Showing papers by "University of Freiburg published in 2007"

Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes

Abstract: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002). Conclusions In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. (ClinicalTrials.gov number, NCT00097591.)

Improved Techniques for Grid Mapping With Rao-Blackwellized Particle Filters

Abstract: Recently, Rao-Blackwellized particle filters (RBPF) have been introduced as an effective means to solve the simultaneous localization and mapping problem. This approach uses a particle filter in which each particle carries an individual map of the environment. Accordingly, a key question is how to reduce the number of particles. In this paper, we present adaptive techniques for reducing this number in a RBPF for learning grid maps. We propose an approach to compute an accurate proposal distribution, taking into account not only the movement of the robot, but also the most recent observation. This drastically decreases the uncertainty about the robot's pose in the prediction step of the filter. Furthermore, we present an approach to selectively carry out resampling operations, which seriously reduces the problem of particle depletion. Experimental results carried out with real mobile robots in large-scale indoor, as well as outdoor, environments illustrate the advantages of our methods over previous approaches

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration.

Abstract: Much medical research is observational. The reporting of observational studies is often of insufficient quality. Poor reporting hampers the assessment of the strengths and weaknesses of a study and the generalizability of its results. Taking into account empirical evidence and theoretical considerations, a group of methodologists, researchers, and editors developed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations to improve the quality of reporting of observational studies. The STROBE Statement consists of a checklist of 22 items, which relate to the title, abstract, introduction, methods, results and discussion sections of articles. Eighteen items are common to cohort studies, case-control studies and cross-sectional studies and four are specific to each of the three study designs. The STROBE Statement provides guidance to authors about how to improve the reporting of observational studies and facilitates critical appraisal and interpretation of studies by reviewers, journal editors and readers.This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the STROBE Statement. The meaning and rationale for each checklist item are presented. For each item, one or several published examples and, where possible, references to relevant empirical studies and methodological literature are provided. Examples of useful flow diagrams are also included. The STROBE Statement, this document, and the associated web site (http://www.strobe-statement.org) should be helpful resources to improve reporting of observational research.

Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks

Abstract: Gamma frequency oscillations are thought to provide a temporal structure for information processing in the brain. They contribute to cognitive functions, such as memory formation and sensory processing, and are disturbed in some psychiatric disorders. Fast-spiking, parvalbumin-expressing, soma-inhibiting interneurons have a key role in the generation of these oscillations. Experimental analysis in the hippocampus and the neocortex reveals that synapses among these interneurons are highly specialized. Computational analysis further suggests that synaptic specialization turns interneuron networks into robust gamma frequency oscillators.

Modelling radiation fluxes in simple and complex environments—application of the RayMan model

Abstract: Short- and long-wave radiation flux densities absorbed by people have a significant influence on their energy balance. The heat effect of the absorbed radiation flux densities is parameterised by the mean radiant temperature. This paper presents the physical basis of the RayMan model, which simulates the short- and long-wave radiation flux densities from the three-dimensional surroundings in simple and complex environments. RayMan has the character of a freely available radiation and human-bioclimate model. The aim of the RayMan model is to calculate radiation flux densities, sunshine duration, shadow spaces and thermo-physiologically relevant assessment indices using only a limited number of meteorological and other input data. A comparison between measured and simulated values for global radiation and mean radiant temperature shows that the simulated data closely resemble measured data.

Microfluidic platforms for lab-on-a-chip applications

Abstract: We review microfluidic platforms that enable the miniaturization, integration and automation of biochemical assays. Nowadays nearly an unmanageable variety of alternative approaches exists that can do this in principle. Here we focus on those kinds of platforms only that allow performance of a set of microfluidic functions—defined as microfluidic unit operations—which can be easily combined within a well defined and consistent fabrication technology to implement application specific biochemical assays in an easy, flexible and ideally monolithically way. The microfluidic platforms discussed in the following are capillary test strips, also known as lateral flow assays, the “microfluidic large scale integration” approach, centrifugal microfluidics, the electrokinetic platform, pressure driven droplet based microfluidics, electrowetting based microfluidics, SAW driven microfluidics and, last but not least, “free scalable non-contact dispensing”. The microfluidic unit operations discussed within those platforms are fluid transport, metering, mixing, switching, incubation, separation, droplet formation, droplet splitting, nL and pL dispensing, and detection.

