@phdthesis{Sadek2020, author = {Sadek, Alexander}, title = {Elektrochemisch gest{\"u}tzte Abscheidung kupfer- und zinkdotierter Magnesiumphosphatschichten auf Titan}, doi = {10.25972/OPUS-20916}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209166}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Zur Entwicklung von Implantaten, welche eine komplikations{\"a}rmere Einheilung aufweisen, wurde eine d{\"u}nne, homogene Beschichtung von Titanprobenk{\"o}rpern mit Struvit mithilfe elektrochemischer Abscheidung generiert. Hierbei wurden dem Basiselektrolyt in den Versuchsreihen unterschiedliche Konzentrationen an Kupfer-(II)-nitrat-3-hydrat- und/oder Zinknitrat-6-hydratl{\"o}sung hinzugef{\"u}gt. Die experimentelle Freisetzung erfolgte in drei unterschiedlichen physiologischen N{\"a}hrmedien: simulated body fluid (SBF), fetal calf serum (FCS) und Dulbecco's Modified Eagle Medium (DMEM). Es konnte gezeigt werden, dass eine antibakteriell wirkende Menge an Kupfer- und Zinkionen freigesetzt wurde. Zusammenfassend stellt die elektrochemische Abscheidung von mit Kupfer- und Zink-dotierten Struvit auf Titanoberfl{\"a}chen einen vielversprechenden Ansatz in der Implantologie hinsichtlich der Einheilzeit im Knochen sowie der Risikominimierung des Verlustes dar.}, subject = {Struvit}, language = {de} } @phdthesis{Toeppner2020, author = {T{\"o}ppner, Verena}, title = {Therapie und Outcome von Patienten mit aneurysmatischer Subarachnoidalblutung am Universit{\"a}tsklinikum W{\"u}rzburg}, doi = {10.25972/OPUS-20912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209129}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die aneurysmatische SAB ist trotz etablierter Therapieverfahren (Coiling und Clipping) weiterhin ein Krankheitsbild mit hoher Mortalit{\"a}t. In unserer Arbeit haben wir retrospektiv die Patientenakten der Patienten, die mit der Diagnose aneurysmatische SAB am Universit{\"a}tsklinikum W{\"u}rzburg zwischen dem 01.01.1999 und dem 31.12.2009 aufgenommen wurden, ausgewertet. Es konnte dargestellt werden das als Hauptrisikofaktoren f{\"u}r ein schlechtes Therapieergebnis ein schlechter Aufnahmestatus des Patienten und das Auftreten von Komplikationen im Verlauf verantwortlich sind.}, subject = {Subarachnoidalblutung}, language = {de} } @phdthesis{Mayer2020, author = {Mayer, Lisa}, title = {Detaillierte radio-morphologische Analyse der Sternumanatomie an einem chirurgischen Patientengut}, doi = {10.25972/OPUS-20955}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209557}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Hintergrund: Nach einer Sternotomie m{\"u}ssen die beiden Sternumh{\"a}lften postoperativ wieder suffizient miteinander verbunden werden. Etablierte Sternum-Verschluss-Systeme fangen longitudinale Scherkr{\"a}fte zwischen den beiden Sternumh{\"a}lften nur eingeschr{\"a}nkt ab. F{\"u}r die Entwicklung stabilerer Verschlusssysteme sind zus{\"a}tzliche Informationen {\"u}ber die Sternumanatomie erforderlich. Methode: Single-Center Kohortenanalyse von Patienten, die sich einer Sternotomie f{\"u}r einen elektiven chirurgischen Eingriff unterzogen haben. Datengrundlage waren die pr{\"a}operativ angefertigten CT-Thorax-Aufnahmen sowie der postoperative klinische Verlauf. Mittels definierter Messpunkte wurden L{\"a}nge, W{\"o}lbung, Breite und Dicke des Sternums sowie die Ausdehnung der angrenzenden Rippen und Interkostalr{\"a}ume erfasst. Weitere statistische Untersuchungen umfassten die Suche nach Korrelationen der einzelnen Sternummesswerte untereinander, die {\"U}berpr{\"u}fung m{\"o}glicher Einflussfaktoren auf die Sternumausdehnung (Geschlecht, K{\"o}rpergr{\"o}ße, Alter, COPD-Erkrankung, BMI) sowie das Auftreten einer sternalen Wundheilungsst{\"o}rung. Ergebnis: Von insgesamt 120 Patienten lag eine CT-Bildgebung vor Sternotomie vor. Patienten mit vorbestehenden anatomischen Variationen und von einer longitudinalen medianen Sternotomie abweichendem Zugangsweg wurden ausgeschlossen, sodass 83 Patienten in die Analyse eingingen (51\% weiblich; 73 ± 10 Jahre; 167 ± 9 cm). Aus jedem CT-Datensatz wurden 40 Messpunkte f{\"u}r jedes Sternum erhoben. H{\"o}hergradige Korrelationen der einzelnen Sternumparameter untereinander konnten nicht festgestellt werden. Den gr{\"o}ßten Einflussfaktor auf die Sternumanatomie stellt das Geschlecht dar. K{\"o}rpergr{\"o}ßen-, alters- und gewichtsspezifische Modulationen der Sternumanatomie sowie ein Einfluss durch eine COPD-Erkrankung konnten nicht nachgewiesen werden. 