hope will stimulate future research in the area. In summary, this article is the first review of lipid status in animal and human studies of hyperbilirubinemia and explores possible mechanisms that could contribute to lowering circulating lipid parameters and further explain cardiovascular protection in Gilbert's syndrome. © 2013 Elsevier Ltd. All rights reserved.


Renne B.,University of Groningen
Journal of Logic and Computation | Year: 2011

Justification Logic is a framework for reasoning about evidence and justification in multi-agent systems. Most accounts of Justification Logic are essentially static, in that the (justified) beliefs of agents are immutable. In this article, we add public communication, a dynamic operation of belief change studied in the area of Dynamic Epistemic Logic, to the language of Justification Logic. Introducing notions of bisimulation for the languages of Justification Logic with and without public communication, we catalogue the expressive relationships that exist between almost all of the well-known static fragments of Justification Logic and then determine whether the addition of public communication affects the various expressive relationships existing between these fragments. © 2010 The Author.


Back I.H.,University of Groningen
Evolution and Human Behavior | Year: 2010

Evidence across the social and behavioral sciences points to psychological mechanisms that facilitate the formation and maintenance of interpersonal commitment. In addition, evolutionary simulation studies suggest that a tendency for increased, seemingly irrational commitment is an important trait of successful exchange strategies. However, empirical research that tests corresponding psychological mechanisms is still largely lacking. Here an experimental test is proposed for one such mechanism, termed the commitment bias, which is hypothesized to increase people's commitment to existing partners beyond instrumental reasons. To exclude one alternative explanation, the commitment bias is distinguished from uncertainty reduction. Results from a cross-culturally replicated laboratory experiment (USA, China, and the Netherlands) provide support for the argument but also point to the importance of culture as an alternative or mediating factor. © 2010 Elsevier Inc. All rights reserved.


Lamoth C.J.,University of Groningen
Studies in health technology and informatics | Year: 2011

The combination of active video gaming and exercise (exergaming) is suggested to improve elderly people's balance, thereby decreasing fall risk. Exergaming has been shown to increase motivation during exercise therapy, due to the enjoyable and challenging nature, which could support long-term adherence for exercising balance. However, scarce evidence is available of the direct effects of exergaming on postural control. Therefore, the aim of the study was to assess the effect of a six-week videogame-based exercise program aimed at improving balance in elderly people. Task performance and postural control were examined using an interrupted time series design. Results of multilevel analyses showed that performance on the dot task improved within the first two weeks of training. Postural control improved during the intervention. After the intervention period task performance and balance were better than before the intervention. Results of this study show that healthy elderly can benefit from a videogame-based exercise program to improve balance and that all subjects were highly motivated to exercise balance because they found gaming challenging and enjoyable.


Garcia-Fernandez A.,University of Groningen
Metal ions in life sciences | Year: 2012

The unique chiral structure and the highly specific Watson-Crick base-pairing interactions that characterize natural double-stranded DNA, make this natural biopolymer an attractive ligand for asymmetric catalytic processes. In this chapter the applications of DNA as scaffold and chiral ligand in enantioselective transition metal catalysis are presented. An overview of the state of the art for the different approaches to metal-DNA based catalysts is given, followed by an overview of the mechanistic studies that have been performed to date.


Courteau S.,Kingston University | Cappellari M.,University of Oxford | De Jong R.S.,Leibniz Institute for Astrophysics Potsdam | Dutton A.A.,Max Planck Institute for Astronomy | And 8 more authors.
Reviews of Modern Physics | Year: 2014

Galaxy masses play a fundamental role in our understanding of structure formation models. This review addresses the variety and reliability of mass estimators that pertain to stars, gas, and dark matter. The different sections on masses from stellar populations, dynamical masses of gas-rich and gas-poor galaxies, with some attention paid to our Milky Way, and masses from weak and strong lensing methods all provide review material on galaxy masses in a self-consistent manner. © 2014 American Physical Society.


Scalisi M.,University of Groningen
Journal of High Energy Physics | Year: 2015

We provide a unified description of cosmological α-attractors and late-time acceleration, in excellent agreement with the latest Planck data. Our construction involves two superfields playing distinctive roles: one is the dynamical field and its evolution determines inflation and dark energy, the other is nilpotent and responsible for a landscape of vacua and supersymmetry breaking. We prove that the attractor nature of the theory is enhanced when combining the two sectors: cosmological attractors are very stable with respect to any possible value of the cosmological constant and, interestingly, to any generic coupling of the inflationary sector with the field responsible for uplifting. Finally, as related result, we show how specific couplings generate an arbitrary inflaton potential in a supergravity framework with varying Kähler curvature. © 2015, The Author(s).


