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Zurich, Switzerland

The University of Zurich , located in the city of Zürich, is the largest university in Switzerland, with over 26,000 students. It was founded in 1833 from the existing colleges of theology, law, medicine and a new faculty of philosophy.Currently, the university has 7 faculties: Philosophy, Human Medicine, Economic science, Law, Mathematics and Natural science, Theology and Veterinary Medicine. The university offers the widest range of subjects and courses at any Swiss higher education institution. Wikipedia.


Eckardt K.-U.,Friedrich - Alexander - University, Erlangen - Nuremberg | Devuyst O.,University of Zurich | Johnson R.J.,University of Colorado at Denver | Kottgen A.,University Hospital Freiburg | And 2 more authors.
The Lancet | Year: 2013

Summary In the past decade, kidney disease diagnosed with objective measures of kidney damage and function has been recognised as a major public health burden. The population prevalence of chronic kidney disease exceeds 10%, and is more than 50% in high-risk subpopulations. Independent of age, sex, ethnic group, and comorbidity, strong, graded, and consistent associations exist between clinical prognosis and two hallmarks of chronic kidney disease: reduced glomerular filtration rate and increased urinary albumin excretion. Furthermore, an acute reduction in glomerular filtration rate is a risk factor for adverse clinical outcomes and the development and progression of chronic kidney disease. An increasing amount of evidence suggests that the kidneys are not only target organs of many diseases but also can strikingly aggravate or start systemic pathophysiological processes through their complex functions and effects on body homoeostasis. Risk of kidney disease has a notable genetic component, and identified genes have provided new insights into relevant abnormalities in renal structure and function and essential homoeostatic processes. Collaboration across general and specialised health-care professionals is needed to fully address the challenge of prevention of acute and chronic kidney disease and improve outcomes. © 2013 Elsevier Ltd.


Freisinger E.,University of Zurich
Metal ions in life sciences | Year: 2013

Metallothioneins (MTs) are low-molecular-mass cysteine-rich proteins with the ability to bind mono- and divalent metal ions with the electron configuration d ( 10 ) in form of metal-thiolate clusters. MTs are thought, among others, to play a role in the homeostasis of essential Zn(II) and Cu(I) ions. Besides these metal ions also Cd(II) can be bound to certain MTs in vivo, giving rise to the perception that another physiological role of MTs is in the detoxification of heavy metal ions. Substitution of the spectroscopically silent Zn(II) ions in metalloproteins by Cd(II) proved to be an indispensable tool to probe the Zn(II) sites in vitro. In this review, methods applied in the studies of structural and chemical properties of Cd-MTs are presented. The first section focuses on the physical basis of spectroscopic techniques such as electronic absorption, circular dichroism (CD), magnetic CD, X-ray absorption, and perturbed angular correlation of γ-rays spectroscopy, as well as mass spectrometry, and their applications to Cd-MTs from different organisms. The following is devoted to the discussion of metal binding affinities of Cd-MTs, cluster dynamics, the reactivity of bound Cd(II) ions with metal ion chelators and of thiolate ligands with alkylating and oxidizing agents. Finally, a brief summary of the known three-dimensional structures of Cd-MTs, determined almost exclusively by multinuclear NMR techniques, is presented. Besides Cd-MTs, the described methods can also be applied to the study of metal binding sites in other metalloproteins.


Weiss D.,University of Zurich | Lang F.R.,Friedrich - Alexander - University, Erlangen - Nuremberg
Psychology and Aging | Year: 2012

Age becomes an important self-defining aspect particularly during advanced age. With increasing age, negative attributes related to age and aging become salient. Aging-related declines, losses, as well as the finitude of life seem to threaten older adults' sense of self. We hypothesize that older adults will try to avoid the negative consequences of their age group membership by distancing themselves from their age group. Study 1 (N = 544, 65% women; 18-85 years of age) examined the role of age-group identification for self-conception and self-image (subjective age and future time perspective) across the life span. Results show that weakly identified older adults feel younger than their chronological age and report a more expanded future time perspective relative to their same-age counterparts. A second experiment (N = 68, 69% women; 65-85 years of age) tested the impact of age stereotypes on older adults' level of age-group identification. Results suggest that older adults are more likely to psychologically dissociate themselves from their age group when negative age stereotypes are salient. Discussion focuses on (mal)adaptive consequences of age-group dissociation in later adulthood. © 2011 American Psychological Association.


Baudis L.,University of Zurich
Physics of the Dark Universe | Year: 2012

Direct dark matter searches are promising techniques to identify the nature of dark matter particles. I describe the future of this field of research, focussing on the question of what can be achieved in the next decade. I will present the main techniques and R&D projects that will allow to build so-called ultimate WIMP detectors, capable of probing spin-independent interactions down to the unimaginably low cross section of 10 48 cm 2, before the irreducible neutrino background takes over. If a discovery is within the reach of a near-future dark matter experiment, these detectors will be able to constrain WIMP properties such as its mass, scattering cross section and possibly spin. With input from the LHC and from indirect searches, direct detection experiments will hopefully allow to determine the local density and to constrain the local phase-space structure of our dark matter halo. © 2012 Elsevier B.V.


Excessive production of reactive oxygen species (ROS) contributes to progression of atherosclerosis, at least in part by causing endothelial dysfunction and inflammatory activation. The class III histone deacetylase SIRT1 has been implicated in extension of lifespan. In the vasculature,SIRT1 gain-of-function using SIRT1 overexpression or activation has been shown to improve endothelial function in mice and rats via stimulation of endothelial nitric oxide (NO) synthase (eNOS). However, the effects of SIRT1 loss-of-function on the endothelium in atherosclerosis remain to be characterized. Thus, we have investigated the endothelial effects of decreased endogenous SIRT1 in hypercholesterolemic ApoE-/- mice. We observed no difference in endothelial relaxation and eNOS (Ser1177) phosphorylation between 20-week old male atherosclerotic ApoE-/- SIRT1+/- and ApoE-/- SIRT1+/+ mice. However, SIRT1 prevented endothelial superoxide production, inhibited NF-kappaB signaling, and diminished expression of adhesion molecules. Treatment of young hypercholesterolemic ApoE-/- SIRT1+/- mice with lipopolysaccharide to boost NF-kappaB signaling led to a more pronounced endothelial expression of ICAM-1 and VCAM-1 as compared to ApoE-/- SIRT1+/+ mice. In conclusion, endogenous SIRT1 diminishes endothelial activation in ApoE-/- mice, but does not affect endothelium-dependent vasodilatation.


Ballmer-Weber B.K.,University of Zurich
Chemical Immunology and Allergy | Year: 2015

In young children, food allergy is usually acquired via the gastrointestinal tract and directed toward egg and milk. Adolescent and adult patients, however, mainly acquire food allergy via primary sensitization to inhalant allergens on the basis of cross-reactivity between proteins in inhalant sources and in food. This type of food allergy is frequently mediated by sensitization to broadly represented allergens, or so-called panallergens. Food allergic reactions in adult patients - similar to those in children - range in severity from very mild and local symptoms, as in contact urticaria of the oral mucosa, to systemic symptoms involving distal organs, to a fatal outcome. Plant foods, such as fruits, nuts, and vegetables, are the most prevalent allergenic foods in this age group. © 2015 S. Karger AG, Basel.


Schmitt B.,University of Zurich
Neuropediatrics | Year: 2015

Sleep and epilepsy have a close relationship. About 20% of patients suffer seizures only during the night, approximately 40% only during the day and approximately 35% during the day and night. In certain epilepsy syndromes, the occurrence of seizures is strongly related to sleep or awakening. Infantile spasms appear predominately on awakening, and hypsarrhythmia is sometimes visible only in sleep. Children with Panayiotopoulos syndrome or benign epilepsy with centrotemporal spikes (BECTS) have seizures mostly when asleep, and in both syndromes interictal spike waves are markedly accentuated in slow wave sleep. Electrical status epilepticus during slow sleep/continuous spike wave discharges during sleep (ESES/CSWS), atypical benign partial epilepsy, and Landau-Kleffner syndrome are epileptic encephalopathies with substantial behavioral and cognitive deficits, various seizures, and continuous spike-wave activity during non-rapid eye movement (NREM) sleep. The hallmark of juvenile myoclonic epilepsy and grand mal seizures on awakening are seizure symptoms within 2 hours after awakening, often provoked by sleep deprivation. Nocturnal frontal lobe epilepsy is sometimes mistaken for parasomnia. Differentiation is possible when the clinical symptoms and the frequency of the paroxysmal events per night and month are carefully observed and nocturnal video electroencephalography (EEG) performed. Sleep EEG recordings may be helpful in patients with suspected epilepsy and nonconclusive awake EEG. Depending on the clinical question, sleep recordings should be performed during nap (natural sleep or drug induced), during the night, or after sleep deprivation. © 2015 Georg Thieme Verlag KG Stuttgart New York.


Kowalewski M.P.,University of Zurich
Reproductive Biology | Year: 2014

Canine reproductive physiology exhibits several unusual features. Among the most interesting of these are the lack of an acute luteolytic mechanism, coinciding with the apparent luteal independency of a uterine luteolysin in absence of pregnancy, contrasting with the acute prepartum luteolysis observed in pregnant animals. These features indicate the existence of mechanisms different from those in other species for regulating the extended luteal regression observed in non-pregnant dogs, and the actively regulated termination of luteal function observed prepartum as a prerequisite for parturition. Nevertheless, the supply of progesterone (P4) depends on corpora lutea (CL) as its primary source in both conditions, resulting in P4 levels that are similar in pregnant and non-pregnant bitches during almost the entire luteal life span prior to the prepartum luteolysis. Consequently, the duration of the prolonged luteal phase in non-pregnant bitches frequently exceeds that of pregnant ones, which is a peculiarity when compared with other domestic animal species. Both LH and prolactin (PRL) are endocrine luteotrophic factors in the dog, the latter being the predominant one. In spite of increased availability of these hormones, luteal regression/luteolysis still takes place. Recently, possible mechanisms regulating the expression and function of PRL receptor have been implicated in the local, i.e., intraluteal regulation of PRL bioavailability and thus its steroidogenic potential. Similar mechanisms may relate to the luteal LH receptor. Most recently, evidence has been provided for an autocrine/paracrine role of prostaglandin E2 (PGE2) as a luteotrophic factor in the canine CL acting at the level of steroidogenic acute regulatory (STAR)-protein mediated supply of steroidogenic substrate, without having a significant impact on the enzymatic activity of the respective steroidogenic enzymes, 3β-hydroxysteroid-dehydrogenase (3βHSD, HSD3B2) and cytochrome P450 side-chain cleavage enzyme (P450scc, CYP11A1). Together with the strongly time-dependent expression of prostaglandin transporter, luteal prostaglandins seem to be involved more in the process of luteal formation than in termination of CL function in the dog. The possible roles of other factors such as vasoactive compounds, growth factors or cytokines have not been extensively studied but should not be neglected. © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn.


Massen J.J.M.,University of Vienna | Koski S.E.,University of Zurich
Evolution and Human Behavior | Year: 2014

Several recent studies show that animal friendships, like human friendships, are durable and have fitness benefits by increasing survival, infant survival, or reproductive success. However, the determinants of especially non-kin friendships are unclear. Human non-kin friendships are partly determined by similarity in personality. We investigated personality similarity of friends in 38 captive chimpanzees. Within-subject comparisons revealed that friends are more similar than non-friends in their Sociability and Boldness. Subsequent analyses, including both kin- and non-kin dyads, revealed higher similarity in Sociability among all individuals who sat in contact more often, while in Boldness and Grooming Equity the positive effect of similarity was only found in non-kin individuals' contact-sitting. Our results show that similar to humans, chimpanzees' friendships are related to homophily in certain personality characteristics, particularly those relevant for socio-positive and cooperative behaviour. We suggest that having friends similar to self in personality decreases uncertainty in interactions by promoting reliability especially in cooperative contexts, and is consequently adaptive. Further, we suggest that homophily in human friendships dates back at least to our last common ancestor with chimpanzees. © 2014 Elsevier Inc.


Rajendran L.,University of Zurich | Annaert W.,Center for Human Genetics euven
Traffic | Year: 2012

Membrane proteins are constantly being trafficked in cells and the relevant proteins in Alzheimer's disease (AD), such as the amyloid precursor protein (APP) and its processing enzymes, are not exempted from that. Molecular cell biologists have been endeavoring to ascertain a roadmap for APP processing and trafficking in various cell types including neurons. This has led to the identification of numerous regulatory sorting mechanisms, protein-protein interactions and lipidic microenvironments that largely define how and where the substrate APP meets its processing enzymes. However, the cell biology of tau, and the formation of neurofibrillary tangles, has long been regarded as a separate field. Nonetheless, recent progress is bringing both worlds together in a new paradigm on how Aβ toxicity and tau are physiologically connected. Here, we discuss an update of our current appraisal on how membrane trafficking may play an important role in the pathogenesis of the disease and how this could be exploited for effective therapy. © 2012 John Wiley & Sons A/S.


Greber U.F.,University of Zurich
Biophysical Journal | Year: 2014

During replication, the physical state of a virus is controlled by assembly and disassembly processes, when particles are put together and dismantled by cellular cues, respectively. A fundamental question has been how a cell can assemble an infectious virus, and dismantle a virus entering an uninfected cell and thereby trigger a new round of infection. This apparent paradox might be explained by considering that infected and uninfected cells are functionally different, or that assembly and disassembly take place along different cellular pathways. A third possibility is that the physical properties of newly assembled viruses are different from the infection-ready viruses. Recent biophysical experiments measured the stiffness of single Influenza viruses and combined this with biochemical measurements and cell biological assays. Besides inducing the fusogenic state of hemagglutinin, low pH cues softened the virus and precluded aggregation of viral ribonucleoprotein particles with the matrix protein M1. The recent experiments suggest a two-step model for Influenza virus entry and uncoating involving low pH in early and late endosomes, respectively. I conclude with a short outlook into how combined biophysical and cell biological approaches might lead to the identification of new cellular cues controlling viral uncoating and infection. © 2014 Biophysical Society.


Akdis C.A.,University of Zurich
Nature Medicine | Year: 2012

Current therapies for asthma and allergy are relatively safe and effective at controlling symptoms but do not change the chronic course of disease. There is no established method to prevent asthma and allergy, and major unmet needs in this area include the better control of the severe forms of these diseases and the developments of curative therapies. Two major therapeutic strategies for asthma and allergy are currently being developed, and I here discuss the advances and challenges for future therapeutic development in these two areas. The first approach, allergen-specific immunotherapy, aims to induce specific immune tolerance and has a long-term disease-modifying effect. The second approach is the use of biological immune response modifiers to decrease pathological immune responses. Combination strategies using both of these approaches may also provide a route for addressing the unmet clinical needs in allergic diseases. © 2012 Nature America, Inc. All rights reserved.


Hennet T.,University of Zurich
Biochimica et Biophysica Acta - General Subjects | Year: 2012

Background: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. Scope of review: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. Major conclusions: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. General significance: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics. © 2012 Elsevier B.V. All rights reserved.


Kellenberger C.J.,University of Zurich
Pediatric radiology | Year: 2010

Although anomalies of the aortic arch and its branches are relatively uncommon malformations, they are often associated with congenital heart disease. Isolated lesions may be clinically significant when the airways are compromised by a vascular ring. In this article, the development and imaging appearance of the aortic arch system and its various malformations are reviewed.


Torgerson P.R.,University of Zurich
Bulletin of the World Health Organization | Year: 2013

Objective To estimate the global burden of congenital toxoplasmosis (CT), which results from infection of pregnant women with Toxoplasma gondii. Methods The authors systematically searched 9 major databases for published and unpublished sources and established direct contact with the authors of source materials. Searches were country-specific. To be included, studies had to report on the incidence of CT, on positivity to Toxoplasma-specific IgM in infants and pregnant women (including seroconversion results) or on positivity to Toxoplasma-specific IgG in the general population. Various modelling techniques were used, depending on the country-specific data available, to estimate the CT incidence and burden in each country. These data were then synthesized into an estimate of the global incidence of CT and of the global burden of CT in disability-adjusted life years (DALYs). Findings The global annual incidence of congenital toxoplasmosis was estimated to be 190 100 cases (95% credible interval, CI: 179 300-206 300). This was equivalent to a burden of 1.20 million DALYs (95% CI: 0.76-1.90). High burdens were seen in South America and in some Middle Eastern and low-income countries. Conclusion Congenital toxoplasmosis poses a substantial burden of poor health globally. Toxoplasmosis should be included in future updates of the global burden of disease and the corresponding data should be used to support public health interventions to reduce disease burden.


Barton M.,University of Zurich | Prossnitz E.R.,University of New Mexico
Trends in Endocrinology and Metabolism | Year: 2015

The G protein-coupled estrogen receptor (GPER) is a 7-transmembrane receptor implicated in rapid estrogen signaling. Originally cloned from vascular endothelial cells, GPER plays a central role in the regulation of vascular tone and cell growth as well as lipid and glucose homeostasis. This review highlights our knowledge of the physiological and pathophysiological functions of GPER in the pancreas, peripheral and immune tissues, and the arterial vasculature. Recent findings on its roles in obesity, diabetes, and atherosclerosis, including GPER-dependent regulation of lipid metabolism and inflammation, are presented. The therapeutic potential of targeting GPER-dependent pathways in chronic diseases such as coronary artery disease and diabetes and in the context of menopause is also discussed. © 2015 Elsevier Ltd.


Pessi G.,University of Zurich
PloS one | Year: 2013

B. cenocepacia is an opportunistic human pathogen that is particularly problematic for patients suffering from cystic fibrosis (CF). In the CF lung bacteria grow to high densities within the viscous mucus that is limited in oxygen. Pseudomonas aeruginosa, the dominant pathogen in CF patients, is known to grow and survive under oxygen-limited to anaerobic conditions by using micro-oxic respiration, denitrification and fermentative pathways. In contrast, inspection of the genome sequences of available B. cenocepacia strains suggested that B. cenocepacia is an obligate aerobic and non-fermenting bacterium. In accordance with the bioinformatics analysis we observed that B. cenocepacia H111 is able to grow with as little as 0.1% O2 but not under strictly anoxic conditions. Phenotypic analyses revealed that H111 produced larger amounts of biofilm, pellicle and proteases under micro-oxic conditions (0.5%-5% O2, i.e. conditions that mimic those encountered in CF lung infection), and was more resistant to several antibiotics. RNA-Seq and shotgun proteomics analyses of cultures of B. cenocepacia H111 grown under micro-oxic and aerobic conditions showed up-regulation of genes involved in the synthesis of the exopolysaccharide (EPS) cepacian as well as several proteases, two isocitrate lyases and other genes potentially important for life in micro-oxia. RNA-Seq raw data files are accessible through the GEO Series accession number GSE48585. MS data have been deposited in the ProteomeXchange database (PXD000270).


Hottiger M.O.,University of Zurich
Annual Review of Biochemistry | Year: 2015

Protein ADP-ribosylation is an ancient posttranslational modification with high biochemical complexity. It alters the function of modified proteins or provides a scaffold for the recruitment of other proteins and thus regulates several cellular processes. ADP-ribosylation is governed by ADP-ribosyltransferases and a subclass of sirtuins (writers), is sensed by proteins that contain binding modules (readers) that recognize specific parts of the ADP-ribosyl posttranslational modification, and is removed by ADP-ribosylhydrolases (erasers). The large amount of experimental data generated and technical progress made in the last decade have significantly advanced our knowledge of the function of ADP-ribosylation at the molecular level. This review summarizes the current knowledge of nuclear ADP-ribosylation reactions and their role in chromatin plasticity, cell differentiation, and epigenetics and discusses current progress and future perspectives. Copyright © 2015 by Annual Reviews. All rights reserved.


Hess B.J.M.,University of Zurich
Journal of Neurophysiology | Year: 2013

Although the motion of the line of sight is a straightforward consequence of a particular rotation of the eye, it is much trickier to predict the rotation underlying a particular motion of the line of sight in accordance with Listing's law. Helmholtz's notion of the direction-circle together with the notion of primary and secondary reference directions in visual space provide an elegant solution to this reverse engineering problem, which the brain is faced with whenever generating a saccade. To test whether these notions indeed apply for saccades, we analyzed three-dimensional eye movements recorded in four rhesus monkeys. We found that on average saccade trajectories closely matched with the associated direction-circles. Torsional, vertical, and horizontal eye position of saccades scattered around the position predicted by the associated direction-circles with standard deviations of 0.5°, 0.3°, and 0.4°, respectively. Comparison of saccade trajectories with the likewise predicted fixed-axis rotations yielded mean coefficients of determinations (±SD) of 0.72 (±0.26) for torsion, 0.97 (±0.10) for vertical, and 0.96 (±0.11) for horizontal eye position. Reverse engineering of three-dimensional saccadic rotations based on visual information suggests that motor control of saccades, compatible with Listing's law, not only uses information on the fixation directions at saccade onset and offset but also relies on the computation of secondary reference positions that vary from saccade to saccade. © 2013 the American Physiological Society.


Objectives: IgM antibodies are usually the first to be produced during treponemal infection. Three commercially available enzyme immunoassays (EIA) for detection of IgM antibodies against Treponema pallidum were evaluated. Methods: Results of the Anti-Treponema-pallidum-ELISA (IgM; Euroimmun), Pathozyme Syphilis M Capture (Omega Diagnostics) and recomWell Treponema IgM (Mikrogen) were compared with those of the T. pallidum particle agglutination (TPPA) and the Venereal Disease Research Laboratory (VDRL) tests for 307 serum samples. Results: The overall sensitivity (95% confidence interval [CI]) of the TPPA was 100% (97.7-100%) compared to 83.3% (76.5-88.8%) of the VDRL, 88.5% (82.4-93.0%) of the Pathozyme, 84.6% (78.0-89.9) of the Euroimmun, and 73.6% (66.1-80.4%) of a modified recomWell test procedure. Specificities were in the range of 91.4-100%. In primary syphilis, sensitivities of the Pathozyme (89.8%; 95% CI, 79.2-96.2%) and Euroimmun tests (81.4%; 95% CI, 69.1-90.3%) were significantly higher (p<0.05) than the sensitivity of the VDRL test (61%; 95% CI, 47.4-73.5%). IgM EIAs even were positive in some cases of suspected very early infection where the VDRL was non-reactive and the TPPA was indeterminate. Conclusions: In cases of suspected early infection specific IgM EIAs should be used in addition to other screening tests. The VDRL is not recommended for screening. © 2013 The British Infection Association.


Borsig L.,University of Zurich
Blood | Year: 2015

In this issue of Blood, Bauer et al1 provide an explanation for the formation of luminal von Willebrand factor (VWF) fibers observed in cancer patients, which is initiated through tumor-derived vascular endothelial growth factor-A (VEGF-A). Platelet aggregation on VWF fibers correlated with a prothrombic state associated with decreased a disintegrin-like and metalloproteinase with thrombospondin type I repeats 13 (ADAMTS13) activity in cancer patients © 2015 by The American Society of Hematology.


Gredeback G.,Uppsala University | Daum M.M.,University of Zurich
Child Development Perspectives | Year: 2015

In this article, we review recent evidence of infants' early competence in perceiving and interpreting the actions of others. We present a theoretical model that decomposes the timeline of action perception into a series of distinct processes that occur in a particular order. Once an agent is detected, covert attention can be allocated to the future state of the agent (priming), which may lead to overt gaze shifts that predict goals (prediction). Once these goals are achieved, the consequence of the agents' actions and the manner in which the actions were performed can be evaluated (evaluation). We propose that all of these processes have unique requirements, both in terms of timing and cognitive resources. To understand more fully the rich social world of infants, we need to pay more attention to the temporal structure of social perception and ask what information is available to infants and how this changes over time. © 2015 The Authors.


Vayena E.,University of Zurich
Journal of Medical Ethics | Year: 2015

Direct-to-consumer (DTC) genetic services have generated enormous controversy from their first emergence. A dramatic recent manifestation of this is the Food and Drug Administration's (FDA) cease and desist order against 23andMe, the leading provider in the market. Critics have argued for the restrictive regulation of such services, and even their prohibition, on the grounds of the harm they pose to consumers. Their advocates, by contrast, defend them as a means of enhancing the autonomy of those same consumers. Autonomy emerges as a key battle-field in this debate, because many of the 'harm' arguments can be interpreted as identifying threats to autonomy. This paper assesses whether DTC genomic services are a threat to, or instead, an enhancement of, personal autonomy. It deploys Joseph Raz's account of personal autonomy, with its emphasis on choice from a range of valuable options. It then seeks to counter claims that DTC genomics threatens autonomy because it involves manipulation in contravention of consumers' independence or because it does not generate valuable options which can be meaningfully engaged with by consumers. It is stressed that the value of the options generated by DTC genomics should not be judged exclusively from the perspective of medical actionability, but should take into consideration plural utilities. Finally, the paper ends by broaching policy recommendations, suggesting that there is a strong autonomy-based argument for permitting DTC genomic services, and that the key question is the nature of the regulatory conditions under which they should be permitted. The discussion of autonomy in this paper helps illuminate some of these conditions.


Gehrmann T.,University of Zurich | Greiner N.,Max Planck Institute for Physics | Heinrich G.,Max Planck Institute for Physics
Physical Review Letters | Year: 2013

We compute the cross section for the production of a high-mass photon pair in association with two hadronic jets to next-to-leading order in quantum chromodynamics. Our results allow us for the first time to reliably predict the absolute normalization of this process and demonstrate that the shape of important kinematical distributions is modified by higher-order effects. The perturbative corrections will be an important ingredient in precision studies of Higgs boson properties from its production in association with two jets. © 2013 American Physical Society.


Pinto-Carbo M.,University of Zurich
ISME Journal | Year: 2016

Bacteria of the genus Burkholderia establish an obligate symbiosis with plant species of the Rubiaceae and Primulaceae families. The bacteria, housed within the leaves, are transmitted hereditarily and have not yet been cultured. We have sequenced and compared the genomes of eight bacterial leaf nodule symbionts of the Rubiaceae plant family. All of the genomes exhibit features consistent with genome erosion. Genes potentially involved in the biosynthesis of kirkamide, an insecticidal C7N aminocyclitol, are conserved in most Rubiaceae symbionts. However, some have partially lost the kirkamide pathway due to genome erosion and are unable to synthesize the compound. Kirkamide synthesis is therefore not responsible for the obligate nature of the symbiosis. More importantly, we find evidence of intra-clade horizontal gene transfer (HGT) events affecting genes of the secondary metabolism. This indicates that substantial gene flow can occur at the early stages following host restriction in leaf nodule symbioses. We propose that host-switching events and plasmid conjugative transfers could have promoted these HGTs. This genomic analysis of leaf nodule symbionts gives, for the first time, new insights in the genome evolution of obligate symbionts in their early stages of the association with plants. © 2016 International Society for Microbial Ecology


Jaeggi A.V.,University of Zurich | Gurven M.,University of California at Santa Barbara
Evolutionary Anthropology | Year: 2013

The study of cooperation is rich with theoretical models and laboratory experiments that have greatly advanced our knowledge of human uniqueness, but have sometimes lacked ecological validity. We therefore emphasize the need to tie discussions of human cooperation to the natural history of our species and its closest relatives, focusing on behavioral contexts best suited to reveal underlying selection pressures and evolved decision rules. Food sharing is a fundamental form of cooperation that is well-studied across primates and is particularly noteworthy because of its central role in shaping evolved human life history, social organization, and cooperative psychology. Here we synthesize available evidence on food sharing in humans and other primates, tracing the origins of offspring provisioning, mutualism, trade, and reciprocity throughout the primate order. While primates may gain some benefits from sharing, humans, faced with more collective action problems in a risky foraging niche, expanded on primate patterns to buffer risk and recruit mates and allies through reciprocity and signaling, and established co-evolving social norms of production and sharing. Differences in the necessity for sharing are reflected in differences in sharing psychology across species, thus helping to explain unique aspects of our evolved cooperative psychology. © 2013 Wiley Periodicals, Inc.


Hartnack S.,University of Zurich
Veterinary Anaesthesia and Analgesia | Year: 2014

Method comparison studies are needed for validation of new methods of measurements, for example, non-invasive blood pressure measurements against standard reference methods. After a brief introduction into method comparison studies, this paper is organized in three sections. The first section deals with the widely, though not always appropriately, used classical Bland-Altman plot with the limits of agreement and its extensions with non-constant bias and multiple observations. The second section comments on other statistical approaches including correlation coefficients, linear regressions and sensitivities and specificities which are sometimes seen in method comparison studies. The third section proposes the usage of linear mixed effects models as a flexible way to deal with questions associated with method comparison studies. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.


Jelkmann W.,University of Lubeck | Lundby C.,University of Zurich
Blood | Year: 2011

Hemoglobin mass is a key factor for maximal exercise capacity. Some athletes apply prohibited techniques and substances with intent to increase hemoglobin mass and physical performance, and this is often difficult to prove directly. Autologous red blood cell transfusion cannot be traced on reinfusion, and also recombinant erythropoietic proteins are detectable only within a certain timeframe. Novel erythropoietic substances, such as mimetics of erythropoietin (Epo) and activators of the Epo gene, may soon enter the sports scene. In addition, Epo gene transfer maneuvers are imaginable. Effective since December 2009, the World Anti-Doping Agency has therefore implemented "Athlete Biologic Passport Operating Guidelines," which are based on the monitoring of several parameters for mature red blood cells and reticulocytes. Blood doping may be assumed, when these parameters change in a nonphysiologic way. Hematologists should be familiar with blood doping practices as they may play an important role in evaluating blood profiles of athletes with respect to manipulations, as contrasted with the established diagnosis of clinical disorders and genetic variations. © 2011 by The American Society of Hematology.


Pfeifer R.,University of Zurich | Iida F.,ETH Zurich | Lungarella M.,Dynamic Devices AG
Trends in Cognitive Sciences | Year: 2014

Traditionally, in cognitive science the emphasis is on studying cognition from a computational point of view. Studies in biologically inspired robotics and embodied intelligence, however, provide strong evidence that cognition cannot be analyzed and understood by looking at computational processes alone, but that physical system-environment interaction needs to be taken into account. In this opinion article, we review recent progress in cognitive developmental science and robotics, and expand the notion of embodiment to include soft materials and body morphology in the big picture. We argue that we need to build our understanding of cognition from the bottom up; that is, all the way from how our body is physically constructed. © 2014 Elsevier Ltd.


Vigeolas H.,University of Liege | Huhn D.H.,University of Zurich | Geigenberger P.,Ludwig Maximilians University of Munich
Plant Physiology | Year: 2011

Nonsymbiotic hemoglobins are ubiquitously expressed in plants and divided into two different classes based on gene expression pattern and oxygen-binding properties. Most of the published research has been on the function of class 1 hemoglobins. To investigate the role of class 2 hemoglobins, transgenic Arabidopsis (Arabidopsis thaliana) plants were generated overexpressing Arabidopsis hemoglobin-2 (AHb2) under the control of a seed-specific promoter. Overexpression of AHb2 led to a 40% increase in the total fatty acid content of developing and mature seeds in three subsequent generations. This was mainly due to an increase in the polyunsaturated C18:2 (ω-6) linoleic and C18:3 (ω-3) α-linolenic acids. Moreover, AHb2 overexpression led to an increase in the C18:2/C18:1 and C18:3/C18:2 ratios as well as in the C18:3 content in mol % of total fatty acids and in the unsaturation/saturation index of total seed lipids. The increase in fatty acid content was mainly due to a stimulation of the rate of triacylglycerol synthesis, which was attributable to a 3-fold higher energy state and a 2-fold higher sucrose content of the seeds. Under low external oxygen, AHb2 overexpression maintained an up to 5-fold higher energy state and prevented fermentation. This is consistent with AHb2 overexpression results in improved oxygen availability within developing seeds. In contrast to this, overexpression of class 1 hemoglobin did not lead to any significant increase in the metabolic performance of the seeds. These results provide evidence for a specific function of class 2 hemoglobin in seed oil production and in promoting the accumulation of polyunsaturated fatty acids by facilitating oxygen supply in developing seeds. © 2011 American Society of Plant Biologists.


Background. Sentinel lymph node (SLN) detection and biopsy is gaining popularity in the treatment of Head and Neck cancer. Various methods in this regard have been described, each with their respective advantages and disadvantages. The aim of this paper was to evaluate the potential application of Indocyanin Green (ICG) in the mapping and detection of sentinel lymph nodes (SLN) in cancers of the head and neck. Methods. Patients with oropharyngeal cancer and N0 neck who were scheduled for primary tumor ablation as well as a neck dissection were selected. One milliliter of Indocyanin green was injected around the tumor and the sentinel node detection was performed by aiming the infra red video camera on the cervical area. When no detection was possible transcutaneously, a cervical incision was made, a sub-platysmal flap raised and further detection was done to visualize the fluorescing lymph nodes. Results. Detection of cervical SLN was only possible when 5 mm or less tissue covered the sentinel lymph node. Accurate and clear detection of the lymph drainage pattern and SLN was possible. There is some uptake in other tissues such as the submandibular gland which is easily distinguishable from lymphatic tissue. Conclusion. Indocyanin green fluorescence is a potential valuable potential tool in the detection of SLN in patients with oropharyngeal cancer which warrants further investigation. © 2010 Bredell; licensee BioMed Central Ltd.


