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The geometric arena here is a smooth manifold of dimension n equipped with a Riemannian or pseudo-Riemannian metric and an affine connection. Field theories following from a variational principle are considered on this basis. In this context, all invariants which are quadratic in the curvature are determined. The work derives several manifestly covariant formulas for the Euler-Lagrange derivatives or the field equations. Some of these field theories can be interpreted as gravitational theories alternatively to Einstein´s general relativity theory. The work also touches the difficult problem to define and to calculate energy and momentum of a gravitational field.
Effectiveness of Varenicline as an Aid to Smoking Cessation in Primary Care: An Observational Study
(2012)
Aims: Although varenicline is commonly prescribed in primary care, information on smoking-related comorbidities and the effectiveness of varenicline in this context in Germany is scarce. This study assessed the efficacy and safety of varenicline in a large sample of patients seeking smoking cessation treatment through their general practitioners. The frequency of comorbidities was also evaluated. Methods: This was a 12-week, prospective, observational, non-comparative phase IV trial conducted in Germany. Abstinence rates at week 12 were evaluated by verbal reporting using the nicotine use inventory. Results: Overall, 1,391 subjects were enrolled; 1,177 received study medication and were evaluated for effectiveness and safety. At the end of the study, 71.1% (95% confidence interval 68.5–73.7) of subjects were abstinent. There were a total of 205 all-causality adverse events; 2.2% were classified as serious or severe. There were no fatal adverse events. At inclusion, 66.7% of participants had at least 1 concurrent comorbidity, with chronic obstructive pulmonary disease (35.5%), hypertension (29.6%) and depression (10.4%) being the most commonly reported. Conclusion: These real-world data indicate that varenicline is an effective and well-tolerated smoking cessation treatment when used in the primary care setting including patients with smoking-related comorbidities.
Streptococcus pneumoniae (pneumococci) are Gram-positive cocci and commensals of the human upper respiratory tract. Pneumococcal pathogenesis requires adherence to host cells and dissemination through cellular barriers and to evade host defense mechanisms. The Pneumococcal surface protein C (PspC) is an important virulence factor which has a crucial role in pneumococcal adhesion to host cells and immune evasion by manipulating the host complement system. To elucidate the pneumococcal adherence and uptake mechanism via factor H glycosaminoglycans (dermatan sulfate and heparin) were employed as competitive inhibitors in infection experiments with epithelial cells or human polymorphonuclear leukocytes (PMNs). Glycosaminoglycans significantly inhibited the FH mediated pneumococcal adherence and subsequent invasion to host epithelial cells. Furthermore, the short consensus repeats of FH which promotes the adhesion of pneumococci to host cells were identified by blocking experiments with domain mapped antibodies for specific regions of FH. Moreover, this study indicates that FH acts as adhesion molecule via cellular receptors recognized as integrin CR3 on human PMNs. Binding of Factor H loaded pneumococci to integrins CR3 was assessed by flow cytometry. Pneumococci coated with Factor H showed a significantly increased association with PMNs. This interaction was blocked by anti-CR3 antibodies and Pra1. This project further aims to study mechanisms of pneumococcal endocytosis by host cells, their intracellular fate, and the pathogen induced host cell signal transduction cascades including the calcium signaling upon pneumococcal infection of host cells via the PspC-hpIgR interaction. To assess now the role of protein tyrosine kinases (PTKs) during pneumococcal infection via PspC, cell culture infections were performed in presence of pharmacological inhibitors of PTKs and MAPKs or by employing genetic interference techniques. Blocking the function of Src or ER1/2 and JNK and genetic-knock down of Src and FAK reduced significantly internalization of pneumococci. These data indicated the importance of a coordinated signaling between Src PTKs, ERK1/2, and JNK during PspC-pIgR-mediated uptake of pneumococci by host epithelial cells. The impact of host cells intracellular calcium concentrations on pneumococcal PspC-hpIgR mediated internalization was studied. Intracellular calcium measurement of epithelial cells performed in the presence of pneumococci suggested a calcium influx in host epithelial cells and importantly this calcium influx was PspC- hpIgR specific as pspC-deficient pneumococci were unable to mediate calcium mobilization in host cells. The increase in intracellular calcium [Ca2+]i was dependent on phospholipase C as pretreatment of cells with a phospholipase C-specific inhibitor abolished the increase in [Ca2+]i. Furthermore, role of host intracellular calcium concentrations during pneumococcal internalization was demonstrated by employing