Stamps J.A.,University of California at Davis | Groothuis T.G.G.,University of Groningen
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Developmental processes can have major impacts on the correlations in behaviour across contexts (contextual generality) and across time (temporal consistency) that are the hallmarks of animal personality. Personality can and does change: at any given age or life stage it is contingent upon a wide range of experiential factors that occurred earlier in life, from prior to conception through adulthood. We show how developmental reaction norms that describe the effects of prior experience on a given behaviour can be used to determine whether the effects of a given experience at a given age will affect contextual generality at a later age, and to illustrate how variation within individuals in developmental plasticity leads to variation in contextual generality across individuals as a function of experience. We also show why niche-picking and niche-construction, behavioural processes which allow individuals to affect their own developmental environment, can affect the contextual generality and the temporal consistency of personality. We conclude by discussing how an appreciation of developmental processes can alert behavioural ecologists studying animal personality to critical, untested assumptions that underlie their own research programmes, and outline situations in which a developmental perspective can improve studies of the functional significance and evolution of animal personality. © 2010 The Royal Society.


Kallenberg C.G.M.,University of Groningen
Current Opinion in Rheumatology | Year: 2016

Purpose of review Antineutrophil cytoplasmic autoantibodies (ANCAs) are considered important diagnostic tests in the workup of patients suspected of vasculitis. Here we discuss new developments in the methodology of testing, the pitfalls in using these tests as diagnostic tools, and the value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis including treatment decisions. Recent findings Both the indirect immunofluorescence (IIF) test and antigen-specific assays should be performed. New methodologies include automated reading in the IIF test and third-generation assays (anchor ELISA and bead-based multiplex assay) for the antigenic-specific assays. ANCA testing should be done in the right clinical context as positive results for PR3-ANCA and MPO-ANCA do occur in other conditions than vasculitis as well. These ANCAs develop in about 10% of patients with infective endocarditis. The occurrence of drug-induced ANCA and ANCA, also directed against elastase, following use of levamisoleadulterated cocaine should be recognized. In the right clinical context, ANCA are highly sensitive and specific for their associated disease. The value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis is still under discussion but may be relevant in patients with renal involvement and in patients treated with rituximab. Summary The techniques for ANCA testing improve further but new tests should be standardized and validated. Their diagnostic value in the right clinical context is undisputed. Their value for the follow-up of patients is still under discussion. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.


Wang Z.,University of Groningen
Current Opinion in Lipidology | Year: 2016

PURPOSE OF REVIEW: The gut microbiome has now been convincingly linked to human metabolic health but the underlying causality and mechanisms remain poorly understood. This review focuses on the recent progress in establishing the associations between gut microbiome species and lipid metabolism in humans and discusses how to move from association toward causality and mechanistic understanding, which is essential knowledge to bring the observed associations into clinical use. RECENT FINDINGS: Recent population-based association studies have shown that the gut microbiota composition can explain a substantial proportion of the interindividual variation in blood triglycerides and HDL-cholesterol level and predict metabolic response to diet and drug. Faecal transplantation has suggested that this is a causal effect of microbiome on host metabolism, although the underlying mechanism remains largely unexplored. SUMMARY: The gut microbiome is transitioning from being a ‘missing’ organ to a potential target for therapeutic applications. Due to the complex interplay between the gut microbiome, the host genome, and diet, a systematic approach is required to pave the way for therapeutic development. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Yu H.,University of Groningen
The Angle orthodontist | Year: 2011

The hypothesis of the present study is that overexpression of osteoprotegerin (OPG) promotes preosteoblast maturation. The preosteoblast cell line MC3T3-E1 was transfected with OPG overexpression. OPG expression was confirmed by enzyme-linked immunosorbent assay (ELISA) and Western blot. Changes in the transcription factors in OPG-expressing cells were assessed by real-time polymerase quantitative polymerase chain reaction (RT-qPCR). Alkaline phosphate (ALP) expression was measured by ELISA. The success of stable transfection of MC3T3-E1 cells with OPG overexpression was confirmed by MoFlow sorting followed by G418 selection. RT-qPCR showed that expression of RunX2, the most important osteoblast differentiation controlling factor, was suppressed. Smad1 and Akt1, as well as ALP, were upregulated in the OPG overexpressing cells. Results from the present study provide evidence that overexpression of OPG in preosteoblasts promotes its differentiation into mature osteoblasts.