Gehrmann-De Ridder A.,ETH Zurich | Gehrmann T.,University of Zurich | Glover E.W.N.,Durham University | Pires J.,ETH Zurich
Physical Review Letters | Year: 2013

We report the calculation of next-to-next-to-leading order QCD corrections in the purely gluonic channel to dijet production and related observables at hadron colliders. Our result represents the first next-to-next-to-leading order calculation of a massless jet observable at hadron colliders, and opens the path towards precision QCD phenomenology with the LHC. © 2013 American Physical Society.


Jancke L.,University of Zurich
Annals of the New York Academy of Sciences | Year: 2012

This paper reports a preliminary study based on the theoretical assumption that continuous closed-loop audio-motor control could be disadvantageous for pianists. It is argued that the functional relationship between the intracerebral electrical activations in the auditory and premotor cortex should be rhythmically decreased and increased. To test this hypothesis, intracerebral electrical activations for the auditory and premotor cortex were estimated using scalp EEG and standardized low-resolution electrical tomography (sLORETA). The extracted times series were subjected to a Granger causality analysis, revealing a causal relationship from the auditory cortex to the premotor cortex that was considerably stronger during piano playing and weaker during rest. Importantly, this relationship varied rhythmically during the course of piano playing, with lags (obtained with cross-correlations) between 666 ms and 820 milliseconds. This study thus delivers evidence that the functional coupling between the auditory and premotor cortex varies during piano playing. © 2012 New York Academy of Sciences..


Rossler W.,University of Zurich | Rossler W.,Luneburg University
European Archives of Psychiatry and Clinical Neuroscience | Year: 2012

As the industrial world has transformed toward a service economy, a particular interest has developed in mental health problems at the workplace. The risk for burnout is significantly increased in certain occupations, notably for health care workers. Beyond the effects of an extensive workload, many working hours, or long night shifts, the medical field has specific stressors. Physicians work in emotionally demanding environments with patients, families, or other medical staff. They must make quick decisions while faced with a quite frequent information overload. All of these stressors have to be weighed against a rapidly changing organizational context within medicine. Today, economics objectives have priority over medical values in health care. In principal, mental health workers should experience similar work stressors and the same contextual factors as health professionals from other medical disciplines. However, several studies have identified stressors that are unique to the psychiatric profession. These challenges range from the stigma of this profession, to particularly demanding relationships with patients and difficult interactions with other mental health professionals as part of multidisciplinary teams to personal threats from violent patients. Other sources of stress are a lack of positive feedback, low pay, and a poor work environment. Finally, patient suicide is a major stressor, upon which a majority of mental health workers report post-traumatic stress symptoms. © 2012 Springer-Verlag.


Duhr C.,ETH Zurich | Duhr C.,Durham University | Gehrmann T.,University of Zurich | Gehrmann T.,University of California at Santa Barbara
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2013

The soft current describes the factorization behavior of quantum chromodynamics (QCD) scattering amplitudes in the limit of vanishing energy of one of the external partons. It is process-independent and can be expanded in a perturbative series in the coupling constant. To all orders in the dimensional regularization parameter, we compute the two-loop correction to the soft current for processes involving two hard partons. © 2013.


Many genes have several, sometimes divergent functions during development. Therefore, timing of gene knockdown for functional analysis during development has to be done with precise temporal control, as loss of a gene's function at early stages prevents its analysis later in development. RNAi, in combination with the accessibility of chicken embryos, is an effective approach for temporally controlled analysis of gene function during neural development. Here, we describe novel plasmid vectors that contain cell type-specific promoters/enhancers to drive the expression of a fluorescent marker, followed directly by a miR30-RNAi transcript for gene silencing. These vectors allow for direct tracing of cells experiencing gene silencing by the bright fluorescence. The level of knockdown is sufficient to reproduce the expected pathfinding defects upon perturbation of genes with known axon guidance functions. Mixing different vectors prior to electroporation enables the simultaneous knockdown of multiple genes in independent regions of the spinal cord. This permits complex cellular and molecular interactions to be examined during development, in a fast and precise manner. The advancements of the in ovo RNAi technique that we describe will not only markedly enhance functional gene analysis in the chicken, but also could be adapted to other organisms in developmental studies.


Helbing J.,University of Zurich
Chemical Physics | Year: 2012

When azide binds to ferric Myoglobin it forms either a low-spin or a high-spin complex, which give rise to two well-separated asymmetric stretch bands of the ligand. Both electronic excitation of the Q-band and vibrational excitation of N3- in the mid-IR lead to a similar ultrafast population redistribution in favor of the high spin configuration, which is characterized by a 8° reorientation of the ligand transition dipole moment. The more stable low spin complex subsequently re-emerges with a 18 ps time-constant. It is argued that the observed spin state changes are caused by the participation of low-lying electronic excitations in the cooling process of heme. © 2011 Elsevier B.V. All rights reserved.


Sommer L.,University of Zurich
Pigment Cell and Melanoma Research | Year: 2011

The neural crest is a transient structure in vertebrate embryos that generates multiple neural and mesenchymal cell types as well as melanocytes. Melanocytes in the skin either derive directly from neural crest cells populating the skin via a dorsolateral migratory pathway or arise by detaching from nerves innervating the skin. Several transcription factors, such as FoxD3, Sox10, Pax3, and Mitf, take part in a genetic network regulating melanocyte formation from the neural crest. The activity of these intrinsic factors is controlled and modulated by extracellular signals including canonical Wnt, Edn, Kitl, and other signals that remain to be identified. Here, we summarize the current view of how melanocytes are specified from the neural crest and put this process into the context of spatiotemporal lineage decisions in neural crest cells. © 2011 John Wiley & Sons A/S.


Schmidt B.R.,University of Zurich | Hodl W.,University of Vienna | Schaub M.,University of Bern
Ecology | Year: 2012

Performance in one stage of a complex life cycle may affect performance in the subsequent stage. Animals that start a new stage at a smaller size than conspecifics may either always remain smaller or they may be able to "catch up" through plasticity, usually elevated growth rates. We study how size at and date of metamorphosis affected subsequent performance in the terrestrial juvenile stage and lifetime fitness of spadefoot toads (Pelobates fuscus). We analyzed capture-recapture data of .3000 individuals sampled during nine years with mark-recapture models to estimate first-year juvenile survival probabilities and age-specific first-time breeding probabilities of toads, followed by model selection to assess whether these probabilities were correlated with size at and date of metamorphosis. Males attained maturity after two years, whereas females reached maturity 2-4 years after metamorphosis. Age at maturity was weakly correlated with metamorphic traits. In both sexes, first-year juvenile survival depended positively on date of metamorphosis and, in males, also negatively on size at metamorphosis. In males, toads that metamorphosed early at a small size had the highest probability to reach maturity. However, because very few toadlets metamorphosed early, the vast majority of male metamorphs had a very similar probability to reach maturity. A matrix projection model constructed for females showed that different juvenile life history pathways resulted in similar lifetime fitness. We found that the effects of date of and size at metamorphosis on different juvenile traits cancelled each other out such that toads that were small or large at metamorphosis had equal performance. Because the costs and benefits of juvenile life history pathways may also depend on population fluctuations, ample phenotypic variation in life history traits may be maintained. © 2012 by the Ecological Society of America.


Mohler H.,University of Zurich
Biochemical Pharmacology | Year: 2012

The cognitive deficits in Down syndrome (DS) are attributed to an excessive hippocampal inhibition, which obstructs neuronal plasticity and normal learning and memory, a view which is largely based on studies of Ts65Dn mice, the best characterized mouse model of DS. The cognitive behavioral deficits of Ts65Dn mice can be rescued by reducing GABAergic inhibition, most selectively by partial inverse agonists acting on α5 GABA-A receptors, of which one compound has recently entered clinical trials in DS. Most remarkably, the improved cognitive performance of Ts65Dn can persist for weeks and months after cessation of drug treatment, as demonstrated for the non-specific GABA antagonist pentylenetetrazole. The Alzheimer drugs, memantine and donepezil largely fail to show any benefit. Finally, repeated non-invasive sensory stimulation such as over-training or enriching the environment, are able to enhance the learning performance which underlines the reversibility of an obstructed neuronal plasticity in Ts65Dn mice. © 2012 Elsevier Inc.


Kubli E.,University of Zurich
Current Biology | Year: 2010

Pregnancy in humans induces cravings for special food: the same occurs in Drosophila females. New work now shows that mating throws a nutritional switch in favor of a high-protein diet and that modulation of nutritional balance depends on the sex peptide receptor and involves neuronal TOR-S6 kinase signaling. © 2010 Elsevier Ltd. All rights reserved.


Barton M.,University of Zurich
Acta Pharmacologica Sinica | Year: 2012

Childhood obesity has become major health concern for physicians, parents, and health agencies around the world. Childhood obesity is associated with an increased risk for other diseases not only during youth but also later in life, including diabetes, arterial hypertension, coronary artery disease, and fatty liver disease. Importantly, obesity accelerates atherosclerosis progression already in children and young adults. With regard to pathophysiological changes in the vasculature, the striking similarities between physiological changes related to aging and obesity-related abnormalities are compatible with the concept that obesity causes premature vascular aging. This article reviews factors underlying the accelerated vascular disease development due to obesity. It also highlights the importance of recognizing childhood obesity as a disease condition and its permissive role in aggravating the development of other diseases. The importance of childhood obesity for disease susceptibility later in life, and the need for prevention and treatment are also discussed. © 2012 CPS and SIMM All rights reserved.


Schaer D.J.,University of Zurich | Buehler P.W.,U.S. Food and Drug Administration | Alayash A.I.,U.S. Food and Drug Administration | Belcher J.D.,University of Minnesota | Vercellotti G.M.,University of Minnesota
Blood | Year: 2013

Hemolysis occurs in many hematologic and nonhematologic diseases. Extracellular hemoglobin (Hb) has been found to trigger specific pathophysiologies that are associated with adverse clinical outcomes in patients with hemolysis, such as acute and chronic vascular disease, inflammation, thrombosis, and renal impairment. Among the molecular characteristics of extracellular Hb, translocation of the molecule into the extravascular space, oxidative and nitric oxide reactions, hemin release, and molecular signaling effects of hemin appear to be the most critical. Limited clinical experience with a plasma-derived haptoglobin (Hp) product in Japan and more recent preclinical animal studies suggest that the natural Hb and the hemin-scavenger proteins Hp and hemopexin have a strong potential to neutralize the adverse physiologic effects of Hb and hemin. This includes conditions that are as diverse as RBC transfusion, sickle cell disease, sepsis, and extracorporeal circulation. This perspective reviews the principal mechanisms of Hb and hemin toxicity in different disease states, updates how the natural scavengers efficiently control these toxic moieties, and explores critical issues in the development of human plasma-derived Hp and hemopexin as therapeutics for patients with excessive intravascular hemolysis.


Rebholz-Schuhmann D.,European Bioinformatics Institute | Rebholz-Schuhmann D.,University of Zurich | Oellrich A.,European Bioinformatics Institute | Hoehndorf R.,University of Cambridge
Nature Reviews Genetics | Year: 2012

In response to the unbridled growth of information in literature and biomedical databases, researchers require efficient means of handling and extracting information. As well as providing background information for research, scientific publications can be processed to transform textual information into database content or complex networks and can be integrated with existing knowledge resources to suggest novel hypotheses. Information extraction and text data analysis can be particularly relevant and helpful in genetics and biomedical research, in which up-to-date information about complex processes involving genes, proteins and phenotypes is crucial. Here we explore the latest advancements in automated literature analysis and its contribution to innovative research approaches. © 2012 Macmillan Publishers Limited. All rights reserved.


Barton M.,University of Zurich
Contributions to nephrology | Year: 2011

Endothelin (ET)-1 is a powerful mitogen and vasoconstrictor that contributes to cardiovascular and renal pathologies. In the kidney, ET causes vasoconstriction, sodium retention, mesangial cell inflammation and proliferation, hypertrophy of glomerular capillaries, and podocyte injury. The latter, due to destruction of the glomerular filtration barrier, is a key factor for renal protein loss. Experimental and recent clinical studies suggest that orally active drugs inhibiting ET(A) receptors are capable of not only inhibiting the progression, but also reversing glomerulosclerosis-related renal injury. Clinical studies using ET receptor antagonists (ERAs) have found regression of proteinuria which serves as a functional indicator of glomerular filtration barrier injury. The effects of ERA therapy can be observed in the presence of inhibition of the renin-angiotensin system, suggesting arenin-angiotensin system-independent therapeutic effect of ERAs. Thus, ET blockade is not an 'add-on' treatment, but represents an independent therapeutic principle. This article will discuss the underlying mechanisms of the antiproteinuric effects of ET antagonists, and summarize recent clinical trials in the field and the therapeutic potential of the ERA class of drugs for renal medicine. Copyright © 2011 S. Karger AG, Basel.


There is ample evidence that glucose metabolism in the pregenual anterior cingulate cortex (PACC) is increased in major depressive disorder (MDD), whereas it is still unknown whether glucose levels per se are also elevated. Elevated cerebrospinal fluid (CSF) lactate concentrations in MDD patients might indicate that increased glycolytical metabolization of glucose to lactate in astrocytes either alone or in conjunction with mitochondrial dysfunction results in an accumulation of lactate and contributes to pathophysiological mechanisms of MDD. However, until now, no study investigated in vivo PACC glucose and lactate levels in MDD. Proton magnetic resonance spectroscopy was therefore used to test the hypothesis that patients with MDD have increased PACC glucose and lactate levels. In 40 healthy and depressed participants, spectra were acquired from the PACC using a maximum echo J-resolved spectroscopy protocol. Results show significant increases of glucose and lactate in patients, which are also associated with depression severity. These findings indicate impaired brain energy metabolism in MDD with increased fraction of energy utilization via glycolysis and reduced mitochondrial oxidative clearance of lactate. Targeting these metabolic disturbances might affect the balance of metabolic pathways regulating neuronal energetics and result in an attenuation of the elevated basal activity of brain regions within the neural circuitry of depression.Molecular Psychiatry advance online publication, 17 May 2016; doi:10.1038/mp.2016.73. © 2016 Macmillan Publishers Limited


Yu S.,Michigan State University | Pleskac T.J.,Max Planck Institute for Human Development | Zeigenfuse M.D.,University of Zurich
Journal of Experimental Psychology: General | Year: 2015

Most cognitive theories assume that confidence and choice happen simultaneously and are based on the same information. The 3 studies presented in this article instead show that confidence judgments can arise, at least in part, from a postdecisional evidence accumulation process. As a result of this process, increasing the time between making a choice and confidence judgment improves confidence resolution. This finding contradicts the notion that confidence judgments are biased by decision makers seeking confirmatory evidence. Further analysis reveals that the improved resolution is due to a reduction in confidence in incorrect responses, while confidence in correct responses remains relatively constant. These results are modeled with a sequential sampling process that allows evidence accumulation to continue after a choice is made and maps the amount of accumulated evidence onto a confidence rating. The cognitive modeling analysis reveals that the rate of evidence accumulation following a choice does slow relative to the rate preceding choice. The analysis also shows that the asymmetry between confidence in correct and incorrect choices is compatible with state-dependent decay in the accumulated evidence: Evidence consistent with the current state results in a deceleration of accumulated evidence and consequently evidence appears to have a decreasing impact on observed confidence. In contrast, evidence inconsistent with the current state results in an acceleration of accumulated evidence toward the opposite direction and consequently evidence appears to have an increasing impact on confidence. Taken together, this process-level understanding of confidence suggests a simple strategy for improving confidence accuracy: take a bit more time to make confidence judgments. © 2015 American Psychological Association.


Schiestl F.P.,University of Zurich | Johnson S.D.,University of KwaZulu - Natal
Trends in Ecology and Evolution | Year: 2013

Because most plants rely on animals for pollination, insights from animal sensory ecology and behavior are essential for understanding the evolution of flowers. In this review, we compare and contrast three main types of pollinator responses to floral signals - receiver bias, 'adaptive' innate preferences, and associative learning - and discuss how they can shape selection on floral signals. We show that pollinator-mediated selection on floral signals can be strong and that the molecular bases of floral signal variation are often surprisingly simple. These new empirical and conceptual insights into pollinator-mediated evolution provide a framework for understanding patterns of both convergent (pollination syndromes) and advergent (floral mimicry) floral signal evolution. © 2013 Elsevier Ltd.


Bodenmiller B.,University of Zurich
Cell Systems | Year: 2016

The study of organs and tissues on a molecular level is necessary as we seek an understanding of health and disease. Over the last few years, powerful highly multiplexed epitope-based imaging approaches that rely on the serial imaging of tissues with fluorescently labeled antibodies and the simultaneous analysis using metal-labeled antibodies have emerged. These techniques enable analysis of dozens of epitopes in thousands of cells in a single experiment providing a systems level view of normal and disease processes at the single-cell level with spatial resolution in tissues. In this Review, I discuss, first, the highly multiplexed epitope-based imaging approaches and the generated data. Second, I describe challenges that must be overcome to implement these imaging methods from bench to bedside, including issues with tissue processing and analyses of the large amounts of data generated. Third, I discuss how these methods can be integrated with readouts of genome, transcriptome, metabolome, and live cell information, and fourth, the novel applications possible in tissue biology, drug development, and biomarker discovery. I anticipate that highly multiplexed epitope-based imaging approaches will broadly complement existing imaging methods and will become a cornerstone of tissue biology and biomedical research and of precision medical applications. © 2016 Elsevier Inc.


Barton M.,University of Zurich
Pflugers Archiv European Journal of Physiology | Year: 2010

Endothelial cells are both the source and target of factors contributing to atherosclerosis. After the discovery of the endothelium-derived relaxing factor (EDRF) by Robert F. Furchgott in 1980 it soon became clear that endothelial cells also release vasoactive factors distinct from nitric oxide (NO) namely, endothelium-derived contracting factors (EDCF) as well as hyperpolarizing factors (EDHF). Vasoactive factors derived from endothelial cells include NO/EDRF, reactive oxygen species, endothelins and angiotensins which have either EDRF or EDCF functions, cyclooxygenase-derived EDCFs and EDRFs, and EDHFs. Endothelial factors are formed by enzymes such as NO synthase, cyclooxygenase, converting enyzmes, NADPH oxidases, and epoxigenases, among others, and participate in the regulation of vascular homeostasis under physiological conditions; however, their abnormal regulation due to endothelial cell dysfunction contributes to disease processes such as atherosclerosis, arterial hypertension, and renal disease. Because of recent changes in world demographics and the declining health status of the world's population, both aging and obesity as independent risk factors for atherosclerosis-related diseases such as coronary artery disease and stroke, will continue to increase in the years to come. Obesity and associated conditions such as arterial hypertension and diabetes are now also some of the primary health concerns among children and adolescents. The similarities of pathomechanisms activated in obesity and aging suggest that obesity-at least in the vasculature-can be considered to have effects consistent with accelerated, "premature" aging. Pathomechanisms as well as the clinical issues of obesity- and aging-associated vascular changes important for atherosclerosis development and prevention are discussed. © 2010 Springer-Verlag.


Brown S.A.,University of Zurich
Trends in Endocrinology and Metabolism | Year: 2016

The circadian clock directs nearly all aspects of diurnal physiology, including metabolism. Current research identifies several major axes by which it exerts these effects, including systemic signals as well as direct control of cellular processes by local clocks. This redundant network can transmit metabolic and timing information bidirectionally for optimal synchrony of metabolic processes. Recent advances in cellular profiling and metabolomics technologies have yielded unprecedented insights into the mechanisms behind this control. They have also helped to illuminate individual variation in these mechanisms that could prove important in personalized therapy for metabolic disease. Finally, these technologies have provided platforms with which to screen for the first potential drugs affecting clock-modulated metabolic function. Bidirectional molecular relationships link the circadian clock to energy homeostasis.These links occur at both cellular and systemic levels.Metabolomics, transcriptomics, and cellular assays have illuminated mechanisms and interindividual differences in this control.Cellular circadian assays have provided screening platforms for clock-specific drugs that could be useful for metabolic disorders. © 2016 Elsevier Ltd.


Corrigan P.W.,Illinois Institute of Technology | Kosyluk K.A.,Illinois Institute of Technology | Rusch N.,University of Zurich
American Journal of Public Health | Year: 2013

Self-stigma has a pernicious effect on the lives of people with mental illness. Although a medical perspective might discourage patients from identifying with theirillness,publicdisclosure maypromoteempowerment and reduce self-stigma. We reviewed the extensive research that supports this assertion and assessed a program that might diminish stigma's effect by helping some people to disclose to colleagues, neighbors,and others their experiences with mental illness, treatment, and recovery. The program encompasses weighing the costs and benefits of disclosure in deciding whether to come out, considering different strategies for coming out, and obtaining peer support through the disclosure process. This type of program may also pose challenges for public health research.


Starck C.T.,University of Zurich
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | Year: 2013

In this retrospective study we compared different lead extraction techniques. Between January 2009 and December 2012 we performed transvenous lead extraction procedures on 206 leads in 122 patients. Mean implant duration (MID) was 69.6 months (1-384 months). Leads with lead implant duration ≥ 12 months were assigned to groups according to the extraction technique: Group A: no extraction tool; Group B: laser approach; and Group C: mechanical approach. Overall clinical success was 93.3%. Group A showed a significantly lower MID [38.1 (19-122) months] compared with Groups B and C [83.1 (13-168) months; P < 0.0001 vs. 95.4 (12-384) months; P < 0.0001]. Mean implant duration between Groups B and C did not differ significantly (P = 0.28). Clinical and complete procedural success was 100% in Group A. Clinical success rate was higher in Group C than in Group B (97.0 vs. 76.9%, P = 0.018). Complete procedural success did not differ significantly between Groups B and C (88.9 vs. 76.9%; P = 0.132). In Groups B and C, absence of complete procedural success occurred in long implanted leads (MID 107.8 ± 36.4 and 137.6 ± 89.2 months). Relative costs per extracted lead were 49% higher in Group B than in Group C. In case of long implanted leads a laser and a mechanical approach are comparable in complete procedural success and safety. Clinical success and cost effectiveness analysis favours the mechanical approach. Regardless of the extraction technique efficacy and safety optimization has to focus on long implanted leads.


Schiestl F.P.,University of Zurich
Current Biology | Year: 2010

Why do plants mimic female insects to attract males for pollination? A new study gives insights into the advantages of sexual mimicry and documents this pollination system for the first time outside the orchid family, in a South African daisy. © 2010 Elsevier Ltd All rights reserved.


Yeressian K.,University of Zurich
Interfaces and Free Boundaries | Year: 2015

In this paper we prove the optimal nondegeneracy of the solution u of the obstacle problem Δu = fX(u>0) in a bounded domain D ⊂ ℝn, where we only require f to have a nondegeneracy of the type f (x) ≥ γ|(x1,...xp)|α for some γ > 0, 1 ≤ p ≤ n (an integer) and α > 0. We prove optimal (2 + α)-th order nondegeneracy. We also prove the optimal growth with the assumption |f(x)| ≤ |(x1...xp)|α for some λ > 0 and the porosity of the free boundary. © European Mathematical Society 2015.


Aalberse R.C.,Sanquin Research and Academic Medical Center | Crameri R.,University of Zurich
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

Here, we discuss various questions related to IgE epitopes: What are the technical possibilities and pitfalls, what is currently known, how can we put this information into hypothetical frameworks and the unavoidable question: how useful is this information for patient care or allergenicity prediction? We discuss the information obtained by (i) 3D structures of allergen-antibody complexes; (ii) analysis of allergen analogues; (iii) mimics without obvious structural similarity; (iv) mAbs competing with IgE; (v) repertoire analysis of cloned IgEs, and other developments. Based on limited data, four suggestions are presented in the literature: (i) IgE might be more cross-reactive than IgG; (ii) IgE might be more often directed to immunologically 'uninviting' surfaces; (iii) IgE epitopes may tend to cluster and (iv) IgE paratopes might have a higher intrinsic flexibility. While these are not proven facts, they still can generate hypotheses for future research. The hypothesis is put forward that the IgE repertoire of switched B-cells is less influenced by positive selection, because positive selection might not be able to rescue IgE-switched B cells. While this might be of interest for the discussion about mechanisms leading to allergen-sensitization, we need to be modest in answering the 'clinical relevance' question. Current evidence indicates the IgE-epitope repertoire is too big to make specific IgE epitopes a realistic target for diagnosis, treatment or allergenicity prediction. In-depth analysis of a few selected IgE epitope-peptides or mimitopes derived from allergen-sequences and from random peptide libraries, respectively, might well prove rewarding in relation to diagnosis and prognosis of allergy, particularly food allergy. © 2011 John Wiley & Sons A/S.


Ballmer-Weber B.K.,University of Zurich | Hoffmann-Sommergruber K.,Medical University of Vienna
Current Opinion in Allergy and Clinical Immunology | Year: 2011

Purpose of review: The purpose of this paper is to review and discuss studies on molecular diagnosis in fruit and vegetable allergy. Recent findings: Celeriac, carrot and tomato are the most prevalent allergenic vegetables, whereas fruit allergy is mainly induced by apple, peach and kiwi. Component-resolved molecular diagnosis has been recently applied in two well-defined patient groups with kiwifruit and celeriac allergy, respectively. In kiwifruit allergy Act d 1 and Act d 3 were identified as potential marker allergens for severe symptoms. For celeriac allergy, however, such markers are still missing. In both studies component-resolved molecular diagnosis approach improved in particular sensitivity compared to extract-based diagnostic test assays. Summary: Food and vegetable allergy can be acquired both via a direct sensitization over the gastrointestinal tract and via a primary sensitization to pollen or latex. The diagnosis of fruit and vegetable allergy in birch pollen-sensitized patients should not be excluded on a negative IgE testing to extracts. Bet v 1-related allergens are often under-represented in extracts. Few recombinant allergens derived from fruits and vegetables are nowadays commercially available and facilitate diagnosis of fruit and vegetable allergies. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Mohammed I.,University of Zurich | Seljak U.,Lawrence Berkeley National Laboratory
Monthly Notices of the Royal Astronomical Society | Year: 2014

We develop a model for the matter power spectrum as the sum of Zeldovich approximation and even powers of k, i.e. A0 - A2k2 + A4k4 - . . . , compensated at low k. With terms up to k4, the model can predict the true power spectrum to a few per cent accuracy up to k ~ 0.7 h Mpc-1, over a wide range of redshifts and models. The An coefficients contain information about cosmology, in particular amplitude of fluctuations. We write a simple form of the covariance matrix as a sum of Gaussian part and A0 variance, which reproduces the simulations remarkably well. In contrast, we show that one needs an N-body simulation volume of more than 1000 (Gpc h-1)3 to converge to 1 per cent accuracy on covariance matrix. We investigate the supersample variance effect and show it can be modelled as an additional parameter that can be determined from the data. This allows a determination of σ8 amplitude to about 0.2 per cent for a survey volume of 1(Gpc h-1)3, compared to 0.4 per cent otherwise.We explore the sensitivity of these coefficients to baryonic effects using hydrodynamic simulations of van Daalen et al. We find that because of baryons redistributing matter inside haloes all the coefficients A2n for n > 0 are strongly affected by baryonic effects, while A0 remains almost unchanged, a consequence of halo mass conservation. Our results suggest that observations such as weak lensing power spectrum can be effectively marginalized over the baryonic effects, while still preserving the bulk of the cosmological information contained in 0 and Zeldovich terms. © 2014 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.


Wuthrich B.,University of Zurich
Chemical Immunology and Allergy | Year: 2014

In this chapter we will first consider whether there is real evidence on the basis of literature for early descriptions in antiquity of pathogenic reactions after food intake that could be comparable to allergy, for instance in the scriptures of Hippocrates or Lucretius. On this topic we are skeptical, which is in agreement with the medical historian Hans Schadewaldt. We also assert that it is unlikely that King Richard III was the first food-allergic individual in medical literature. Most probably it was not a well-planned poisoning ('allergy') with strawberries, but rather a birth defect ('... his harm was ever such since his birth') that allowed the Lord Protector to bring Mylord of Ely to the scaffold in the Tower, as we can read in The History of King Richard III by Thomas More (1478-1535; published by his son-in-law, Rastell, in 1557). In 1912, the American pediatrician Oscar Menderson Schloss (1882-1952) was probably the first to describe scratch tests in the diagnosis of food allergy. Milestones in the practical diagnosis of food allergy are further discussed, including scratch tests, intradermal tests, modified prick tests and prick-to-prick tests. False-negative results can be attributed to the phenomenon of a 'catamnestic reaction' according to Max Werner (1911-1987), or to the fermentative degradation of food products. Prior to the discovery of immunoglobulin E, which marked a turning point in allergy diagnosis, and the introduction of the radioallergosorbent test in 1967, several more or less reliable techniques were used in the diagnosis of food allergy, such as pulse rate increase after food intake according to Coca, the leukopenic index, drop in basophils or drastic platelet decrease. The 'leukocytotoxic test' (Bryan's test), today called the 'ALCAT' test, shows no scientific evidence. The double-blind placebo-controlled food challenge test remains the gold standard in the diagnosis of food allergy. For the future, component-resolved diagnostics with the use of recombinant molecular allergens or chip arrays, such as the ISAC technique, hold a lot of promise. With regard to the clinical situation, a subjective selection is given, touching on the pollen-associated food allergies ('birch-mugwort-celery-spice syndrome'), as well as the new phenomenon of lethal food allergies that have appeared since the 1980s. Finally, rare ways of elicitation of a 'derivative allergy', first described by Erich Fuchs (1921-2008), for example by kissing, as well as 'oral allergy syndrome' and oral hyposensitization are considered. © 2014 S. Karger AG, Basel.


Brucale M.,CNR Institute of Nanostructured Materials | Schuler B.,University of Zurich | Samori B.,University of Bologna
Chemical Reviews | Year: 2014

Single-molecule techniques have started to provide important new types of information on the structural and dynamic behavior of intrinsically disordered proteins (IDPs). All single-molecule experiments are by definition able to avoid ensemble averaging since they give information on the smallest possible subensembles of a population. Two of the key strengths of the approaches are their ability to resolve structural and dynamic heterogeneity and to provide quantitative information that can be used for testing physical models. The single-molecule fluorescence approaches available, ranging from Förster Resonance Energy Transfer (FRET) to Positron Emission Topography (PET) and (FCS), can provide information on intra and intermolecular distances and, even more importantly, distance distributions, dynamics on time scales from nanoseconds to seconds, and changes in molecular size or dimensions. Combination of single-molecule fluorescence and ionic current measurements in single-ion channels was developed to monitor structural changes in single channels.


Stuparu M.C.,University of Zurich
Tetrahedron | Year: 2012

In this study, we explore the potential of copper(I)-catalyzed cycloaddition reaction between azides and terminal alkynes to prepare corannulene-rich materials. For this purpose, a practical route is established to yield corannulene-based azide building blocks. The newly prepared corannulene-azides are then coupled with known corannulene-alkynes. The chemical yields of the dimerization reactions ranged from 80 to 90%. In this way, a number of triazole-linked corannulene derivatives varying in the geometry, length, and the triazole-content are prepared. These results suggest that alkyne-azide click reaction can serve as a useful synthetic tool in the preparation of corannulene-rich discrete oligomers as well as polymers. © 2011 Elsevier Ltd. All rights reserved.


Rischatsch M.,University of Zurich
European Journal of Health Economics | Year: 2014

While most countries separate drug prescription and dispensation to ensure independent drug choice, some allow this combination to increase pharmaceutical access in rural areas or to increase the utilization of pharmacist skills. A drawback of this approach is that dispensing physicians or prescribing pharmacists may be incentivized to increase their own profits through the prescription of cost-inefficient drug packages, leading to an increase in pharmaceutical spending. Switzerland constitutes an interesting example of where dispensing and non-dispensing physicians coexist, permitting a comparison of their prescribing behavior. The present study shows that drug margin optimization is possible under the current drug price regulation scheme in Switzerland. Using drug claims data, empirical findings indicate a 5-10 % higher margin per dose for dispensing physicians compared to pharmacists. Cost per dose is 3-5 % higher when dispensed by physicians instead of pharmacists. © 2013 Springer-Verlag.


Kakebeeke T.H.,University of Zurich
Developmental medicine and child neurology | Year: 2013

The aim of this cross-sectional study was to provide normative data (ordinal scores and timed performances) for gross and fine motor tasks in typically developing children between 3 and 5 years of age using the Zurich Neuromotor Assessment (ZNA). Typically developing children (n=101; 48 males, 53 females) between 3 and 5 years of age were enrolled from day-care centres in the greater Zurich area and tested using a modified version of the ZNA; the tests were recorded digitally on video. Intraobserver reliability was assessed on the videos of 20 children by one examiner. Interobserver reliability was assessed by two examiners. Test-retest reliability was performed on an additional 20 children. The modelling approach summarized the data with a linear age effect and an additive term for sex, while incorporating informative missing data in the normative values. Normative data for adaptive motor tasks, pure motor tasks, and static and dynamic balance were calculated with centile curves (for timed performance) and expected ordinal scores (for ordinal scales). Interobserver, intraobserver, and test-retest reliability of tasks were moderate to good. Nearly all tasks showed significant age effects, whereas sex was significant only for stringing beads and hopping on one leg. These results indicate that timed performance and ordinal scales of neuromotor tasks can be reliably measured in preschool children and are characterized by developmental change and high interindividual variability. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.