specific pharmacological inhibitors and calcium chelators in epithelial cell culture infection assays. The results revealed that elevated host cells calcium concentrations diminished pneumococcal internalization while lower calcium concentration in host epithelial cells promoted pneumococcal uptake. This study further demonstrates that dynamin, clathrin and caveolin play a key role during pneumococcal endocytosis into host cells via PspC-hpIgR. The use of specific pharmacological inhibitors or genetic interference approaches against dynamin, clathrin and caveolin in epithelial cell culture infection assays significantly blocked pneumococcal uptake. Furthermore, confocal microscopy revealed that pneumococci co-localize with clathrin. At later stages of the infection the pathogen is sorted to early, late and recycling endosomes as indicated by co-localization of pneumococci with endosomal markers such as Rab5, Rab4, Rab 7, and Lamp1. In order to get further insights into PspC-hpIgR mediated uptake mechanisms, a chimeric PspC was constructed and expressed heterologously on the surface of Lactococcus lactis. Immunofluorescence staining, immunoblot and flow cytometric analysis of L. lactis confirmed the expression of PspC on the bacterial surface. Moreover the ability of recombinant lactococci expressing PspC to adhere to and to invade pIgR-expressing epithelial cells confirmed the functional activity of PspC when exposed on the lactococcal surface. PspC expressing lactococci confirmed the specificity of PspC-hpIgR mediated endocytosis in host epithelial cells as PspC deficient lactococci were not taken up by these host cells. Confocal microscopic analysis demonstrated that only PspC expressing lactococci were sorted to early, late and recycling endosomes, similar to the intracellular fate of S. pneumoniae.
Abstract
In the 21st century, most of the world’s glaciers are expected to retreat due to further global warming. The range of this predicted retreat varies widely as a result of uncertainties in climate and glacier models. To calibrate and validate glacier models, past records of glacier mass balance are necessary, which often only span several decades. Long-term reconstructions of glacier mass balance could increase the precision of glacier models by providing the required calibration data. Here we show the possibility of applying shrub growth increments as an on-site proxy for glacier summer mass balance, exemplified by Salix shrubs in Finse, Norway. We further discuss the challenges which this method needs to meet and address the high potential of shrub growth increments for reconstructing glacier summer mass balance in remote areas.
Heart Rate Reduction by Ivabradine Improves Aortic Compliance in Apolipoprotein E-Deficient Mice
(2012)
Background: Impaired vascular compliance is associated with cardiovascular mortality. The effects of heart rate on vascular compliance are unclear. Therefore, we characterized effects of heart rate reduction (HRR) by I(f) current inhibition on aortic compliance and underlying molecular mechanisms in apolipoprotein E-deficient (ApoE<sup>–</sup>/<sup>–</sup>) mice. Methods: ApoE<sup>–</sup>/<sup>–</sup> mice fed a high-cholesterol diet and wild-type (WT) mice were treated with ivabradine (20 mg/kg/d) or vehicle for 6 weeks. Compliance of the ascending aorta was evaluated by MRI. Results: Ivabradine reduced heart rate by 113 ± 31 bpm (∼19%) in WT mice and by 133 ± 6 bpm (∼23%) in ApoE<sup>–</sup>/<sup>–</sup> mice. Compared to WT controls, ApoE<sup>–</sup>/<sup>–</sup> mice exhibited reduced distensibility and circumferential strain. HRR by ivabradine increased distensibility and circumferential strain in ApoE<sup>–</sup>/<sup>–</sup> mice but did not affect both parameters in WT mice. Ivabradine reduced aortic protein and mRNA expression of the angiotensin II type 1 (AT1) receptor and reduced rac1-GTPase activity in ApoE<sup>–</sup>/<sup>–</sup> mice. Moreover, membrane translocation of p47<sup>phox</sup> was inhibited. In ApoE<sup>–</sup>/<sup>–</sup> mice, HRR induced anti-inflammatory effects by reduction of aortic mRNA expression of IL-6, TNF-alpha and TGF-beta. Conclusion: HRR by ivabradine improves vascular compliance in ApoE<sup>–</sup>/<sup>–</sup> mice. Contributing mechanisms include downregulation of the AT1 receptor, attenuation of oxidative stress and modulation of inflammatory cytokine expression.
In order to identify possible experimental signatures of the superfluid to Mott-insulator quantum phase transition we calculate the charge structure factor S(k, ω) for the one-dimensional Bose-Hubbard model using the dynamical density-matrix renormalisation group (DDMRG) technique. Particularly we analyse the behaviour of S(k, ω) by varying – at zero temperature–the Coulomb interaction strength within the first Mott lobe. For strong interactions, in the Mott-insulator phase, we demonstrate that the DDMRG results are well reproduced by a strong-coupling expansion, just as the quasi-particle dispersion. In the super-fluid phase we determine the linear excitation spectrum near k = 0. In one dimension, the amplitude mode is absent which mean-field theory suggests for higher dimensions.