5 Patienten (6\%) entwickelten postoperativ eine oberfl{\"a}chliche oder tiefe Wundheilungsst{\"o}rung. Eine Aussage {\"u}ber Anatomie-bedingte Risikofaktoren f{\"u}r eine postoperative sternale Wundheilungsst{\"o}rung kann aufgrund der kleinen Fallzahl nicht gemacht werden. Schlussfolgerung: Die Gr{\"o}ßenausdehnung des Sternums in allen drei Raumebenen ist sehr individuell ausgepr{\"a}gt. Die anhand der klinischen CT-Bildgebung erarbeitete Datenmatrix ist Grundlage f{\"u}r die Konfektionierung neuer Verschluss-Systeme f{\"u}r den operativen Sternumverschluss.}, subject = {Sternum}, language = {de} } @phdthesis{Emmert2020, author = {Emmert, Adrian Alexander}, title = {The Internal Structure of Periglacial Landforms - Assessments of Subsurface Variations in Permafrost-related and Frost-related Phenomena by Multi-dimensional Geophysical Investigations}, edition = {1. Auflage}, publisher = {W{\"u}rzburg University Press}, address = {W{\"u}rzburg}, isbn = {978-3-95826-138-9}, doi = {10.25972/WUP-978-3-95826-139-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202437}, school = {W{\"u}rzburg University Press}, pages = {xix, 167}, year = {2020}, abstract = {The internal structure of periglacial landforms contains valuable information on past and present environmental conditions. To benefit from this archive, however, an enhanced understanding of subsurface variations is crucial. This enables to assess the influence of the internal structure on prevailing process regimes and to evaluate the sensitivity of different landform units to environmental changes. This thesis investigates structural variations in the subsurface of (i) rock glaciers,(ii) solifluction lobes, (iii) palsas/ lithalsas and (iv) patterned ground, which occur between the different landform types, but also between landform units of the same type. Investigated variables comprise (i) the spatial distribution of permafrost, (ii) ground ice content, (iii) the origin of ground ice, (iv) thickness of the active layer and (v) frost table topography. Multi-dimensional investigations by the geophysical methods Electrical Resistivity Imaging (ERI) and Ground-Penetrating Radar (GPR) were performed in six study areas (a-f): four of them are located in high-alpine environments in Switzerland and two of them are located in the subarctic highlands of Iceland. Additionally, surface and subsurface temperature values were continuously recorded at selected study sites. At one study site, pF-values, representing the matric potential (or water potential), were recorded. From a methodological view, this thesis focuses on the application of quasi-3-D ERI, an approach in which many two-dimensional data sets are combined to create one three-dimensional data set. This permits e.g., a three-dimensional delimitation of subsurface structures and a spatial investigation of the distribution of ground ice. Besides the analysis of field data, this thesis incudes a comparison between inversion models produced with different software products, based on two synthetic data sets. The detection of resistivity structures and reflection patterns provides valuable insights into the internal structure of the investigated landform units: At the high-alpine study site at (a) Piz Nair, a highly variable ice content indicates a complex development of the investigated rock glacier assembly. The local formation of ground ice is attributed to an embedding of surface patches of snow or ice into the subsurface by rockfall. Results of geoelectric monitoring surveys on selected rock glaciers show the influence of seasonal alterations in the internal structure on subsurface meltwater flow. At the study site at (b) Piz {\"U}ertsch, results indicate the occurrences of isolated ground ice patches in a significantly larger rock glacier. Detected characteristics of the internal structure enable to reconstruct the development of the rock glacier, in which a temporary override of an adjacent glacier tongue on the rock glacier is considered crucial for the current distribution of ground ice. However, results of this thesis clearly show the absence of buried glacier ice in the subsurface of the rock glacier. Results from a rock glacier near the (c) Las Trais Fluors mountain ridge affirm the existence of a water-permeable frozen layer, which