Acute Exacerbations of Idiopathic Pulmonary Fibrosis

Abstract: The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.

Conserved factors regulate signalling in Arabidopsis thaliana shoot and root stem cell organizers

Abstract: Throughout the lifespan of a plant, which in some cases can last more than one thousand years, the stem cell niches in the root and shoot apical meristems provide cells for the formation of complete root and shoot systems, respectively. Both niches are superficially different and it has remained unclear whether common regulatory mechanisms exist. Here we address whether root and shoot meristems use related factors for stem cell maintenance. In the root niche the quiescent centre cells, surrounded by the stem cells, express the homeobox gene WOX5 (WUSCHEL-RELATED HOMEOBOX 5), a homologue of the WUSCHEL (WUS) gene that non-cell-autonomously maintains stem cells in the shoot meristem. Loss of WOX5 function in the root meristem stem cell niche causes terminal differentiation in distal stem cells and, redundantly with other regulators, also provokes differentiation of the proximal meristem. Conversely, gain of WOX5 function blocks differentiation of distal stem cell descendents that normally differentiate. Importantly, both WOX5 and WUS maintain stem cells in either a root or shoot context. Together, our data indicate that stem cell maintenance signalling in both meristems employs related regulators.

Simulation of networks of spiking neurons: A review of tools and strategies

Abstract: We review different aspects of the simulation of spiking neural networks. We start by reviewing the different types of simulation strategies and algorithms that are currently implemented. We next review the precision of those simulation strategies, in particular in cases where plasticity depends on the exact timing of the spikes. We overview different simulators and simulation environments presently available (restricted to those freely available, open source and documented). For each simulation tool, its advantages and pitfalls are reviewed, with an aim to allow the reader to identify which simulator is appropriate for a given task. Finally, we provide a series of benchmark simulations of different types of networks of spiking neurons, including Hodgkin-Huxley type, integrate-and-fire models, interacting with current-based or conductance-based synapses, using clock-driven or event-driven integration strategies. The same set of models are implemented on the different simulators, and the codes are made available. The ultimate goal of this review is to provide a resource to facilitate identifying the appropriate integration strategy and simulation tool to use for a given modeling problem related to spiking neural networks.

Formation of nanotubes and hollow nanoparticles based on Kirkendall and diffusion processes: a review.

Abstract: The Kirkendall effect is a consequence of the different diffusivities of atoms in a diffusion couple causing a supersaturation of lattice vacancies. This supersaturation may lead to a condensation of extra vacancies in the form of so-called “Kirkendall voids” close to the interface. On the macroscopic and micrometer scale these Kirkendall voids are generally considered as a nuisance because they deteriorate the properties of the interface. In contrast, in the nanoworld the Kirkendall effect has been positively used as a new fabrication route to designed hollow nano-objects. In this Review we summarize and discuss the demonstrated examples of hollow nanoparticles and nanotubes induced by the Kirkendall effect. Merits of this route are compared with other general methods for nanotube fabrication. Theories of the kinetics and thermodynamics are also reviewed and evaluated in terms of their relevance to experiments. Moreover, nanotube fabrication by solid-state reactions and non-Kirkendall type diffusion processes are covered.