Wagner C.A.,University of Zurich
Kidney International | Year: 2013

Capasso et al. show a role of the calcium-sensing receptor (CaSR) in enhancing proximal tubular fluid absorption and urinary acidification by stimulation of luminal Na+/H+ exchanger (NHE) activity. NHE3 is required for sodium and fluid absorption, and its activity is coupled to passive reabsorption of a major fraction of calcium through the paracellular route. These data shed new light on the regulation of the kidney by the CaSR and whether it directly affects proximal tubular functions. © 2013 International Society of Nephrology.


Postma E.,University of Zurich
Biology Letters | Year: 2014

Females often prefer to mate with high quality males, and one aspect of quality is physical performance. Although a preference for physically fitter males is therefore predicted, the relationship between attractiveness and performance has rarely been quantified. Here, I test for such a relationship in humans and ask whether variation in (endurance) performance is associated with variation in facial attractiveness within elite professional cyclists that finished the 2012 Tour de France. I show that riders that performed better were more attractive, and that this preference was strongest in women not using a hormonal contraceptive. Thereby, I show that, within this preselected but relatively homogeneous sample of the male population, facial attractiveness signals endurance performance. Provided that there is a relationship between performance-mediated attractiveness and reproductive success, this suggests that human endurance capacity has been subject to sexual selection in our evolutionary past. © 2014 The Authors.


Leutert C.R.,University of Zurich
The International journal of oral & maxillofacial implants | Year: 2012

The aim of this study was to examine the bending moments and fracture patterns of different zirconia abutments with internal implant-abutment connections after static loading and to compare their bending moments to those of internally connected titanium abutments. Materials and Three types of customized zirconia abutments (Straumann CARES abutments/Straumann BL implants [T1], Astra ZirDesign abutments/Astra Micro Thread OsseoSpeed implants [T2], Zirabut prototype abutments/Straumann SP implants [T3]) and one type of customized titanium abutment (control group, Straumann CARES abutments/Straumann BL implants [C]) were included. All abutments were one-piece abutments with an internal implant-abutment connection and were customized to the same shape but featured different implant-abutment connection designs. For each group, 20 identical copies of a master abutment were fabricated and fixed on their corresponding implants. Half of the abutments in each group were left unrestored, and the other 10 received glass-ceramic crowns. Static loading was applied at a 30-degree angle to the palatal surface until failure, and bending moments were calculated. The type of failure was characterized visually by dismounting the abutments and by examination of cross-sections of the embedded specimens. The results were analyzed statistically. The mean range of bending moments was higher for the unrestored groups (158.2 to 678.2 Ncm) than for the restored groups (117.9 to 419.4 Ncm). The highest mean bending moments were seen in the control group, both restored and unrestored (419.4/678.2 Ncm). Unrestored, T1 and T2 exhibited significantly higher bending moments than T3. This was also observed in the restored groups. Both the abutment material and the implant-abutment connection design affected the bending moments of abutments after static loading. Internally connected zirconia abutments with horizontal mismatch to the implant exhibited significantly higher bending moments compared to those without horizontal mismatch.


Michaelowa A.,University of Zurich
Wiley Interdisciplinary Reviews: Climate Change | Year: 2013

In 30 years of climate policy in Germany, a high level of declared ambition has coexisted with an eclectic mix of climate policy measures. Well-organized lobbies were either exempt from policy instruments such as the energy tax or directly benefitted from them, as in the case of the renewable feed-in tariff or windfall profits from free allocation of emissions allowances. As a result, German emissions mitigation is much more costly than it would have to be. Moreover, the challenges because of the imminent phase-out of nuclear power are increasing due to failures in a number of relevant policy fields such as offshore wind, grid reinforcement, and carbon capture and storage (CCS). WIREs Clim Change 2013, 4:315-320. doi: 10.1002/wcc.224 Conflict of interest: The author has declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. © 2013 John Wiley & Sons, Ltd.


BACKGROUND: Bovine paratuberculosis is an incurable chronic granulomatous enteritis caused by Mycobacterium avium subspecies paratuberculosis (MAP). The prevalence of MAP in the Swiss cattle population is hard to estimate, since only a few cases of clinical paratuberculosis are reported to the Swiss Federal Food Safety and Veterinary Office each year.Fecal samples from 1,339 cattle (855 animals from 12 dairy herds, 484 animals from 11 suckling cow herds, all herds with a history of sporadic paratuberculosis) were investigated by culture and real-time polymerase chain reaction (PCR) for shedding of MAP.RESULTS: By culture, MAP was detected in 62 of 445 fecal pools (13.9%), whereas PCR detected MAP in 9 of 445 pools (2.0%). All 186 samples of the 62 culture-positive pools were reanalyzed individually. By culture, MAP was grown from 59 individual samples (31.7%), whereas PCR detected MAP in 12 individual samples (6.5%), all of which came from animals showing symptoms of paratuberculosis during the study. Overall, MAP was detected in 10 out of 12 dairy herds (83.3%) and in 8 out of 11 suckling cow herds (72.7%).CONCLUSIONS: There is a serious clinically inapparent MAP reservoir in the Swiss cattle population. PCR cannot replace culture to identify individual MAP shedders but is suitable to identify MAP-infected herds, given that the amount of MAP shed in feces is increasing in diseased animals or in animals in the phase of transition to clinical disease.


Manser M.B.,University of Zurich
Animal Behaviour | Year: 2013

The research field of semantic communication in animals was initiated by the study on alarm calls of vervet monkeys, Chlorocebus pygerythrus (then known as Cercopithecus aethiops) by Seyfarth, Cheney and Marler (Animal Behaviour, 1980, 28, 1070-1094). Based on observations of alarm call production and playback experiments in the natural habitat of the monkeys, Seyfarth, Cheney and Marler provided evidence that the alarm calls designated predators as external referents and conveyed sufficient information to listeners to make distinct adaptive responses in the absence of the stimulus. Their interpretation that 'these calls show semantic properties, potentially based on the formation of internal perceptual concepts' contrasted with the existing consensus of the time, which saw animal signals as 'affective', providing information only about the internal motivational state of the signaller and/or the signaller's likely behaviour. This study, particularly its semantic approach, was hugely influential in revitalizing the discussion of what animal calls 'mean', specifically how they are interpreted in the minds of the animals, and ultimately acted as the impetus for the construction of the 'functionally referential' framework in animal communication. Although this semantic approach has been criticized in terms of anthropomorphizing animal communication, understanding the underlying cognitive mechanisms is a crucial component of deconstructing animal communication systems and hence we can greatly profit from such a research trajectory. Applying linguistic concepts to animal vocal communication has opened up an enormous research field regarding the continuity between animal vocalizations and human language, integrating different disciplines including animal behaviour, comparative psychology, neurobiology, linguistics and philosophy. © 2013 The Association for the Study of Animal Behaviour.


Van Buskirk J.,University of Zurich
Ecology and Evolution | Year: 2012

For organisms that reproduce in discrete habitat patches, land cover between patches (known as the matrix) is important for dispersal among breeding sites. Models of patchy populations often incorporate information on the permeability of the matrix to dispersal, sometimes based on expert opinion. I estimated the relative resistance to gene flow of land cover types and barriers using FST calculated from microsatellite markers in two amphibians, within an 800-km2 area in northern Switzerland. The species included a frog (Rana temporaria: 996 individuals, 48 populations, seven markers) and a newt (Triturus alpestris: 816 individuals, 41 populations, seven markers). Open fields and urban areas were more resistant to gene flow than forested land; roads and highways also reduced permeability. Results were similar for the two species. However, differences in resistance among matrix elements were relatively low: gene flow through urban areas was reduced by only 24-42% relative to forest; a divided highway reduced gene flow by 11-40% and was 7-8 times more resistant than a secondary road. These data offer an empirically based alternative to expert opinion for setting relative resistance values in landscape models.© 2012 The Authors. Ecology and Evolution published by Blackwell Publishing Ltd.


Willems E.P.,University of Zurich
Proceedings. Biological sciences / The Royal Society | Year: 2013

Group-living animals often do not maintain territories, but instead have highly overlapping ranges, even though in principle these are economically defendable. We investigate whether this absence of range defence reflects a collective action problem, since a territory can be considered a public good. In a comparative analysis comprising 135 primate species, we find a positive association between range overlap and group size, controlling for economic defendability and phylogenetic non-independence. We subsequently demonstrate that groups with multiple adults of both sexes suffer levels of range overlap twice as high as groups with only a single adult representative of either sex, consistent with the presence of a collective action problem. Finally, we reveal that this collective action problem can be overcome through philopatry of the larger sex. These results suggest that a social complication of group living is a stronger determinant of between-group relations among social animals than ecological factors, but also that collective defence is still achieved where the dominant sex is philopatric and effective defence is critical to reproductive success and survival. In addition, our findings support the idea that human-like warfare, defined as escalated collective territorial conflict, has an evolutionary basis reflected by cases of convergent evolution among non-human primates.


Reber S.A.,University of Zurich
Proceedings. Biological sciences / The Royal Society | Year: 2013

Social monitoring of the actions of group members is thought to be a key development associated with group living. Humans constantly monitor the behaviour of others and respond to them in a flexible way depending on past interactions and the current social context. While other primates have also been reported to change their behaviour towards other group members flexibly based on the current state of their relationship, empirical evidence is typically linked to contextually specific events such as aggressive or reproductive interactions. In the cooperatively breeding meerkat (Suricata suricatta), we investigated whether subordinate females use frequently emitted, non-agonistic close calls to monitor the location of the dominant female and whether they subsequently adjust their response based on recent social interactions during conflict and non-conflict periods. Subjects discriminated between the close calls of the dominant female and control playbacks, responding by approaching the loudspeaker and displaying submissive behaviour only if they were currently threatened by eviction. Our results suggest that meerkats assess the risk for aggressive interactions with close associates depending on social circumstances, and respond accordingly. We argue that social monitoring based on non-agonistic cues is probably a common mechanism in group-living species that allows the adjustment of behaviour depending on variation in relationships.


Rademakers R.,Mayo Medical School | Neumann M.,University of Zurich
The Lancet Neurology | Year: 2010

Abnormal intracellular protein aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The seminal discoveries of accumulation of TDP-43 in most cases of ALS and the most frequent form of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions, followed by identification of FUS as the novel pathological protein in a small subset of patients with ALS and various FTD subtypes provide clear evidence that these disorders are related. The creation of a novel molecular classification of ALS and FTD based on the identity of the predominant protein abnormality has, therefore, been possible. The striking functional and structural similarities of TDP-43 and FUS, which are both DNA/RNA binding proteins, imply that abnormal RNA metabolism is a pivotal event, but the mechanisms leading to TDP-43 and FUS accumulation and the resulting neurodegeneration are currently unknown. Nonetheless, TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies. © 2010 Elsevier Ltd.


Meulman E.J.,University of Zurich
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

Many species use tools, but the mechanisms underpinning the behaviour differ between species and even among individuals within species, depending on the variants performed. When considering tool use 'as adaptation', an important first step is to understand the contribution made by fixed phenotypes as compared to flexible mechanisms, for instance learning. Social learning of tool use is sometimes inferred based on variation between populations of the same species but this approach is questionable. Specifically, alternative explanations cannot be ruled out because population differences are also driven by genetic and/or environmental factors. To better understand the mechanisms underlying routine but non-universal (i.e. habitual) tool use, we suggest focusing on the ontogeny of tool use and individual variation within populations. For example, if tool-using competence emerges late during ontogeny and improves with practice or varies with exposure to social cues, then a role for learning can be inferred. Experimental studies help identify the cognitive and developmental mechanisms used when tools are used to solve problems. The mechanisms underlying the route to tool-use acquisition have important consequences for our understanding of the accumulation in technological skill complexity over the life course of an individual, across generations and over evolutionary time.


Fiddes J.,University of Zurich | Gruber S.,Carleton University
Geoscientific Model Development | Year: 2014

Simulation of land surface processes is problematic in heterogeneous terrain due to the the high resolution required of model grids to capture strong lateral variability caused by, for example, topography, and the lack of accurate meteorological forcing data at the site or scale it is required. Gridded data products produced by atmospheric models can fill this gap, however, often not at an appropriate spatial resolution to drive land-surface simulations. In this study we describe a method that uses the well-resolved description of the atmospheric column provided by climate models, together with high-resolution digital elevation models (DEMs), to downscale coarse-grid climate variables to a fine-scale subgrid. The main aim of this approach is to provide high-resolution driving data for a land-surface model (LSM). The method makes use of an interpolation of pressure-level data according to topographic height of the subgrid. An elevation and topography correction is used to downscale short-wave radiation. Long-wave radiation is downscaled by deriving a cloud-component of all-sky emissivity at grid level and using downscaled temperature and relative humidity fields to describe variability with elevation. Precipitation is downscaled with a simple non-linear lapse and optionally disaggregated using a climatology approach. We test the method in comparison with unscaled grid-level data and a set of reference methods, against a large evaluation dataset (up to 210 stations per variable) in the Swiss Alps. We demonstrate that the method can be used to derive meteorological inputs in complex terrain, with most significant improvements (with respect to reference methods) seen in variables derived from pressure levels: air temperature, relative humidity, wind speed and incoming long-wave radiation. This method may be of use in improving inputs to numerical simulations in heterogeneous and/or remote terrain, especially when statistical methods are not possible, due to lack of observations (i.e. remote areas or future periods).


Di Iorio L.,University of Zurich | Clark C.W.,Cornell University
Biology Letters | Year: 2010

The ability to perceive biologically important sounds is critical to marine mammals, and acoustic disturbance through human-generated noise can interfere with their natural functions. Sounds from seismic surveys are intense and have peak frequency bands overlapping those used by baleen whales, but evidence of interference with baleen whale acoustic communication is sparse. Here we investigated whether blue whales (Balaenoptera musculus) changed their vocal behaviour during a seismic survey that deployed a low-medium power technology (sparker). We found that blue whales called consistently more on seismic exploration days than on non-exploration days as well as during periods within a seismic survey day when the sparker was operating. This increase was observed for the discrete, audible calls that are emitted during social encounters and feeding. This response presumably represents a compensatory behaviour to the elevated ambient noise from seismic survey operations. © 2009 The Royal Society.


Hoff P.,University of Zurich
Dialogues in Clinical Neuroscience | Year: 2015

Emil Kraepelin (1856-1926) was an influential figure in the history of psychiatry as a clinical science. This paper, after briefly presenting his biography, discusses the conceptual foundations of his concept of mental illness and follows this line of thought through to late 20th-century "Neo-Kraepelinianism," including recent criticism, particularly of the nosological dichotomy of endogenous psychoses. Throughout his professional life, Kraepelin put emphasis on establishing psychiatry as a clinical science with a strong empirical background. He preferred pragmatic attitudes and arguments, thus underestimating the philosophical presuppositions of his work. As for nosology, his central hypothesis is the existence and scientific accessibility of "natural disease entities" ("natürliche Krankheitseinheiten") in psychiatry. Notwithstanding contemporary criticism that he commented upon, this concept stayed at the very center of Kraepelin's thinking, and therefore profoundly shaped his clinical nosology. © 2015, AICH - Servier Research Group.


Zimmermann H.-P.,University of Zurich
Zeitschrift fur Gerontologie und Geriatrie | Year: 2015

Growing old differently: the phrase is intended to call something other to mind than merely the fact that images and forms of old age and aging have multiplied and diversified to an enormous extent. The suggestion put forward here is that otherness (as opposed to mere differences) should be positively reinforced. In other words, it is not just a matter of noting different forms of old age and aging but more than this, of seeking out opportunities for aging differently. In order to explore this, the article follows an older strand of theory, which has recently come to be frequently quoted in gerontology: the phenomenology of difference as reasoned analytically by Lévinas and Sartre and applied to gerontology by Améry and de Beauvoir. Here, opportunities for aging crucially depend on the way we look at it, how we observe and describe it and not least, how gerontology frames it. A distinction is made between two perspectives and their associated consequences for old age: alienation and alterity. Alienation means looking at old age above all as a disconcerting “other”, as a perplexing, problematic deviation from the norm of vitality. Alterity, by contrast, refers to different options for living life in old age: options to be explored and opened up in contradistinction to cultural or academic alienation. Not least, the article appeals for diversity in scholarly approaches and for cross-disciplinary perspectives. © 2015, Springer-Verlag Berlin Heidelberg.


The cannabinoid system is known to be involved in the regulation of inflammatory processes. Therefore, drugs targeting cannabinoid receptors are considered as candidates for anti-inflammatory and tissue protective therapy. We demonstrated that the prototypical cannabinoid agonist R(+)WIN55,212-2 (WIN) reduced the secretion of matrix metalloproteinase-9 (MMP-9) in a murine model of cigarette-smoke induced lung inflammation. In experiments using primary cells and cell lines of the monocyte-macrophage-system we found that binding of the cannabinoid-receptor agonist WIN to a stereo-selective, specific binding site in cells of the monocyte-macrophage-system induced a significant down-regulation of MMP-9 secretion and disturbance of intracellular processing, which subsequently down-regulated MMP-9 mRNA expression via a ERK1/2-phosphorylation-dependent pathway. Surprisingly, the anti-inflammatory effect was independent from classical cannabinoid receptors. Our experiments supposed an involvement of TRPV1, but other yet unidentified sites are also possible. We conclude that cannabinoid-induced control of MMP-9 in the monocyte-macrophage system via a cannabinoid-receptor independent pathway represents a general option for tissue protection during inflammation, such as during lung inflammation and other diseases associated with inflammatory tissue damage.


Biro P.,University of Zurich
Acta Anaesthesiologica Scandinavica | Year: 2014

Background The assessment of volatile agents' consumption can be performed by weighing vapourisers before and after use. This method is technically demanding and unavailable for retrospective analysis of anaesthesia records. Therefore, a method based on calculations from fresh gas flow and agent concentration is presented here. Methods The presented calculation method herein enables a precise estimation of volatile agent consumption when average fresh gas flows and volatile agent concentrations are known. A pre-condition for these calculations is the knowledge of the vapour amount deriving from 1 ml fluid volatile agent. The necessary formulas for these calculations and an example for a sevoflurane anaesthesia are presented. Results The amount of volatile agent vapour deriving from 1 ml of fluid agent are for halothane 229 ml, isoflurane 195 ml, sevoflurane 184 m, and desflurane 210 ml. The constant for sevoflurane is used in a fictitious clinical case to exemplify the calculation of its consumption in daily routine resulting in a total expenditure of 23.6 ml liquid agent. Conclusions By application of the presented specific volatile agent constants and equations, it becomes easy to calculate volatile agent consumption if the fresh gas flows and the resulting inhaled concentration of the volatile agent are known. By this method, it is possible to extract data about volatile agent consumption both ways: (1) retrospectively from sufficiently detailed and accurate anaesthesia recordings, as well as (2) by application of this method in a prospective setting. Therefore, this method is a valuable contribution to perform pharmacoeconomical surveys. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.


Ballmer-Weber B.K.,University of Zurich
Digestive Diseases | Year: 2014

Eosinophilic esophagitis (EoE) is a chronic T helper 2-type inflammatory disorder. Concurrent allergic diseases have been observed in EoE cases at a high prevalence. The observation that EoE responds to dietary treatment suggests that EoE is an antigen-driven process. However, the pathogenesis by which allergens mediate the eosinophilic disease in the esophagus needs further clarification. In immediate-type food allergy, diagnosis is based on a careful case history followed by a search for food-specific IgE either by skin testing [skin prick test (SPT)] or in vitro (e.g. ImmunoCAP). In children with atopic dermatitis and a food allergy to milk, eggs, peanuts, fish or wheat, the SPT and in vitro determination of specific IgE show excellent sensitivity and negative predictive values, whereas the positive predictive values are low. In pollen-related secondary food allergy, sensitivity and negative predictive values of IgE testing is much lower. Consequently, oral food provocation is the gold standard for the diagnosis of food allergy. Similarly, in EoE patients, SPT, atopy patch test and in vitro determination of IgE to foods do not reliably predict food allergy, and the average positive predictive values of these allergy tests are below 50%. In conclusion, the value of allergy tests to identify triggering foods are limited, and triggering foods have to be identified by an elimination diet and consequent reintroduction of single foods under biopsy control. However, due to the high prevalence of concurrent allergic diseases among EoE patients, an allergy work-up is urgently indicated in each patient with EoE. © 2014 S. Karger AG, Basel.


Dietz V.,University of Zurich
Handbook of Clinical Neurology | Year: 2013

This chapter deals with the neuronal mechanisms underlying impaired gait. The aim is, first, a better understanding of the underlying pathophysiology and, second, the selection of an adequate treatment. One of the first symptoms of a lesion within the central motor system perceived by patients is a movement disorder, which is most characteristic during locomotion, e.g. in patients suffering spasticity after stroke or a spinal cord injury or Parkinson disease. By the recording and analysis of electrophysiological and biomechanical signals during a movement, the significance of impaired reflex behavior or muscle tone and its contribution to the movement disorder can reliably be assessed. Adequate treatment should not be restricted to the correction of an isolated clinical sign but should be based on the mechanisms underlying the movement disorder that impairs the patient. Therapy should be directed toward functional training, which takes advantage of the plasticity of the nervous system. In the future a combination of repair and functional training will further improve the mobility of disabled patients. © 2013 Elsevier B.V.


Spengler C.M.,University of Zurich
Medicine and Science in Sports and Exercise | Year: 2011

PURPOSE: Overweight and obese subjects often perceive increased breathlessness during minor exertion and therefore avoid exercise. Respiratory muscle endurance training (RMET) can reduce the perception of breathlessness. We hypothesized that RMET 1 month before and during a 6-month (3 months supervised + 3 months unsupervised) exercise and nutrition counseling program (EN) would improve the benefits of EN. METHODS: Twenty-six overweight and obese subjects with significant perception of breathlessness during exercise (age = 33 ± 9 yr, body mass index (BMI) = 31.3 ± 4.9 kg·m) were randomized to RMET+EN (R+EN) or EN alone. R+EN performed 30 min of normocapnic hyperpnea 5 wk before and 2 wk during EN. EN consisted of two strength and three endurance training sessions per week, as well as prescribed nutritional composition and a 2.1-kJ (500-kcal) energy deficit per day. Both groups had an equal number of laboratory visits during the 7 months. Before and after 4 and 7 months, subjects performed a 12-min time trial (TT; 6 + 6 min, 2-min pause) and an incremental cycling test (ICT) to exhaustion, and blood lipids were assessed. RESULTS: Weight loss was significant and similar in both groups (-4.2 vs -3.7 kg; both P < 0.05). During the first 4 months, distance covered in 12 min improved more (P < 0.05) with R+EN (1678 vs 1824 m; P < 0.001) than with EN alone (1638 vs 1698 m; P < 0.05), whereas after R+EN, breathlessness during the ICT was reduced. Blood lipids of the pooled group improved in those subjects with pathologic values before the study. Despite reduced training compliance during the unsupervised period, subjects of both groups maintained the benefits attained during the supervised period. CONCLUSIONS: R+EN improved TT performance more than EN alone, despite similar weight loss, possibly owing to the reduced perception of breathlessness. © 2011 The American College of Sports Medicine.


Ciliopathies are a large group of human disorders caused by dysfunction of primary or motile cilia and unified by their overlapping clinical features (brain malformations, retinal dystrophy, cystic kidney disease, liver fibrosis and skeletal abnormalities). Ciliopathies are mendelian disorders with prominent genetic heterogeneity and marked allelism between different clinical entities, which are in part explained by the recently identified functional modules and multi-protein complexes formed by ciliopathy-associated gene products. The current review provides an updated snapshot of this complex evolving field, highlighting the key phenotypic features and causative genes for commonly-studied ciliopathies and summarizing our emerging understanding of the correlations between the functions of subgroups of genes and clinical sub-types of ciliopathies. Using the example of Joubert syndrome, a ciliopathy characterized by a distinctive hindbrain malformation and caused by mutations in more than 20 different genes, this work also reviews the principal methods used for new gene identification, including candidate gene approaches, homozygosity mapping as well as high throughput next-generation and exome sequencing. © 2014 médecine/sciences-Inserm.


Bischoff-Ferrari H.,University of Zurich
International Journal for Vitamin and Nutrition Research | Year: 2012

Vitamin D is essential in bone and muscle health. Severe deficiency (25-hydroxyvitamin D serum levels < 25 nmol/l) can result in rickets and osteomalacia, fractures, myopathy and falls. All recent recommendations on vitamin D agree that children and adults should reach a target 25-hydroxyvitamin D range of at least 50 nmol/l (threshold for normal vitamin D status) and 50 % of the population may be below that threshold. A vitamin D intake of 600 to 800 IU per day as recommended today will prevent about 97 % of children and adults from vitamin D defi ciency. Notably, a higher 25-hydroxyvitamin D threshold of more than 60 nmol/l is needed for optimal functionality, fall and fracture in adults age 65 and older. © 2012 Hans Huber Publishers.


Maggiorini M.,University of Zurich
Progress in Cardiovascular Diseases | Year: 2010

We distinguish two forms of high altitude illness, a cerebral form called acute mountain sickness and a pulmonary form called high-altitude pulmonary edema (HAPE). Individual susceptibility is the most important determinant for the occurrence of HAPE. The hallmark of HAPE is an excessively elevated pulmonary artery pressure (mean pressure 36-51 mm Hg), caused by an inhomogeneous hypoxic pulmonary vasoconstriction which leads to an elevated pulmonary capillary pressure and protein content as well as red blood cell-rich edema fluid. Furthermore, decreased fluid clearance from the alveoli may contribute to this noncardiogenic pulmonary edema. Immediate descent or supplemental oxygen and nifedipine or sildenafil are recommended until descent is possible. Susceptible individuals can prevent HAPE by slow ascent, average gain of altitude not exceeding 300 m/d above an altitude of 2500 m. If progressive high altitude acclimatization would not be possible, prophylaxis with nifedipine or tadalafil for long sojourns at high altitude or dexamethasone for a short stay of less then 5 days should be recommended. © 2010 Elsevier Inc.


Spahn D.R.,University of Zurich | Goodnough L.T.,Stanford University
The Lancet | Year: 2013

The use of alternatives to allogeneic blood continues to rest on the principles that blood transfusions have inherent risks, associated costs, and affect the blood inventory available for health-care delivery. Increasing evidence exists of a fall in the use of blood because of associated costs and adverse outcomes, and suggests that the challenge for the use of alternatives to blood components will similarly be driven by costs and patient outcomes. Additionally, the risk-benefit profiles of alternatives to blood transfusion such as autologous blood procurement, erythropoiesis-stimulating agents, and haemostatic agents are under investigation. Nevertheless, the inherent risks of blood, along with the continued rise in blood costs are likely to favour the continued development and use of alternatives to blood transfusion. We summarise the current roles of alternatives to blood in the management of medical and surgical anaemias.


Huhn D.,University of Zurich
Swiss medical weekly | Year: 2013

Genomic instability, a hallmark of almost all human cancers, drives both carcinogenesis and resistance to therapeutic interventions. Pivotal to the ability of a cell to maintain genome integrity are mechanisms that signal and repair deoxyribonucleic acid (DNA) double-strand breaks (DSBs), one of the most deleterious lesions induced by ionising radiation and various DNA-damaging chemicals. On the other hand, many current therapeutic regimens that effectively kill cancer cells are based on the induction of excessive DSBs. However, these drugs often lack selectivity for tumour cells, which results in severe side effects for the patients, thus compromising their therapeutic potential. Therefore, the development of novel tumour-specific treatment strategies is required. Unlike normal cells, however, cancer cells are often characterised by abnormalities in the DNA damage response including defects in cell cycle checkpoints and/or DNA repair, rendering them particularly sensitive to the induction of DSBs. Therefore, new anticancer agents designed to exploit these vulnerabilities are becoming promising drugs for enhancing the specificity and efficacy of future cancer therapies. Here, we summarise the latest preclinical and clinical developments in cancer therapy based on the current knowledge of DSB signalling and repair, with a special focus on the combination of small molecule inhibitors with synthetic lethality approaches.


Haeberli W.,University of Zurich
Cold Regions Science and Technology | Year: 2013

Advanced methodologies such as core drilling, borehole logging/monitoring, geophysical tomography, high-precision photogrammetry, laser altimetry, GPS/SAR surveying, miniature temperature data logging, geotechnical laboratory analyses, numerical modelling, or GIS-based simulation of spatial distribution patterns in complex topography at regional to global scales have created a rapidly increasing knowledge basis concerning permafrost in cold mountain ranges. Based on a keynote presentation about mountain permafrost at CFG8 in Obergurgl 2012, a brief summary is provided concerning primary research frontiers and the long-term challenge related to the increasing probability of far-reaching flood waves in high-mountain regions originating at newly forming lakes as a consequence of large rock falls and landslides from destabilising steep rock walls with conditions of warming and degrading permafrost often in combination with de-buttressing by vanishing glaciers. Research is especially intense in the densely populated European Alps. © 2013 Elsevier B.V.


Vayena E.,University of Zurich | Mastroianni A.,University of Washington | Kahn J.,Johns Hopkins University
Science Translational Medicine | Year: 2013

A context-specif c approach to informed consent for Web-based health research can facilitate a dynamic research enterprise and maintain the public trust. Copyright © 2013, American Association for the Advancement of Science.


Knechtle B.,University of Zurich
International Journal of Sports Physiology and Performance | Year: 2012

Ultramarathon running is increasingly popular. An ultramarathon is defined as a running event involving distances longer than the length of a traditional marathon of 42.195 km. In ultramarathon races, ∼80% of the finishers are men. Ultramarathoners are typically ∼45 y old and achieve their fastest running times between 30 and 49 y for men, and between 30 and 54 y for women. Most probably, ultrarunners start with a marathon before competing in an ultramarathon. In ultramarathoners, the number of previously completed marathons is significantly higher than the number of completed marathons in marathoners. However, recreational marathoners have a faster personal-best marathon time than ultramarathoners. Successful ultramarathoners have 7.6 ± 6.3 y of experience in ultrarunning. Ultramarathoners complete more running kilometers in training than marathoners do, but they run more slowly during training than marathoners. To summarize, ultramarathoners are master runners, have a broad experience in running, and prepare differently for an ultramarathon than marathoners do. However, it is not known what motivates male ultramarathoners and where ultramarathoners mainly originate. Future studies need to investigate the motivation of male ultramarathoners, where the best ultramarathoners originate, and whether they prepare by competing in marathons before entering ultramarathons. © 2012 Human Kinetics, Inc.


The electronic description of octahedral (fac-[M(CO)3L 3]n, with M = Re, Ru, and Mn, and [Cr(CO) 5L]n), square-planar (cis-[Pt(CO)2L 2]n), and tetrahedral ([Ni(CO)3L]n) carbonyl complexes (where L = monodentate ligand) was obtained via density functional theory and natural population analyses in order to understand what effects are probed in these species by vibrational spectroscopy and electrochemistry as a function of the ligand electronic parameter of the associated L. The analysis indicates that while ligand electronic parameters may be considered as a measure of the net donor power of the ligand, the net transfer of the electron density (or charge) does not occur from the ligand to the metal ion. In [M(CO)xLy]ncarbonyl species, the charge transfer occurs from the ligand L to the oxygen atom of the bound carbon monoxides. This charge transfer translates into changes of the polarization (or permanent dipole) and the covalency of the C≡O bonds, and it is this effect that is probed in IR spectroscopy. As the analysis shifts from IR radiations to electrochemical potentials, the parameters best describe the relative thermodynamic stability of the oxidized and reduced [M(CO) xLy]n/n+1species. No relationship is found between the metal natural charge of the [M(CO)xLy] nfragments analyzed and the parameters. Brief considerations are given on the possible design of CO-releasing molecules. © 2010 American Chemical Society.


Bleul U.,University of Zurich
Livestock Science | Year: 2011

There have been many studies on perinatal and postnatal mortality in calves, but most are limited to small numbers of breeds or herds. The goal of this study was to determine the perinatal (first 24. h) and postnatal mortality rates during the first four months in 22 breeds and cross-breeds commonly occurring in Switzerland and to identify possible risk factors. From 2005 to 2007, 2,122,184 calvings were analysed, which yielded an overall perinatal mortality rate of 2.4%. There was a significant yearly increase in the mortality rate. The postnatal mortality rates from days 2 to 7, 8 to 28 and 29 to 120 were 0.5%, 1.3% and 0.7%, respectively. Dystocia was associated with a relative risk of perinatal mortality of 12.2, and significantly affected the postnatal mortality rates in all time periods investigated. The overall dystocia rate associated with bull calves was more than twice that of heifers, but there was no sex-related difference in Dexter, Hereford, Highland cattle, Hinterwälder, Jersey und Normande breeds. There were significant correlations between the mean birth weights of the different breeds and the dystocia rate (r = 0.6), and between the mean difference in male and female birth weights of the different breeds and the dystocia rate (r = 0.6). Perinatal mortality was also significantly affected by age of dam, gestation length, sex and weight of calf, season and herd size. Breed had a significant effect on perinatal and postnatal mortality rates, and there were significant interactions between breed and other risk factors of mortality. The identification of breed-specific risk factors of perinatal and postnatal mortality could help to develop strategies to alleviate the problem. © 2010 Elsevier B.V.