was assumed in previous studies. Furthermore, results show that the rock glacier contains large amounts of rockfall deposits. A joint interpretation of ERI and GPR results from the investigated scree slope at the mountain (d) Blauberg (Furka Pass) reveals characteristic structures in the subsurface, which enable a differentiation between solifluction lobes and pebbly rock glaciers. At the subarctic study site (e) Orravatnsr{\´u}stir, results show that the internal structure of palsas can be used to deduce their current development stage and to assess past and future developments. Presented results affirm a long history of palsa development at the study site, as assumed in previous studies, but indicate recently changing environmental conditions. The investigated occurrences of patterned ground in the proglacial area of the glacier (f) Hofsj{\"o}kull are currently not influenced by the detected occurrence of permafrost, according to the presented results. Therefore, a temporary formation of pattered ground is assumed, which is linked to the retreat of the glacier. This thesis shows discrepancies between the internal structure of some of the investigated landform units and the recent environmental conditions. This indicates a delayed adaption and a low sensitivity of the landform units to environmental changes. Findings indicate that the future development of permafrost will be strongly affected by variations in snowfall. Furthermore, the detection of isolated occurrences of ground ice at several study sites contradicts the widely assumed effectivity of balancing heat fluxes to create homogenous subsurface conditions in relatively fine-grained subsurface materials.}, subject = {Permafrost}, language = {en} } @phdthesis{Unger2020, author = {Unger, Nina}, title = {Stability of Tryptophan in Parenteral Amino Acid Solutions: Identification of Degradation Products and Development of HPLC Analysis Methods}, doi = {10.25972/OPUS-19982}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199825}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {The stability of Trp in pure solutions and in parenteral AA formulations was evaluated with regard to typically used manufacturing processes, storage conditions and primary packaging. Therefore, thorough stability studies on Trp solutions were conducted beforehand. The applied stressing method, i.e. steam sterilization by autoclave, are chemically seen relatively mild but showed to be efficient to induce Trp degradation in the presence of oxygen. Subsequent identification, separation and characterization were challenging due to similar substance properties, numerous stereoisomers and pairs of diastereomers found amongst them. However, the identified o-aminoacetophenone compounds, Kyn and NFK, are associated with photo reactivity and have photo-oxidizing properties. Thus, best possible protection from UV-light, together with strict oxygen expulsion, are the most important criteria to impede Trp degradation after autoclaving. The identification of Trp degradation products was assisted by the compilation of a substance library, which included manifold reported and chemically plausible Trp degradation substances. The substances were classified for priority and their early or late-stage occurrence. The large number of possible substances and stereoisomers was narrowed down with the information retrieved from LC-UV/MS experiments. However, final identification was achieved by the synthesis of proposed substances as references. The following eight substances were characterized as Trp degradation substances: Kyn, NFK and three pairs of diastereomers R,R/R,S DiOia, R,R/R,S Oia and cis/trans PIC. Fig. 33 shows the proposed degradation pathway and demonstrates the close chemical relationship, which may be an explanation for the conversion of some substances into each other during the storage period. The proposed pathway brings together the results of different Trp stability and stressing studies, respectively [89, 94, 97, 98, 103, 133]. To our knowledge, the simultaneous formation of the identified degradation substances has not been reported before and especially not under the stressing conditions applied. The application of a traditional RP-HPLC method was compared to two developed IP-HPLC methods and a RP-HPLC methods using a modified perfluorinated column. Orthogonal analyses methods and especially the