Bertossa R.C.,University of Groningen
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Development and evolution of animal behaviour and morphology are frequently addressed independently, as reflected in the dichotomy of disciplines dedicated to their study distinguishing object of study (morphology versus behaviour) and perspective (ultimate versus proximate). Although traits are known to develop and evolve semi-independently, they are matched together in development and evolution to produce a unique functional phenotype. Here I highlight similarities shared by both traits, such as the decisive role played by the environment for their ontogeny. Considering the widespread developmental and functional entanglement between both traits, many cases of adaptive evolution are better understood when proximate and ultimate explanations are integrated. A field integrating these perspectives is evolutionary developmental biology (evo-devo), which studies the developmental basis of phenotypic diversity. Ultimate aspects in evo-devo studies-which have mostly focused on morphological traits-could become more apparent when behaviour, 'the integrator of form and function', is integrated into the same framework of analysis. Integrating a trait such as behaviour at a different level in the biological hierarchy will help to better understand not only how behavioural diversity is produced, but also how levels are connected to produce functional phenotypes and how these evolve. A possible framework to accommodate and compare form and function at different levels of the biological hierarchy is outlined. At the end, some methodological issues are discussed. © 2011 The Royal Society.


Kok R.M.,Parnassia Psychiatric Institute | Heeren T.J.,Symfora Group Centres of Mental Health Care | Nolen W.A.,University of Groningen
American Journal of Geriatric Psychiatry | Year: 2011

Objective: To establish the efficacy and tolerability of continuing treatment with antidepressants in preventing relapses and recurrences in elderly depressed patients and to analyze differences between tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Design: The authors conducted a systematic literature search to identify all randomized, placebo-controlled, double-blinded clinical trials (RCTs) in elderly patients. Data were pooled from eight double-blinded RCTs of continuation and maintenance treatment in the elderly with 925 participating patients. Results: The number of patients needed to treat (NNT) for antidepressants to prevent one additional relapse or recurrence was 3 6 (95% confidence interval [CI]: 2.8-4.8). The NNT for TCAs was 2.9 (95% CI: 2.2-4.6), compared with a NNT for SSRIs of 4.2 (95% CI: 3.2-5.9). In the five studies that provide drop out data, 14 of 330 patients (4.2%) using an antidepressant dropped out due to side effects compared with 17 of 330 patients (5.2%) using a placebo (x = 0.305, df = 1, p = 0.581). Tolerability did not differ between TCAs and SSRIs. Conclusion: Continuing treatment with anti-depressants in elderly patients is efficacious compared with placebo in preventing relapses and recurrences. Efficacy and tolerability during long-term treatment does not differ between TCAs and SSRIs. © 2011 American Association for Geriatric Psychiatry.


Although NOD-SCID IL2Rγ-/- (NSG) xenograft mice are currently the most frequently used model to study human leukemia in vivo, the absence of a human niche severely hampers faithful recapitulation of the disease. We used NSG mice in which ceramic scaffolds seeded with human mesenchymal stromal cells were implanted to generate a human bone marrow (huBM-sc)-like niche. We observed that, in contrast to the murine bone marrow (mBM) niche, the expression of BCR-ABL or MLL-AF9 was sufficient to induce both primary acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). Stemness was preserved within the human niches as demonstrated by serial transplantation assays. Efficient engraftment of AML MLL-AF9 and blast-crisis chronic myeloid leukemia patient cells was also observed, whereby the immature blast-like phenotype was maintained in the huBM-sc niche but to a much lesser extent in mBM niches. We compared transcriptomes of leukemias derived from mBM niches versus leukemias from huBM-like scaffold-based niches, which revealed striking differences in the expression of genes associated with hypoxia, mitochondria and metabolism. Finally, we utilized the huBM-sc MLL-AF9 B-ALL model to evaluate the efficacy of the I-BET151 inhibitor in vivo. In conclusion, we have established human niche models in which the myeloid and lymphoid features of BCR-ABL+ and MLL-AF9+ leukemias can be studied in detail.Leukemia advance online publication, 17 May 2016; doi:10.1038/leu.2016.108. © 2016 Macmillan Publishers Limited


