Lahu G.,Nycomed GmbH |
Lahu G.,University of Tu Bingen |
Hnnemeyer A.,Nycomed GmbH |
Diletti E.,Nycomed GmbH |
And 5 more authors.
Clinical Pharmacokinetics | Year: 2010
Background: Roflumilast is an oral, selective phosphodiesterase (PDE)-4 inhibitor in development for the treatment of chronic obstructive pulmonary disease (COPD). Both roflumilast and its metabolite roflumilast N-oxide have anti-inflammatory properties that contribute to overall pharmacological activity. Objectives: To model the pharmacokinetics of roflumilast and roflumilast N-oxide, evaluate the influence of potential covariates, use the total PDE4 inhibitory activity (tPDE4i) concept to estimate the combined inhibition of PDE4 by roflumilast and roflumilastN-oxide, and use individual estimates of tPDE4i to predict the occurrence of adverse events (AEs) in patients with moderate-to-severe COPD. Methods:Wemodelled exposure to roflumilast and roflumilastN-oxide (21 studies provided the index dataset and five separate studies provided the validation dataset), extended the models to COPD (using data from two studies) and assessed the robustness of the parameter estimates. A parametric bootstrap estimation was used to quantify tPDE4i in subpopulations. We established logistic regression models for each AE occurring in >2% of patients in a placebo-controlled trial that achieved a p-value of <0.2 in a permutation test. The exposure variables were the area under the plasma concentration-time curve (AUC) of roflumilast, the AUC of roflumilast N-oxide and tPDE4i. Individual AUC values were estimated from population models. Results: Roflumilast pharmacokinetics were modelled with a two-compartment model with first-order absorption including a lag time. A one-compartment model with zero-order absorption was used for roflumilast N-oxide. The final models displayed good descriptive and predictive performance with no appreciable systematic trends versus time, dose or study. Posterior predictive checks and robustness analysis showed that the models adequately described the pharmacokinetic parameters and the covariate effects on disposition. For roflumilast, the covariates of sex, smoking and race influenced clearance; and food influenced the absorption rate constant and lag time. For roflumilast N-oxide, age, sex and smoking influenced clearance; age, sex and race influenced the fraction metabolized; bodyweight influenced the apparent volume of distribution; and food influenced the apparent duration of formation. The COPD covariate increased the central volume of distribution of roflumilast by 184% and reduced its clearance by 39%; it also reduced the estimated volume of distribution of roflumilast N-oxide by 21% and reduced its clearance by 7.9%. Compared with the reference population (male, non-smoking, White, healthy, 40-year-old subjects), the relative geometric mean [95%CI] tPDE4i was higher in patients withCOPD(12.6%[-6.6, 35.6]), women (19.3%[8.2, 31.6]), Black subjects (42.1% [16.4, 73.4]), Hispanic subjects (28.2% [4.1, 57.9]) and older subjects (e.g. 8.3% [-11.2, 32.2] in 60-year-olds), and was lower in smokers (-19.1% [-34.0,-0.7]). Among all possible subgroups in this analysis, the subgroup with maximal tPDE4i comprised elderly, Black, female, non-smoking, COPD patients (tPDE4i 217% [95% CI 107, 437] compared with the value in the reference population). The probability of a patient with tPDE4i at the population geometric mean [95% CI] was 13.0% [7.5, 18.5] for developing diarrhoea, 6.0% [2.6, 9.4] for nausea and 5.1% [1.9, 8.6] for headache.Conclusions: Covariate effects have a limited impact on tPDE4i. There was a general association between tPDE4i and the occurrence of common AEs in patients with COPD. © 2010 Adis Data Information BV. All rights reserved.
Schleuning M.,University of Mainz |
Schleuning M.,Biodiversity and Climate Research Center |
Bluthgen N.,University of Würzburg |
FloRchinger M.,University of Mainz |
And 5 more authors.