Maierhofer P.,University of Zurich | Marquard P.,Karlsruhe Institute of Technology
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2013

We present the result for the three-loop singlet QCD corrections to the decay of a Higgs boson into two photons and improve the calculation for the non-singlet case. With the new result presented, the decay width Γ(H → γγ) is completely known at O(GFα2αs 2,GFα3). © 2013 Elsevier B.V.


Van Tubergen A.,Maastricht University | Weber U.,University of Zurich
Nature Reviews Rheumatology | Year: 2012

Spondyloarthritis (SpA) defines a group of interrelated diseases, including ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, enteropathic-related spondylitis and arthritis, and undifferentiated SpA. The clinical presentation of SpA is heterogeneous, and no single shared distinguishing feature exists for the conditions comprising SpA; in daily practice, diagnosis is usually made on the basis of a combination of symptoms, the findings of physical examination, imaging and laboratory investigations. Several classification criteria have been developed for AS and SpA, which are useful in a research setting but cannot be automatically applied to the diagnosis of individual patients. Currently, MRI is the most sensitive imaging modality available for detection of sacroiliitis, often enabling detection of axial inflammation long before structural lesions are observed radiographically, thus facilitating early diagnosis of axial SpA. However, MRI will never capture all facets of SpA and the expert opinion of a rheumatologist will remain the crucial step in recognition of this disease. In this Review, we discuss diagnosis and classification of AS and SpA, and highlight how MRI might facilitate both processes. © 2012 Macmillan Publishers Limited All rights reserved.


Baroux C.,University of Zurich | Autran D.,Montpellier University
Plant Journal | Year: 2015

Sexual reproduction in flowering plants offers a number of remarkable aspects to developmental biologists. First, the spore mother cells - precursors of the plant reproductive lineage - are specified late in development, as opposed to precocious germline isolation during embryogenesis in most animals. Second, unlike in most animals where meiosis directly produces gametes, plant meiosis entails the differentiation of a multicellular, haploid gametophyte, within which gametic as well as non-gametic accessory cells are formed. These observations raise the question of the factors inducing and modus operandi of cell fate transitions that originate in floral tissues and gametophytes, respectively. Cell fate transitions in the reproductive lineage imply cellular reprogramming operating at the physiological, cytological and transcriptome level, but also at the chromatin level. A number of observations point to large-scale chromatin reorganization events associated with cellular differentiation of the female spore mother cells and of the female gametes. These include a reorganization of the heterochromatin compartment, the genome-wide alteration of the histone modification landscape, and the remodeling of nucleosome composition. The dynamic expression of DNA methyltransferases and actors of small RNA pathways also suggest additional, global epigenetic alterations that remain to be characterized. Are these events a cause or a consequence of cellular differentiation, and how do they contribute to cell fate transition? Does chromatin dynamics induce competence for immediate cellular functions (meiosis, fertilization), or does it also contribute long-term effects in cellular identity and developmental competence of the reproductive lineage? This review attempts to review these fascinating questions. Significance Statement The establishment of the female reproductive lineage in flowering plants involves several cell fate transitions associated with large-scale chromatin dynamics underlying cellular reprogramming. The next challenge is to understand how chromatin dynamics functionally contributes to cell fate transition. © 2015 The Authors.


Luyckx V.A.,University of Zurich | Brenner B.M.,Harvard University
Nature Reviews Nephrology | Year: 2015

An adverse intrauterine environment is associated with an increased risk of elevated blood pressure and kidney disease in later life. Many studies have focused on low birth weight, prematurity and growth restriction as surrogate markers of an adverse intrauterine environment; however, high birth weight, exposure to maternal diabetes and rapid growth during early childhood are also emerging as developmental risk factors for chronic diseases. Altered programming of nephron number is an important link between exposure to developmental stressors and subsequent risk of hypertension and kidney disease. Maternal, fetal, and childhood nutrition are crucial contributors to these programming effects. Resource-poor countries experience the sequential burdens of fetal and childhood undernutrition and subsequent overnutrition, which synergistically act to augment the effects of developmental programming; this observation might explain in part the disproportionate burden of chronic disease in these regions. Numerous nutritional interventions have been effective in reducing the short-term risk of low birth weight and prematurity. Understanding the potential long-term benefits of such interventions is crucial to inform policy decisions to interrupt the developmental programming cycle and stem the growing epidemics of hypertension and kidney disease worldwide. © 2015 Macmillan Publishers Limited. All rights reserved.


Gruenbaum Y.,Hebrew University of Jerusalem | Medalia O.,University of Zurich | Medalia O.,Ben - Gurion University of the Negev
Current Opinion in Cell Biology | Year: 2015

Lamins are nuclear intermediate filament (IF) proteins. They assemble to fibrous structures that are positioned between the inner nuclear membrane and the peripheral chromatin. A small fraction of lamins is also present in the nucleoplasm. Lamins are required to maintain the nuclear structure and, together with their associated proteins, are involved in most nuclear activities. Mutations in lamins cause >14 distinct diseases, called laminopathies, that include heart, muscle, fat and early aging diseases. However, it is not clear how lamins are organized in vivo and how the disease mutations affect lamin organization and functions. Here, we will review structural aspects of lamin assembly, discuss differences between peripheral and nucleoplasmic lamins and describe the protein complexes that lamins form. © 2014 Elsevier Ltd.


Hutter J.,University of Zurich
Wiley Interdisciplinary Reviews: Computational Molecular Science | Year: 2012

The Car-Parrinello (CP) method made molecular dynamics simulation with on-the-fly computation of interaction potentials from electronic structure theory computationally feasible. The method reformulates ab initio molecular dynamics (AIMD) as a two-component classical dynamical system. This approach proved to be valuable far beyond the original CP molecular dynamics method. The modern formulation of Born-Oppenheimer (BO) dynamics is based on the same basic principles and can be derived from the same Lagrange function as the CP method. These time-reversible BO molecular dynamics methods allow higher accuracy and efficiency while providing similar longtime stability as the CP method. AIMD is used in many fields of computational physics and chemistry. Its applications are instrumental in fields as divers as enzymatic catalysis and the study of the interior of planets. With its versatility and predictive power, AIMD has become a major approach in atomistic simulations. © 2011 John Wiley & Sons, Ltd.


Hubscher U.,University of Zurich | Maga G.,CNR Institute of Neuroscience
Current Opinion in Chemical Biology | Year: 2011

Maintenance of genetic stability is of crucial importance for any form of life. Before cell division in each mammalian cell, the process of DNA replication must faithfully duplicate three billion bases with an absolute minimum of mistakes. This is complicated by the fact that DNA itself is highly reactive and is constantly attacked by endogenous and exogenous factors leading to 50,000-100,000 different damages in the DNA of human cells every day. In this mini-review we will focus on lesion bypass by DNA polymerase machines either in replication or repair, with particular focus on the repair of oxidative lesions. © 2011 Elsevier Ltd.


Freisinger E.,University of Zurich
Journal of Biological Inorganic Chemistry | Year: 2011

The metallothionein (MT) superfamily combines a large variety of small cysteine-rich proteins from nearly all phyla of life that have the ability to coordinate various transition metal ions, including Zn II, Cd II, and Cu I. The members of the plant MT family are characterized by great sequence diversity, requiring further subdivision into four subfamilies. Very peculiar and not well understood is the presence of rather long cysteine-free amino acid linkers between the cysteine-rich regions. In light of the distinct differences in sequence to MTs from other families, it seems obvious to assume that these differences will also be manifested on the structural level. This was already impressively demonstrated with the elucidation of the three-dimensional structure of the wheat E c-1 MT, which revealed two metal cluster arrangements previously unprecedented for any MT. However, as this structure is so far the only one available for the plant MT family, other sources of information are in high demand. In this review the focus is thus set on any structural features known, deduced, or assumed for the plant MT proteins. This includes the determination of secondary structural elements by circular dichroism, IR, and Raman spectroscopy, the analysis of the influence of the long linker regions, and the evaluation of the spatial arrangement of the sequence separated cysteine-rich regions with the aid of, e.g., limited proteolytic digestion. In addition, special attention is paid to the contents of divalent metal ions as the metal ion to cysteine ratios are important for predicting and understanding possible metal-thiolate cluster structures. © SBIC 2011.


Leventhal G.E.,ETH Zurich | Gunthard H.F.,University of Zurich | Bonhoeffer S.,ETH Zurich | Stadler T.,ETH Zurich
Molecular Biology and Evolution | Year: 2014

The control, prediction, and understanding of epidemiological processes require insight into how infectious pathogens transmit in a population. The chain of transmission can in principle be reconstructed with phylogenetic methods which analyze the evolutionary history using pathogen sequence data. The quality of the reconstruction, however, crucially depends on the underlying epidemiological model used in phylogenetic inference. Until now, only simple epidemiological models have been used, which make limiting assumptions such as constant rate parameters, infinite total population size, or deterministically changing population size of infected individuals. Here, we present a novel phylogenetic method to infer parameters based on a classical stochastic epidemiological model. Specifically, we use the susceptible-infected-susceptible model, which accounts for density-dependent transmission rates and finite total population size, leading to a stochastically changing infected population size. We first validate our method by estimating epidemic parameters for simulated data and then apply it to transmission clusters from the Swiss HIV epidemic. Our estimates of the basic reproductive number R0 for the considered Swiss HIV transmission clusters are significantly higher than previous estimates, which were derived assuming infinite population size. This difference in key parameter estimates highlights the importance of careful model choice when doing phylogenetic inference. In summary, this article presents the first fully stochastic implementation of a classical epidemiological model for phylogenetic inference and thereby addresses a key aspect in ongoing efforts to merge phylogenetics and epidemiology. © 2013 The Author 2013. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.


Panicker J.N.,University College London | Fowler C.J.,University College London | Kessler T.M.,University of Zurich
The Lancet Neurology | Year: 2015

Lower urinary tract (LUT) dysfunction is a common sequela of neurological disease, resulting in symptoms that have a pronounced effect on quality of life. The site and nature of the neurological lesion affect the pattern of dysfunction. The risk of developing upper urinary tract damage and renal failure is much lower in patients with slowly progressive non-traumatic neurological disorders than in those with spinal cord injury or spina bifida; this difference in morbidity is taken into account in the development of appropriate management algorithms. Clinical assessment might include tests such as uroflowmetry, post-void residual volume measurement, renal ultrasound, (video-)urodynamics, neurophysiology, and urethrocystoscopy, depending on the indication. Incomplete bladder emptying is most often managed by intermittent catheterisation, and storage dysfunction by antimuscarinic drugs. Intradetrusor injections of onabotulinumtoxinA have transformed the management of neurogenic detrusor overactivity. Neuromodulation offers promise for managing both storage and voiding dysfunction. An individualised, patient-tailored approach is required for the management of LUT dysfunction associated with neurological disorders. © 2015 Elsevier Ltd.


Alcott B.,University of Zurich
Journal of Cleaner Production | Year: 2013

Degrowth should consider the right to work - a Job Guarantee (JG) - as a way of making a smaller economy more just and socially sustainable. Economic shrinkage in richer countries is accompanied by increased unemployment, a bad enough problem in itself but also a barrier to voters' acceptance of the degrowth path. Since being out of work is distinct from being poor, anti-poverty income policies should be approached separately. The JG is one of several paths to full employment, including reduced working time. This essay only briefly mentions some real-world JG programs and some technical objections. The main suggestion is to move employment from being a matter of economics, particularly economic growth, to being a political right. A right to work is necessarily effective and would avoid sacrificing the ecological and social goals of degrowth on the altar of full employment. © 2011 Elsevier Ltd. All rights reserved.


Kuhn T.,University of Zurich | Kuhn T.,University of Malta
Semantic Web | Year: 2013

Different kinds of controlled natural language (CNL) have been proposed as a front-end for Semantic Web systems, in order to make them more accessible to users with no background in formal notations and methods. This paper investigates whether OWL statements in CNL are indeed easier to understand than in other notations. To this aim, an experiment with 64 participants was conducted that compares a controlled natural language to a classical OWL notation. Concretely, Attempto Controlled English was compared to a simplified version of the Manchester OWL Syntax. For a reliable and tool-independent evaluation of understandability, the experiment is based on a novel evaluation framework making use of simple and intuitive diagrams. The results show that CNL is easier to understand, needs less learning time, and is more accepted by its users. © 2012 -IOS Press and the authors.


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

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


Mischo A.,University of Zurich
Current drug targets | Year: 2015

Renal cell cancer is a heterogeneous group of cancers with different histologic subtypes. The majority of renal tumors in adults are clear cell renal cell carcinomas, which are characterized by von Hippel- Lindau (VHL) gene alterations. Recent advances in defining the genetic landscape of renal cancer has shown the genetic heterogeneity of clear cell renal cell carcinomas (ccRCC) and the presence of at least 3 additional ccRCC tumor suppressor genes on chromosome 3p. Due to inactivation of VHL, renal cancer cells produce the HIF-responsive growth factor VEGF. The PI3K--mTORC1 signaling axis also represents a target for therapy. The new systemic therapies, including tyrosine kinase inhibitors, monoclonal antibodies, and mTOR inhibitors, aim to suppress angiogenesis with vascular endothelial growth factor as a target. Various VEGF-inhibitors are approved for the treatment of ccRCC and we discuss recent advancements in the treatment of metastatic ccRCC. Other gene alterations have been identified in hereditary cancer syndromes, e.g. FLCN, TSC1, TSC2, TFE3, TFEB, MITF, FH, SDHB, SDHD, MET, and PTEN and we review their role in renal tumor carcinogenesis, prognosis, and targeted therapy. By reviewing the associations between morphologic features and molecular genetics of renal cancer we provide insight into the basis for targeted renal cancer therapy.


Hadorn M.,University of Zurich | Hotz P.E.,University of Southern Denmark
PLoS ONE | Year: 2010

Background: Although multicompartment systems made of single unilamellar vesicles offer the potential to outperform single compartment systems widely used in analytic, synthetic, and medical applications, their use has remained marginal to date. On the one hand, this can be attributed to the binary character of the majority of the current tethering protocols that impedes the implementation of real multicomponent or multifunctional systems. On the other hand, the few tethering protocols theoretically providing multicompartment systems composed of several distinct vesicle populations suffer from the readjustment of the vesicle formation procedure as well as from the loss of specificity of the linking mechanism over time. Methodology/Principal Findings: In previous studies, we presented implementations of multicompartment systems and resolved the readjustment of the vesicle formation procedure as well as the loss of specificity by using linkers consisting of biotinylated DNA single strands that were anchored to phospholipid-grafted biotinylated PEG tethers via streptavidin as a connector. The systematic analysis presented herein provides evidences for the incorporation of phospholipid-grafted biotinylated PEG tethers to the vesicle membrane during vesicle formation, providing specific anchoring sites for the streptavidin loading of the vesicle membrane. Furthermore, DNA-mediated vesicle-vesicle self-assembly was found to be sequence-dependent and to depend on the presence of monovalent salts. Conclusions/Significance: This study provides a solid basis for the implementation of multi-vesicle assemblies that may affect at least three distinct domains. (i) Analysis. Starting with a minimal system, the complexity of a bottom-up system is increased gradually facilitating the understanding of the components and their interaction. (ii) Synthesis. Consecutive reactions may be implemented in networks of vesicles that outperform current single compartment bioreactors in versatility and productivity. (iii) Personalized medicine. Transport and targeting of long-lived, pharmacologically inert prodrugs and their conversion to short-lived, active drug molecules directly at the site of action may be accomplished if multi-vesicle assemblies of predefined architecture are used. Copyright: © 2010 Hadorn et al.


To integrate the amount of hepatic steatosis in modern liver allocation models. The aim of this study was to combine the 2 largest liver transplant databases (United States and Europe) in 1 comprehensive model to predict outcome after liver transplantation, with a novel focus on the impact of the presence of steatosis in the graft. We adjusted the balance of risk (BAR) score for its application to the European Liver Transplant Registry (ELTR) database containing 11,942 patients. All liver transplants from ELTR and United Network for Organ Sharing with recorded liver biopsies were then combined in one survival analysis in relation to the presence of graft micro- (n = 9,677) and macrosteatosis (n = 11,516). Microsteatosis, regardless of the amount, was associated with a similar relationship between mortality and BAR score as nonsteatotic livers. Low-grade macrosteatotic liver grafts (≤30% macrosteatosis) resulted in 5-year graft-survival rates of 60% or more up to BAR 18, comparable to nonsteatotic grafts. However, use of moderate or severely steatotic liver grafts (>30% macrosteatosis) resulted in acceptable outcome only if the cumulative risk at transplant was low, that is, BAR score of 9 or less. Microsteatotic or 30% or less macrosteatotic liver grafts can be used safely up to BAR score of 18 or less, but liver grafts with more than 30% macrosteatotis should be used with risk adjustment, that is, up to BAR score of 9 or less.


Weller M.,University of Zurich | Stupp R.,University of Lausanne | Wick W.,University of Heidelberg
The Lancet Oncology | Year: 2012

The lifetime risk of having epileptic seizures is profoundly increased in patients with cancer: about 20% of all patients with systemic cancer may develop brain metastases. These patients and those with primary brain tumours have a lifetime risk of epilepsy of 20-80%. Moreover, exposure to chemotherapy or radiotherapy to the brain, cancer-related metabolic disturbances, stroke, and infection can provoke seizures. The management of epilepsy in patients with cancer includes diagnosis and treatment of the underlying cerebral pathological changes, secondary prophylaxis with antiepileptic drugs, and limiting of the effect of epilepsy and its treatment on the efficacy and tolerability of anticancer treatments, cognitive function, and quality of life. Because of the concern of drug-drug interactions, the pharmacological approach to epilepsy requires a multidisciplinary approach, specifically in a setting of rapidly increasing choices of agents both to treat cancer and cancer-associated epilepsy. © 2012 Elsevier Ltd.


Combined pelvic floor electromyography (EMG) and videocystourethrography (VCUG) during urodynamic investigation are the most acceptable and widely agreed methods for diagnosing detrusor external sphincter dyssynergia (DESD). Theoretically, external urethral sphincter pressure (EUSP) measurement would provide enough information for the diagnosis of DESD and could simplify the urodynamic investigation replacing combined pelvic floor EMG and VCUG. Thus, we evaluated the diagnostic accuracy of EUSP measurement for DESD. PATIENTS #ENTITYSTARTX00026; A consecutive series of 72 patients (36 women, 36 men) with neurogenic lower urinary tract dysfunction able to void spontaneously was prospectively evaluated at a single university spinal cord injury center. Diagnosis of DESD using EUSP measurement (index test) versus combined pelvic floor EMG and VCUG (reference standard) was assessed according to the recommendations of the Standards for Reporting of Diagnostic Accuracy Initiative. Using EUSP measurement (index test) and combined pelvic floor EMG and VCUR (reference standard), DESD was diagnosed in 10 (14%) and in 41 (57%) patients, respectively. More than half of the patients presented discordant diagnosis between the index test and the reference standard. Among 41 patients with DESD diagnosed by combined pelvic floor EMG and VCUR, EUSP measurement identified only 6 patients. EUSP measurement had a sensitivity of 15% (95% CI 5%-25%), specificity of 87% (95% CI 76%-98%), positive predictive value of 60% (95% CI 30%-90%), and negative predictive value of 56% (95% CI 44%-68%) for the diagnosis of DESD. For diagnosis of DESD, EUSP measurement is inaccurate and cannot replace combined pelvic floor EMG and VCUR.


Kempf W.,Kempf und Pfaltz. Histologische Diagnostik | Kempf W.,University of Zurich | Kazakov D.V.,Charles University | Panizzon R.G.,Center Hospitalier University Vaud
American Journal of Surgical Pathology | Year: 2013

Lymphomatoid papulosis (LyP) belongs to the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Clinically, LyP is characterized by a variable number of self-healing papulo-nodular lesions, with the typical waxing and waning course. Histologically, 4 types (A, B, C, and D) have been delineated. Angioinvasive growth and large ulcers are rare findings in LyP and simulate aggressive lymphoma. We retrospectively analyzed the clinicopathologic and molecular features of angioinvasive LyP in a series of 16 patients. This new form of LyP is characterized by oligolesional papules that rapidly ulcerate and evolve into large necrotic eschar-like lesions with a diameter of 1 to 4 cm and an angiocentric and angiodestructive infiltrate of small-sized to medium-sized atypical lymphocytes expressing CD30 and frequently CD8. As in other forms of LyP, the lesions underwent spontaneous regression after a few weeks. Recurrences were common, but the prognosis was excellent with no extracutaneous spread or disease-related deaths. Complete remission occurred in 9 of 16 patients (56%). This LyP variant should be distinguished from aggressive forms of angiocentric and angiodestructive and cytotoxic T-cell lymphomas. We propose the term LyP type E for this clinically and histologically unusual variant. Copyright © 2012 by Lippincott Williams &Wilkins.


Fourie C.,University of Zurich
Bioethics | Year: 2015

Much research is currently being conducted on health care practitioners' experiences of moral distress, especially the experience of nurses. What moral distress is, however, is not always clearly delineated and there is some debate as to how it should be defined. This article aims to help to clarify moral distress. My methodology consists primarily of a conceptual analysis, with especial focus on Andrew Jameton's influential description of moral distress. I will identify and aim to resolve two sources of confusion about moral distress: (1) the compound nature of a narrow definition of distress which stipulates a particular cause, i.e. moral constraint, and (2) the distinction drawn between moral dilemma (or, more accurately, moral conflict) and moral distress, which implies that the two are mutually exclusive. In light of these concerns, I argue that the definition of moral distress should be revised so that moral constraint should not be a necessary condition of moral distress, and that moral conflict should be included as a potential cause of distress. Ultimately, I claim that moral distress should be understood as a specific psychological response to morally challenging situations such as those of moral constraint or moral conflict, or both. © 2015 John Wiley & Sons Ltd.


Barton M.,University of Zurich
Current Opinion in Lipidology | Year: 2013

Purpose of review Oestrogens are important modulators of lipid metabolism, inflammation and vascular homeostasis. Endogenous oestrogens contribute to the low prevalence of atherosclerotic vascular disease in premenopausal women with intact ovarian function, and cessation of oestrogen production following menopause increases cardiovascular risk. Orally administered oestrogens such as postmenopausal hormone therapy increase HDL and reduce LDL cholesterol levels, and they increase triglyceride levels. Current guidelines do not recommend postmenopausal hormone therapy for cardiovascular prevention. Recent findings Recent clinical studies have suggested potential benefits of natural oestrogen or selective oestrogen receptor modulators on cardiovascular outcomes, effects that are associated with lipid profile improvements. In contrast to earlier studies such as the Women's Health Initiative, the Heart and Estrogen/Progestin Replacement Study or the Estrogen Replacement and Atherosclerosis trial, in which investigators used hormone mixtures derived from horse urine (misleadingly named 'conjugated oestrogens' with unknown activity on oestrogen receptors), triphasic oestrogen therapy started early after menopause as primary prevention study protocol improved outcome. New studies suggest therapeutic potential of natural oestrogens and certain selective oestrogen receptor modulators to reduce coronary artery disease risk in postmenopausal women. Summary Endogenous oestrogens are important regulators of lipid metabolism and inhibit inflammation, vascular cell growth and plaque progression in premenopausal women. The recent trials warrant further studies, which should also determine how much of the potential benefits are due to improvements of lipid metabolism. © 2013 Wolters Kluwer Health | Lippincott Williams amp; Wilkins.


Leitner A.,ETH Zurich | Walzthoeni T.,ETH Zurich | Aebersold R.,ETH Zurich | Aebersold R.,University of Zurich
Nature Protocols | Year: 2014

Chemical cross-linking in combination with LC-MS/MS (XL-MS) is an emerging technology to obtain low-resolution structural (distance) restraints of proteins and protein complexes. These restraints can also be used to characterize protein complexes by integrative modeling of the XL-MS data, either in combination with other types of structural information or by themselves, to establish spatial relationships of subunits in protein complexes. Here we present a protocol that has been successfully used to generate XL-MS data from a multitude of native proteins and protein complexes. It includes the experimental steps for performing the cross-linking reaction using disuccinimidyl suberate (a homobifunctional, lysine-reactive cross-linking reagent), the enrichment of cross-linked peptides by peptide size-exclusion chromatography (SEC; to remove smaller, non-cross-linked peptides), instructions for tandem MS analysis and the analysis of MS data via the open-source computational software pipeline xQuest and xProphet (available from http://proteomics.ethz.ch). Once established, this robust protocol should take ∼4 d to complete, and it is generally applicable to purified proteins and protein complexes. © 2013 Nature America, Inc. All rights reserved.


Lutterotti A.,Innsbruck Medical University | Martin R.,University of Zurich
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: Inhibition of self-reactive T cells through induction of antigen-specific immune tolerance holds the promise of effective treatment of autoimmune pathology with few side effects and preservation of normal immune functions. In multiple sclerosis (MS) several approaches have been tested already in clinical trials or are currently ongoing with the aim to inhibit myelin-reactive immune responses. Areas covered: This article provides an overview of the recent and ongoing strategies to inhibit specific immune responses in MS, including different applications of myelin peptide-based approaches, T-cell vaccination, DNA vaccination and antigen-coupled cells. Expert opinion: Despite difficulties in translation of antigen-specific therapies in MS, novel approaches have the potential to effectively induce immune tolerance and ameliorate the disease. To improve efficacy of treatments, future trials should include patients in the early phases of the disease, when the autoimmune response is predominant and immune reactivity still focused. The target antigens are not fully defined yet, and robust immunomonitoring assays should developed to provide mechanistic proof of concept in parallel to showing efficacy with respect to inhibiting inflammatory disease activity in the central nervous system (CNS). © 2014 Informa UK, Ltd.


Rogler G.,University of Zurich
Best Practice and Research: Clinical Gastroenterology | Year: 2010

Drugs used for treating inflammatory bowel disease are known to have a number of gastrointestinal and liver adverse effects. 5-ASA products are relatively safe and have few adverse events. In contrast sulfasalazine has side effects in 11-40% of treated patients including fatigue, nausea, abdominal pain and diarrhoea. Glucocorticoids can induce or propagate peptic ulcers and upper GI bleeding especially in combination with NSAIDs. Thioguanins may have severe gastrointestinal side effects including gastrointestinal complaints (in up to 12%), hepatotoxicity (up to 4%) and pancreatitis (1%). Nodular regenerative hyperplasia (NRH) is an important potential side effect of thiopurine therapy especially in men with Crohn's disease after ileocecal resection. NRH may ultimately lead to portal hypertension. A major concern of methotrexate therapy in IBD besides myelosuppression and pulmonary fibrosis is hepatotoxicity. 5 mg of folic acid substitution per week potentially decreases gastrointestinal side effects by 80% without interfering with the efficacy of methotrexate. Besides renal dysfunction, tremor, hirsutism, hypertension and gum hyperplasia cyclosporine is known to have a number of gastrointestinal side effects that occur with less frequency such as diarrhoea (up to 8%) nausea and vomiting (up to 10%) and hepatotoxicity in 1-4%. Rare gastrointestinal adverse events are gastritis and peptic ulcers. Paying attention to these potential deleterious side effects is mandatory for physicians treating IBD patients. © 2009 Elsevier Ltd. All rights reserved.


Fischer D.R.,University of Zurich
Seminars in Nuclear Medicine | Year: 2013

The convenience of 18F-fluoride imaging is undeniable both because of its favorable tracer and because of its technical characteristics, including high image quality and short examination times leading to increased patient comfort. Depending on the activity administered, the radiation dose to patients is about comparable to higher using 18F-fluoride for bone imaging compared with conventional scintigraphy using 99mTc-methylene diphosphonate. In times of molybdenum shortage, 18F-fluoride represents a good alternative to 99mTc-based bone tracers. Besides malignant skeletal disease18F-fluoride PET/CT has in the last decade been investigated in a variety of nononcologic musculoskeletal disorders of all parts of the skeleton. Studies included imaging of the skull with a special focus on bisphosphonate-induced osteonecrosis of the jaw in patients treated with bisphosphonates due to benign or malignant bone changes. Further studies evaluated the appendicular skeleton with emphasis on postsurgical changes including patients after knee and hip surgery and patients having received bone grafts of their limbs. Also, therapeutic effect of 18F-fluoride PET/CT on patients with unclear foot pain was investigated. Finally imaging of the axial skeleton was analyzed including patients with ankylosing spondylitis and with Paget disease as well as patients after spine surgery including assessment of cage incorporation after cervical and lumbar spine fusion surgery. Furthermore, children suspected of child abuse as well as young patients with back pain were investigated by either 18F-fluoride PET or PET/CT. Regarding its favorable technical aspects as well as study results presented, it is imaginable that 18F-fluoride PET/(CT) will be increasingly used for nononcologic musculoskeletal imaging in the future either as an adjunct or alternative to so far established imaging modalities and seems to be promising regarding decision making in the therapeutic management of patients with nononcologic musculoskeletal disorders. © 2013 Elsevier Inc.


Bozinov O.,University of Zurich
Acta neurochirurgica. Supplement | Year: 2011

Three-dimensional ultrasound (US) technology is supposed to help combat some of the orientation difficulties inherent to two-dimensional US. Contemporary navigation solutions combine reconstructed 3D US images with common navigation images and support orientation. New real-time 3D US (without neuronavigation) is more time effective, but whether it further assists in orientation remains to be determined. An integrated US system (IGSonic, VectorVision, BrainLAB, Munich Germany) and a non-integrated system with real-time 3D US (iU22, Philips, Bothell, USA) were recently compared in neurosurgical procedures in our group. The reconstructed navigation view was time-consuming, but images were displayed in familiar planes (e.g., axial, sagittal, coronal). Further potential applications of US angiography and pure US navigation are possible. Real-time 3D images were displayed without the need for an additional acquisition and reconstruction process, but spatial orientation remained challenging in this preliminary testing phase. Reconstructed 3D US navigation appears to be superior with respect to spatial orientation, and the technique can be combined with other imaging data. However, the potential of real-time 3D US imaging is promising.


Schneider T.,University of Zurich
Proteomics | Year: 2010

Fungi and bacteria are key players in the decomposition of leaf litter, but their individual contributions to the process and their interactions are still poorly known. We combined semi-quantitative proteome analyses (1-D PAGE-LC-MS/MS) with qualitative and quantitative analyses of extracellular degradative enzyme activities to unravel the respective roles of a fungus and a bacterium during litter decomposition. Two model organisms, a mesophilic Gram-negative bacterium (Pectobacterium carotovorum) and an ascomycete (Aspergillus nidulans), were grown in both, pure culture and co-culture on minimal medium containing either glucose or beech leaf litter as sole carbon source. P. carotovorum grew best in co-culture with the fungus, whereas growth of A. nidulans was significantly reduced when the bacterium was present. This observation suggests that P. carotovorum has only limited capabilities to degrade leaf litter and profits from the degradation products of A. nidulans at the expense of fungal growth. In accordance with this interpretation, our proteome analysis revealed that most of the extracellular biodegradative enzymes (i.e. proteases, pectinases, and cellulases) in the cultures with beech litter were expressed by the fungus, the bacterium producing only low levels of pectinases.


Pluckthun A.,University of Zurich
Methods in Molecular Biology | Year: 2012

Ribosome display is an in vitro evolution technology for proteins. It is based on in vitro translation, but prevents the newly synthesized protein and the mRNA encoding it from leaving the ribosome. It thereby couples phenotype and genotype. Since no cells need to be transformed, very large libraries can be used directly in selections, and the in vitro amplification provides a very convenient integration of random mutagenesis that can be incorporated into the procedure. This review highlights concepts, mechanisms, and different variations of ribosome display and compares it to related methods. Applications of ribosome display are summarized, e.g., the directed evolution of proteins for higher binding affinity, for higher stability or other improved biophysical parameters and enzymatic properties. Ribosome display has developed into a robust technology used in academia and industry alike, and it has made the cell-free Darwinian evolution of proteins over multiple generations a reality. © 2012 Springer Science+Business Media, LLC.


Teyssier R.,University of Zurich
Annual Review of Astronomy and Astrophysics | Year: 2015

In this review, the equations of hydrodynamics, magnetohydrodynamics, and radiation hydrodynamics are presented, together with their corresponding nonideal source terms. I overview the current landscape of modern grid-based numerical techniques with an emphasis on numerical diffusion, which plays a fundamental role in stabilizing the solution but is also the main source of errors associated with these numerical techniques. I discuss in great detail the inclusion of additional important source terms, such as cooling and gravity. I also show how to modify classic operator-splitting techniques to avoid undesirable numerical errors associated with these additional source terms, in particular in the presence of highly supersonic flows. I finally present various mesh adaptation strategies that can be used to minimize these numerical errors. To conclude, I review existing astrophysical software that is publicly available to perform simulations for such astrophysical fluids. © 2015 by Annual Reviews.