The ground- and the lowest singlet excited-state potential energy surfaces of the bis-thiaxanthylidene (3) molecular switch are investigated using a density functional method specifically designed to treat molecular systems typified by strong non-dynamic electron correlation. The results of the theoretical calculations suggest that the unique ability of substituted bis-thiaxanthylidenes to switch between three states of luminescence-non- fluorescent state, blue fluorescent state, and red fluorescent state-can be explained by specific features on the excited state potential energy surface: the potential barrier around the Franck-Condon point of the anti-folded conformer and the existence of conical intersection in the vicinity of the syn-folded conformer. It is suggested that the twisted conformer, if made more stable via chemical modification, should fluoresce in the near-infrared region (λ≈740-760 nm), thus offering a possibility for a four-state switching of luminescence in a single-component molecular system. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


van der Klei I.J.,University of Groningen
Sub-cellular biochemistry | Year: 2013

Peroxisomes are ubiquitous and versatile cell organelles. They consist of a single membrane that encloses a proteinaceous matrix. Conserved functions are fatty acid β-oxidation and hydrogen peroxide metabolism. In filamentous fungi, many other metabolic functions have been identified. Also, they contain highly specialized peroxisome-derived structures termed Woronin bodies, which have a structural function in plugging septal pores in order to prevent cytoplasmic bleeding of damaged hyphae.In filamentous fungi peroxisomes play key roles in the production of a range of secondary metabolites such as antibiotics. Most likely the atlas of fungal peroxisomal metabolic pathways is still far from complete. Relative recently discovered functions include their role in biotin biosynthesis as well as in the production of several toxins, among which polyketides. Finally, in filamentous fungi peroxisomes are important for development and pathogenesis.In this contribution we present an overview of our current knowledge on fungal peroxisome formation as well as on their functional diversity.


Fawcett T.W.,University of Groningen | Johnstone R.A.,University of Cambridge
Proceedings of the Royal Society B: Biological Sciences | Year: 2010

Winner and loser effects, in which the outcome of an aggressive encounter influences the tendency to escalate future conflicts, have been documented in many taxa, but we have limited understanding of why they have evolved. One possibility is that individuals use previous victories and defeats to assess their fighting ability relative to others. We explored this idea by modelling a population of strong and weak individuals that do not know their own strength, but keep track of how many fights they have won. Under these conditions, adaptive behaviour generates clear winner and loser effects: individuals who win fights should escalate subsequent conflicts, whereas those who lose should retreat from aggressive opponents. But these effects depend strongly on age and experience. Young, naive individuals should show highly aggressive behaviour and pronounced loser effects. For these inexperienced individuals, fighting is especially profitable because it yields valuable information about their strength. Aggression should then decline as an individual ages and gains experience, with those who lose fights becoming more submissive. Older individuals, who have a better idea of their own strength, should be more strongly influenced by victories than losses. In conclusion, we predict that both aggressiveness and the relative magnitude of winner and loser effects should change with age, owing to changes in how individuals perceive their own strength. © 2010 The Royal Society.