Non-thermal atmospheric pressure plasma has recently been shown to have broad application potential for medical as well as industrial purposes. Improved wound healing and tissue decontamination have been described as consequences of non- thermal plasma treatment. However, thus far the underlying molecular mechanisms in human tissues have only been partially characterized. In this work a two-dimensional difference in-gel electrophoresis (2D-DIGE) approach was used and an analysis-workflow to study the response of human cells to atmospheric pressure non-thermal plasma was established. Human S9 bronchial epithelial cells were used as a model for airway epithelial cells. They were treated with atmospheric pressure plasma jet (APPJ) for different periods of time. Subsequently, time-resolved comparative proteome analysis was used to study the complex cellular adaptation reactions after a 120 sec plasma treatment, which accelerated wound healing in a clinically relevant model. The results indicate, that intracellular oxidative stress due to the non-thermal plasma treatment either leads to cell death or to proliferation. The oxidative stress response, mediated by Nrf2, appears to play a pivotal role in molecular signalling and might be a key pathway determining the fate of stressed cells. This thesis demonstrates changes in Nrf2-expression after non-thermal plasma treatment. Furthermore, potential protein biomarker candidates for evaluation of oxidative stress after non-thermal plasma treatment were identified. Finally, it is shown, that the cytosolic concentrations of IL-1beta and IL-33 were decreased following non-thermal plasma treatment. Thus, modulation of innate immune response by non-thermal plasma treatment of epithelial cells (ENTplas treatment) is concluded.
Background: Controversy surrounds the questions whether co-occurring depression has negative effects on cognitivebehavioral therapy (CBT) outcomes in patients with panic disorder (PD) and agoraphobia (AG) and whether treatment for PD and AG (PD/AG) also reduces depressive symptomatology. Methods: Post-hoc analyses of randomized clinical trial data of 369 outpatients with primary PD/AG (DSM-IV-TR criteria) treated with a 12-session manualized CBT (n = 301) and a waitlist control group (n = 68). Patients with comorbid depression (DSM-IV-TR major depression, dysthymia, or both: 43.2% CBT, 42.7% controls) were compared to patients without depression regarding anxiety and depression outcomes (Clinical Global Impression Scale [CGI], Hamilton Anxiety Rating Scale [HAM-A], number of panic attacks, Mobility Inventory [MI], Panic and Agoraphobia Scale, Beck Depression Inventory) at post-treatment and follow-up (categorical). Further, the role of severity of depressive symptoms on anxiety/depression outcome measures was examined (dimensional). Results: Comorbid depression did not have a significant overall effect on anxiety outcomes at post-treatment and follow-up, except for slightly diminished post-treatment effect sizes for clinician-rated CGI (p = 0.03) and HAM-A (p = 0.008) when adjusting for baseline anxiety severity. In the dimensional model, higher baseline depression scores were associated with lower effect sizes at post-treatment (except for MI), but not at follow-up (except for HAM-A). Depressive symptoms improved irrespective of the presence of depression. Conclusions: Exposure-based CBT for primary PD/AG effectively reduces anxiety and depressive symptoms, irrespective of comorbid depression or depressive symptomatology.