Munz C.,University of Zurich
Frontiers in Immunology | Year: 2012

T cells recognize proteolytic fragments of antigens that are presented to them on major histocompatibility complex (MHC) molecules. MHC class I molecules present primarily products of proteasomal proteolysis to CD8+ T cells, while MHC class II molecules display mainly degradation products of lysosomes for stimulation of CD4+T cells. Macroautophagy delivers intracellular proteins to lysosomal degradation, and contributes in this fashion to the pool of MHC class II displayed peptides. Both selfand pathogen-derived MHC class II ligands are generated by this pathway. In addition, however, recent evidence points also to regulation of extracellular antigen processing by macroautophagy. In this review, I will discuss these two aspects of antigen processing for MHC class II presentation via macroautophagy, namely its influence on intracellular and extracellular antigen presentation to CD4+ T cells. © 2012 Münz.


Bischoff-Ferrari H.A.,University of Zurich
Scandinavian Journal of Clinical and Laboratory Investigation | Year: 2012

Vitamin D deficiency is prevalent in about 50 % of adults and limited data support a similar prevalence in children. This is of concern, as vitamin D deficiency is a risk factor for falls and fractures and several double-blind RCTs provide evidence that supplementation reduces the risk of fall and fractures among the senior population. Further, large epidemiologic studies consistently report that vitamin D deficiency confers an increased risk of mortality, cardiovascular disease and cancer, especially colo-rectal cancer. However, as large clinical trials for non-musculoskeletal endpoints are missing today, public health recommendations are based primarily on bone health to argue vitamin D repletion in the population. © 2012 Informa Healthcare.


BACKGROUND: The control of the lower urinary tract is a complex, multilevel process involving both the peripheral and central nervous system. Due to lesions of the neuraxis, most spinal cord injury patients suffer from neurogenic lower urinary tract dysfunction, which may jeopardise upper urinary tract function and has a negative impact on health-related quality of life. However, the alterations to the nervous system following spinal cord injury causing neurogenic lower urinary tract dysfunction and potential effects of treatments such as intradetrusor onabotulinumtoxinA injections on lower urinary tract control are poorly understood.METHODS/DESIGN: This is a prospective structural and functional magnetic resonance imaging study investigating the supraspinal lower urinary tract control in healthy subjects and spinal cord injury patients undergoing intradetrusor onabotulinumtoxinA injections for treating neurogenic detrusor overactivity.Neuroimaging data will include structural magnetic resonance imaging (T1-weighted imaging and diffusion tensor imaging) as well as functional, i.e. blood oxygen level-dependent sensitive magnetic resonance imaging using a 3 T magnetic resonance scanner. The functional magnetic resonance imaging will be performed simultaneously to three different bladder stimulation paradigms using an automated magnetic resonance compatible and synchronised pump system.All subjects will undergo two consecutive and identical magnetic resonance imaging measurements. Healthy subjects will not undergo any intervention between measurements but spinal cord injury patients will receive intradetrusor onabotulinumtoxinA injections for treating neurogenic detrusor overactivity.Parameters of the clinical assessment including bladder diary, urinalysis, medical history, neuro-urological examination, urodynamic investigation as well as standardised questionnaires regarding lower urinary tract function and quality of life will serve as co-variates in the magnetic resonance imaging analysis.DISCUSSION: This study will identify structural and functional alterations in supraspinal networks of lower urinary tract control in spinal cord injury patients with neurogenic detrusor overactivity compared to healthy controls. Post-treatment magnetic resonance imaging measurements in spinal cord injury patients will provide further insights into the mechanism of action of treatments such as intradetrusor onabotulinumtoxinA injections and the effect on supraspinal lower urinary tract control.TRIAL REGISTRATION: ClinicalTrials.gov NCT01768910.


Rogler G.,University of Zurich
Digestive Diseases | Year: 2011

During the last few years a significant advance has been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). From twin studies it was evident that there is more that 50% concordance of Crohn's disease (CD) in monozygotic twin pairs, however it is only 3.6% among dizygotic twins. These data indicate that the genetic background may be responsible for 50% of the risk or 'susceptibility' to develop CD. Obviously it is not a sufficient condition as otherwise there would be 100% concordance of disease in monozygotic twin pairs. Environmental factors as well must play an important role. This is further supported by the fact that there is only low development in genetic risk factors over ten thousands of years. In contrast, the incidence of CD and ulcerative colitis (UC) has dramatically increased in Western countries in the last 100 years. This further supports the concept of a 'Western lifestyle factor(s)' that triggers chronic intestinal inflammation in a genetically susceptible host. The proof of the concept of a genetic susceptibility was achieved in 2001 with the discovery that NOD2 is the most important susceptibility gene for CD. The function of NOD2 has been investigated in detail. NOD2 is an intracellular 'alarm button', a receptor recognizing invading bacteria that entered the mucosal wall. NOD2 mutants associated with susceptibility to CD seem to be deficient in their recognition of bacterial wall products. In a genome-wide association study a disease association was found in the autophagy-related 16-like 1 gene (ATG16L1). The ATG16L1 gene encodes a protein in the autophagosome pathway that processes intracellular bacteria. Based on these findings, CD is now discussed as an impaired and inadequate immune reaction to the gut bacteria which are a part of our environment (or perhaps 'in-vironment'). In addition to NOD2 and ATG16L1, there are more 'innate' pathways by which commensal and pathogenic bacteria can directly interact with cells of the intestinal mucosa. The 'environment concept' and the 'genetic concept' of IBD pathophysiology are converging. With the finding that most susceptibility genes for CD and UC are involved in innate immune mechanisms and the primary defense against bacteria entering the mucosa, for the first time a unifying concept of the 'genetic pathophysiology hypothesis' and the 'environment pathophysiology hypothesis' of IBD was possible. Bacteria are the link between the environment and mucosal defense system. Copyright © 2011 S. Karger AG, Basel.


Asarian L.,University of Zurich
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2013

Hypothalamic-pituitary-gonadal (HPG) axis function fundamentally affects the physiology of eating. We review sex differences in the physiological and pathophysiological controls of amounts eaten in rats, mice, monkeys, and humans. These controls result from interactions among genetic effects, organizational effects of reproductive hormones (i.e., permanent early developmental effects), and activational effects of these hormones (i.e., effects dependent on hormone levels). Male-female sex differences in the physiology of eating involve both organizational and activational effects of androgens and estrogens. An activational effect of estrogens decreases eating 1) during the periovulatory period of the ovarian cycle in rats, mice, monkeys, and women and 2) tonically between puberty and reproductive senescence or ovariectomy in rats and monkeys, sometimes in mice, and possibly in women. Estrogens acting on estrogen receptor-α (ERα) in the caudal medial nucleus of the solitary tract appear to mediate these effects in rats. Androgens, prolactin, and other reproductive hormones also affect eating in rats. Sex differences in eating are mediated by alterations in orosensory capacity and hedonics, gastric mechanoreception, ghrelin, CCK, glucagon-like peptide-1 (GLP-1), glucagon, insulin, amylin, apolipoprotein A-IV, fatty-acid oxidation, and leptin. The control of eating by central neurochemical signaling via serotonin, MSH, neuropeptide Y, Agouti-related peptide (AgRP), melanin-concentrating hormone, and dopamine is modulated by HPG function. Finally, sex differences in the physiology of eating may contribute to human obesity, anorexia nervosa, and binge eating. The variety and physiological importance of what has been learned so far warrant intensifying basic, translational, and clinical research on sex differences in eating. © 2013 the American Physiological Society.


Von Eckardstein A.,University of Zurich
Expert Review of Cardiovascular Therapy | Year: 2010

Owing to many potentially anti-atherogenic functions and the inverse correlation of high-density lipoprotein (HDL)-cholesterol (C) plasma levels with cardiovascular risk, HDLs have evolved as an attractive target for the prevention and therapy of coronary heart disease. Previously, the failure of torcetrapib, the frequent confounding of low HDL-C with other pro-atherogenic conditions, as well as inconsistent data from patients and animal models with genetic HDL dyslipidemias, left in doubt the suitability of HDL-C as a target for anti-atherogenic therapy. However, HDL-C is an integrative but nonfunctional measure of particle size and number. Therefore, biomarkers reflecting the functionality of HDL particles are needed to assess and monitor the cardiovascular risk exerted by disturbances and treatments of HDL metabolism, respectively. Moreover, the discovery of novel therapeutics that improve HDL metabolism, mimic HDL function, or cure the regulatory network underlying dyslipidemias and dysfunctions of HDL should be a major aim of atherosclerosis research. © 2010 Expert Reviews Ltd.


Wiegand A.,University of Zurich
Oral health & preventive dentistry | Year: 2010

The present review summarises the effects of titanium tetrafluoride (TiF(4)) on the development and progression of carious and erosive lesions. The mode of action of TiF(4) is due to the formation of an acid-stable surface layer, which provides mechanical protection to the surface, and to an increased fluoride uptake, which might chemically reduce demineralisation of dental hard tissues. Most in vitro studies showed that TiF(4) is effective in reducing the formation of carious and erosive enamel and dentine lesions. Thereby, TiF(4) was equally or more effective than sodium fluoride (NaF), amine fluoride (AmF) or stannous fluoride (SnF(2)). While clinical data confirm the caries-preventive effect, clinical trials analysing the anti-erosive effect of TiF(4) are lacking. Few data available from in situ studies revealed conflicting results by showing either no effect or a beneficial effect of TiF(4) on enamel erosion. Even though research focused on TiF(4), there is also evidence to show that other metal fluorides, such as zirconium and hafnium tetrafluorides, affect enamel and dentine demineralisation. CONCLUSION: The potential of TiF(4) to prevent acid demineralisation requires further research to confirm the promising in vitro results obtained by in situ studies and clinical trials.


Mullhaupt B.,University of Zurich
Swiss Medical Weekly | Year: 2012

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. Two first-generation protease inhibitors, telaprevir and boceprevir, have recently been approved for the treatment of chronic hepatitis C genotype 1. Triple therapy comprising pegylated interferon-α, ribavirin and telaprevir or boceprevir increases sustained virological response rates to ∼70% and allows to shorten treatment duration in ∼1/2 of treatment-naïve patients with chronic hepatitis C genotype 1. Sustained virological response rates in treatment-experienced patients depend on the response to previous treatment, ranging from >80% in previous relapsers to ∼30% in previous null responders. These advances come at the expense of new adverse effects and increased cost. In addition, treatment of chronic hepatitis C will become more complex. In these times of changing medical practice, the present expert opinion statement by the Swiss Association for the Study of the Liver shall provide guidance on the treatment of chronic hepatitis C with triple therapy comprising telaprevir or boceprevir.


Bailly A.,University of Zurich
Plant signaling & behavior | Year: 2012

Bacteria interact with plants in many different ways. In recent years, bacterial production of volatiles has emerged as a novel process by which bacteria modulate plant growth. Exposure to the volatiles produced by certain bacterial strains has been shown to lead to up to 5-fold increased plant biomass or to plant death. Despite these drastic growth alterations, the elucidation of the molecules responsible, of the mechanism of perception by the plant and of the specific metabolic changes induced in planta is still in its infancy. This review summarizes the current knowledge and highlights future lines of research that should increase our knowledge of the volatile-mediated dialogue between bacteria and plants.


The aim of this randomised controlled double-blinded clinical trial was to determine the efficacy of a new cross-linked membrane (VN) in guided bone regeneration (GBR) around exposed dental implants compared to a native collagen membrane (BG). A total of 16 patients in need of implant treatment at two different sites with osseous defects were planned for this split-mouth study. After inserting the dental implants, peri-implant defects were treated according to the GBR technique using a VN membrane with prolonged resorption time in the randomised test site and a BG membrane in the control site. After a healing time of 6 months, mucoperiosteal flaps were elevated for the evaluation of the primary (vertical bone fill [ΔDL] and quality of newly formed tissue [QT]) and secondary outcome variables (infrabony defect height [DH], defect width [DW], defect depth [DD] and augmentation depth [AD]) and the sampling of biopsies apical to the implant shoulder. A total of 16 patients fulfilled the initial non-surgical inclusion and exclusion criteria. However, the study was discontinued early after 9 surgically treated patients because unacceptable safety issues arose and severe infection related to the VN membranes. The VN membrane revealed statistically significantly more soft tissue dehiscence than the BG membrane (56% and 11%, respectively, P = 0.0455). In 3 of these 9 patients the VN membrane had to be removed due to infection early after the first follow-up visit. For the statistical analyses these sites were designated as the value of the baseline. The mean ΔDL values were 1.8 ± 1.6 mm at the VN site and 4.7 ± 3.3 mm at the BG site. The ΔDD values were 0.6 ± 1.0 mm and 1.1 ± 1.2 mm, respectively, and reached statistical significance (P = 0.0208, CI 95% = -2.9 [-5.2;-0.6]). The corresponding linear defect fill (DF) values were 44% and 78%, respectively. The clinical assessment of QT showed comparable median values at sites treated with VN (3, interquartile range: 0; 3.5) and BG (3, interquartile range: 3; 4) without statistical significance. The histomorphometric analysis showed an average area density of 24.4% (SD 10.3, range 8-35%) newly formed bone at the test sites and of 35.0% (SD 20.6, range 8-60%) at the control sites. The histological data showed only some trends and did not reach statistical significance. In the present study, the VN membranes with prolonged resorption time demonstrated significantly more adverse events and insufficient bone regeneration compared to the native BG membranes and no advantages in favour of the VN membranes were detectable.


Kouskoura T.,University of Zurich
Schweizer Monatsschrift für Zahnmedizin = Revue mensuelle suisse d'odonto-stomatologie = Rivista mensile svizzera di odontologia e stomatologia / SSO | Year: 2011

The embryonic head development, including the formation of dental structures, is a complex and delicate process guided by specific genetic programs. Genetic changes and environmental factors can disturb the execution of these programs and result in abnormalities in orofacial and dental structures. Orofacial clefts and hypodontia/ oligodontia are examples of such abnormalities frequently seen in dental clinics. An insight into the mechanisms and genes involved in the formation of orofacial and dental structures has been gradually gained by genetic analysis of families and by the use of experimental vertebrate models such as the mouse and chick models. The development of novel clinical therapies for orofacial and dental pathological conditions depends very much on a detailed knowledge of the molecular and cellular processes that are involved in head formation.


Huellner M.W.,University of Zurich | Strobel K.,Lucerne Cantonal Hospital
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2014

Today, SPECT/CT is increasingly used and available in the majority of larger nuclear medicine departments. Several applications of SPECT/CT as a supplement to or replacement for traditional conventional bone scintigraphy have been established in recent years. SPECT/CT of the upper and lower extremities is valuable in many conditions with abnormal bone turnover due to trauma, inflammation, infection, degeneration or tumour. SPECT/CT is often used in patients if conventional radiographs are insufficient, if MR image quality is impaired due to metal implants or in patients with contraindications to MR. In complex joints such as those in the foot and wrist, SPECT/CT provides exact anatomical correlation of pathological uptake. In many cases SPECT increases the sensitivity and CT the specificity of the study, increasing confidence in the final diagnosis compared to planar images alone. The CT protocol should be adapted to the clinical question and may vary from very low-dose (e.g. attenuation correction only), to low-dose for anatomical correlation, to normal-dose protocols enabling precise anatomical resolution. The aim of this review is to give an overview of SPECT/CT imaging of the extremities with a focus on the hand and wrist, knee and foot, and for evaluation of patients after joint arthroplasty. © Springer-Verlag Berlin Heidelberg 2013.


To compare efficacy and safety of the dopamine agonist pramipexole (PPX) versus reference treatment with dual release levodopa/benserazide (L/B) in de novo patients with restless legs syndrome (RLS). A total of 39 men and women between 25 and 85 years old, fulfilling all clinical criteria for diagnosis of idiopathic RLS, previously untreated, participated. The study was performed as a randomised, double-blind, double-dummy crossover trial with two treatment periods of four weeks and took place in six Swiss certified sleep-centres. Interventions were PPX 0.25-0.75 mg and dual-release L/B 125-375 mg. The primary outcome measure was the frequency of periodic limb movements while in bed (PLM index, PLMI). Secondary endpoints included the changes in patient ratings on the International RLS Study Group Rating Scale (IRLS). Both pramipexole and dual-release L/B were effective in reducing PLM and RLS symptoms. Mean PLMI reduction was -11.5 for PPX and -7.7 for L/B (baseline 21.1 and 21.5), and the mean IRLS score reduction was -7.2 and -4.0 (baseline 20.8 and 21.1). In patients with an IRLS score >20 (38%), a significantly (p = 0.047) higher PLMI reduction for PPX (-8.5), as compared to L/B (-4.3), was found. A higher incidence of "augmentations" and "involuntary movements" for L/B, and "nausea or vomiting" and "hypotension with dizziness" for PPX treatment were noted as adverse effects. This study showed comparable effects of PPX versus dual-release L/B for short-term treatment of de novo patients with mild to moderate RLS.


Belibasakis G.N.,University of Zurich
Archives of Oral Biology | Year: 2014

Peri-implant diseases are a cluster of "contemporary" oral infections in humans that have emerged as a result of the routine application of osseointegrated dental implants in clinical practice. They are characterized by the inflammatory destruction of the implant-supporting tissues, as a result of biofilm formation on the implant surface. Peri-implant mucositis and peri-implantitis are analogous to gingivitis and periodontitis that affect natural teeth. The aim of this comprehensive review was to provide insights into the infectious aetiology and immuno-pathology of peri-implant diseases, and to identify similarities and differences with periodontal diseases. The microbial composition of peri-implantitis-associated biofilms is mixed, non-specific and very similar to that of periodontitis. A considerable exception is the frequent presence of high numbers of staphylococci and enteric bacteria in peri-implantitis. The sequence of immuno-pathological events and the qualitative composition of the immune cells in peri-implant infections are similar to that of periodontal infections. The lesions are characterized predominantly by neutrophils, macrophages, T- and B-cells. Nevertheless, compared to periodontitis, peri-implantitis is marked by a more extensive inflammatory infiltrate and innate immune response, a greater severity of tissue destruction and a faster progression rate. This could well account for the structural differences between the two tissue types, predominantly the lack of periodontal ligament and Sharpey's fibres around implants. In order to support the early diagnosis and prevention of peri-implantitis, it is crucial to explain its fast progression rate by elucidating the underlying molecular mechanisms. This could be achieved, for instance, by utilizing the non-invasive collection and analysis of peri-implant crevicular fluid. © 2013 Elsevier Ltd.


Corti R.,University of Zurich | Fuster V.,Mount Sinai Medical Center
European Heart Journal | Year: 2011

Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in the industrialized countries. Despite advances in our understanding of the pathophysiology, pathogenesis, and new treatment modalities, the absence of an adequate non-invasive imaging tool for early detection limits both the prevention and treatment of patients with various degrees and anatomical localizations of atherothrombotic disease. An ideal clinical imaging modality for atherosclerotic vascular disease should be safe, inexpensive, non-invasive or minimally invasive, accurate, and reproducible, and the results should correlate with the extent of atherosclerotic disease and have high predictive values for future clinical events. High-resolution magnetic resonance imaging (MRI) has emerged as the most promising technique for studying atherothrombotic disease in humans in vivo. Most importantly, MRI allows for the characterization of plaque composition, i.e. the discrimination of lipid core, fibrosis, calcification, and intraplaque haemorrhage deposits. Magnetic resonance imaging also allows for the detection of arterial thrombi and in defining thrombus age. Magnetic resonance imaging has been used to monitor plaque progression and regression in several animal models of atherosclerosis and in humans. Emerging MRI techniques capable of imaging biological processes, including inflammation, neovascularization, and mechanical forces, may aid in advancing our understanding of the atherothrombotic disease. Advances in diagnosis do prosper provided they march hand-in-hand with advances in treatment. We stand at the threshold of accurate non-invasive assessment of atherosclerosis. Thus, MRI opens new strategies ranging from screening of high-risk patients for early detection and treatment as well as monitoring of the target lesions for pharmacological intervention. Identification of subclinical atherosclerosis and early treatment initiation has the potential to surpass conventional risk factor assessment and management in terms of overall impact on cardiovascular morbidity and mortality. Such strategy is currently under clinical investigation. © 2011 The Author.


Pato M.,University of Zurich
Journal of Cosmology and Astroparticle Physics | Year: 2011

Direct searches for dark matter have prompted in recent years a great deal of excitement within the astroparticle physics community, but the compatibility between signal claims and null results of different experiments is far from being a settled issue. In this context, we study here the prospects for constraining the dark matter parameter space with the next generation of ton-scale detectors. Using realistic experimental capabilities for a wide range of targets (including fluorine, sodium, argon, germanium, iodine and xenon), the role of target complementarity is analysed in detail while including the impact of astrophysical uncertainties in a self-consistent manner. We show explicitly that a multi-target signal in future direct detection facilities can determine the sign of the ratio of scalar couplings fn/fp, but not its scale. This implies that the scalar-proton cross-section is left essentially unconstrained if the assumption fp ∼ fn is relaxed. Instead, we find that both the axial-proton cross-section and the ratio of axial couplings an/ap can be measured with fair accuracy if multi-ton instruments using sodium and iodine will eventually come online. Moreover, it turns out that future direct detection data can easily discriminate between elastic and inelastic scatterings. Finally, we argue that, with weak assumptions regarding the WIMP couplings and the astrophysics, only the dark matter mass and the inelastic parameter (i.e. mass splitting) may be inferred from the recoil spectra - specifically, we anticipate an accuracy of tens of GeV (tens of keV) in the measurement of the dark matter mass (inelastic parameter). © 2011 IOP Publishing Ltd and SISSA.


Chiochia V.,University of Zurich
Nuclear Physics A | Year: 2011

This article summarizes the first measurements of inclusive beauty production cross section in proton-proton collisions at √s=7TeV and central rapidities. The results are based on different techniques, such as the identification of semileptonic b-decays into muons and inclusive jet measurements with secondary vertex tagging. The measurements probe b-quark production in different regions of transverse momenta. The experimental results are compared with next-to-leading order QCD predictions and various Monte Carlo models. © 2011 Elsevier B.V.


Zhang J.,CAS Lanzhou Institute of Chemical Physics | Wang A.,CAS Lanzhou Institute of Chemical Physics | Seeger S.,University of Zurich
Advanced Functional Materials | Year: 2014

Nepenthes pitcher inspired anti-wetting coatings, fluoro-SNs/Krytox, are successfully fabricated by the combination of fluoro-silicone nanofilaments (fluoro-SNs) and Krytox liquids, perfluoropolyethers. Fluoro-SNs with different microstructure are grown onto glass slides using trichloromethylsilane by simply repeating the coating step, and then modified with 1H,1H,2H,2H- perfluorodecyltrichlorosilane. Subsequently, the Krytox liquid is spread on the fluoro-SNs coatings via capillary effect. The fluoro-SNs/Krytox coatings feature ultra-low sliding angle for various liquids, excellent stability, and transparency. The sliding speed of liquid drops on the fluoro-SNs/Krytox coating is obviously slower than on the lotus inspired superhydrophobic and superoleophobic coatings, and is controlled by composition of the coating (e.g., morphology of the fluoro-SNs, type of Krytox and its thickness) and properties of the liquid drops (e.g., density and surface tension). In addition, the self-cleaning property of the fluoro-SNs/Krytox coating is closely related to properties of liquid drops and dirt. Nepenthes pitcher inspired anti-wetting coatings are fabricated by the combination of fluoro-silicone nanofilaments and a perfluoropolyether liquid. The sliding speed of liquid drop and the self-cleaning property can be controlled by composition of the coating, properties of liquid drop, and dirt. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Malek A.,University of Zurich
Expert Review of Clinical Immunology | Year: 2013

During human pregnancy, the maternal immune system develops and changes, providing protection for the growing placenta and fetus. These protective changes provide mechanisms allowing two genetically different individuals to interact with each other without allograft rejection. In addition to normal pregnancy, some pregnancies may develop under immunologic diseases, during which specific monitoring and medical treatments are essential. The aim of this current review is to provide information regarding the development of human placental function during pregnancy, the immunology of human pregnancy and the role of the placenta in providing the fetal tissue with antibodies (IgG and its subclasses 1-4), which are required for the passive immunization of the newborn. In addition, the available methods for the determination of placental function will be explored. Furthermore, immunologic diseases observed during pregnancy and the possible therapies for these diseases will be assessed. © 2013 Expert Reviews Ltd.


Ong A.C.M.,University of Sheffield | Ong A.C.M.,Sheffield Kidney Institute | Devuyst O.,University of Zurich | Devuyst O.,Catholic University of Louvain | And 2 more authors.
The Lancet | Year: 2015

Autosomal dominant polycystic kidney disease is the most common inherited kidney disease and accounts for 7-10% of all patients on renal replacement therapy worldwide. Although first reported 500 years ago, this disorder is still regarded as untreatable and its pathogenesis is poorly understood despite much study. During the past 40 years, however, remarkable advances have transformed our understanding of how the disease develops and have led to rapid changes in diagnosis, prognosis, and treatment, especially during the past decade. This Review will summarise the key findings, highlight recent developments, and look ahead to the changes in clinical practice that will likely arise from the adoption of a new management framework for this major kidney disease. © 2015 Elsevier Ltd.


Jutel M.,Wroclaw Medical University | Akdis C.A.,University of Zurich
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

The studies on the mechanisms of specific immunotherapy (SIT) point out its targets that decide on the efficacy of SIT and hence might be used for its further improvement. Several mechanisms have been proposed to explain the beneficial effects of immunotherapy. The knowledge of the mechanisms underlying allergic diseases and curative treatment possibilities has experienced exciting advances over the last three decades. Studies in several clinical trials in allergen-SIT have demonstrated that the induction of a tolerant state against allergens in many ways represents a key step in the development of a healthy immune response against allergens. Several cellular and molecular mechanisms have been demonstrated: allergen-specific suppressive capacities of both inducible subsets of CD4 + CD25 + forkhead box P3 + T-regulatory and IL-10-secreting type 1 T-regulatory cells increase in peripheral blood; suppression of eosinophils, mast cells, and basophils; Ab isotype change from IgE to IgG4. This review aims at the better understanding of the observed immunological changes associated with allergen SIT. © 2011 John Wiley & Sons A/S.


Catheter-based renal nerve ablation (RNA) using radiofrequency energy is a novel treatment for drug-resistant essential hypertension. However, the local endothelial and vascular injury induced by RNA has not been characterized, although this importantly determines the long-term safety of the procedure. Optical coherence tomography (OCT) enables in vivo visualization of morphologic features with a high resolution of 10-15 μm. The objective of this study was to assess the morphological features of the endothelial and vascular injury induced by RNA using OCT. In a prospective observational study, 32 renal arteries of patients with treatment-resistant hypertension underwent OCT before and after RNA. All pre- and post-procedural OCT pullbacks were evaluated regarding vascular changes such as vasospasm, oedema (notches), dissection, and thrombus formation. Thirty-two renal arteries were evaluated, in which automatic pullbacks were obtained before and after RNA. Vasospasm was observed more often after RNA then before the procedure (0 vs. 42%, P < 0.001). A significant decrease in mean renal artery diameter after RNA was documented both with the EnligHTN (4.69 ± 0.73 vs. 4.21 ± 0.87 mm; P < 0.001) and with the Simplicity catheter (5.04 ± 0.66 vs. 4.57 ± 0.88 mm; P < 0.001). Endothelial-intimal oedema was noted in 96% of cases after RNA. The presence of thrombus formations was significantly higher after the RNA then before ablation (67 vs. 18%, P < 0.001). There was one evidence of arterial dissection after RNA with the Simplicity catheter, while endothelial and intimal disruptions were noted in two patients with the EnligHTN catheter. Here we show that diffuse renal artery constriction and local tissue damage at the ablation site with oedema and thrombus formation occur after RNA and that OCT visualizes vascular lesions not apparent on angiography. This suggests that dual antiplatelet therapy may be required during RNA.


Guggenheim B.,University of Zurich
Schweizer Monatsschrift für Zahnmedizin = Revue mensuelle suisse d'odonto-stomatologie = Rivista mensile svizzera di odontologia e stomatologia / SSO | Year: 2011

The aim of this study was to use the Zurich polyspecies biofilm model to compare the antimicrobial effects of chlorhexidine mouth rinses available on the Swiss market. As positive and negative controls, aqueous 0.15% CHX solution and water were used, respectively. In addition, Listerine® without CHX was tested. Biofilms in batch culture were grown in 24- well polystyrene tissue culture plates on hydroxyapatite discs in 70% mixed (1:1 diluted) unstimulated saliva and 30% complex culture medium. During the 64.5-hour culturing period, the biofilms were exposed to the test solutions for 1 minute twice a day on two subsequent days. Thereafter, the biofilms were dip-washed 3 times in physiological NaCl. Following the last exposure, the incubation of biofilms was continued for another 16 h. They were then harvested at 64.5 h. The dispersed biofilms were plated on 2 agar media. After incubation, colonies (CFU) were counted. All solutions containing CHX as well as Listerine ® significantly reduced the number of microorganisms in biofilms. According to their efficacy, the mouth rinses were classified into 2 groups. The two Curasept ADS solutions, Parodentosan, and the Listerine® mouth rinse reduced the number of total CFU by 3 log10 steps. This seems sufficient for a long-lasting prophylactic application. The two PlakOut® mouth rinses and the CHX control fell into the other group, where the number of CFU was reduced by 7 log10 steps. These mouth rinses are predestined for short-term therapeutic use. However, reversible side effects must be taken into account. It has thus far not been possible to formulate CHX products with effective ADS (Anti Discoloration System) additives without reducing antimicrobial activity.


Grossniklaus U.,University of Zurich | Kelly B.,Emory University | Ferguson-Smith A.C.,University of Cambridge | Pembrey M.,University College London | And 2 more authors.
Nature Reviews Genetics | Year: 2013

Much attention has been given to the idea of transgenerational epigenetic inheritance, but fundamental questions remain regarding how much takes place and the impact that this might have on organisms. We asked five leading researchers in this area-working on a range of model organisms and in human disease-for their views on these topics. Their responses highlight the mixture of excitement and caution that surrounds transgenerational epigenetic inheritance and the wide gulf between species in terms of our knowledge of the mechanisms that may be involved. © 2013 Macmillan Publishers Limited. All rights reserved.


Prainsack B.,Kings College London | Vayena E.,University of Zurich
Pharmacogenomics | Year: 2013

This article provides an overview of commercial pharmacogenetics and pharmacogenomics testing services offered online. The concept of 'beyond-the-clinic (BTC) genomic testing is introduced to refer to the variety of formats in which these tests are offered and a typology of BTC models is developed. The authors review such models in relation to tests for individual drug response that are currently on offer. In conclusion, the authors argue that the evolving BTC domain provides opportunities for the pioneering of integrated data repositories, whose gatekeepers are patients or citizens. The authors anticipate that such developments will benefit pharmacogenomics sooner than other areas of medical practice. © 2013 Future Medicine Ltd.


In 2007, leading international experts in the field of inflammatory bowel disease (IBD) recommended intravenous (IV) iron supplements over oral (PO) ones because of superior effectiveness and better tolerance. We aimed to determine the percentage of patients with IBD undergoing iron therapy and to assess the dynamics of iron prescription habits (IV versus PO). We analyzed anonymized data on patients with Crohn's disease and ulcerative colitis extracted from the Helsana database. Helsana is a Swiss health insurance company providing coverage for 18% of the Swiss population (1.2 million individuals). In total, 629 patients with Crohn's disease (61% female) and 398 patients with ulcerative colitis (57% female) were identified; mean observation time was 31.8 months for Crohn's disease and 31.0 months for ulcerative colitis patients. Of all patients with IBD, 27.1% were prescribed iron (21.1% in males; 31.1% in females). Patients treated with steroids, immunomodulators, and/or anti-tumor necrosis factor drugs were more frequently treated with iron supplements when compared with those not treated with any medications (35.0% versus 20.9%, odds ratio, 1.94; P < 0.001). The frequency of IV iron prescriptions increased significantly from 2006 to 2009 for both genders (males: from 2.6% to 10.1%, odds ratio = 3.84, P < 0.001; females: from 5.3% to 12.1%, odds ratio = 2.26, P = 0.002), whereas the percentage of PO iron prescriptions did not change. Twenty-seven percent of patients with IBD were treated with iron supplements. Iron supplements administered IV were prescribed more frequently over time. These prescription habits are consistent with the implementation of guidelines on the management of iron deficiency in IBD.