Ecology | Year: 2011
The degree of interdependence and potential for shared coevolutionary history of frugivorous animals and fleshy-fruited plants are contentious topics. Recently, network analyses revealed that mutualistic relationships between fleshy-fruited plants and frugivores are mostly built upon generalized associations. However, little is known about the determinants of network structure, especially from tropical forests where plants' dependence on animal seed dispersal is particularly high. Here, we present an in-depth analysis of specialization and interaction strength in a plant-frugivore network from a Kenyan rain forest. We recorded fruit removal from 33 plant species in different forest strata (canopy, midstory, understory) and habitats (primary and secondary forest) with a standardized sampling design (3447 interactions in 924 observation hours). We classified the 88 frugivore species into guilds according to dietary specialization (14 obligate, 28 partial, 46 opportunistic frugivores) and forest dependence (50 forest species, 38 visitors). Overall, complementary specialization was similar to that in other plant-frugivore networks. However, the plant-frugivore interactions in the canopy stratum were less specialized than in the mid- and understory, whereas primary and secondary forest did not differ. Plant specialization on frugivores decreased with plant height, and obligate and partial frugivores were less specialized than opportunistic frugivores. The overall impact of a frugivore increased with the number of visits and the specialization on specific plants. Moreover, interaction strength of frugivores differed among forest strata. Obligate frugivores foraged in the canopy where fruit resources were abundant, whereas partial and opportunistic frugivores were more common on mid- and understory plants, respectively. We conclude that the vertical stratification of the frugivore community into obligate and opportunistic feeding guilds structures this plant-frugivore network. The canopy stratum comprises stronger links and generalized associations, whereas the lower strata are composed of weaker links and more specialized interactions. Our results suggest that seed-dispersal relationships of plants in lower forest strata are more prone to disruption than those of canopy trees. © 2011 by the Ecological Society of America.
Haak W.,University of Adelaide |
Lazaridis I.,Harvard University |
Lazaridis I.,The Broad Institute of MIT and Harvard |
Patterson N.,The Broad Institute of MIT and Harvard |
And 54 more authors.
Nature | Year: 2015
We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost 400,000 polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of Western and Far Eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ∼8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ∼24,000-year-old Siberian. By ∼6,000-5,000 years ago, farmers throughout much of Europe had more hunter-gatherer ancestry than their predecessors, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but also from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ∼4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ∼75% of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ∼3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for a steppe origin of at least some of the Indo-European languages of Europe. © 2015 Macmillan Publishers Limited. All rights reserved.
Preuss B.,University of Tu bingen |
Berg C.,University of Tübingen |
Dengjel J.,University of Tübingen |
Dengjel J.,Albert Ludwigs University of Freiburg |
And 2 more authors.
Liver International | Year: 2012
Background and Aims: Recently, a non-M2-related mitochondrial 60 kDa protein found to be recognized by antimitochondrial antibody (AMA) negative sera from patients with primary biliary cirrhosis (PBC) has been shown to contain parts of the five F 1-ATPase subunits α, β, γ, δ and ε. In this study, we examined whether this enzyme is, indeed, a target antigen in PBC. Methods: Analysed were 60 AMA-positive/anti-M2-negative and 103 anti-M2-positive PBC patients, 46 patients with autoimmune hepatitis (AIH), 35 patients with primary sclerosing cholangitis (PSC), 110 patients with viral hepatitis, 40 patients with inflammatory bowel diseases (IBD), 33 patients with connective tissue diseases (systemic lupus erythematosus, mixed connective tissue disease, Sjögren disease, systemic sclerosis) and 25 blood donors. The F 1-ATPase-subunits α-δ were recombinantly expressed in Escherichia coli, purified and applied to ELISA and Western blotting. Results: In all, 40 of the 60 AMA-positive/anti-M2-negative (67%) and 44 (43%) of the 103 anti-M2-positive PBC-sera reacted with at least one of the F 1-subunits α-δ. The β- and γ-subunits were preferentially recognized. However, also up to 57% of patients with AIH and 34% of patients with PSC had anti-β- or γ-antibodies, while patients with viral hepatitis had these antibodies in up to 13%. Patients with IBD had anti-β and anti-γ-antibodies in up to 20 and 5% respectively. None of the patients with connective tissue diseases had antibodies to the β- and only 6% to the γ-subunit. Sera from healthy blood donors were negative. Conclusions: Antibodies to the β- and γ-subunits of F 1-ATPase are further AMAs in PBC but occur also in other autoimmune liver disorders; they may be, therefore, indicators for a general autoimmune process of the liver. © 2011 John Wiley & Sons A/S.
Herbert C.,University of Tu bingen |
Herbert C.,University of Wu rzburg |
Kissler J.,Bielefeld University
Neuroscience | Year: 2014
In sentences such as dogs cannot fly/bark, evaluation of the truth-value of the sentence is assumed to appear after the negation has been integrated into the sentence structure. Moreover negation processing and truth-value processing are considered effortful processes, whereas processing of the semantic relatedness of the words within sentences is thought to occur automatically. In the present study, modulation of event-related brain potentials (N400 and late positive potential, LPP) was investigated during an implicit task (silent listening) and active truth-value evaluation to test these theoretical assumptions and determine if truth-value evaluation will be modulated by the way participants processed the negated information implicitly prior to truth-value verification. Participants first listened to negated sentences and then evaluated these sentences for their truth-value in an active evaluation task. During passive listening, the LPP was generally more pronounced for targets in false negative (FN) than true negative (TN) sentences, indicating enhanced attention allocation to semantically-related but false targets. N400 modulation by truth-value (FN. >. TN) was observed in 11 out of 24 participants. However, during active evaluation, processing of semantically-unrelated but true targets (TN) elicited larger N400 and LPP amplitudes as well as a pronounced frontal negativity. This pattern was particularly prominent in those 11 individuals, whose N400 modulation during silent listening indicated that they were more sensitive to violations of the truth-value than to semantic priming effects. The results provide evidence for implicit truth-value processing during silent listening of negated sentences and for task dependence related to inter-individual differences in implicit negation processing. © 2014 IBRO.