Can modified natural cycle IVF or ICSI (MNC) be a cost-effective alternative for controlled ovarian hyperstimulation IVF or ICSI (COH)? The comparison of simulated scenarios indicates that a strategy of three to six cycles of MNC with minimized medication is a cost-effective alternative for one cycle of COH with strict application of single embryo transfer (SET). MNC is cheaper per cycle than COH but also less effective in terms of live birth rate (LBR). However, strict application of SET in COH cycles reduces effectiveness and up to three MNC cycles can be performed at the same costs as one COH cycle. The cost-effectiveness of MNC versus COH was evaluated in three simulated treatment scenarios: three cycles of MNC versus one cycle of COH with SET or double embryo transfer (DET) and subsequent transfer of cryopreserved embryos (Scenario 1); six cycles of MNC versus one cycle of COH with strictly SET and subsequent transfer of cryopreserved embryos (Scenario 2); six cycles of MNC with minimized medication (hCG ovulation trigger only) versus one cycle of COH with SET or DET and subsequent transfer of cryopreserved embryos (Scenario 3). We used baseline data obtained from two retrospective cohorts of consecutive patients (2005-2008) undergoing MNC in the University Medical Center Groningen (n = 499, maximum six cycles per patient) or their first COH cycle with subsequent transfer of cryopreserved embryos in the Academic Medical Center Amsterdam (n = 392). Data from 1994 MNC cycles (958 MNC-IVF and 1036 MNC-ICSI) and 392 fresh COH cycles (one per patient, 196 COH-IVF and 196 COH-ICSI) with subsequent transfer of cryopreserved embryos (n = 72 and n = 94 in MNC and COH cycles, respectively) in ovulatory, subfertile women <36 years of age served as baseline for the three simulated scenarios. To compare the scenarios, the incremental cost-effectiveness ratio (ICER) was calculated, defined as the ratio of the difference in IVF costs up to 6 weeks postpartum to the difference in LBR. Live birth was the primary outcome measure and was defined as the birth of at least one living child after a gestation of ≥25 weeks. In the baseline data, MNC was not cost-effective, as COH dominated MNC with a higher cumulative LBR (27.0 versus 24.0%) and lower cost per patient (€3694 versus €5254). The simulations showed that in scenario 1 three instead of six cycles lowered the costs of MNC to below the level of COH (€3390 versus €3694, respectively), but also lowered the LBR per patient (from 24.0 to 16.2%, respectively); Scenario 2: COH with strict SET was less effective than six cycles MNC (LBR 17.5 versus 24.0%, respectively), but also less expensive per patient (€2908) than MNC (€5254); Scenario 3: improved the cost-effectiveness of MNC but COH still dominated MNC when medication was minimized in terms of costs, i.e. €855 difference in favor of COH and 3% difference in LBR in favor of COH (ICER: €855/-3.0%). Owing to the retrospective nature of the study, the analyses required some assumptions, for example regarding the costs of pregnancy and delivery, which had to be based on the literature rather than on individual data. Furthermore, costs of IVF treatment were based on tariffs and not on actual costs. Although this may limit the external generalizability of the results, the limitations will influence both treatments equally, and would therefore not bias the comparison of MNC versus COH. The combined results suggest that MNC with minimized medication might be a cost-effective alternative for COH with strict SET. The scenarios reflect realistic alternatives for daily clinical practice. A preference for MNC depends on the willingness to trade off effectiveness in terms of LBR against the benefits of a milder stimulation regimen, including a very low rate of multiple pregnancies and hyperstimulation syndrome and ensuing lower costs per live birth. The study was supported by research grants from Merck Serono and Ferring Pharmaceuticals. The authors declare no conflicts of interest. Not applicable.


The number of hematopoietic stem cells (HSCs) that contributes to blood formation and the dynamics of their clonal contribution is a matter of ongoing discussion. Here, we use cellular barcoding combined with multiplex high-throughput sequencing to provide a quantitative and sensitive analysis of clonal behavior of hundreds of young and old HSCs. The majority of transplanted clones steadily contributes to hematopoiesis in the long-term, although clonal output in granulocytes, T cells, and B cells is substantially different. Contributions of individual clones to blood are dynamically changing; most of the clones either expand or decline with time. Finally, we demonstrate that the pool of old HSCs is composed of multiple small clones, whereas the young HSC pool is dominated by fewer, but larger, clones.


Borst J.P.,Carnegie Mellon University | Borst J.P.,University of Groningen | Anderson J.R.,Carnegie Mellon University
NeuroImage | Year: 2015

In this paper we propose a new method for identifying processing stages in human information processing. Since the 1860s scientists have used different methods to identify processing stages, usually based on reaction time (RT) differences between conditions. To overcome the limitations of RT-based methods we used hidden semi-Markov models (HSMMs) to analyze EEG data. This HSMM-EEG methodology can identify stages of processing and how they vary with experimental condition. By combining this information with the brain signatures of the identified stages one can infer their function, and deduce underlying cognitive processes. To demonstrate the method we applied it to an associative recognition task. The stage-discovery method indicated that three major processes play a role in associative recognition: a familiarity process, an associative retrieval process, and a decision process. We conclude that the new stage-discovery method can provide valuable insight into human information processing. © 2014 Elsevier Inc.


This article presents a history of the early electroencephalography (EEG) of psychopathy, delinquency, and immorality in Great Britain and the United States in the 1940s and 1950s. Then, EEG was a novel research tool that promised ground-breaking insights in psychiatry and criminology. Experts explored its potential regarding the diagnosis, classification, etiology, and treatment of unethical and unlawful persons. This line of research yielded tentative and inconsistent findings, which the experts attributed to methodological and theoretical shortcomings. Accordingly, the scientific community discussed the reliability, validity, and utility of EEG, and launched initiatives to calibrate and standardize the novel tool. The analysis shows that knowledge production, gauging of the research tool, and attempts to establish credibility for EEG in the study of immoral persons occurred simultaneously. The paper concludes with a reflection on the similarities between EEG and neuroimaging-the prime research tool in the current neuroscience of morality-and calls for a critical assessment of their potentials and limitations in the study of immorality and crime. © 2014 Schirmann.


Yu W.,Nanjing Southeast University | Yu W.,RMIT University |