Full publication of results initially presented in abstracts

Abstract: BACKGROUND: Abstracts of presentations at scientific meetings are usually available only in conference proceedings If subsequent full publication of abstract results is based on the magnitude or direction of study results, publication bias may result Publication bias, in turn, creates problems for those conducting systematic reviews or relying on the published literature for evidence OBJECTIVES: To determine the rate at which abstract results are subsequently published in full, and the time between meeting presentation and full publication To assess the association between study characteristics and full publication SEARCH STRATEGY: We searched MEDLINE, EMBASE, The Cochrane Library, Science Citation Index, reference lists, and author files Date of most recent search: June 2003 SELECTION CRITERIA: We included all reports that examined the subsequent full publication rate of biomedical results initially presented as abstracts or in summary form Follow-up of abstracts had to be at least two years DATA COLLECTION AND ANALYSIS: Two reviewers extracted data We calculated the weighted mean full publication rate and time to full publication Dichotomous variables were analyzed using relative risk and random effects models We assessed time to publication using Kaplan-Meier survival analyses MAIN RESULTS: Combining data from 79 reports (29,729 abstracts) resulted in a weighted mean full publication rate of 445% (95% confidence interval (CI) 439 to 451) Survival analyses resulted in an estimated publication rate at 9 years of 526% for all studies, 631% for randomized or controlled clinical trials, and 493% for other types of study designs'Positive' results defined as any 'significant' result showed an association with full publication (RR = 130; CI 114 to 147), as did 'positive' results defined as a result favoring the experimental treatment (RR =117; CI 102 to 135), and 'positive' results emanating from randomized or controlled clinical trials (RR = 118, CI 107 to 130)Other factors associated with full publication include oral presentation (RR = 128; CI 109 to 149); acceptance for meeting presentation (RR = 178; CI 150 to 212); randomized trial study design (RR = 124; CI 114 to 136); and basic research (RR = 079; CI 070 to 089) Higher quality of abstracts describing randomized or controlled clinical trials was also associated with full publication (RR = 130, CI 100 to 171) AUTHORS' CONCLUSIONS: Only 63% of results from abstracts describing randomized or controlled clinical trials are published in full 'Positive' results were more frequently published than not 'positive' results

Comparative analysis of the complete genome sequence of the plant growth-promoting bacterium Bacillus amyloliquefaciens FZB42.

Abstract: Bacillus amyloliquefaciens FZB42 is a Gram-positive, plant-associated bacterium, which stimulates plant growth and produces secondary metabolites that suppress soil-borne plant pathogens. Its 3,918-kb genome, containing an estimated 3,693 protein-coding sequences, lacks extended phage insertions, which occur ubiquitously in the closely related Bacillus subtilis 168 genome. The B. amyloliquefaciens FZB42 genome reveals an unexpected potential to produce secondary metabolites, including the polyketides bacillaene and difficidin. More than 8.5% of the genome is devoted to synthesizing antibiotics and siderophores by pathways not involving ribosomes. Besides five gene clusters, known from B. subtilis to mediate nonribosomal synthesis of secondary metabolites, we identified four giant gene clusters absent in B. subtilis 168. The pks2 gene cluster encodes the components to synthesize the macrolactin core skeleton.

ProbLog: a probabilistic prolog and its application in link discovery

Abstract: We introduce ProbLog, a probabilistic extension of Prolog. A ProbLog program defines a distribution over logic programs by specifying for each clause the probability that it belongs to a randomly sampled program, and these probabilities are mutually independent. The semantics of ProbLog is then defined by the success probability of a query, which corresponds to the probability that the query succeeds in a randomly sampled program. The key contribution of this paper is the introduction of an effective solver for computing success probabilities. It essentially combines SLD-resolution with methods for computing the probability of Boolean formulae. Our implementation further employs an approximation algorithm that combines iterative deepening with binary decision diagrams. We report on experiments in the context of discovering links in real biological networks, a demonstration of the practical usefulness of the approach.

y-Randomization and its variants in QSPR/QSAR

Abstract: y-Randomization is a tool used in validation of QSPR/QSAR models, whereby the performance of the original model in data description (r2) is compared to that of models built for permuted (randomly shuffled) response, based on the original descriptor pool and the original model building procedure. We compared y-randomization and several variants thereof, using original response, permuted response, or random number pseudoresponse and original descriptors or random number pseudodescriptors, in the typical setting of multilinear regression (MLR) with descriptor selection. For each combination of number of observations (compounds), number of descriptors in the final model, and number of descriptors in the pool to select from, computer experiments using the same descriptor selection method result in two different mean highest random r2 values. A lower one is produced by y-randomization or a variant likewise based on the original descriptors, while a higher one is obtained from variants that use random number pse...