Oyanedel C.N.,University of Tu bingen |
Binder S.,University of Lu beck |
Kelemen E.,University of Tu bingen |
Petersen K.,University of Lu beck |
And 3 more authors.
Behavioural Brain Research | Year: 2014
Our previous experiments showed that sleep in rats enhances consolidation of hippocampus dependent episodic-like memory, i.e. the ability to remember an event bound into specific spatio-temporal context. Here we tested the hypothesis that this enhancing effect of sleep is linked to the occurrence of slow oscillatory and spindle activity during slow wave sleep (SWS). Rats were tested on an episodic-like memory task and on three additional tasks covering separately the where (object place recognition), when (temporal memory), and what (novel object recognition) components of episodic memory. In each task, the sample phase (encoding) was followed by an 80-min retention interval that covered either a period of regular morning sleep or sleep deprivation. Memory during retrieval was tested using preferential exploration of novelty vs. familiarity. Consistent with previous findings, the rats which had slept during the retention interval showed significantly stronger episodic-like memory and spatial memory, and a trend of improved temporal memory (although not significant). Object recognition memory was similarly retained across sleep and sleep deprivation retention intervals. Recall of episodic-like memory was associated with increased slow oscillatory activity (0.85-2.0. Hz) during SWS in the retention interval. Spatial memory was associated with increased proportions of SWS. Against our hypothesis, a relationship between spindle activity and episodic-like memory performance was not detected, but spindle activity was associated with object recognition memory. The results provide support for the role of SWS and slow oscillatory activity in consolidating hippocampus-dependent memory, the role of spindles in this process needs to be further examined. © 2014 The Authors.
Fleurie A.,University of Lyon |
Fleurie A.,Fudan University |
Lesterlin C.,University of Oxford |
Manuse S.,University of Lyon |
And 11 more authors.
Nature | Year: 2014
In every living organism, cell division requires accurate identification of the division site and placement of the division machinery. In bacteria, this process is traditionally considered to begin with the polymerization of the highly conserved tubulin-like protein FtsZinto a ringthat locates precisely atmid-cell1.Over thepast decades, several systems have been reported to regulate the spatiotemporal assembly and placement of the FtsZ ring2-5. However, the human pathogen Streptococcus pneumoniae, in common withmany other organisms, is devoid of these canonical systems and the mechanisms of positioning the divisionmachinery remain unknown4,6.Herewe characterize a novel factor that locates at the division site before FtsZ and guides septumpositioning in pneumococcus. Mid-cell-anchored protein Z (MapZ) forms ring structures at the cell equator and moves apart as the cell elongates, therefore behaving as a permanent beacon of division sites.MapZ then positions the FtsZ ring through direct protein-proteininteractions.MapZ-mediated control differs frompreviously described systems mostly on the basis of negative regulation of FtsZ assembly.Furthermore,MapZis an endogenous targetof the Ser/Thr kinase StkP, which was recently shown to have a central role in cytokinesis and morphogenesis of S. pneumoniae7-9.Weshow that both phosphorylated andnon-phosphorylated forms ofMapZare required for proper Z-ring formation and dynamics. Altogether, this work uncovers a newmechanismfor bacterial cell division that is regulated by phosphorylation and illustrates that nature has evolved a diversity of cell division mechanisms adapted to the different bacterial clades. © 2014 Macmillan Publishers Limited.
Fotin-Mleczek M.,CureVac GmbH |
Zanzinger K.,CureVac GmbH |
Heidenreich R.,CureVac GmbH |
Lorenz C.,CureVac GmbH |
And 3 more authors.