The goal of this thesis was to study the systematic relationships within the superfamily Sylvioidea (Aves: Passeriformes) in general and within the closely related families Acrocephalidae and Locustellidae in particular, by means of DNA sequences. Sylvioidea itself and families therein were the focus of many studies based as well on morphological characters as on DNA. Due to their morphological similarity and their presumably rapid radiation most studies failed to solve relationships between sylvioidean families and also demarcations of single families and relations within are still in progress. In this study, an enlargement of previous datasets, both taxa and number of DNA sequences, and more sophisticated analysis methods were used to improve the resolution in Sylvioidea, Acrocephalidae and Locustellidae. In addition, the applicability of barcoding in Acrocephalidae was tested. The monophyly of Sylvioidea could be supported and the families Paridae and Remizidae, which were sometimes still included, clustered among the outgroup taxa. Four families, Nicatoridae, Panuridae, Alaudidae, and Macrosphenidae constitute basal splits within Sylvioidea. The division of the former sylviid/timaliid clade in five families, Sylviidae, Leiothrichidae, Pellorneidae, Timaliidae, and Zosteropidae was supported. Scotocerca, Erythrocercus, and Hylia, previously supposed to be members of Cettiidae, were shown not to belong to this family. As the three genera are also morphologically and ecologically different, they were here proposed to be elevated to family rank, Scotocercidae, Erythrocercidae and Hyliidae, respectively. The family Acrocephalidae consisted of the four genera, Nesillas, Acrocephalus, Hippolais, and Chloropeta. In the analysis for this thesis, the latter three appeared to be non-monophyletic. One Acrocephalus species, A. aedon was sister to a clade containing four species of Hippolais as well as two out of three Chloropeta species. They were all merged in the genus Iduna, based on the DNA evidence and shared morphological and ecological characters. Iduna had priority over Hippolais or Chloropeta according to the International Code of Zoological Nomenclature. The one remaining Chloropeta species (C. gracilirostris) had to be renamed to Calamonastides as Chloropeta was no longer available for this taxon. Seven genera were included in the re-analysis of the family Locustellidae: Locustella, Bradypterus, Megalurus, Dromaeocercus, Schoenicola, Cincloramphus, and Eremiornis. Apart from the monotypic genera Dromaeocercus and Eremiornis and Schoenicola, of which only one species was included, the remaining genera were found to be non-monophyletic. One clade contained all Locustella species, Megalurus pryeri and all Asian/Oriental Bradypterus species. All species in this clade were synonymized with Locustella, as the type species of Locustella was included, whereas the type species of Bradypterus fell in a different clade. Therefore, the remaining African Bradypterus species retained their genus name, and Dromaeocercus was renamed to Bradypterus as it clustered within Bradypterus. Cincloramphus, intermingling with the remaining Megalurus species, was synonymized with the latter. Barcoding, growing in popularity for delimiting species, was tested in its applicability for Acrocephalidae. Fourteen taxa currently recognized as full species would fall under the 2% threshold of sequence divergence proposed for delimiting species using the mitochondrial cytochrome b gene. It was also shown that it is important to clarify which part of a DNA sequence is used, as different parts can give different results regarding the 2% threshold. In addition, the choice of “complete deletion” or “pairwise deletion” in calculating genetic distances is important, if incomplete are sequences used.
The biological decontamination and sterilization is a crucial processing step in producing and reprocessing of medical devices. Since polymer-based materials are increasingly used for the production of medical devices, the application of conventional sterilization processes are restricted to a certain extent. Conventional sterilization techniques on the basis of high temperatures, toxic gases, or ionizing radiation can be detrimental to the functionality and performance of polymeric materials. For this reason, alternative, gentle, and efficient decontamination processes are required. One possible approach is the use of non-thermal physical plasmas. Especially atmospheric pressure plasma is receiving great interest due to the absence of vacuum systems which is highly attractive for the practical applicability. Its mechanisms of action enable the efficient killing and inactivation of micro-organisms which are attributed to the interaction of plasma-generated reactive oxygen and nitrogen species (ROS, RNS) as well as plasma-emitted (V)UV radiation. Owing to the moderate gas temperatures (near or at room temperature) so-called cold plasmas are well-suitable for the treatment of heat-sensitive materials, such as polymers, without affecting their bulk properties. The present work focuses on the investigation of atmospheric pressure plasma processes for the biological decontamination of polymers. The objective is to help elucidate on the one hand the impact of varied plasma process parameters on the inactivation of micro-organisms and on the other hand the influence of plasma on the surface properties of the substrate. The investigations were performed by means of a high-frequency driven plasma jet (from the product line kINPen) operated with argon and argon-oxygen mixtures. Three main aspects were analyzed: 1. The effect of plasma on the viability of micro-organisms dependent on working gas, treatment time, and the sample distance (distance between the jet nozzle and the substrate). 2. The plasma-based removal of microbial biofilms. 3. The effects of the plasma treatment on the surface properties of selected polymers. Additionally to the capability of the applied plasma jet in killing microbes the efficacy of this plasma jet for the removal of complex biological systems (e.g. biofilms) is shown. To model cell constituents of bacteria different synthetic polymers were chosen to gain insight into the decomposition process responsible for biofilm degradation. By investigating the impact of atmospheric pressure plasma on physico-chemical surface properties of various synthetic aliphatic and aromatic polymers the interaction mechanisms between plasma and plasma-exposed material are discussed. These studies are accompanied by applying different optical plasma diagnostic techniques (optical emission spectroscopy and two-photon absorption laser induced fluorescence spectroscopy) to obtain information on the plasma gas phase which contributes to the elucidation of the reaction mechanisms occurring during plasma exposure. Moreover, it is presented to which extent the plasma treatment influences the surface properties of polymers during the plasma-based bio-decontamination process and further, the benefits of surface-functionalized polymers for biomedical application is discussed.