Buddeberg-Fischer B.,University of Zurich
Swiss medical weekly : official journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology | Year: 2010

The profile of the medical profession is changing in terms of employment conditions, attitudes towards the profession and the lifestyle of young physicians. The aim of this study was to investigate (1) what modifications should be made in the specialty-qualification curriculum to allow for a better balance of career and personal life, (2) what institutional conditions and (3) what personal attitudes and behaviour are required for physicians to successfully combine career and family. As part of a prospective survey on the career development of Swiss medical school graduates (SwissMedCareer Study) begun in 2001, 526 physicians (274 females, 52.1%; 252 males, 47.9%) participated in the sixth assessment in 2010. The graduates were asked by mail-out questionnaires to provide free response answers to the three questions formulated above. Their statements were transcribed, content categories were inductively formulated for each question, and their descriptions were written down in a code manual. Responses were encoded according to the said manual and assigned to content categories (Mayring's content analysis). Frequency distributions were given for categories and tested with chi-square tests for gender differences. The 526 participants made 457 statements on the first question, 1,038 on the second, and 937 on the third. Content analysis of the physicians' answers yielded nine categories dealing with desired changes to the specialty qualification curriculum, eight categories addressing changes in institutional conditions, and nine categories concerning personal attitudes and behaviour. Of all responses to the first question, 70% fell into the top three ranking categories of "specialty qualification requirements", "part-time jobs" and "structured residency programmes". The three top-ranking categories ("childcare facilities", part-time jobs", "working hours") yielded by responses to the second question accounted for 87% of the statements. Distribution of the responses concerning personal attitudes and behaviour was more widespread across the nine categories. Marked organisational skills and the ability to adapt flexibly to various everyday demands at work and home were recognised as essential in one third of the statements. In order to meet the needs of the medical profession's changing profile in terms of feminisation and modern lifestyle, changes must be initiated at different levels. Postgraduate training must be provided in structured programmes, and curriculum requirements must be revamped. Hospital authorities should offer more part-time jobs as well as adequate and affordable childcare facilities for physicians with young children. Physicians should engage critically and to a greater extent with the continued development of their profession.


Dianov G.L.,University of Oxford | Hubscher U.,University of Zurich
Nucleic Acids Research | Year: 2013

Base excision repair (BER) is a frontline repair system that is responsible for maintaining genome integrity and thus preventing premature aging, cancer and many other human diseases by repairing thousands of DNA lesions and strand breaks continuously caused by endogenous and exogenous mutagens. This fundamental and essential function of BER not only necessitates tight control of the continuous availability of basic components for fast and accurate repair, but also requires temporal and spatial coordination of BER and cell cycle progression to prevent replication of damaged DNA. The major goal of this review is to critically examine controversial and newly emerging questions about mammalian BER pathways, mechanisms regulating BER capacity, BER responses to DNA damage and their links to checkpoint control of DNA replication. © The Author(s) 2013. Published by Oxford University Press.


Schmidt A.,University of Hamburg | Ivanova A.,University of Hamburg | Schafer M.S.,University of Zurich
Global Environmental Change | Year: 2013

Climate change is a global phenomenon, and its outcomes affect societies around the world. So far, however, studies on media representations of climate change have mostly concentrated on Western societies. This paper goes beyond this limited geographical scope by presenting a comparative analysis of issue attention in 27 countries. The sample includes, among others, countries that have committed themselves to greenhouse gas emission reductions under the Kyoto Protocol such as Germany as well as countries that are strongly affected by the consequences of climate change like India. In a first step, it describes the development of media attention for climate change in these countries from 1996 to 2010. Second, it compares the amount of media attention and explores whether it corresponds with indicators measuring the relevance of climate change and climate policies for a country. The analyses show that climate change coverage has increased in all countries. Still, overall media attention levels, as well as the extent of growth over time, differ strongly between countries. Media attention is especially high in carbon dependent countries with commitments under the Kyoto Protocol. © 2013 Elsevier Ltd.


Dumbgen L.,University of Bern | Rufibach K.,University of Zurich
Journal of Statistical Software | Year: 2011

Maximum likelihood estimation of a log-concave density has attracted considerable attention over the last few years. Several algorithms have been proposed to estimate such a density. Two of those algorithms, an iterative convex minorant and an active set algorithm, are implemented in the R package logcondens. While these algorithms are discussed elsewhere, we describe in this paper the use of the logcondens package and discuss functions and datasets related to log-concave density estimation contained in the package. In particular, we provide functions to (1) compute the maximum likelihood estimate (MLE) as well as a smoothed log-concave density estimator derived from the MLE, (2) evaluate the estimated density, distribution and quantile functions at arbitrary points, (3) compute the characterizing functions of the MLE, (4) sample from the estimated distribution, and finally (5) perform a two-sample permutation test using a modified Kolmogorov-Smirnov test statistic. In addition, logcondens makes two datasets available that have been used to illustrate log-concave density estimation.


Kraus W.L.,University of Texas Southwestern Medical Center | Hottiger M.O.,University of Zurich
Molecular Aspects of Medicine | Year: 2013

Poly(ADP-ribose) polymerase-1 (PARP-1), also referred to as ADP-ribosyltransferase Diphtheria toxin-like 1 (ARTD1), is an abundant nuclear protein that plays key roles in a variety of nuclear processes, including the regulation of transcription. PARP-1 possesses an intrinsic enzymatic activity that catalyzes the transfer of ADP-ribose (ADPR) units from nicotinamide adenine dinucleotide (NAD+) onto target gene regulatory proteins, thereby modulating their activities. Although great strides have been made in the past decade in deciphering the seemingly opposing and varied roles of PARP-1 in gene regulation, many puzzles remain. In this review, we discuss the current state of understanding in this area, especially how PARP-1 interfaces with various components of gene regulatory pathways (e.g., the basal transcription machinery, DNA-binding transcription factors, coregulators, chromatin remodeling, histone modifications, and DNA methylation). In addition, we discuss some gene-specific, cell type-specific, and cell state-specific effects of PARP-1 on gene regulation, which might contribute to its biological functions. Finally, we review some of the recent progress targeting PARPs using chemical inhibitors, some of which may alter PARP-1-dependent gene regulatory programs to promote therapeutic outcomes. © 2013 Elsevier Ltd. All rights reserved.


Kohan D.E.,University of Utah | Barton M.,University of Zurich
Kidney International | Year: 2014

The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020. Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident. Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD. Endothelin receptor antagonists (ERAs) have been demonstrated to ameliorate or even reverse renal injury and/or fibrosis in experimental models of CKD, whereas clinical trials indicate a substantial antiproteinuric effect of ERAs in diabetic and nondiabetic CKD patients even on top of maximal renin-angiotensin system blockade. This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach. © 2014 International Society of Nephrology.


Hagenbuch B.,University of Kansas Medical Center | Hagenbuch B.,University of Kansas | Stieger B.,University of Zurich
Molecular Aspects of Medicine | Year: 2013

The members of the organic anion transporting polypeptide superfamily (OATPs) are classified within the SLCO solute carrier family. All functionally well characterized members are predicted to have 12 transmembrane domains and are sodium-independent transport systems that mediate the transport of a broad range of endo- as well as xenobiotics. Substrates are mainly amphipathic organic anions with a molecular weight of more than 300 Da, but some of the known transported substrates are also neutral or even positively charged. Among the well characterized substrates are numerous drugs including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensives and anticancer drugs. Based on their amino acid sequence identities, the different OATPs cluster into families (in general with more than 40% amino acid sequence identity) and subfamilies (more than 60% amino acid identity). With the sequencing of genomes from different species and the computerized prediction of encoded proteins more than 300 OATPs can be found in the databases, however only a fraction of them have been identified in humans, rodents, and some additional species important for pharmaceutical research like the rhesus monkey (Macaca mulatta), the dog (Canis lupus familiaris) and the pig (Sus scrofa). These OATPs form 6 families (OATP1-OATP6) and 13 subfamilies. In this review we try to summarize what is currently known about OATPs with respect to endogenous substrates, tissue distribution, transport mechanisms, regulation of expression, structure-function relationship and mutations and polymorphisms. © 2012 Elsevier Ltd. All rights reserved.


Angst J.,University of Zurich | Grobler C.,Walter Sisulu University
European Archives of Psychiatry and Clinical Neuroscience | Year: 2015

In the classification of mood disorders, major depressive disorder is separate from bipolar disorders whereas mania is not. Studies on pure mania are therefore rare. Our paper reviews the evidence for distinguishing pure mania (M) and mania with mild depression (Md) from bipolar disorder. Two large epidemiological studies found a prevalence of 1.7–1.8 % of M/Md in adolescents and adults. Several clinical follow-up studies demonstrated good stability of the diagnosis after a previous history of three manic episodes. Compared to bipolar disorder, manic disorder is characterised by a weaker family history for depression, an earlier onset, fewer recurrences and better remission, and is less comorbid with anxiety disorders. In addition, mania is strongly associated with a hyperthymic temperament, manifests more psychotic symptoms and is more often treated with antipsychotics. Twin and family studies find mania to be more heritable than depression and show no significant transmission from depression to mania or from mania to depression. Cardiovascular mortality is elevated among patients with mood disorders generally and is highest among those with mania. In non-Western countries, mania and the manic episodes in bipolar disorder are reported to occur more frequently than in Western countries. © 2015, Springer-Verlag Berlin Heidelberg.


Burg G.,University of Zurich
Clinics in Dermatology | Year: 2015

Mycosis fungoides (MF) represents almost 50% of all primary cutaneous lymphomas and more than 70% of cutaneous T-cell lymphomas (CTCL). Arising from preferentially skin-homing lymphocytes with genetic instability, MF evolves through stages (IA-IVB), producing inconspicuous inflammatory features in the beginning and finally resulting in a proliferation of cytomorphologic, phenotypic, and genotypic abnormal tumor cells. Over the past 200 years, there has been much confusion in the classification of lymphomas due to semantic disagreements (MF, CTCL, parapsoriasis, lymphosarcoma, reticulum cell sarcoma, and many other terms), lack of diagnostic standard criteria, and new molecular diagnostic methods. Studies on extracutaneous involvement in early stages (IA-IIA) are almost completely lacking. In advanced stages of MF (IIB-IVB), discovery of extracutaneous involvement is dependent on the methods used (physical examination, technology, molecular diagnostics, autopsy, and laparoscopy) and reveals a wide range of results. Due to the inflammation-simulating features in the beginning of the disease, early diagnosis is very difficult to assess. Extracutaneous involvement has previously been documented in more than 70% of autopsies. More recent studies give much lower figures. Like all lymphomas, MF is a systemic disease from the very beginning, with distinct homing preferences in tumor cells. Organs most commonly involved during the lengthy course of the disease are, in descending frequency, lymph node/peripheral blood, liver, spleen, lung, bone marrow, GI tract, pancreas, and kidney. © 2015.


Trajkovski M.,ETH Zurich | Trajkovski M.,University College London | Ahmed K.,ETH Zurich | Esau C.C.,Regulus Therapeutics | And 2 more authors.
Nature Cell Biology | Year: 2012

Brown adipose tissue (BAT) uses the chemical energy of lipids and glucose to produce heat, a function that can be induced by cold exposure or diet. A key regulator of BAT is the gene encoding PR domain containing 16 (Prdm16), whose expression can drive differentiation of myogenic and white fat precursors to brown adipocytes. Here we show that after cold exposure, the muscle-enriched miRNA-133 is markedly downregulated in BAT and subcutaneous white adipose tissue (SAT) as a result of decreased expression of its transcriptional regulator Mef2. miR-133 directly targets and negatively regulates PRDM16, and inhibition of miR-133 or Mef2 promotes differentiation of precursors from BAT and SAT to mature brown adipocytes, thereby leading to increased mitochondrial activity. Forced expression of miR-133 in brown adipogenic conditions prevents the differentiation to brown adipocytes in both BAT and SAT precursors. Our results point to Mef2 and miR-133 as central upstream regulators of Prdm16 and hence of brown adipogenesis in response to cold exposure in BAT and SAT. © 2012 Macmillan Publishers Limited. All rights reserved.


Perren S.,University of Zurich | Ettekal I.,Arizona State University | Ladd G.,Arizona State University
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2013

Background: Evidence indicates that being a victim of bullying or peer aggression has negative short- and long-term consequences. In this study, we investigated the mediating and moderating role of two types of attributional mechanisms (hostile and self-blaming attributions) on children's maladjustment (externalizing and internalizing problems). Methods: In total, 478 children participated in this longitudinal study from grade 5 to grade 7. Children, parents, and teachers repeatedly completed questionnaires. Peer victimization was assessed through peer reports (T1). Attributions were assessed through self-reports using hypothetical scenarios (T2). Parents and teachers reported on children's maladjustment (T1 and T3). Results: Peer victimization predicted increases in externalizing and internalizing problems. Hostile attributions partially mediated the impact of victimization on increases in externalizing problems. Self-blame was not associated with peer victimization. However, for children with higher levels of self-blaming attributions, peer victimization was linked more strongly with increases in internalizing problems. Conclusions: Results imply that hostile attributions may operate as a potential mechanism through which negative experiences with peers lead to increases in children's aggressive and delinquent behavior, whereas self-blame exacerbates victimization's effects on internalizing problems. © 2012 The Authors. Journal of Child Psychology and Psychiatry © 2012 Association for Child and Adolescent Mental Health.


Maercker A.,University of Zurich
Torture : quarterly journal on rehabilitation of torture victims and prevention of torture | Year: 2013

Studies on the long-term consequences of traumatization found different diagnostic trajectories: chronic, recovered, delayed and resilient. This distinction, however, was never studied in victims of torture or severe political persecution. We aimed to verify the trajectory classes of PTSD empirically and to analyze potential predictors of such trajectories. Former political prisoners from East Germany, first interviewed in 1995, were re-assessed fourteen years later. In 1995, retrospective symptom reports dating back to shortly after the prisoners' release dates were assessed. Predictors of the four different trajectories were divided into pre-trauma, peri-trauma, and post-trauma factors. As a result, the four long-term trajectories were validated in the current sample with the following percentages: chronic (36%), resilient (27%), recovered (26%) and delayed (11%) trajectories. Trajectories were mainly distinguished by pre- and post-traumatic factors, e.g. pre-trauma education or post-trauma disclosure opportunities. We conclude that the four long-term trajectories of trauma sequelae deserve more attention to adequately deal with survivors of severe persecution. Furthermore, the specific predictors of long-term trajectory deserve more attention for re-integration or in rehabilitation.


Lepers R.,University of Burgundy | Knechtle B.,University of Zurich | Stapley P.J.,University of Wollongong
Sports Medicine | Year: 2013

The influences of sex and age upon endurance performance have previously been documented for both running and swimming. A number of recent studies have investigated how sex and age influence triathlon performance, a sport that combines three disciplines (swimming, cycling and running), with competitions commonly lasting between 2 (short distance: 1.5-km swim, 40-km cycle and 10-km run) and 8 h (Ironman distance: 3.8-km swim, 180-km cycle and 42-km run) for elite triathletes. Age and sex influences upon performance have also been investigated for ultra-triathlons, with distances corresponding to several Ironman distances and lasting several days, and for off-road triathlons combining swimming, mountain biking and trail running. Triathlon represents an intriguing alternative model for analysing the effects of age and sex upon endurance and ultra-endurance (>6 h) performance because sex differences and age-related declines in performance can be analysed in the same individuals across the three separate disciplines. The relative participation of both females and masters athletes (age >40 years) in triathlon has increased consistently over the past 25 years. Sex differences in triathlon performance are also known to differ between the modes of locomotion adopted (swimming, cycling or running) for both elite and non-elite triathletes. Generally, time differences between sexes in swimming have been shown to be smaller on average than during cycling and running. Both physiological and morphological factors contribute to explaining these findings. Performance density (i.e. The time difference between the winner and tenth-placed competitor) has progressively improved (time differences have decreased) for international races over the past two decades for both males and females, with performance density now very similar for both sexes. For age-group triathletes, sex differences in total triathlon performance time increases with age. However, the possible difference in age-related changes in the physiological determinants of endurance and ultra-endurance performances between males and females needs further investigation. Non-physiological factors such as low rates of participation of older female triathletes may also contribute to the greater age-related decline in triathlon performance shown by females. Total triathlon performance has been shown to decrease in a curvilinear manner with advancing age. However, when triathlon performance is broken down into its three disciplines, there is a smaller age-related decline in cycling performance than in running and swimming performances. Age-associated changes in triathlon performance are also related to the total duration of triathlon races. The magnitude of the declines in cycling and running performances with advancing age for short triathlons are less pronounced than for longer Ironman-distance races. Triathlon distance is also important when considering how age affects the rate of the decline in performance. Off-road triathlon performances display greater decrements with age than road-based triathlons, suggesting that the type of discipline (road vs. mountain bike cycling and road vs. trail running) is an important factor in age-associated changes in triathlon performance. Finally, masters triathletes have shown relative improvements in their performances across the three triathlon disciplines and total triathlon event times during Ironman races over the past three decades. This raises an important issue as to whether older male and female triathletes have yet reached their performance limits during Ironman triathlons. © 2013 Springer International Publishing Switzerland.


Gysin C.,University of Zurich
ORL | Year: 2013

Possible indications for tonsillectomy include sleep apnea and other obstructive sleep-related breathing disorders, recurrent tonsillitis, peritonsillar abscess, periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA), and other miscellaneous rare conditions. Over the last century indications have changed, with a decrease in infectious causes and an increase in sleep apnea disorders. Sleep apnea in children is difficult to diagnose short of polysomnography (PSG) which is expensive and disturbing, especially in young children. In sleep apnea confirmed by PSG, tonsillectomy relieves the trouble in close to 80% of patients. What remains unclear is how to diagnose sleep-related breathing disorders without PSG and the efficacy of tonsillectomy in this population. Recurrent tonsillitis is generally poorly documented and randomized studies assessing the efficacy of tonsillectomy are sparse. When frequent infections are present for several years (>7 episodes/1 year, >5/2, >3/3) some benefit from tonsillectomy could be found. If fewer infectious episodes are present, the benefit of tonsillectomy is low. Peritonsillar abscess tends to be treated with quinsy tonsillectomy. Some PFAPA and psoriasis children might benefit from tonsillectomy. Tonsillectomy for other conditions is not warranted. Copyright © 2013 S. Karger AG, Basel.


Gorr T.A.,University of Zurich
Acta physiologica (Oxford, England) | Year: 2011

The unexpected identification of myoglobin (MB) in breast cancer prompted us to evaluate the clinico-pathological value of MB, haemoglobin (HB) and cytoglobin (CYGB) in human breast carcinoma cases. We further screened for the presence of neuroglobin (NGB) and CYGB in tumours of diverse origin, and assessed the O(2) -response of HB, MB and CYGB mRNAs in cancer cell lines, to better elicit the links between this ectopic globin expression and tumour hypoxia. Breast tumours were analysed by immunohistochemistry for HB, MB and CYGB and correlated with clinico-pathological parameters. Screening for CYGB and NGB mRNA expression in tumour entities was performed by hybridization, quantitative PCR (qPCR) and bioinformatics. Hypoxic or anoxic responses of HB, MB and CYGB mRNAs was analysed by qPCR in human Hep3B, MCF7, HeLa and RCC4 cancer cell lines. 78.8% of breast cancer cases were positive for MB, 77.9% were positive for HB and 55.4% expressed CYGB. The closest correlation with markers of hypoxia was observed for CYGB. Compared to the weakly positive status of MB in healthy breast tissues, invasive tumours either lost or up-regulated MB. Breast carcinomas showed the tendency to silence CYGB. HB was not seen in normal tissues and up-regulated in tumours. Beyond breast malignancies, expression levels of NGB and CYGB mRNAs were extremely low in brain tumours (glioblastoma, astrocytoma). NGB was not observed in non-brain tumours. CYGB mRNA, readily detectable in breast cancer and other tumours, is down-regulated in lung adenocarcinomas. Alpha1 globin (α1 globin) and Mb were co-expressed in MCF7 and HeLa cells; CYGB transcription was anoxia-inducible in Hep3B and RCC4 cells. This is the first time that HB and CYGB are reported in breast cancer. Neither NGB nor CYGB are systematically up-regulated in tumours. The down-regulated CYGB expression in breast and lung tumours is in line with a tumour-suppressor role. Each of the screened cancer cells expresses at least one globin (i.e. main globin species: CYGB in Hep3B; α1 globin + MB in MCF7 and HeLa). Thus, globins exist in a wide variety of solid tumours. However, the generally weak expression of the endogenous proteins in the cancer argues against a significant contribution to tumour oxygenation. Future studies should consider that cancer-expressed globins might function in ways not directly linked to the binding and transport of oxygen. © 2010 The Authors. Acta Physiologica © 2010 Scandinavian Physiological Society.


Lewis F.I.,University of Zurich | McCormick B.J.J.,U.S. National Institutes of Health
American Journal of Epidemiology | Year: 2012

An epidemiologic systems analysis of diarrhea in children in Pakistan is presented. Application of additive Bayesian network modeling to 2005-2006 data from the Pakistan Social and Living Standards Measurement Survey reveals the complexity of child diarrhea as a disease system. The key distinction between standard analytical approaches, such as multivariable regression, and Bayesian network analyses is that the latter attempt to not only identify statistically associated variables but also, additionally and empirically, separate these into those directly and indirectly dependent upon the outcome variable. Such discrimination is vastly more ambitious but has the potential to reveal far more about key features of complex disease systems. Additive Bayesian network analyses across 41 variables from the Pakistan Social and Living Standards Measurement Survey identified 182 direct dependencies but with only 3 variables: 1) access to a dry pit latrine (protective; odds ratio 0.67); 2) access to an atypical water source (protective; odds ratio 0.49); and 3) no formal garbage collection (unprotective; odds ratio 1.32), supported as directly dependent with the presence of diarrhea. All but 2 of the remaining variables were also, in turn, directly or indirectly dependent upon these 3 key variables. These results are contrasted with the use of a standard approach (multivariable regression). © 2012 The Author.


Frick T.W.,University of Zurich
Surgery (United States) | Year: 2012

Until recently, it was unclear whether calcium is more than a bystander in the development of acute pancreatitis. Now important evidence has been accumulated supporting a pivotal role of intracellular levels of calcium in the early pathogenesis of the disease. A sustained increase of cytosolic calcium concentrations, as observed in various models of acute pancreatitis, was identified as sabotaging crucial cellular defense mechanisms and initiating premature trypsinogen activation. These processes lead the acinar cell to necrosis, with spillage of activated proteases into the interstitial space, affecting surrounding acinar cells and initiating a vicious circle that ends in macroscopic acute pancreatitis and systemic inflammatory response syndrome. Comprehensive knowledge of the pathobiology of cytosolic calcium in the pancreatic acinar cell is leading to the understanding of coherent molecular pathways of early events in the pathogenesis of acute pancreatitis and is opening horizons for research into directly targeted therapeutic agents. © 2012 Mosby, Inc. All rights reserved.


Dudler R.,University of Zurich
Trends in Microbiology | Year: 2014

The ubiquitin-26S proteasome degradation system (UPS) plays a pivotal role in almost all aspects of plant life, including defending against pathogens. Although the proteasome is important for plant immunity, it has been found to be also exploited by pathogens using effectors to increase their virulence. Recent work on the XopJ effector and syringolin A/syrbactins has highlighted host proteasome inhibition as a virulence strategy of pathogens. This review will focus on these recent developments. © 2013 Elsevier Ltd.


Berndt C.,University of Zurich
Environment and Planning A | Year: 2013

Using an ongoing land conflict in Ciudad Juárez as a case study, I seek to show how maquiladora decision makers stabilize a regional development model even at times of extreme social and economic crisis. I argue that the current killings associated with drug trafficking play an ambivalent role in the reproduction of order in Juárez. At first sight, the violence is represented as a threat, unmasking as it does a regional development model as failure. Decision makers accordingly respond by doing everything possible to distance the maquiladora industry from the violence. On the one hand, this is being done by familiar means, not unlike in previous moments of crises. But on the other hand the events around Lomas del Poleo additionally assume a new quality, as maquiladorization goes hand in hand with an explicit strategy of spatial distanciation, integrating places and people that have hitherto been linked only marginally to the industry. And it is here that the narco-related violence plays different roles: as a convenient veil that allows what might be termed 'ordinary' assertions of brute force to be used under the cover of extraordinary, excessive, violence; and as a welcome excuse in moments of emergency that legitimize violent measures for the sake of a greater good. © 2013 Pion and its Licensors.


Ruhli F.J.,University of Zurich | Henneberg M.,University of Adelaide
BMC Medicine | Year: 2013

Evolutionary medicine (EM) is a growing field focusing on the evolutionary basis of human diseases and their changes through time. To date, the majority of EM studies have used pure theories of hominin macroevolution to explain the present-day state of human health. Here, we propose a different approach by addressing more empirical and health-oriented research concerning past, current and future microevolutionary changes of human structure, functions and pathologies. Studying generation-to-generation changes of human morphology that occurred in historical times, and still occur in present-day populations under the forces of evolution, helps to explain medical conditions and warns clinicians that their current practices may influence future humans. Also, analyzing historic tissue specimens such as mummies is crucial in order to address the molecular evolution of pathogens, of the human genome, and their coadaptations. © 2013 Ruhli and Henneberg; licensee BioMed Central Ltd.


Rizza A.,University of Zurich
BMC family practice | Year: 2012

General practitioners often care for patients with several concurrent chronic medical conditions (multimorbidity). Recent data suggest that multimorbidity might be observed more often than isolated diseases in primary care. We explored the age- and gender-related prevalence of multimorbidity and compared these estimates to the prevalence estimates of other common specific diseases found in Swiss primary care. We analyzed data from the Swiss FIRE (Family Medicine ICPC Research using Electronic Medical Record) project database, representing a total of 509,656 primary care encounters in 98,152 adult patients between January 1, 2009 and July 31, 2011. For each encounter, medical problems were encoded using the second version of the International Classification of primary Care (ICPC-2). We defined chronic health conditions using 147 pre-specified ICPC-2 codes and defined multimorbidity as 1) two or more chronic health conditions from different ICPC-2 rubrics, 2) two or more chronic health conditions from different ICPC-2 chapters, and 3) two or more medical specialties involved in patient care. We compared the prevalence estimates of multimorbidity defined by the three methodologies with the prevalence estimates of common diseases encountered in primary care. Overall, the prevalence estimates of multimorbidity were similar for the three different definitions (15% [95%CI 11-18%], 13% [95%CI 10-16%], and 14% [95%CI 11-17%], respectively), and were higher than the prevalence estimates of any specific chronic health condition (hypertension, uncomplicated 9% [95%CI 7-11%], back syndrome with and without radiating pain 6% [95%CI 5-7%], non-insulin dependent diabetes mellitus 3% [95%CI 3-4%]), and degenerative joint disease 3% [95%CI 2%-4%]). The prevalence estimates of multimorbidity rose more than 20-fold with age, from 2% (95%CI 1-2%) in those aged 20-29 years, to 38% (95%CI 31-44%) in those aged 80 or more years. The prevalence estimates of multimorbidity were similar for men and women (15% vs. 14%, p=0.288). In primary care, prevalence estimates of multimorbidity are higher than those of isolated diseases. Among the elderly, more than one out of three patients suffer from multimorbidity. Management of multimorbidity is a principal concern in this vulnerable patient population.


Van Schaik C.P.,University of Zurich
Current Biology | Year: 2012

Culture-like phenomena in wild animals have received much attention, but how good is the evidence and how similar are they to human culture? New data on chimpanzees suggest their culture may even have an element of conformity. © 2012 Elsevier Ltd.


Cardiovascular disease plays an important role regarding the morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Sympathetic overactivity has been suggested to underpin the association between COPD and the development of cardiovascular disease. However, the pathophysiological basis by which sustained sympathetic overactivity affects cardiovascular function in patients with COPD is complex and incompletely understood. Different simple and more sophisticated measures of sympathetic activity, such as assessment of heart rate, blood pressure variability, and baroreflex sensitivity, provide information on the potential dysregulation of the autonomous nervous system. This review summarizes the findings from studies in animal models and humans on the potential relationship between COPD, sympathetic overactivity, and cardiovascular disease. There is preliminary evidence of sympathetic overactivity in COPD. However, direct evidence of a cause-effect relationship between sympathetic overactivity and cardiovascular disease from studies in COPD patients is lacking. Data from large cohorts of COPD patients and well-designed interventional studies looking at the relationship between COPD and autonomic nervous system function are urgently needed, hopefully leading to novel therapeutic and preventive approaches in the care of patients with COPD.


Fehr T.,University of Zurich | Stussi G.,Oncology Institute of Southern Switzerland
Current Opinion in Organ Transplantation | Year: 2012

PURPOSE OF REVIEW: A dramatic shortage of available organs around the world encouraged attempts to cross previously forbidden immunological boundaries in kidney transplantation. This review focuses on the recent results of ABO-incompatible kidney transplantation. RECENT FINDINGS: The outcome of ABO-incompatible kidney transplantation in terms of patient and graft survival is comparable to ABO-compatible transplantation for adult and pediatric recipients. Splenectomy has been replaced by the B-cell-depleting agent rituximab to avoid isoagglutinin titer rebound, prevent antibody-mediated rejection, and improve graft survival. However, the risk for infections may be increased and warrants caution. Corticosteroids remain a necessary component of any ABO-incompatible protocol; early as well as late steroid withdrawal may bear an enhanced risk for acute rejection and should only be performed with careful follow-up including protocol biopsies. The few studies that have long-term outcomes using protocol biopsies have characterized a state of accommodation by up-regulation of complement inhibitors, down-regulation of A/B antigens, and establishment of endothelial chimerism over time. SUMMARY: The experience accumulated around the world indicates that ABO-incompatible kidney transplantation is well tolerated and effective in adults and in children, and it represents an important step forward in expanding the living donor pool. Further understanding of ABO-incompatible graft accommodation may have broader implication also for human leukocyte antigen-sensitized allograft recipients. © 2012 Wolters Kluwer Health | Lippincott Williams &. Wilkins.


Hortensteiner S.,University of Zurich | Krautler B.,University of Innsbruck
Biochimica et Biophysica Acta - Bioenergetics | Year: 2011

Chlorophyll breakdown is an important catabolic process of leaf senescence and fruit ripening. Structure elucidation of colorless linear tetrapyrroles as (final) breakdown products of chlorophyll was crucial for the recent delineation of a chlorophyll breakdown pathway which is highly conserved in land plants. Pheophorbide a oxygenase is the key enzyme responsible for opening of the chlorin macrocycle of pheophorbide a characteristic to all further breakdown products. Degradation of chlorophyll was rationalized by the need of a senescing cell to detoxify the potentially phototoxic pigment, yet recent investigations in leaves and fruits indicate that chlorophyll catabolites could have physiological roles. This review updates structural information of chlorophyll catabolites and the biochemical reactions involved in their formation, and discusses the significance of chlorophyll breakdown. This article is part of a Special Issue entitled: Regulation of Electron Transport in Chloroplasts. © 2010 Elsevier B.V. All rights reserved.


Dill H.,University of Wurzburg | Linder B.,University of Wurzburg | Fehr A.,University of Wurzburg | Fehr A.,University of Zurich | Fischer U.,University of Wurzburg
Genes and Development | Year: 2012

Differentiation of neural stem cells (NSCs) to neurons requires the activation of genes controlled by the repressor element 1 (RE1) silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) protein complex. Important components of REST/NRSF are phosphatases (termed RNA polymerase II C-terminal domain small phosphatases [CTDSPs]) that inhibit RNA polymerase II and suppress neuronal gene expression in NSCs. Activation of genes controlled by CTDSPs is required for neurogenesis, but how this is achieved is not fully understood. Here we show that ctdsp2 is a target ofmiR-26b, a microRNA that is encoded in an intron of the ctdsp2 primary transcript. This intrinsic negative feedback loop is inactive in NSCs because miR-26b biogenesis is inhibited at the precursor level. Generation of mature miR-26b is activated during neurogenesis, where it suppresses Ctdsp2 protein expression and is required for neuronal cell differentiation in vivo. © 2012 by Cold Spring Harbor Laboratory Press.


To present the combined 14-year experience of 2 university centers performing endovascular aneurysm repair (EVAR) on 100% of noninfected ruptured abdominal aortic aneurysms (RAAA) over the last 32 months. Endovascular aneurysm repair for RAAA feasibility is reported to be 20% to 50%, and EVAR for RAAA has been reported to have better outcomes than open repair. We retrospectively analyzed prospectively gathered data on 473 consecutive RAAA patients (Zurich, 295; Örebro, 178) from January 1, 1998, to December 31, 2011, treated by an "EVAR-whenever-possible" approach until April 2009 (EVAR/OPEN period) and thereafter according to a "100% EVAR" approach (EVAR-ONLY period).Straightforward cases were treated by standard EVAR. More complex RAAA were managed during EVAR-ONLY with adjunctive procedures in 17 of 70 patients (24%): chimney, 3; open iliac debranching, 1; coiling, 8; onyx, 3; and chimney plus onyx, 2. Since May 2009, all RAAA but one have been treated by EVAR (Zurich, 31; Örebro, 39); 30-day mortality for EVAR-ONLY was 24% (17 of 70). Total cohort mortality (including medically treated patients) for EVAR/OPEN was 32.8% (131 of 400) compared with 27.4% (20 of 73) for EVAR-ONLY (P = 0.376). During EVAR/OPEN, 10% (39 of 400) of patients were treated medically compared with 4% (3 of 73) of patients during EVAR-ONLY. In EVAR/OPEN, open repair showed a statistically significant association with 30-day mortality (adjusted odds ratio [OR] = 3.3; 95% confidence interval [CI], 1.4-7.5; P = 0.004). For patients with no abdominal decompression, there was a higher mortality with open repair than EVAR (adjusted OR = 5.6; 95% CI, 1.9-16.7). In patients with abdominal decompression by laparotomy, there was no difference in mortality (adjusted OR = 1.1; 95% CI, 0.3-3.7). The "EVAR-ONLY" approach has allowed EVAR treatment of nearly all incoming RAAA with low mortality and turndown rates. Although the observed association of a higher EVAR mortality with abdominal decompression needs further study, our results support superiority and more widespread adoption of EVAR for the treatment of RAAA.