ACSAR: software model checking with transfinite refinement

Abstract: ACSAR (Automatic Checker of Safety properties based on Abstraction Refinement) is a software model checker for C programs in the spirit of Blast [6], F-Soft [7], Magic [5] and Slam [1]. It is based on the counterexample-guided abstraction refinement (CEGAR) paradigm. Its specificity lies in the way it overcomes a problem common to all tools based on this paradigm. The problem arises from creating more and more spurious counterexamples by unfolding the same (while- or for-) loop over and over again; this leads to an infinite or at least too large sequence of refinement steps. The idea behind ACSAR is to abstract not just states but also the state changes induced by structured program statements, including for- and while-statements. The use of the new abstraction allows one to shortcut such a “transfinite” sequence of refinement steps.

A 3-Hydroxypropionate/4-Hydroxybutyrate Autotrophic Carbon Dioxide Assimilation Pathway in Archaea

Abstract: The assimilation of carbon dioxide (CO2) into organic material is quantitatively the most important biosynthetic process. We discovered that an autotrophic member of the archaeal order Sulfolobales, Metallosphaera sedula, fixed CO2 with acetyl–coenzyme A (acetyl-CoA)/propionyl-CoA carboxylase as the key carboxylating enzyme. In this system, one acetyl-CoA and two bicarbonate molecules were reductively converted via 3-hydroxypropionate to succinyl-CoA. This intermediate was reduced to 4-hydroxybutyrate and converted into two acetyl-CoA molecules via 4-hydroxybutyryl-CoA dehydratase. The key genes of this pathway were found not only in Metallosphaera but also in Sulfolobus, Archaeoglobus, and Cenarchaeum species. Moreover, the Global Ocean Sampling database contains half as many 4-hydroxybutyryl-CoA dehydratase sequences as compared with those found for another key photosynthetic CO2-fixing enzyme, ribulose-1,5-bisphosphate carboxylase-oxygenase. This indicates the importance of this enzyme in global carbon cycling.

The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity

Abstract: Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of transcription factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumourigenesis, we identified transcriptional targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell-cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo, and strongly repressed promotor activities in reporter assays. ZEB1 downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of these cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro. In human colorectal cancer, ZEB1 expression was limited to the tumour-host interface and was accompanied by loss of intercellular adhesion and tumour cell invasion. In invasive ductal and lobular breast cancer, upregulation of ZEB1 was stringently coupled to cancer cell dedifferentiation. Our data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression.

Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression.

Abstract: Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression

SOX9 is required for maintenance of the pancreatic progenitor cell pool

Abstract: The factors necessary to maintain organ-specific progenitor cells are poorly understood and yet of extreme clinical importance. Here, we identify the transcription factor SOX9 as the first specific marker and maintenance factor of multipotential progenitors during pancreas organogenesis. In the developing pancreas, SOX9 expression is restricted to a mitotically active, Notch-responsive subset of PDX1+ pluripotent progenitors and is absent from committed endocrine precursors or differentiated cells. Similar to Notch mutations, organ-specific Sox9 inactivation in mice causes severe pancreatic hypoplasia resulting from depletion of the progenitor cell pool. We show that Sox9 maintains pancreatic progenitors by stimulating their proliferation, survival, and persistence in an undifferentiated state. Our finding that SOX9 regulates the Notch-effector HES1 suggests a Notch-dependent mechanism and establishes a possible genetic link between SOX factors and Notch. These findings will be of major significance for the development of in vitro protocols for cell replacement therapies.

Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C

Abstract: In contrast to a detailed understanding of antiviral cellular immune responses, the impact of neutralizing antibodies for the resolution of acute hepatitis C is poorly defined. The analysis of neutralizing responses has been hampered by the fact that patient cohorts as well as hepatitis C virus (HCV) strains are usually heterogeneous, and that clinical data from acute-phase and long-term follow-up after infection are not readily available. Using an infectious retroviral HCV pseudoparticle model system, we studied a cohort of women accidentally exposed to the same HCV strain of known sequence. In this single-source outbreak of hepatitis C, viral clearance was associated with a rapid induction of neutralizing antibodies in the early phase of infection. Neutralizing antibodies decreased or disappeared after recovery from HCV infection. In contrast, chronic HCV infection was characterized by absent or low-titer neutralizing antibodies in the early phase of infection and the persistence of infection despite the induction of cross-neutralizing antibodies in the late phase of infection. These data suggest that rapid induction of neutralizing antibodies during the early phase of infection may contribute to control of HCV infection. This finding may have important implications for understanding the pathogenesis of HCV infection and for the development of novel preventive and therapeutic antiviral strategies.

ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer

Abstract: Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with non-small cell lung cancer (NSCLC) is of paramount importance. It will guide choices of treatment and determine prognosis and outcome. Over the last years, different techniques have become available. They vary in accuracy and procedure-related morbidity. The Council of the ESTS initiated a workshop on preoperative mediastinal lymph node staging. This resulted in guidelines for primary staging and restaging. For primary staging, mediastinoscopy remains the gold standard for the superior mediastinal lymph nodes. Invasive procedures can be omitted in patients with peripheral tumors and negative mediastinal positron emission tomography (PET) images. However, in case of central tumors, PET hilar N1 disease, low fluorodeoxyglucose uptake of the primary tumor and LNs > or = 16 mm on CT scan, invasive staging remains indicated. PET positive mediastinal findings should always be cyto-histologically confirmed. Transbronchial needle aspiration (TBNA), ultrasound-guided bronchoscopy with fine needle aspiration (EBUS-FNA) and endoscopic esophageal ultrasound-guided fine needle aspiration (EUS-FNA) are new techniques that provide cyto-histological diagnosis and are minimally invasive. Their specificity is high but the negative predictive value is low. Because of this, if they yield negative results, an invasive surgical technique is indicated. However, if fine needle aspiration is positive, this result may be valid as proof for N2 or N3 disease. For restaging, invasive techniques providing cyto-histological information are advisable despite the encouraging results supported with the use of PET/CT imaging. Both endoscopic techniques and surgical procedures are available. If they yield a positive result, non-surgical treatment is indicated in most patients.

Mindfulness Training as an Intervention for Fibromyalgia: Evidence of Postintervention and 3-Year Follow-Up Benefits in Well-Being

Abstract: Background: Mindfulness-based stress reduction (MBSR) proposes a systematic program for reduction of suffering associated with a wide range of medical conditions. Studies suggest improvements in general aspects of well-being, including quality of life (QoL), coping and positive affect, as well as decreased anxiety and depression. Methods: A quasi-experimental study examined effects of an 8-week MBSR intervention among 58 female patients with fibromyalgia (mean, 52 8 8 years) who underwent MBSR or an active social support procedure. Participants were assigned to groups by date of entry, and 6 subjects dropped out during the study. Self-report measures were validated German inventories and included the following scales: visual analog pain, pain perception, coping with pain, a symptom checklist and QoL. Pre- and postintervention measurements were made. Additionally, a 3-year follow-up was carried out on a subgroup of 26 participants. Results: Pre- to postintervention analyses indicated MBSR to provide significantly greater benefits than the control intervention on most dimensions, including visual analog pain, QoL subscales, coping with pain, anxiety, depression and somatic complaints (Cohen d