combination of UV and MS detection are necessary in order to indicate potentially undetected degradation substances. Main evaluation criteria were the separation performance, analyses time, reproducibility and feasibility. The best results upon assessment of all Trp degradation products, in both; pure Trp solutions and pharmaceutical formulations, were obtained by a traditional RP-HPLC. The optimized method was validated according to ICH guidelines Q2(R1) and meets the criteria of a stability-indicating HPLC-UV method. The validated method has a sufficient separation performance with an adequate selectivity indicating the Trp degradation substances next to each other and next to other AAs in finished pharmaceutical formulations. The detailed knowledge of Trp degradation and the method presented may be transferred practically to the pharmaceutical industry processing Trp-containing products. In general, the findings might contribute to the quality management of such pharmaceutical products during manufacturing and storage. Additionally, the study results provide basic information for the establishment of an impurity consideration following the ICH guidelines Q3B (R2) (impurities in new drug products) for products containing Trp. However, further development of the method applying more sophisticated detectors or more potent HPLC techniques like e.g. UHPLC and the implication of more sensitive (MS) detectors like ToF-MS would be advantageous with regard to economic and practical aspects.}, subject = {Stabilit{\"a}t}, language = {en} } @phdthesis{Taigel2020, author = {Taigel, Fabian Michael}, title = {Data-driven Operations Management: From Predictive to Prescriptive Analytics}, doi = {10.25972/OPUS-20651}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206514}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Autonomous cars and artificial intelligence that beats humans in Jeopardy or Go are glamorous examples of the so-called Second Machine Age that involves the automation of cognitive tasks [Brynjolfsson and McAfee, 2014]. However, the larger impact in terms of increasing the efficiency of industry and the productivity of society might come from computers that improve or take over business decisions by using large amounts of available data. This impact may even exceed that of the First Machine Age, the industrial revolution that started with James Watt's invention of an efficient steam engine in the late eighteenth century. Indeed, the prevalent phrase that calls data "the new oil" indicates the growing awareness of data's importance. However, many companies, especially those in the manufacturing and traditional service industries, still struggle to increase productivity using the vast amounts of data [for Economic Co-operation and Development, 2018]. One reason for this struggle is that companies stick with a traditional way of using data for decision support in operations management that is not well suited to automated decision-making. In traditional inventory and capacity management, some data - typically just historical demand data - is used to estimate a model that makes predictions about uncertain planning parameters, such as customer demand. The planner then has two tasks: to adjust the prediction with respect to additional information that was not part of the data but still might influence demand and to take the remaining uncertainty into account and determine a safety buffer based on the underage and overage costs. In the best case, the planner determines the safety buffer based on an optimization model that takes the costs and the distribution of historical forecast errors into account; however, these decisions are usually based on a planner's experience and intuition, rather than on solid data analysis. This two-step approach is referred to as separated estimation and optimization (SEO). With SEO, using more data and better models for making the predictions would improve only the first step, which would still improve decisions but would not automize (and, hence, revolutionize) decision-making. Using SEO is like using a stronger horse to pull the plow: one still has to walk behind. The real potential for increasing productivity lies in moving from predictive to prescriptive approaches, that is, from the two-step SEO approach, which uses predictive models in the estimation step, to a prescriptive approach, which