Weller M.,University of Zurich | Cloughesy T.,University of California at Los Angeles | Perry J.R.,University of Toronto | Wick W.,University of Heidelberg
Neuro-Oncology | Year: 2013

Newly diagnosed glioblastoma is now commonly treated with surgery, if feasible, or biopsy, followed by radiation plus concomitant and adjuvant temozolomide. The treatment of recurrent glioblastoma continues to be a moving target as new therapeutic principles enrich the standards of care for newly diagnosed disease. We reviewed PubMed and American Society of Clinical Oncology abstracts from January 2006 to January 2012 to identify clinical trials investigating the treatment of recurrent or progressive glioblastoma with nitrosoureas, temozolomide, bevacizumab, and/or combinations of these agents. At recurrence, a minority of patients are eligible for second surgery or reirradiation, based on appropriate patient selection. In temozolomide- pretreated patients, progression-free survival rates at 6 months of 20%-30% may be achieved either with nitrosoureas, temozolomide in various dosing regimens, or bevacizumab. Combination regimens among these agents or with other drugs have not produced evidence for superior activity but commonly produce more toxicity. More research is needed to better define patient profiles that predict benefit from the limited therapeutic options available after the current standard of care has failed. © 2012 The Author(s).


Ohgaki H.,International Agency for Research on Cancer | Kleihues P.,University of Zurich
Brain Tumor Pathology | Year: 2011

Low-grade diffuse gliomas WHO grade II (diffuse astrocytoma, oligoastrocytoma, oligodendroglioma) are characterized by frequent IDH1/2 mutations (>80%) that occur at a very early stage. In addition, the majority of diffuse astrocytomas (about 60%) carry TP53 mutations, which constitute a prognostic marker for shorter survival. Oligodendrogliomas show frequent loss at 1p/19q (about 70% of cases), which is associated with longer survival. With respect to clinical outcome, molecular classification on the basis of IDH1/2 mutations, TP53 mutations, and 1p/19q loss showed a predictive power similar to histological classification. IDH1/2 mutations are frequent (>80%) in secondary glioblastomas that have progressed from low-grade or anaplastic astrocytomas. Primary (de novo) glioblastomas with IDH1/2 mutations are very rare (<5%); they show an age distribution and genetic profile similar to secondary glioblastomas and are probably misclassified. Using the presence of IDH1/2 mutations as a diagnostic criterion, secondary glioblastomas account for approximately 10% of all glioblastomas. IDH1/2 mutations are the most significant predictor of favorable outcome of glioblastoma patients. The high frequency of IDH1/2 mutations in oligodendrogliomas, astrocytomas, and secondary glioblastomas derived thereof suggests these tumors share a common progenitor cell population. The absence of this molecular marker in primary glioblastomas suggests a different cell of origin; both glioblastoma subtypes acquire a similar histological phenotype as a result of common genetic alterations, including the loss of tumor suppressor genes on chromosome 10q. © 2011 The Japan Society of Brain Tumor Pathology.


Grunblatt E.,University of Zurich
Parkinsonism and Related Disorders | Year: 2012

Parkinson's disease (PD) is a progressive neurodegenerative disorder second only to Alzheimer's disease. Diagnosis remains clinical, based on phenotypic patterns. In the last decade many attempts to develop early differential pre-clinical markers have been reported. In this presentation, the molecular risk factors that may link between the etiopathogenesis leading to PD and peripheral markers will be discussed. Genetic variation known to be involved in familial forms of PD will be shown to be linked to sporadic cases, as for example leucine-rich repeat kinase 2 (LRRK2) that was found to regulate microRNA-mediated translation regulation. In addition postmortem microarray findings of transcription alterations will be compared to the peripheral findings of mRNA profiles. Molecular processes involved in ubiquitination and proteasome, autophagy, mitochondrial dysfunction and the nicotinic and adenosine A2 protection will be discussed. The question of what time-point should be used measuring the different markers and the course of the disease considered, and the future possibilities in exploring these techniques will be debated. © 2011 Elsevier Ltd.


Policy makers in several industrial countries are seeking to limit the rise in health care cost growth by supporting coordinated or integrated care programs, which differ from most prevailing forms of medical organization in how physicians are paid and how they work in groups. However, as long as fee-for-service payment systems remain an option, general practitioners will be reluctant to embrace coordinated care because it would give them less autonomy in how they practice. A study in Switzerland indicates that general practitioners will require a pay increase of up to 40 percent before they are willing to accept coordinated care, and a similar study found that Swiss consumers wanted a substantial reduction in premiums to accept it. These findings suggest that provisions of US health care reform designed to encourage the growth of coordinated care-such as accountable care organizations and medical homes-may face a challenging future. © 2011 by Project HOPE - The People-to-People Health Foundation, Inc.


All animals are anatomically constrained in the number of discrete call types they can produce. Recent studies suggest that by combining existing calls into meaningful sequences, animals can increase the information content of their vocal repertoire despite these constraints. Additionally, signalers can use vocal signatures or cues correlated to other individual traits or contexts to increase the information encoded in their vocalizations. However, encoding multiple vocal signatures or cues using the same components of vocalizations usually reduces the signals' reliability. Segregation of information could effectively circumvent this trade-off. In this study we investigate how banded mongooses (Mungos mungo) encode multiple vocal signatures or cues in their frequently emitted graded single syllable close calls. The data for this study were collected on a wild, but habituated, population of banded mongooses. Using behavioral observations and acoustical analysis we found that close calls contain two acoustically different segments. The first being stable and individually distinct, and the second being graded and correlating with the current behavior of the individual, whether it is digging, searching or moving. This provides evidence of Marler's hypothesis on temporal segregation of information within a single syllable call type. Additionally, our work represents an example of an identity cue integrated as a discrete segment within a single call that is independent from context. This likely functions to avoid ambiguity between individuals or receivers having to keep track of several context-specific identity cues. Our study provides the first evidence of segmental concatenation of information within a single syllable in non-human vocalizations. By reviewing descriptions of call structures in the literature, we suggest a general application of this mechanism. Our study indicates that temporal segregation and segmental concatenation of vocal signatures or cues is likely a common, but so far neglected, dimension of information coding in animal vocal communication. We argue that temporal segregation of vocal signatures and cues evolves in species where communication of multiple unambiguous signals is crucial, but is limited by the number of call types produced.


Mitsiadis T.A.,University of Zurich
Advances in dental research | Year: 2011

Stem cells guarantee tissue repair and regeneration throughout life. The decision between cell self-renewal and differentiation is influenced by a specialized microenvironment called the 'stem cell niche'. In the tooth, stem cell niches are formed at specific anatomic locations of the dental pulp. The microenvironment of these niches regulates how dental pulp stem cell populations participate in tissue maintenance, repair, and regeneration. Signaling molecules such as Notch proteins are important regulators of stem cell function, with various capacities to induce proliferation or differentiation. Dental injuries often lead to odontoblast apoptosis, which triggers activation of dental pulp stem cells followed by their proliferation, migration, and differentiation into odontoblast-like cells, which elaborate a reparative dentin. Better knowledge of the regulation of dental pulp stem cells within their niches in pathological conditions will aid in the development of novel treatments for dental tissue repair and regeneration.


: To elucidate the possible organ-protective effect of pharmacological postconditioning in patients undergoing liver resection with inflow occlusion. : Inflow occlusion reduces blood loss during liver transection in selected patients but is potentially harmful due to ischemia-reperfusion injury. Preventive strategies include the use of repetitive short periods of ischemia interrupted by a reperfusion phase (intermittent clamping), application of a short period of ischemia before transection (ischemic preconditioning), or pharmacological preconditioning before transection. Whether intervention after resection (postconditioning) may confer protection is unknown. : A 3 arm, prospective, randomized trial was designed for patients undergoing liver resection with inflow occlusion to compare the effects of pharmacological postconditioning with the volatile anesthetic agent sevoflurane (n = 48), intermittent clamping (n = 50), or no protective intervention (continuous inflow occlusion, n = 17). Endpoints included peak serum aspartate transaminase level, postoperative complications, and hospital stay. All patients were intravenously anesthetized with propofol. In patients with postconditioning, propofol infusion was stopped upon reperfusion and replaced with sevoflurane for 10 minutes. : Compared with the control group, both postconditioning (P = 0.044) and intermittent clamping (P = 0.015) significantly reduced aspartate transaminase levels. The risk of complications was significantly decreased by postconditioning, odds ratio, 0.08 [95% confidence interval (CI), 0.02-0.36; P = 0.001]) and intermittent clamping, odds ratio, 0.50 [95% CI, 0.26-0.96; P = 0.038], compared with controls. Both interventions reduced length of hospital stay, postconditioning -4 days [95% CI, -6 to -1; P = 0.009], and intermittent clamping -2 days, [95% CI, -4 to 0; P = 0.019]. : Pharmacological postconditioning reduces organ injury and postoperative complications. This easily applicable strategy should be used in patients with prolonged continuous inflow occlusion.


To evaluate the outcome after Hartmann's procedure (HP) versus primary anastomosis (PA) with diverting ileostomy for perforated left-sided diverticulitis. The surgical management of left-sided colonic perforation with purulent or fecal peritonitis remains controversial. PA with ileostomy seems to be superior to HP; however, results in the literature are affected by a significant selection bias. No randomized clinical trial has yet compared the 2 procedures. Sixty-two patients with acute left-sided colonic perforation (Hinchey III and IV) from 4 centers were randomized to HP (n = 30) and to PA (with diverting ileostomy, n = 32), with a planned stoma reversal operation after 3 months in both groups. Data were analyzed on an intention-to-treat basis. The primary end point was the overall complication rate. The study was discontinued following an interim analysis that found significant differences of relevant secondary end points as well as a decreasing accrual rate (NCT01233713). Patient demographics were equally distributed in both groups (Hinchey III: 76% vs 75% and Hinchey IV: 24% vs 25%, for HP vs PA, respectively). The overall complication rate for both resection and stoma reversal operations was comparable (80% vs 84%, P = 0.813). Although the outcome after the initial colon resection did not show any significant differences (mortality 13% vs 9% and morbidity 67% vs 75% in HP vs PA), the stoma reversal rate after PA with diverting ileostomy was higher (90% vs 57%, P = 0.005) and serious complications (Grades IIIb-IV: 0% vs 20%, P = 0.046), operating time (73 minutes vs 183 minutes, P < 0.001), hospital stay (6 days vs 9 days, P = 0.016), and lower in-hospital costs (US $16,717 vs US $24,014) were significantly reduced in the PA group. This is the first randomized clinical trial favoring PA with diverting ileostomy over HP in patients with perforated diverticulitis.


Borsig L.,University of Zurich
Thrombosis research | Year: 2010

Heparin is commonly used for prevention or treatment of cancer-associated thromboembolism. Recent clinical evidence indicates that heparin, and low-molecular weight heparin improves survival of cancer patients. Experimental evidence from various animal models consistently supports the ability of heparin to attenuate metastasis. Heparin, apart from its anticoagulant activity contains a variety of biological activities possibly affecting cancer progression, including: inhibition of heparanase, blocking of P- and L-selectin mediated cell adhesion, and inhibition of angiogenesis. The delineation of antimetastatic activity of heparin is in the focus of several ongoing investigations. This review summarizes the current experimental evidence on the biology of heparin as a potential treatment cancer progression.


Fritschy J.-M.,University of Zurich | Fritschy J.-M.,ETH Zurich | Panzanelli P.,University of Turin
European Journal of Neuroscience | Year: 2014

GABAA receptors (GABAARs) are ligand-gated Cl- channels that mediate most of the fast inhibitory neurotransmission in the central nervous system (CNS). Multiple GABAAR subtypes are assembled from a family of 19 subunit genes, raising the question of the significance of this heterogeneity. In this review, we discuss the evidence that GABAAR subtypes represent distinct receptor populations with a specific spatio-temporal expression pattern in the developing and adult CNS, being endowed with unique functional and pharmacological properties, as well as being differentially regulated at the transcriptional, post-transcriptional and translational levels. GABAAR subtypes are targeted to specific subcellular domains to mediate either synaptic or extrasynaptic transmission, and their action is dynamically regulated by a vast array of molecular mechanisms to adjust the strength of inhibition to the changing needs of neuronal networks. These adaptations involve not only changing the gating or kinetic properties of GABAARs, but also modifying the postsynaptic scaffold organised by gephyrin to anchor specific receptor subtypes at postsynaptic sites. The significance of GABAAR heterogeneity is particularly evident during CNS development and adult neurogenesis, with different receptor subtypes fulfilling distinct steps of neuronal differentiation and maturation. Finally, analysis of the specific roles of GABAAR subtypes reveals their involvement in the pathophysiology of major CNS disorders, and opens novel perspectives for therapeutic intervention. In conclusion, GABAAR subtypes represent the substrate of a multifaceted inhibitory neurotransmission system that is dynamically regulated and performs multiple operations, contributing globally to the proper development, function and plasticity of the CNS. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.


Matheeussen V.,University of Antwerp | Jungraithmayr W.,University of Zurich | De Meester I.,University of Antwerp
Pharmacology and Therapeutics | Year: 2012

Dipeptidyl peptidase 4 (DPP4, DPPIV, CD26, EC 3.4.14.5) was discovered more than four decades ago as a serine protease that cleaves off N-terminal dipeptides from peptide substrates. The development of potent DPP4 inhibitors during the past two decades has led to the identification of DPP4 as a target in the treatment of type 2 diabetes. The favorable effect of DPP4 inhibitors is based on prevention of the in vivo inactivation of the incretin hormone, glucagon-like peptide-1 (GLP-1) by DPP4. Apart from GLP-1, a number of other biologically active peptides are truncated by DPP4. For these peptides, the physiological relevance of their truncation has yet to be fully elucidated. Within the last 10 years, DPP4 inhibitors have been employed in several animal models of lung and heart disease, in which injury was induced by an ischemic insult followed by subsequent reperfusion. In this review, we present a state-of-the-art of the ischemia/reperfusion injury (IRI)-related pharmacological actions of DPP4 substrates, including GLP-1, stromal cell-derived factor-1 alpha and vasoactive intestinal peptide. Furthermore, we discuss the large body of experimental work that now provides compelling evidence for the advantageous impact of DPP4 targeting in IRI. However, possible risks as well as underlying mechanisms are yet to be elucidated before translating these promising treatment strategies into clinical practice. © 2012 Elsevier Inc. All rights reserved.


Porro A.,Ecole Polytechnique Federale de Lausanne | Porro A.,University of Zurich | Feuerhahn S.,Ecole Polytechnique Federale de Lausanne | Lingner J.,Ecole Polytechnique Federale de Lausanne
Cell Reports | Year: 2014

Telomeres protect chromosome ends from being recognized as sites of DNA damage. Upon telomere shortening or telomere uncapping induced by loss of telomeric repeat-binding factor 2 (TRF2), telomeres elicit a DNA-damage response leading to cellular senescence. Here, we show that following TRF2 depletion, the levels of the long noncoding RNA TERRA increase and LSD1, which binds TERRA, is recruited to telomeres. At uncapped telomeres, LSD1 associates with MRE11, one of the nucleases implicated in the processing of 3' telomeric G overhangs, and we show that LSD1 is required for efficient removal of these structures. The LSD1-MRE11 interaction is reinforced invivo following TERRA upregulation in TRF2-deficient cells and invitro by TERRA-mimicking RNA oligonucleotides. Furthermore, LSD1 enhances the nuclease activity of MRE11 invitro. Our data indicate that recruitment of LSD1 to deprotected telomeres requires MRE11 and is promoted by TERRA. LSD1 stimulates MRE11 catalytic activity and nucleolytic processing of uncapped telomeres. © 2014 The Authors.


Clarenbach C.F.,University of Zurich
Discovery medicine | Year: 2011

Obstructive sleep apnea (OSA) and type 2 diabetes are both closely related to obesity and their prevalence is increasing due to the rising average body weight in Western countries. The findings of epidemiological studies have implicated that OSA increases the risk for cardiovascular disease, and metabolic disturbances, such as insulin resistance, may link OSA to vascular morbidity. A number of observational clinical studies have evaluated the relationship between OSA and insulin resistance, suggesting an independent association. However, the confounding effect of obesity complicates the establishment of a causal relationship between OSA and insulin resistance. Potential mechanisms that may underpin this relationship were evaluated in animal and human experimental studies and include intermittent hypoxia, arousals from sleep with concomitant sympathetic activation and sleep fragmentation. Currently only three randomized controlled trials investigating the effects of OSA on insulin resistance have been published. In these trials OSA patients were randomly assigned to treatment with continuous positive airway pressure (CPAP) or subtherapeutic CPAP and treatment effects on various measures of insulin resistance were examined. In two of these trials there was no effect of CPAP on glucose metabolism and in one trial a small beneficial effect of CPAP was observed. Further carefully conducted clinical studies and randomized controlled interventional CPAP trials are needed to determine the extent to which OSA is a risk factor for diabetes and its effect on glucose metabolism.


Torgerson P.R.,University of Zurich
Veterinary Parasitology | Year: 2013

Parasitic diseases present a considerable socio-economic impact to society. Zoonotic parasites can result in a considerable burden of disease in people and substantive economic losses to livestock populations. Ameliorating the effects of these diseases may consist of attempts at eradicating specific diseases at a global level, eliminating them at a national or local level or controlling them to minimise incidence. Alternatively with some parasitic zoonoses it may only be possible to treat human and animal cases as they arise. The choice of approach will be determined by the potential effectiveness of a disease control programme, its cost and the cost effectiveness or cost benefit of undertaking the intervention. Furthermore human disease burden is being increasingly measured by egalitarian non-financial measures which are difficult to apply to livestock. This adds additional challenges to the assessment of socio-economic burdens of zoonotic diseases. Using examples from the group of neglected zoonotic diseases, information regarding the socio-economic effects is reviewed together with how this information is used in decision making with regard to disease control and treatment. © 2013 Elsevier B.V.


Liberali P.,University of Zurich
Nature Reviews Genetics | Year: 2014

Large-scale genetic perturbation screens are a classical approach in biology and have been crucial for many discoveries. New technologies can now provide unbiased quantification of multiple molecular and phenotypic changes across tens of thousands of individual cells from large numbers of perturbed cell populations simultaneously. In this Review, we describe how these developments have enabled the discovery of new principles of intracellular and intercellular organization, novel interpretations of genetic perturbation effects and the inference of novel functional genetic interactions. These advances now allow more accurate and comprehensive analyses of gene function in cells using genetic perturbation screens. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Luthi M.P.,ETH Zurich | Luthi M.P.,University of Zurich
Cryosphere | Year: 2014

Mountain glaciers sample a combination of climate fields - temperature, precipitation and radiation - by accumulation and melting of ice. Flow dynamics acts as a transfer function that maps volume changes to a length response of the glacier terminus. Long histories of terminus positions have been assembled for several glaciers in the Alps. Here I analyze terminus position histories from an ensemble of seven glaciers in the Alps with a macroscopic model of glacier dynamics to derive a history of glacier equilibrium line altitude (ELA) for the time span 400-2010 C.E. The resulting climatic reconstruction depends only on records of glacier variations. The reconstructed ELA history is similar to recent reconstructions of Alpine summer temperature and Atlantic Multidecadal Oscillation (AMO) index, but bears little resemblance to reconstructed precipitation variations. Most reconstructed low-ELA periods coincide with large explosive volcano eruptions, hinting at a direct effect of volcanic radiative cooling on mass balance. The glacier advances during the LIA, and the retreat after 1860, can thus be mainly attributed to temperature and volcanic radiative cooling. © Author(s) 2014.


Rezzonico F.,University of Zurich
Astrobiology | Year: 2014

Data from automated orbiters and landers have dashed humankind's hopes of finding complex life-forms elsewhere in the Solar System. The focus of exobiological research was thus forced to shift from the detection of life through simple visual imaging to complex biochemical experiments aimed at the detection of microbial activity. Searching for biosignatures over interplanetary distances is a formidable task and poses the dilemma of what are the proper experiments that can be performed on-site to maximize the chances of success if extraterrestrial life is present but not evident. Despite their astonishing morphological diversity, all known organisms on Earth share the same basic molecular architecture; thus the vast majority of our detection and identification techniques are b(i)ased on Terran biochemistry. There is, however, a distinct possibility that life may have emerged elsewhere by using other molecular building blocks, a fact that is likely to make the outcome of most of the current molecular biological and biochemical life-detection protocols difficult to interpret if not completely ineffective. Nanopore-based sensing devices allow the analysis of single molecules, including the sequence of informational biopolymers such as DNA or RNA, by measuring current changes across an electrically resistant membrane when the analyte flows through an embedded transmembrane protein or a solid-state nanopore. Under certain basic assumptions about their physical properties, this technology has the potential to discriminate and possibly analyze biopolymers, in particular genetic information carriers, without prior detailed knowledge of their fundamental chemistry and is sufficiently portable to be used for automated analysis in planetary exploration, all of which makes it the ideal candidate for the search for life signatures in remote watery environments such as Mars, Europa, or Enceladus. © Copyright 2014, Mary Ann Liebert, Inc.


Devuyst O.,University of Zurich | Devuyst O.,Catholic University of Louvain | Rippe B.,Lund University
Kidney International | Year: 2014

Peritoneal dialysis involves diffusive and convective transports and osmosis through the highly vascularized peritoneal membrane. The capillary endothelium offers the rate-limiting hindrance for solute and water transport. It can be functionally described in terms of a three-pore model including transcellular, ultrasmall pores responsible for free-water transport during crystalloid osmosis. Several lines of evidence have demonstrated that the water channel aquaporin-1 (AQP1) corresponds to the ultrasmall pore located in endothelial cells. Studies in Aqp1 mice have shown that deletion of AQP1 is reflected by a 50% decrease in ultrafiltration and a disappearance of the sodium sieving. Haploinsufficiency in AQP1 is also reflected by a significant attenuation of water transport. Conversely, studies in a rat model and in PD patients have shown that the induction of AQP1 in peritoneal capillaries by corticosteroids is reflected by increased water transport and ultrafiltration, without affecting the osmotic gradient and small-solute transport. Recent data have demonstrated that a novel agonist of AQP1, predicted to stabilize the open-state conformation of the channel, modulates water transport and improves ultrafiltration. Whether increasing the expression of AQP1 or gating the already existing channels would be clinically useful in PD patients remains to be investigated. © 2013 International Society of Nephrology.


Rischatsch M.,University of Zurich
Journal of Health Economics | Year: 2015

Managed Care (MC) is expected to provide health care at a lower cost than conventional provision. Therefore, Switzerland intends to promote MC by forcing health insurers to write MC contracts and introducing budgetary co-responsibility for ambulatory care physicians. A discrete choice experiment conducted in 2011 including 872 physicians reveals a strong preference heterogeneity with respect to network participation and alternative remuneration schemes. The number of physicians working in networks is unlikely to rise on a voluntary basis, while general practitioners are more likely to join networks than specialists with surgical activities. For physicians considering joining networks, cost savings are predicted to be higher than the estimated willingness-to-accept payments. © 2014 Elsevier B.V.


Lutz H.U.,ETH Zurich | Bogdanova A.,University of Zurich
Frontiers in Physiology | Year: 2013

This review focuses on the analysis and evaluation of the diverse senescence markers suggested to prime red blood cells (RBC) for clearance in humans. These tags develop in the course of biochemical and structural alterations accompanying RBC aging, as the decrease of activities of multiple enzymes, the gradual accumulation of oxidative damage, the loss of membrane in form of microvesicles, the redistribution of ions and alterations in cell volume, density, and deformability. The actual tags represent the penultimate galactosyl residues, revealed by desialylation of glycophorins, or the aggregates of the anion exchanger (band 3 protein) to which anti-galactose antibodies bind in the first and anti-band 3 naturally occurring antibodies (NAbs) in the second case. While anti-band 3 NAbs bind to the carbohydrate-free portion of band 3 aggregates in healthy humans, induced anti-lactoferrin antibodies bind to the carbohydrate-containing portion of band 3 and along with anti-band 3 NAbs may accelerated clearance of senescent RBC in patients with anti-neutrophil cytoplasmic antibodies (ANCA). Exoplasmically accessible phosphatidylserine (PS) and the alterations in the interplay between CD47 on RBC and its receptor on macrophages, signal regulatory protein alpha (SIRPalpha protein), were also reported to induce erythrocyte clearance. We discuss the relevance of each mechanism and analyze the strength of the data. © 2013 Lutz and Bogdanova.


Marguerat S.,University College London | Schmidt A.,University of Basel | Codlin S.,University College London | Chen W.,Berlin Institute for Medical Systems Biology | And 3 more authors.
Cell | Year: 2012

Data on absolute molecule numbers will empower the modeling, understanding, and comparison of cellular functions and biological systems. We quantified transcriptomes and proteomes in fission yeast during cellular proliferation and quiescence. This rich resource provides the first comprehensive reference for all RNA and most protein concentrations in a eukaryote under two key physiological conditions. The integrated data set supports quantitative biology and affords unique insights into cell regulation. Although mRNAs are typically expressed in a narrow range above 1 copy/cell, most long, noncoding RNAs, except for a distinct subset, are tightly repressed below 1 copy/cell. Cell-cycle-regulated transcription tunes mRNA numbers to phase-specific requirements but can also bring about more switch-like expression. Proteins greatly exceed mRNAs in abundance and dynamic range, and concentrations are regulated to functional demands. Upon transition to quiescence, the proteome changes substantially, but, in stark contrast to mRNAs, proteins do not uniformly decrease but scale with cell volume. © 2012 Elsevier Inc.


Denner A.,University of Wurzburg | Dittmaier S.,Albert Ludwigs University of Freiburg | Kallweit S.,Paul Scherrer Institute | Pozzorini S.,University of Zurich
Physical Review Letters | Year: 2011

Top-antitop quark pairs belong to the most abundantly produced and precisely measurable heavy-particle signatures at hadron colliders and allow for crucial tests of the standard model and new physics searches. Here we report on the calculation of the next-to-leading order (NLO) QCD corrections to hadronic W+W-bb̄ production, which provides a complete NLO description of the production of top-antitop pairs and their subsequent decay into W bosons and bottom quarks, including interferences, off-shell effects, and nonresonant backgrounds. Numerical predictions for the Tevatron and the LHC are presented. © 2011 American Physical Society.


Rudiger A.,University of Zurich | Singer M.,University College London
Current Vascular Pharmacology | Year: 2013

Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production. In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated. As a result, cells and organs may survive in a non-functioning hibernation-like condition. Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown. Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors. Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins. All these changes are mediated by cytokines. Treatment includes preload optimization with sufficient fluids. However, excessive volume loading is harmful. The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines. During early sepsis, cardiac output can be increased by dobutamine. While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful. Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice. © 2013 Bentham Science Publishers.


Ohgaki H.,International Agency for Research on Cancer | Kleihues P.,University of Zurich
Clinical Cancer Research | Year: 2013

Glioblastoma is the most frequent and malignant brain tumor. The vast majority of glioblastomas (∼90%) develop rapidly de novo in elderly patients, without clinical or histologic evidence of a less malignant precursor lesion (primary glioblastomas). Secondary glioblastomas progress from low-grade diffuse astrocytoma or anaplastic astrocytoma. They manifest in younger patients, have a lesser degree of necrosis, are preferentially located in the frontal lobe, and carry a significantly better prognosis. Histologically, primary and secondary glioblastomas are largely indistinguishable, but they differ in their genetic and epigenetic profiles. Decisive genetic signposts of secondary glioblastoma are IDH1 mutations, which are absent in primary glioblastomas and which are associated with a hypermethylation phenotype. IDH1 mutations are the earliest detectable genetic alteration in precursor low-grade diffuse astrocytomas and in oligodendrogliomas, indicating that these tumors are derived from neural precursor cells that differ from those of primary glioblastomas. In this review, we summarize epidemiologic, clinical, histopathologic, genetic, and expression features of primary and secondary glioblastomas and the biologic consequences of IDH1 mutations. We conclude that this genetic alteration is a definitive diagnostic molecular marker of secondary glioblastomas and more reliable and objective than clinical criteria. Despite a similar histologic appearance, primary and secondary glioblastomas are distinct tumor entities that originate from different precursor cells and may require different therapeutic approaches. Copyright © 2013 American Association for Cancer Research.


Bueter M.,University of Zurich
Journal of visualized experiments : JoVE | Year: 2012

Currently, the most effective therapy for the treatment of morbid obesity to induce significant and maintained body weight loss with a proven mortality benefit is bariatric surgery. Consequently, there has been a steady rise in the number of bariatric operations done worldwide in recent years with the Roux-en-Y gastric bypass (gastric bypass) being the most commonly performed operation. Against this background, it is important to understand the physiological mechanisms by which gastric bypass induces and maintains body weight loss. These mechanisms are yet not fully understood, but may include reduced hunger and increased satiation, increased energy expenditure, altered preference for food high in fat and sugar, altered salt and water handling of the kidney as well as alterations in gut microbiota. Such changes seen after gastric bypass may at least partly stem from how the surgery alters the hormonal milieu because gastric bypass increases the postprandial release of peptide-YY (PYY) and glucagon-like-peptide-1 (GLP-1), hormones that are released by the gut in the presence of nutrients and that reduce eating. During the last two decades numerous studies using rats have been carried out to further investigate physiological changes after gastric bypass. The gastric bypass rat model has proven to be a valuable experimental tool not least as it closely mimics the time profile and magnitude of human weight loss, but also allows researchers to control and manipulate critical anatomic and physiologic factors including the use of appropriate controls. Consequently, there is a wide array of rat gastric bypass models available in the literature reviewed elsewhere in more detail. The description of the exact surgical technique of these models varies widely and differs e.g. in terms of pouch size, limb lengths, and the preservation of the vagal nerve. If reported, mortality rates seem to range from 0 to 35%. Furthermore, surgery has been carried out almost exclusively in male rats of different strains and ages. Pre- and postoperative diets also varied significantly. Technical and experimental variations in published gastric bypass rat models complicate the comparison and identification of potential physiological mechanisms involved in gastric bypass. There is no clear evidence that any of these models is superior, but there is an emerging need for standardization of the procedure to achieve consistent and comparable data. This article therefore aims to summarize and discuss technical and experimental details of our previously validated and published gastric bypass rat model.


Dummer R.,University of Zurich | Flaherty K.T.,Massachusetts General Hospital
Current Opinion in Oncology | Year: 2012

PURPOSE OF REVIEW: After years of therapeutic approaches with limited effects in metastatic melanoma, new inhibitors of serine-threonine and tyrosine kinases have demonstrated impressive clinical efficacy and improved survival. RECENT FINDINGS: This review explains the molecular background for the development of specific kinase inhibitors and briefly summarizes their clinical impact on advanced melanoma. SUMMARY: Despite robust early clinical efficacy, the antiproliferative effect of these kinase inhibitors is limited. The resistance mechanisms are explored currently and will help to identify new targets for melanoma therapy. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Background and Aims Apocynaceae and Orchidaceae are two angiosperm families with extreme flower synorganization. They are unrelated, the former in eudicots, the latter in monocots, but they converge in the formation of pollinia and pollinaria, which do not occur in any other angiosperm family, and for which extreme synorganization of floral organs is a precondition. In each family extensive studies on flower development and evolution have been performed; however, newer comparative studies focusing on flower synorganization and involving both families together are lacking. Scope For this study an extensive search through the morphological literature has been conducted. Based on this and my own studies on flowers in various Apocynaceae and Orchidaceae and complex flowers in other angiosperms with scanning electron microscopy and with microtome section series, a review on convergent floral traits in flower development and architecture in the two families is presented. Key Findings There is a tendency of protracted development of synorganized parts in Apocynaceae and Orchidaceae (development of synorganization of two or more organs begins earlier the more accentuated it is at anthesis). Synorganization (or complexity) also paves the way for novel structures. One of the most conspicuous such novel structures in Apocynaceae is the corona, which is not the product of synorganization of existing organs; however, it is probably enhanced by synorganization of other, existing, floral parts. In contrast to synorganized parts, the corona appears developmentally late. Conclusions Synorganization of floral organs may lead to a large number of convergences in clades that are only very distantly related. The convergences that have been highlighted in this comparative study should be developmentally investigated directly in parallel in future studies. © The Author 2015. Published by Oxford University Press on behalf of the Annals of Botany Company.