Radiation Oncology | Year: 2014
Background: The eradication of large, established tumors by active immunotherapy is a major challenge because of the numerous cancer evasion mechanisms that exist. This study aimed to establish a novel combination therapy consisting of messenger RNA (mRNA)-based cancer vaccines and radiation, which would facilitate the effective treatment of established tumors with aggressive growth kinetics.Methods: The combination of a tumor-specific mRNA-based vaccination with radiation was tested in two syngeneic tumor models, a highly immunogenic E.G7-OVA and a low immunogenic Lewis lung cancer (LLC). The molecular mechanism induced by the combination therapy was evaluated via gene expression arrays as well as flow cytometry analyses of tumor infiltrating cells.Results: In both tumor models we demonstrated that a combination of mRNA-based immunotherapy with radiation results in a strong synergistic anti-tumor effect. This was manifested as either complete tumor eradication or delay in tumor growth. Gene expression analysis of mouse tumors revealed a variety of substantial changes at the tumor site following radiation. Genes associated with antigen presentation, infiltration of immune cells, adhesion, and activation of the innate immune system were upregulated. A combination of radiation and immunotherapy induced significant downregulation of tumor associated factors and upregulation of tumor suppressors. Moreover, combination therapy significantly increased CD4+, CD8+ and NKT cell infiltration of mouse tumors.Conclusion: Our data provide a scientific rationale for combining immunotherapy with radiation and provide a basis for the development of more potent anti-cancer therapies. © 2014 Fotin-Mleczek et al.; licensee BioMed Central Ltd.
Becker E.,University of Tu Bingen |
Karnath H.-O.,University of Tu Bingen
Brain | Year: 2010
Conjugate eye deviation describes the tonic horizontal deviation of the eyes in acute stroke patients. Here we investigate whether measuring patients' eye-in-head position in clinical magnetic resonance imaging or computed tomography scans obtained at admission shows a specific relationship to spatial neglect. We investigated 124 continuously admitted subjects with unilateral, first-ever left-or right-sided stroke. To control for the possibility that the degree of eye deviation is related to lesion size rather than spatial neglect, overall lesion volume was used as a covariate in the statistical analysis. Horizontal eye-in-head deviation on clinical brain scans appeared to be associated with spatial neglect rather than with brain damage per se. In contrast to the subject groups without the disorder, the patients with spatial neglect showed an eye-in-head position that was significantly deviated towards the ipsilesional right. Evaluation of eye-in-head position on clinical scans thus may be an additional helpful tool for diagnosing spatial neglect, particularly in the very early period of the stroke. © The Author 2010.
Nasal high-flow oxygen therapy in patients with hypoxic respiratory failure: Effect on functional and subjective respiratory parameters compared to conventional oxygen therapy and non-invasive ventilation (NIV)
Schwabbauer N.,University of Tu bingen |
Berg B.,University of Tu bingen |
Blumenstock G.,University of Tu bingen |
Haap M.,University of Tu bingen |
And 2 more authors.
BMC Anesthesiology | Year: 2014
Background: Aim of the study was to compare the short-term effects of oxygen therapy via a high-flow nasal cannula (HFNC) on functional and subjective respiratory parameters in patients with acute hypoxic respiratory failure in comparison to non-invasive ventilation (NIV) and standard treatment via a Venturi mask.Methods: Fourteen patients with acute hypoxic respiratory failure were treated with HFNC (FiO2 0.6, gas flow 55 l/min), NIV (FiO2 0.6, PEEP 5 cm H2O Hg, tidal volume 6-8 ml/kg ideal body weight,) and Venturi mask (FiO2 0.6, oxygen flow 15 l/min,) in a randomized order for 30 min each. Data collection included objective respiratory and circulatory parameters as well as a subjective rating of dyspnea and discomfort by the patients on a 10-point scale. In a final interview, all three methods were comparatively evaluated by each patient using a scale from 1 (=very good) to 6 (=failed) and the patients were asked to choose one method for further treatment.Results: PaO2 was highest under NIV (129 ± 38 mmHg) compared to HFNC (101 ± 34 mmHg, p <0.01 vs. NIV) and VM (85 ± 21 mmHg, p <0.001 vs. NIV, p <0.01 vs. HFNC, ANOVA). All other functional parameters showed no relevant differences. In contrast, dyspnea was significantly better using a HFNC (2.9 ± 2.1, 10-point Borg scale) compared to NIV (5.0 ± 3.3, p <0.05), whereas dyspnea rating under HFNC and VM (3.3 ± 2.3) was not significantly different. A similar pattern was found when patients rated their overall discomfort on the 10 point scale: HFNC 2.7 ± 1.8, VM 3.1 ± 2.8 (ns vs. HFNC), NIV 5.4 ± 3.1 (p <0.05 vs. HFNC). In the final evaluation patients gave the best ratings to HFNC 2.3 ± 1.4, followed by VM 3.2 ± 1.7 (ns vs. HFNC) and NIV 4.5 ± 1.7 (p <0.01 vs. HFNC and p <0.05 vs. VM). For further treatment 10 patients chose HFNC, three VM and one NIV.Conclusions: In hypoxic respiratory failure HFNC offers a good balance between oxygenation and comfort compared to NIV and Venturi mask and seems to be well tolerated by patients.Trial registration: German clinical trials register: DRKS00005132. © 2014 Schwabbauer et al.; licensee BioMed Central Ltd.