integrates the optimization problem with the estimation of a model that then provides a direct functional relationship between the data and the decision. Following Akcay et al. [2011], we refer to this integrated approach as joint estimation-optimization (JEO). JEO approaches prescribe decisions, so they can automate the decision-making process. Just as the steam engine replaced manual work, JEO approaches replace cognitive work. The overarching objective of this dissertation is to analyze, develop, and evaluate new ways for how data can be used in making planning decisions in operations management to unlock the potential for increasing productivity. In doing so, the thesis comprises five self-contained research articles that forge the bridge from predictive to prescriptive approaches. While the first article focuses on how sensitive data like condition data from machinery can be used to make predictions of spare-parts demand, the remaining articles introduce, analyze, and discuss prescriptive approaches to inventory and capacity management. All five articles consider approach that use machine learning and data in innovative ways to improve current approaches to solving inventory or capacity management problems. The articles show that, by moving from predictive to prescriptive approaches, we can improve data-driven operations management in two ways: by making decisions more accurate and by automating decision-making. Thus, this dissertation provides examples of how digitization and the Second Machine Age can change decision-making in companies to increase efficiency and productivity.}, subject = {Maschinelles Lernen}, language = {en} } @phdthesis{Waeldchen2020, author = {W{\"a}ldchen, Felix}, title = {3D Single Molecule Imaging In Whole Cells Enabled By Lattice Light-Sheet Illumination}, doi = {10.25972/OPUS-20711}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207111}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Single molecule localization microscopy has seen a remarkable growth since its first experimental implementations about a decade ago. Despite its technical challenges, it is already widely used in medicine and biology and is valued as a unique tool to gain molecular information with high specificity. However, common illumination techniques do not allow the use of single molecule sensitive super-resolution microscopy techniques such as direct stochastic optical reconstruction microscopy (dSTORM) for whole cell imaging. In addition, they can potentially alter the quantitative information. In this thesis, I combine dSTORM imaging in three dimensions with lattice lightsheet illumination to gain quantitative molecular information from cells unperturbed by the illumination and cover slip effects. Lattice light-sheet illumination uses optical lattices for beam shaping to restrict the illumination to the detectable volume. I describe the theoretical background needed for both techniques and detail the experimental realization of the system as well as the software that I developed to efficiently evaluate the data. Eventually, I will present key datasets that demonstrate the capabilities of the developed microscope system with and without dSTORM. My main goal here was to use these techniques for imaging the neural cell adhesion molecule (NCAM, also known as CD56) in whole cells. NCAM is a plasma membrane receptor known to play a key role in biological processes such as memory and learning. Combining dSTORM and lattice light-sheet illumination enables the collection of quantitative data of the distribution of molecules across the whole plasma membrane, and shows an accumulation of NCAM at cell-cell interfaces. The low phototoxicity of lattice light-sheet illumination further allows for tracking individual NCAM dimers in living cells, showing a significant dependence of its mobility on the actin skeleton of the cell.