Background Various groups of flowering plants reveal profound ('saltational') changes of their bauplans (architectural rules) as compared with related taxa. These plants are known as morphological misfits that appear as rather large morphological deviations from the norm. Some of them emerged as morphological key innovations (perhaps 'hopeful monsters') that gave rise to new evolutionary lines of organisms, based on (major) genetic changes. Scope This pictorial report places emphasis on released bauplans as typical for bladderworts (Utricularia, approx. 230 secies, Lentibulariaceae) and river-weeds (Podostemaceae, three subfamilies, approx. 54 genera, approx. 310 species). Bladderworts (Utricularia) are carnivorous, possessing sucking traps. They live as submerged aquatics (except for their flowers), as humid terrestrials or as epiphytes. Most Podostemaceae are restricted to rocks in tropical river-rapids and waterfalls. They survive as submerged haptophytes in these extreme habitats during the rainy season, emerging with their flowers afterwards. The recent scientific progress in developmental biology and evolutionary history of both Lentibulariaceae and Podostemaceae is summarized. Conclusions Lentibulariaceae and Podostemaceae follow structural rules that are different from but related to those of more typical flowering plants. The roots, stems and leaves - as still distinguishable in related flowering plants - are blurred ('fuzzy'). However, both families have stable floral bauplans. The developmental switches to unusual vegetative morphologies facilitated rather than prevented the evolution of species diversity in both families. The lack of one-to-one correspondence between structural categories and gene expression may have arisen from the re-use of existing genetic resources in novel contexts. Understanding what developmental patterns are followed in Lentibulariaceae and Podostemaceae is a necessary prerequisite to discover the genetic alterations that led to the evolution of these atypical plants. Future molecular genetic work on morphological misfits such as bladderworts and river-weeds will provide insight into developmental and evolutionary aspects of more typical vascular plants. © The Author 2015. Published by Oxford University Press on behalf of the Annals of Botany Company.


Steffen R.,University of Zurich
Current Infectious Disease Reports | Year: 2010

Influenza is the most frequent travel related infection preventable by universally available vaccines, but preventive measures were neglected until recently. Since the spread of pandemic (H1N1) 2009, various public health measures have been promoted first to contain, then to mitigate, the pandemic. Some of these measures contradicted recommendations issued by the World Health Organization and were of questionable efficacy. However, travelers may benefit from targeted recommendations on influenza risk reduction (eg, by social distancing or immunization). These recommendations are particularly indicated for those with an increased personal risk profile and for those likely to be exposed to influenza patients. © Springer Science+Business Media, LLC 2010.


Bendas G.,University of Bonn | Borsig L.,University of Zurich
International Journal of Cell Biology | Year: 2012

Cell adhesion molecules play a significant role in cancer progression and metastasis. Cell-cell interactions of cancer cells with endothelium determine the metastatic spread. In addition, direct tumor cell interactions with platelets, leukocytes, and soluble components significantly contribute to cancer cell adhesion, extravasation, and the establishment of metastatic lesions. Clinical evidence indicates that heparin, commonly used for treatment of thromboembolic events in cancer patients, is beneficial for their survival. Preclinical studies confirm that heparin possesses antimetastatic activities that lead to attenuation of metastasis in various animal models. Heparin contains several biological activities that may affect several steps in metastatic cascade. Here we focus on the role of cellular adhesion receptors in the metastatic cascade and discuss evidence for heparin as an inhibitor of cell adhesion. While P- and L-selectin facilitation of cellular contacts during hematogenous metastasis is being accepted as a potential target of heparin, here we propose that heparin may also interfere with integrin activity and thereby affect cancer progression. This review summarizes recent findings about potential mechanisms of tumor cell interactions in the vasculature and antimetastatic activities of heparin. Copyright 2012 Gerd Bendas and Lubor Borsig.


Konieczna P.,University of Zurich
Gut microbes | Year: 2012

There is increasing interest in the administration of microbes or microbial metabolites for the prevention and treatment of aberrant inflammatory activity. The protective effects associated with these microbes are mediated by multiple mechanisms involving epithelial cells, DCs and T cells, but most data are derived from animal models. In this addendum, we summarize our recent data, showing that oral consumption of Bifidobacterium infantis 35624 is associated with enhanced IL-10 secretion and Foxp3 expression in human peripheral blood. In addition, we discuss the potential DC subset-specific mechanisms, which could contribute to DC(REG) and T(REG) programming by specific gut microbes.


Krstic D.,University of Zurich
PloS one | Year: 2013

Since its discovery by Morgan, the Drosophila white gene has become one of the most intensely studied genes and has been widely used as a genetic marker. Earlier reports that over- and misexpression of White protein in Drosophila males leads to male-male courtship implicated white in courtship control. While previous studies suggested that it is the mislocalization of White protein within cells that causes the courtship phenotype, we demonstrate here that also the lack of extra-retinal White can cause very similar behavioral changes. Moreover, we provide evidence that the lack of White function increases the sexual arousal of males in general, of which the enhanced male-male courtship might be an indirect effect. We further show that white mutant flies are not only optomotor blind but also dazzled by the over-flow of light in daylight. Implications of these findings for the proper interpretation of behavioral studies with white mutant flies are discussed.


Acute graft-versus host disease (aGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation (HSCT) occurring in 8% to 59% of the recipients. Currently, the therapeutic mainstay for aGvHD is corticosteroids. However, there is no established standard treatment for steroid-refractory aGvHD. Extracorporeal photopheresis (ECP) is a type of immunomodulatory method amongst different therapeutic options that involves ex vivo collection of peripheral mononuclear cells, exposure to the photoactive agent 8-methoxypsoralen and ultraviolet-A radiation, and re-infusion of these treated blood cells to the patient. The mechanisms of action of ECP are not completely understood To evaluate the effectiveness and safety of ECP for the management of aGvHD in children and adolescents after HSCT. We searched the Cochrane Central Register of Controlled Trials (Issue 9, 2012), MEDLINE/PubMed and EMBASE (Ovid) databases from their inception to 12 September 2012. We searched the reference lists of potentially relevant studies without any language restriction. We searched eight trial registers and four conference proceedings. We also contacted an expert in the field to request information on unpublished study that involves ECP in aGvHD after HSCT. Randomised controlled trials (RCTs) comparing ECP with or without standard treatment versus standard treatment alone in paediatric patients with aGvHD after HSCT. Two review authors independently performed the study selection. We resolved disagreement in the selection of trials by consultation with a third review author. We found no studies meeting the criteria for inclusion in this review. The efficacy of ECP in the treatment of aGvHD in paediatric patients after HSCT is unknown and its use should be restricted within the context of RCTs. Such studies should address a comparison of ECP alone or in combination with standard treatment versus standard treatment alone. 


Dantzer F.,University of Strasbourg | Santoro R.,University of Zurich
FEBS Journal | Year: 2013

Poly(ADP-ribose) polymerases (PARPs) are enzymes that transfer poly(ADP-ribose) (PAR) groups to target proteins, and thereby affect various nuclear and cytoplasmic processes. The activity of PARP family members, such as PARP1 and PARP2, is tied to cellular signalling pathways, and, through poly(ADP-ribosyl)ation, they ultimately promote changes in chromatin architecture, gene expression, and the location and activity of proteins that mediate signalling responses. A growing body of evidence suggest that PARPs, particularly PARP1 and PARP2, also operate at heterochromatic regions such as the inactive X chromosome, telomeres, pericentric heterochromatin and silent ribosomal RNA (rRNA) genes. Both proteins localize to heterochromatic sites and often associate with or poly(ADP-ribosyl)ate histones and heterochromatin- binding proteins, thereby modulating their activities. In this review, we describe current knowledge concerning the role of PARPs in establishment and inheritance of heterochromatic structures, and highlight how their contribution affects biological outcomes. PARP1 and PARP2 are poly(ADP-ribose) polymerases (PARPs/ARTDs), enzymes that transfer poly(ADP-ribose) groups to target proteins and thereby affect cellular processes. The activity of PARP1 and PARP2 is tied to cellular signalling pathways, and through poly(ADP-ribosyl)ation they promote changes in chromatin architecture and gene expression. Here, we describe the role of PARPs in heterochromatin and their contribution in biological outcomes. © 2013 FEBS.


Baumann C.R.,University of Zurich
Parkinsonism and Related Disorders | Year: 2012

The epidemiology of tremor in Parkinson's disease is not well examined. The prevalence of Parkinson's disease is about 100-300 per 100,000, and the majority (70-100%) of these patients may develop tremor during the course of the disorder. The expression of tremor is also influenced by the genetic background of selected patients. On the other hand, Parkinson patients with a predominant tremor phenotype may have a more favourable prognosis in terms of mortality and the development of motor and non-motor complications. The diagnosis of Parkinson tremor is based on a clinical diagnosis of both underlying Parkinson's disease and on the tremor itself. Tremor is a rhythmical, involuntary oscillatory movement of a body part, and includes resting tremor, action tremor including postural and kinetic tremor. The classical type is resting tremor, but other phenotypes may also occur. Misdiagnoses between Parkinson tremor and essential tremor are relatively common. Electrophysiological and functional imaging examinations can be useful in the distinction of the two, but both approaches suffer from some limitations. In general, essential tremor and other tremor forms can be distinguished from Parkinson tremor by their frequency and their expression with different activation. © 2011 Elsevier Ltd.


Kowalewski M.,University of Zurich
Reproduction in Domestic Animals | Year: 2012

Contents: In the domestic dog (Canis familiaris), the corpus luteum (CL) is the only source of progesterone (P4) in non-pregnant and pregnant animals. The progesterone secretion profiles are almost identical in both conditions until the last third of the luteal phase when the gradual P4 decline turns into a steep drop in pregnant bitches, indicating the onset of parturition. Consequently, the length of the CL-phase in non-pregnant dogs exceeds the luteal lifespan in pregnant animals. The canine CL-function is regulated by many species-specific regulatory mechanisms, the most intriguing of which is the reported independence of gonadotropic support during the first third of dioestrus. Recently, PGE2 has been proposed as one of the most important luteotropic factors acting locally during this time, but afterwards prolactin (PRL) appears to be the main luteotropic factor. Luteal regression/luteolysis occurs, however, in spite of an increased gonadotropic support. Lately, by demonstrating the expression of PRL-receptor (PRLr), a new insight into possible regulatory mechanisms has indicated that the supply of P4 could be controlled upstream of the steroidogenic machinery at the level of PRLr expression and/or function, subsequently leading to the functional suppression of the steroidogenic machinery. An endogenous source of a luteolytic agent is apparently lacking, implicating the luteal regression in non-pregnant bitches as a passive, degenerative process even if the PGF2α-receptor is constitutively expressed in canine CL. This is in contrast to pregnant dogs in which prepartum luteolysis seems to be an active process of CL destruction by PGF2α of utero/placental origin targeting the luteal PGF2α-receptor. © 2012 Blackwell Verlag GmbH.


Flury M.,University of Zurich
Journal of pediatric oncology nursing : official journal of the Association of Pediatric Oncology Nurses | Year: 2011

Children and adolescents with cancer are increasingly treated and cared for at home; hospital stays are reduced to a minimum. Taking care of a sick child at home has an impact on the entire family: the sick child, the siblings, and the parents. This qualitative study examines the experiences of parents taking their child home for the first time after the diagnosis. Parents of 10 children newly diagnosed with cancer were interviewed twice around the time of the first discharge; data were analyzed using content analysis methodology. Findings illustrated parents' preparation of and experiences around their child's first discharge, the huge amount of new and changed tasks parents have to fulfill at home when caring for their child with cancer, and consequences for the parents. By providing individualized information and instruction, by having parents anticipate potential problems and solutions, and by describing available community support and integrating district nurses as well as other parents with the same experiences more frequently, health care professionals in the hospital can optimize discharge planning for these parents.


Bischoff-Ferrari H.,University of Zurich
Dermatologic Therapy | Year: 2010

Increasing data suggest that many or most adults in the United States and Europe would benefit from vitamin D supplements. This review summarizes the benefits of vitamin D with the strongest evidence today from randomized controlled trials for fall and fracture prevention. Beyond fall and fracture prevention, vitamin D may also reduce overall morbidity by multiple mechanisms. Prospective epidemiological studies supported by strong mechanistic evidence suggest a reduction of cardiovascular disease (incident hypertension and cardiovascular mortality) and colorectal cancer, extending to weaker evidence on immune-modulatory and anti-inflammatory benefits of vitamin D. © 2010 Wiley Periodicals, Inc.


Castro P.,University of Zurich
Climate Policy | Year: 2012

Under the Kyoto Protocol, developing countries can voluntarily participate in climate change mitigation through the Clean Development Mechanism (CDM), in which industrialized countries, in order to meet their mitigation commitments, can buy emission reduction credits from projects in developing countries. Before its implementation, developing-country experts opposed the CDM, arguing that it would sell-off their countries' cheapest emission reduction options and force them to invest in more expensive measures to meet their future reduction targets. This 'low-hanging fruit' argument is analysed empirically by comparing marginal abatement cost curves. Emissions abatement costs and potentials for CDM projects are estimated for different technologies in eight countries, using capital budgeting tools and information from project documentation. It is found that the CDM is not yet capturing a large portion of the identified abatement potential in most countries. Although the costs of most emissions reduction opportunities grasped are below the average credit price, there are still plenty of available low-cost opportunities. Mexico and Argentina appear to use the CDM predominantly for harvesting the low-hanging fruit, whereas in the other countries more expensive projects are accessing the CDM. This evidence at first sight challenges the low-hanging fruit claim, but needs to be understood in the light of the barriers for the adoption of low-cost abatement options. © 2012 Copyright Taylor and Francis Group, LLC.


Huber H.,University of Zurich
Euro surveillance : bulletin européen sur les maladies transmissibles = European communicable disease bulletin | Year: 2010

A total of 2,662 samples, collected from March to September 2009 in Switzerland, were tested for the presence of meticillin-resistant Staphylococcus aureus (MRSA). The collection comprised nasal swabs from 148 pig farmers, 133 veterinarians, 179 slaughterhouse employees, 800 pigs, 300 calves, 400 cattle, 100 pooled neck skin swabs from chicken carcasses, and 460 food samples of animal origin. Moreover, 142 S. aureus strains, isolated from bovine mastitis milk, were included in the study. Twenty samples (< 1%; four veterinarians, 10 pigs, three calves, one young bull, and two mastitis milk samples) tested positive for MRSA. Genotyping of the MRSA strains was performed by multilocus sequence typing, spa- and SCCmec-typing, and revealed ST398 (n=18), ST8 (n=1), ST 1 (n=1), spa types t011 (n=7), t034 (n=11), t064 (n=1), t127 (n=1), and SCCmec types IV (n=4) and V (n=16). The 20 MRSA strains were subjected to antibiotic susceptibility testing and pulsed-field gel electrophoresis using the restriction enzyme EagI. Supplementary PCR reactions were performed to investigate the presence of Panton-Valentine leukocidin and staphylococcal enterotoxins A to D.


Weber R.H.,University of Zurich
Computer Law and Security Review | Year: 2010

The Internet of Things, an emerging global Internet-based technical architecture facilitating the exchange of goods and services in global supply chain networks has an impact on the security and privacy of the involved stakeholders. Measures ensuring the architecture's resilience to attacks, data authentication, access control and client privacy need to be established. An adequate legal framework must take the underlying technology into account and would best be established by an international legislator, which is supplemented by the private sector according to specific needs and thereby becomes easily adjustable. The contents of the respective legislation must encompass the right to information, provisions prohibiting or restricting the use of mechanisms of the Internet of Things, rules on IT-security-legislation, provisions supporting the use of mechanisms of the Internet of Things and the establishment of a task force doing research on the legal challenges of the IoT. © 2010 Prof Rolf H. Weber.


A personal best marathon time has been reported as a strong predictor variable for an Ironman race time in recreational female Ironman triathletes. This raises the question whether recreational female Ironman triathletes are similar to recreational female marathoners. We investigated similarities and differences in anthropometry and training between 53 recreational female Ironman triathletes and 46 recreational female marathoners. The association of anthropometric variables and training characteristics with race time was investigated using bi- and multi-variate analysis. The Ironman triathletes were younger (P < 0.01), had a lower skin-fold thickness at pectoral (P < 0.001), axillar (P < 0.01), and subscapular (P < 0.05) site, but a thicker skin-fold thickness at the calf site (P < 0.01) compared to the marathoners. Overall weekly training hours were higher in the Ironman triathletes (P < 0.001). The triathletes were running faster during training than the marathoners (P < 0.05). For the triathletes, neither an anthropometric nor a training variable showed an association with overall Ironman race time after bi-variate analysis. In the multi-variate analysis, running speed during training was related to marathon split time for the Ironman triathletes (P = 0.01) and to marathon race time for the marathoners (P = 0.01). To conclude, although personal best marathon time is a strong predictor variable for performance in recreational female Ironman triathletes, there are differences in both anthropometry and training between recreational female Ironman triathletes and recreational female marathoners and different predictor variables for race performance in these two groups of athletes. These findings suggest that recreational female Ironman triathletes are not comparable to recreational female marathoners regarding the association between anthropometric and training characteristics with race time.


Caviglia S.,University of Zurich
Nature Cell Biology | Year: 2016

A crucial yet ill-defined step during the development of tubular networks, such as the vasculature, is the formation of connections (anastomoses) between pre-existing lumenized tubes. By studying tracheal tube anastomosis in Drosophila melanogaster, we uncovered a key role of secretory lysosome-related organelle (LRO) trafficking in lumen fusion. We identified the conserved calcium-binding protein Unc-13-4/Staccato (Stac) and the GTPase Rab39 as critical regulators of this process. Stac and Rab39 accumulate on dynamic vesicles, which form exclusively in fusion tip cells, move in a dynein-dependent manner, and contain late-endosomal, lysosomal, and SNARE components characteristic of LROs. The GTPase Arl3 is necessary and sufficient for Stac LRO formation and promotes Stac-dependent intracellular fusion of juxtaposed apical plasma membranes, thereby forming a transcellular lumen. Concomitantly, calcium is released locally from ER exit sites and apical membrane-associated calcium increases. We propose that calcium-dependent focused activation of LRO exocytosis restricts lumen fusion to appropriate domains within tip cells. © 2016 Nature Publishing Group


Placental mammals occupy a larger morphospace and are taxonomically more diverse than marsupials by an order of magnitude, as shown by quantitative and phylogenetic studies of several character complexes and clades. Many have suggested that life history acts as a constraint on the evolution of marsupial morphology. However, the frequent circumvention of constraints suggests that the pattern of morphospace occupation in marsupials is more a reflection of lack of ecological opportunity than one of biases in the production of variants during development. Features of marsupial physiology are a potential source of biases in the evolution of the group; these could be coupled with past macroevolutionary patterns that followed conditions imposed by global temperature changes. This is evident at the K/Pg boundary and at the Eocene/Oligocene boundary. The geographic pattern of taxonomic and morphological diversity in placental clades mirrors that of extant placentals as a whole versus marsupials: placentals of northern origin are more diverse those of southern one and include the clades that are outliers in taxonomic (rodents and bats) and ecomorphological (whales and bats) richness. © 2012 Springer Science+Business Media New York.


Neurofeedback training (NF) for the treatment of children with ADHD has found increasing acceptance. Until recently, methodologically satisfactory studies on NF efficacy were lacking. This review gives an introduction to NF principles and protocols, followed by a short overview of recent studies and methodological approaches. Different control group designs, imaging findings, and studies investigating the association between outcome and learned cortical regulation are covered. Even though many methodological issues still need to be addressed, evidence is emerging that NF may have some specific effects. Future studies will have to demonstrate to which extent these specific effects contribute directly to clinical improvements. © 2011 Verlag Hans Huber, Hogrefe AG, Bern.


Jung H.H.,University of Zurich
Orphanet journal of rare diseases | Year: 2011

Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis and progressive degeneration of the basal ganglia. NA syndromes are exceptionally rare with an estimated prevalence of less than 1 to 5 per 1'000'000 inhabitants for each disorder. The core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome which have a Huntington's disease-like phenotype consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. In addition, cardiomyopathy may occur in McLeod syndrome. Acanthocytes are also found in a proportion of patients with autosomal dominant Huntington's disease-like 2, autosomal recessive pantothenate kinase-associated neurodegeneration and several inherited disorders of lipoprotein metabolism, namely abetalipoproteinemia (Bassen-Kornzweig syndrome) and hypobetalipoproteinemia leading to vitamin E malabsorption. The latter disorders are characterized by a peripheral neuropathy and sensory ataxia due to dorsal column degeneration, but movement disorders and cognitive impairment are not present. NA syndromes are caused by disease-specific genetic mutations. The mechanism by which these mutations cause neurodegeneration is not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basal ganglia, however, suggests a common pathogenetic pathway. Laboratory tests include blood smears to detect acanthocytosis and determination of serum creatine kinase. Cerebral magnetic resonance imaging may demonstrate striatal atrophy. Kell and Kx blood group antigens are reduced or absent in McLeod syndrome. Western blot for chorein demonstrates absence of this protein in red blood cells of chorea-acanthocytosis patients. Specific genetic testing is possible in all NA syndromes. Differential diagnoses include Huntington disease and other causes of progressive hyperkinetic movement disorders. There are no curative therapies for NA syndromes. Regular cardiologic studies and avoidance of transfusion complications are mandatory in McLeod syndrome. The hyperkinetic movement disorder may be treated as in Huntington disease. Other symptoms including psychiatric manifestations should be managed in a symptom-oriented manner. NA syndromes have a relentlessly progressive course usually over two to three decades.


Leitzmann M.F.,University of Regensburg | Rohrmann S.,University of Zurich
Clinical Epidemiology | Year: 2012

At present, only three risk factors for prostate cancer have been firmly established; these are all nonmodifiable: age, race, and a positive family history of prostate cancer. However, numerous modifiable factors have also been implicated in the development of prostate cancer. In the current review, we summarize the epidemiologic data for age, location, and selected behavioral factors in relation to the onset of prostate cancer. Although the available data are not entirely consistent, possible preventative behavioral factors include increased physical activity, intakes of tomatoes, cruciferous vegetables, and soy. Factors that may enhance prostate cancer risk include frequent consumption of dairy products and, possibly, meat. By comparison, alcohol probably exerts no important influence on prostate cancer development. Similarly, dietary supplements are unlikely to protect against the onset of prostate cancer in healthy men. Several factors, such as smoking and obesity, show a weak association with prostate cancer incidence but a positive relation with prostate cancer mortality. Other factors, such as fish intake, also appear to be unassociated with incident prostate cancer but show an inverse relation with fatal prostate cancer. Such heterogeneity in the relationship between behavioral factors and nonadvanced, advanced, or fatal prostate cancers helps shed light on the carcinogenetic process because it discerns the impact of exposure on early and late stages of prostate cancer development. Inconsistent associations between behavioral factors and prostate cancer risk seen in previous studies may in part be due to uncontrolled detection bias because of current widespread use of prostate-specific antigen testing for prostate cancer, and the possibility that certain behavioral factors are systematically related to the likelihood of undergoing screening examinations. In addition, several genes may modify the study results, but data concerning specific gene-environment interactions are currently sparse. Despite large improvements in our understanding of prostate cancer risk factors in the past two decades, present knowledge does not allow definitive recommendations for specific preventative behavioral interventions. © 2012 Leitzmann and Rohrmann, publisher and licensee Dove Medical Press Ltd.


Prenatal exposure to infectious or inflammatory insults is increasingly recognized to contribute to the etiology of psychiatric disorders with neurodevelopmental components, including schizophrenia, autism and bipolar disorder. It remains unknown, however, if such immune-mediated brain anomalies can be transmitted to subsequent generations. Using an established mouse model of prenatal immune activation by the viral mimetic poly(I:C), we show that reduced sociability and increased cued fear expression are similarly present in the first- and second-generation offspring of immune-challenged ancestors. We further demonstrate that sensorimotor gating impairments are confined to the direct descendants of infected mothers, whereas increased behavioral despair emerges as a novel phenotype in the second generation. These transgenerational effects are mediated via the paternal lineage and are stable until the third generation, demonstrating transgenerational non-genetic inheritance of pathological traits following in-utero immune activation. Next-generation sequencing further demonstrated unique and overlapping genome-wide transcriptional changes in first- and second-generation offspring of immune-challenged ancestors. These transcriptional effects mirror the transgenerational effects on behavior, showing that prenatal immune activation leads to a transgenerational transmission (presence of similar phenotypes across generations) and modification (presence of distinct phenotypes across generations) of pathological traits. Together, our study demonstrates for, we believe, the first time that prenatal immune activation can negatively affect brain and behavioral functions in multiple generations. These findings thus highlight a novel pathological aspect of this early-life adversity in shaping disease risk across generations.Molecular Psychiatry advance online publication, 29 March 2016; doi:10.1038/mp.2016.41. © 2016 Macmillan Publishers Limited


Hofer U.,University of Zurich
PLoS pathogens | Year: 2010

Bacterial translocation from the gut and subsequent immune activation are hallmarks of HIV infection and are thought to determine disease progression. Intestinal barrier integrity is impaired early in acute retroviral infection, but levels of plasma lipopolysaccharide (LPS), a marker of bacterial translocation, increase only later. We examined humanized mice infected with HIV to determine if disruption of the intestinal barrier alone is responsible for elevated levels of LPS and if bacterial translocation increases immune activation. Treating uninfected mice with dextran sodium sulfate (DSS) induced bacterial translocation, but did not result in elevated plasma LPS levels. DSS-induced translocation provoked LPS elevation only when phagocytic cells were depleted with clodronate liposomes (clodrolip). Macrophages of DSS-treated, HIV-negative mice phagocytosed more LPS ex vivo than those of control mice. In HIV-infected mice, however, LPS phagocytosis was insufficient to clear the translocated LPS. These conditions allowed higher levels of plasma LPS and CD8+ cell activation, which were associated with lower CD4+/CD8+ cell ratios and higher viral loads. LPS levels reflect both intestinal barrier and LPS clearance. Macrophages are essential in controlling systemic bacterial translocation, and this function might be hindered in chronic HIV infection.


Controlled secretion of a protective extracellular matrix is required for transmission of the infective stage of a large number of protozoan and metazoan parasites. Differentiating trophozoites of the highly minimized protozoan parasite Giardia lamblia secrete the proteinaceous portion of the cyst wall material (CWM) consisting of three paralogous cyst wall proteins (CWP1-3) via organelles termed encystation-specific vesicles (ESVs). Phylogenetic and molecular data indicate that Diplomonads have lost a classical Golgi during reductive evolution. However, neogenesis of ESVs in encysting Giardia trophozoites transiently provides basic Golgi functions by accumulating presorted CWM exported from the ER for maturation. Based on this "minimal Golgi" hypothesis we predicted maturation of ESVs to a trans Golgi-like stage, which would manifest as a sorting event before regulated secretion of the CWM. Here we show that proteolytic processing of pro-CWP2 in maturing ESVs coincides with partitioning of CWM into two fractions, which are sorted and secreted sequentially with different kinetics. This novel sorting function leads to rapid assembly of a structurally defined outer cyst wall, followed by slow secretion of the remaining components. Using live cell microscopy we find direct evidence for condensed core formation in maturing ESVs. Core formation suggests that a mechanism controlled by phase transitions of the CWM from fluid to condensed and back likely drives CWM partitioning and makes sorting and sequential secretion possible. Blocking of CWP2 processing by a protease inhibitor leads to mis-sorting of a CWP2 reporter. Nevertheless, partitioning and sequential secretion of two portions of the CWM are unaffected in these cells. Although these cysts have a normal appearance they are not water resistant and therefore not infective. Our findings suggest that sequential assembly is a basic architectural principle of protective wall formation and requires minimal Golgi sorting functions.


Pechlaner M.,University of Zurich
Metal ions in life sciences | Year: 2012

Metal ions are inextricably involved with nucleic acids due to their polyanionic nature. In order to understand the structure and function of RNAs and DNAs, one needs to have detailed pictures on the structural, thermodynamic, and kinetic properties of metal ion interactions with these biomacromolecules. In this review we first compile the physicochemical properties of metal ions found and used in combination with nucleic acids in solution. The main part then describes the various methods developed over the past decades to investigate metal ion binding by nucleic acids in solution. This includes for example hydrolytic and radical cleavage experiments, mutational approaches, as well as kinetic isotope effects. In addition, spectroscopic techniques like EPR, lanthanide(III) luminescence, IR and Raman as well as various NMR methods are summarized. Aside from gaining knowledge about the thermodynamic properties on the metal ion-nucleic acid interactions, especially NMR can be used to extract information on the kinetics of ligand exchange rates of the metal ions applied. The final section deals with the influence of anions, buffers, and the solvent permittivity on the binding equilibria between metal ions and nucleic acids. Little is known on some of these aspects, but it is clear that these three factors have a large influence on the interaction between metal ions and nucleic acids.


To measure the long-term rate of radiographic progression in a cohort of patients treated early vs late with conventional DMARDs. The long-term rate of radiographic progression in patients included in the Swiss clinical quality management in rheumatoid arthritis (SCQM-RA) registry who initiated treatment with conventional DMARDs within the first year of symptom onset (early DMARD) vs patients who initiated treatment 1-5 years after symptom onset (late DMARD). Radiographic progression was assessed in 38 joints using a validated score (Ratingen Score). The rate of progression was calculated using a multivariate regression model for longitudinal data, adjusting for potential confounders. A total of 970 RA patients were included. The 368 patients in the early DMARD group started therapy after a median symptom duration of 6 months, whereas the 602 patients in the late DMARD group initiated therapy after median 2.5 years. RF, MTX use and other risk factors for erosive disease progression were similar between the two groups. However, the estimated rate of radiographic progression at baseline was higher in the early DMARD vs the late DMARD group (1.8 vs 0.6, P < 0.01). In spite of this, the long-term rate of radiographic progression was significantly lower in the early DMARD group after adjustment for confounding factors (-0.35 at 5 years, P = 0.012). This result supports the concept of a therapeutic window of opportunity early in the disease course and suggests that early initiation of DMARD therapy results in a long-lasting reduction of radiographic damage.


Arnold I.C.,University of Zurich
Frontiers in cellular and infection microbiology | Year: 2012

Chronic infection with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to a high risk of developing gastric and duodenal ulcers, gastric cancer, and gastric lymphoma, but has also recently been shown to protect against certain allergic and chronic inflammatory disorders. The immunomodulatory properties that allow the bacteria to persist for decades in infected individuals in the face of a vigorous, yet ultimately non-protective, innate, and adaptive immune response may at the same time confer protection against allergies, asthma, and inflammatory bowel diseases. Experimental evidence from mouse models suggests that H. pylori has evolved to skew the adaptive immune response toward immune tolerance rather than immunity, which promotes persistent infection on the one hand, and inhibits auto-aggressive and allergic T-cell responses on the other. Regulatory T-cells mediating peripheral immune tolerance have emerged as key cellular players in facilitating persistent infection as well as protection from allergies, in both observational studies in humans and experimental work in mice. Recent data suggest that H. pylori actively targets dendritic cells to promote tolerance induction. The findings discussed in this review raise the possibility of harnessing the immunomodulatory properties of H. pylori for the prevention and treatment of allergic and auto-immune diseases, and also provide new insights relevant for H. pylori-specific vaccine development.


Yildirim H.,University of Central Florida | Greber T.,University of Zurich | Kara A.,University of Central Florida
Journal of Physical Chemistry C | Year: 2013

The accurate description of interface characteristics between organic molecules and metal surfaces has long been debated in theoretical studies. A well-founded description of interface geometry and adsorption energy is highly desirable for these hybrid inorganic/organic interfaces. Using first principles calculations with the inclusion of five van der Waals functionals (vdW-DF family), benzene (C6H6) adsorption on seven transition metal surfaces is studied to explore the performance of these vdW functionals under varying surface chemistry. Our results reveal that vdW interactions are crucial for an accurate description of bonding on transition metal substrates. We find that vdW interactions increase adsorption energy on coinage metal surfaces (Au, Ag, Cu) by about 0.7 eV, while they lead to even larger increases in the adsorption energies on the reactive transition metal surfaces (Pd, Pt, Rh, Ni). Our calculations also reveal that changes in adsorption energies stemming from vdW functionals show significant variation, and can be grouped. We find the adsorption energies and heights on the reactive transition metal surfaces obtained using vdW-DF and vdW-DF2 functionals to differ significantly from those of the opt-type functionals, revealing the intrinsic strong repulsion character at short ranges for the former functionals. A simple comparison between experimentally determined adsorption energies (averaged) and those of computed suggests that optPBE and optB88 functionals show systematically good agreement. The information acquired from our analysis on the performance of these functionals can be used as a basis for further refinement of these functionals for the adsorption on metal surfaces with varying chemistry. © 2013 American Chemical Society.


Aims: In patients with atrial fibrillation, a relevant stroke risk (CHA2DS2-VASc score ≥2) and a relative or absolute contraindication for oral anticoagulation, catheter-based LAA occlusion is performed increasingly in Europe. The present article summarises the rationale, clinical data, devices, implantation techniques and follow-up drug regimens. Methods and results: European survey data on patients with atrial fibrillation support the need for non-pharmacological approaches for stroke prevention in patients with atrial fibrillation. A relevant bleeding risk remains with novel oral anticoagulants (NOACs), which are also dependent on drug compliance. Recent long-term data from the PROTECT-AF trial and the CAP registry regarding the WATCHMAN LAA occluder device suggest safety and efficacy. First registry data support the safety of two other CE-marked devices, the AMPLATZER Cardiac Plug (ACP) and the Coherex WaveCrest device, which have become available in Europe. Other LAA occlusion devices are in clinical development. Conclusions: Catheter-based LAA occlusion is now being developed further as an interventional approach for stroke prevention in patients with atrial fibrillation. Implantation techniques and devices are being improved, which will probably result in better procedural safety. Appropriate operator training is of major importance for this approach. © Europa Digital & Publishing 2014. All rights reserved.