}, subject = {Einzelmolek{\"u}lmikroskopie}, language = {en} } @phdthesis{Koechel2020, author = {K{\"o}chel, Katrin}, title = {Sekund{\"a}rneoplasien bei Patienten mit prim{\"a}rem Hyperaldosteronismus}, doi = {10.25972/OPUS-20715}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207156}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Der prim{\"a}re Hyperaldosteronismus ist die h{\"a}ufigste Ursache einer sekund{\"a}ren Hypertonie. Ein Aldosteron{\"u}berschuss kann in vitro und in vivo DNA-Sch{\"a}den verursachen. In einzelnen Fallberichten wurde {\"u}ber eine Koinzidenz des prim{\"a}ren Hyperaldosteronismus mit Nierenzellkarzinomen wie auch anderen Tumoren berichtet. Die Pr{\"a}valenz benigner und maligner Neoplasien bei Patienten mit prim{\"a}rem Hyperaldosteronismus wurde bislang jedoch noch nicht untersucht. In der multizentrischen MEPHISTO-Studie wurde die Pr{\"a}valenz von benignen und malignen Tumorerkrankungen bei 338 Patienten mit best{\"a}tigtem prim{\"a}rem Hyperaldosteronismus untersucht. Hypertensive Probanden der populationsbasierten SHIP-Studie dienten als gematchte Kontrollgruppe. Bei 120 (35,5\%) der 338 Patienten mit prim{\"a}rem Hyperaldosteronismus war eine Tumorerkrankung diagnostiziert worden, 30 der Patienten hatten zwei oder mehr Neoplasien. Das Auftreten eines Malignoms wurde bei 9,5\% der Patienten mit prim{\"a}rem Hyperaldosteronismus und bei 6,0\% der hypertensiven Kontrollgruppe dokumentiert (p=0,08). Patienten mit prim{\"a}rem Hyperaldosteronismus und einem Malignom in der Vorgeschichte wiesen bei der Diagnose des prim{\"a}ren Hyperaldosteronismus h{\"o}here Aldosteronspiegel auf (p=0,009). Es konnte zudem ein signifikanter Zusammenhang zwischen der H{\"o}he des Aldosteronspiegels und der Malignompr{\"a}valenz beobachtet werden (p=0,03). Insgesamt wurden unter den Patienten mit prim{\"a}ren Hyperaldosteronismus 158 Neoplasien nachgewiesen, die in 62\% der F{\"a}lle benigne und in 25\% der F{\"a}lle maligne waren (14\% Neoplasien unbekannter Dignit{\"a}t). Ein Nierenzellkarzinom wurde bei 5 Patienten (13\% aller malignen Tumore) diagnostiziert, in der hypertensiven Kontrollgruppe trat kein Nierenzellkarzinom auf. Im Vergleich zur hypertensiven Kontrollgruppe wurde bei Patienten mit prim{\"a}rem Hyperaldosteronismus ein Trend hin zu einer erh{\"o}hten Pr{\"a}valenz von Malignomen beobachtet, der beim Nierenzellkarzinom besonders deutlich ausgepr{\"a}gt und signifikant mit der H{\"o}he des Aldosteronspiegels assoziiert war.}, subject = {Sekund{\"a}rtumor}, language = {de} } @phdthesis{Buchwald2020, author = {Buchwald, Sina}, title = {Autoimmune Enzephalitiden am Universit{\"a}tsklinikum W{\"u}rzburg von 2006-2016}, doi = {10.25972/OPUS-20720}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207202}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {In den Jahren von 2006 bis 2016 sind am Universit{\"a}tsklinikum W{\"u}rzburg insgesamt 26 Patienten mit der Diagnose einer Autoimmunen Enzephalitis behandelt worden. Diese Arbeit zeigt ihre Krankheitsverl{\"a}ufe, Outcome, die gefundenen Antik{\"o}rper und die Therapien der jeweiligen Patienten. Im zweiten Schritt wurden die Daten mit den in der Literatur bereits beschrieben F{\"a}llen verglichen, um Gemeinsamkeiten, aber auch Unterschiede aufzeigen zu k{\"o}nnen.}, subject = {Enzephalitis}, language = {de} } @phdthesis{Vadokas2020, author = {Vadokas, Georg Dimitris}, title = {Experimentelle Subarachnoidalblutung bei Ratten: Methylprednisolon und Minozyklin zur Behandlung der „Early Brain Injury"}, doi = {10.25972/OPUS-20719}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207191}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Fr{\"u}he entz{\"u}ndliche Vorg{\"a}nge scheinen eine große Rolle in der Entstehung der globalen Hirnsch{\"a}digung in der Fr{\"u}hphase nach einer Subarachnoidalblutung (SAB) zu spielen. Ziel der vorliegenden Arbeit war es den Effekt der anti-inflammatorischen Medikamente Methylprednisolon und Minozyklin auf die Gehirndurchblutung und fr{\"u}he Hirnsch{\"a}digung nach SAB zu untersuchen. Hierzu wurde ein randomisiertes und kontrolliertes Tierexperiment durchgef{\"u}hrt. Mit Hilfe des endovaskul{\"a}ren Perforationsmodells wurde bei m{\"a}nnlichen Sprague-Dawley-Ratten eine SAB ausgel{\"o}st. Den Tieren wurde 30 Minuten nach Auftreten der SAB Methylprednisolon, Minozyklin oder Kochsalzl{\"o}sung intraperitoneal verabreicht. Sowohl Methylprednisolon als auch Minozyklin verminderten den Anteil Caspase 3 positiver Zellen in immunhistochemischen F{\"a}rbungen der Hippocampie der Versuchstiere signifikant. In Bezug auf die klinische Untersuchung, den intrakraniellen Druck und die Hirndurchblutung der Ratten ergaben sich keine signifikanten Unterschiede zwischen den Versuchsgruppen. Die Ergebnisse suggerieren, dass Methylprednisolon und Minozyklin den akuten Zellschaden nach SAB reduzieren. Daher k{\"o}nnten sich beide Mittel als geeignet f{\"u}r die Therapie der „Early Brain Injury" nach SAB erweisen. Weitere Studien zum besseren Verst{\"a}ndnis der zugrunde liegenden Wirkmechanismen von Methylprednisolon und Minozyklin auf die Fr{\"u}hphase der SAB sind n{\"o}tig.}, subject = {Subarachnoidalblutung}, language = {de} } @article{GronwaldRogersHoos2020, author = {Gronwald, Thomas and Rogers, Bruce and Hoos, Olaf}, title = {Fractal Correlation Properties of Heart Rate Variability: A New Biomarker for Intensity Distribution in Endurance Exercise and Training Prescription?}, series = {Frontiers in Physiology}, volume = {11}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2020.550572}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212429}, year = {2020}, abstract = {Exercise and training prescription in endurance-type sports has a strong theoretical background with various practical applications based on threshold concepts. Given the challenges and pitfalls of determining individual training zones on the basis of subsystem indicators (e.g., blood lactate concentration, respiratory parameters), the question arises whether there are alternatives for intensity distribution demarcation. Considering that training in a low intensity zone substantially contributes to the performance outcome of endurance athletes and exceeding intensity targets based on a misleading aerobic threshold can lead to negative performance and recovery effects, it would be desirable to find a parameter that could be derived via non-invasive, low cost and commonly available wearable devices. In this regard, analytics conducted from non-linear dynamics of heart rate variability (HRV) have been adapted to gain further insights into the complex cardiovascular regulation during endurance-type exercise. Considering the reciprocal antagonistic behavior and the interaction of the sympathetic and parasympathetic branch of the autonomic nervous system from low to high exercise intensities, it may be promising to use an approach that utilizes information about the regulation quality of the organismic system to determine training-intensity distribution. Detrended fluctuation analysis of HRV and its short-term scaling exponent alpha1 (DFA-alpha1) seems suitable for applied sport-specific settings including exercise from low to high intensities. DFA-alpha1 may be taken as an indicator for exercise prescription and intensity distribution monitoring in endurance-type sports. The present perspective illustrates the potential of DFA-alpha1 for diagnostic and monitoring purposes as a "global" system parameter and proxy for organismic demands.}, language = {en} } @article{StepulaKoenigWangetal.2020, author = {Stepula, Elzbieta and K{\"o}nig, Matthias and Wang, Xin-Ping and Levermann, Janina and Schimming, Tobias and Kasimir-Bauer, Sabine and Schilling, Bastian and Schl{\"u}cker, Sebastian}, title = {Localization of PD-L1 on single cancer cells by iSERS microscopy with Au/Au core/satellite nanoparticles}, series = {Journal of Biophotonics}, volume = {13}, journal = {Journal of Biophotonics}, number = {3}, doi = {10.1002/jbio.201960034}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212655}, year = {2020}, abstract = {Programmed cell death-ligand 1 (PD-L1) is an important predictive biomarker. The detection of PD-L1 can be crucial for patients with advanced cancer where the use of immunotherapy is considered. Here, we demonstrate the use of immuno-SERS microscopy (iSERS) for localizing PD-L1 on single cancer SkBr-3 cells. A central advantage of iSERS is that the disturbing autofluorescence from cells and tissues can be efficiently minimized by red to near-infrared laser excitation. In this study we employed Au/Au core/satellite nanoparticles as SERS nanotags because of their remarkable signal brightness and colloidal stability upon red laser excitation. False-color iSERS images of the positive and negative controls clearly reveal the specific localization of PD-L1 with SERS nanotag-labeled antibodies.}, language = {en} } @article{SchaeferSignoretGenestvonCollenbergetal.2020, author = {Schaefer, Natascha and Signoret-Genest, J{\´e}r{\´e}my and von Collenberg, Cora R. and Wachter, Britta and Deckert, J{\"u}rgen and Tovote, Philip and Blum, Robert and Villmann, Carmen}, title = {Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants}, series = {Frontiers in Molecular Neuroscience}, volume = {13}, journal = {Frontiers in Molecular Neuroscience}, number = {152}, issn = {1662-5099}, doi = {10.3389/fnmol.2020.00152}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-210041}, year = {2020}, abstract = {A GWAS study recently demonstrated single nucleotide polymorphisms (SNPs) in the human GLRB gene of individuals with a prevalence for agoraphobia. GLRB encodes the glycine receptor (GlyRs) β subunit. The identified SNPs are localized within the gene flanking regions (3′ and 5′ UTRs) and intronic regions. It was suggested that these nucleotide polymorphisms modify GlyRs expression and phenotypic behavior in humans contributing to an anxiety phenotype as a mild form of hyperekplexia. Hyperekplexia is a human neuromotor disorder with massive startle phenotypes due to mutations in genes encoding GlyRs subunits. GLRA1 mutations have been more commonly observed than GLRB mutations. If an anxiety phenotype contributes to the hyperekplexia disease pattern has not been investigated yet. Here, we compared two mouse models harboring either a mutation in the murine Glra1 or Glrb gene with regard to anxiety and startle phenotypes. Homozygous spasmodic animals carrying a Glra1 point mutation (alanine 52 to serine) displayed abnormally enhanced startle responses. Moreover, spasmodic mice exhibited significant changes in fear-related behaviors (freezing, rearing and time spent on back) analyzed during the startle paradigm, even in a neutral context. Spastic mice exhibit reduced expression levels of the full-length GlyRs β subunit due to aberrant splicing of the Glrb gene. Heterozygous animals appear normal without an obvious behavioral phenotype and thus might reflect the human situation analyzed in the GWAS study on agoraphobia and startle. In contrast to spasmodic mice, heterozygous spastic animals revealed no startle phenotype in a neutral as well as a conditioning context. Other mechanisms such as a modulatory function of the GlyRs β subunit within glycinergic circuits in neuronal networks important for fear and fear-related behavior may exist. Possibly, in human additional changes in fear and fear-related circuits either due to gene-gene interactions e.g., with GLRA1 genes or epigenetic factors are necessary to create the agoraphobia and in particular the startle phenotype.}, language = {en} } @article{KolokotronisPlutaKlopockietal.2020, author = {Kolokotronis, Konstantinos and Pluta, Natalie and Klopocki, Eva and Kunstmann, Erdmute and Messroghli, Daniel and Maack, Christoph and Tejman-Yarden, Shai and Arad, Michael and Rost, Simone and Gerull, Brenda}, title = {New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis}, series = {Journal of Clinical Medicine}, volume = {9}, journal = {Journal of Clinical Medicine}, number = {7}, doi = {10.3390/jcm9072168}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236094}, year = {2020}, abstract = {Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64\% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69\%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13\% and 5\%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype-genotype correlations, as well as the identification of novel candidate genes.}, language = {en} } @article{ZhouDierksKertelsetal.2020, author = {Zhou, Xiang and Dierks, Alexander and Kertels, Olivia and Samnick, Samuel and Kircher, Malte and Buck, Andreas K. and Haertle, Larissa and Knorz, Sebastian and B{\"o}ckle, David and Scheller, Lukas and Messerschmidt, Janin and Barakat, Mohammad and Truger, Marietta and Haferlach, Claudia and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, K. Martin and Lapa, Constantin}, title = {The link between cytogenetics/genomics and imaging patterns of relapse and progression in patients with relapsed/refractory multiple myeloma: a pilot study utilizing 18F-FDG PET/CT}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {9}, issn = {2072-6694}, doi = {10.3390/cancers12092399}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211157}, year = {2020}, abstract = {Utilizing 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT), we performed this pilot study to evaluate the link between cytogenetic/genomic markers and imaging patterns in relapsed/refractory (RR) multiple myeloma (MM). We retrospectively analyzed data of 24 patients with RRMM who were treated at our institution between November 2018 and February 2020. At the last relapse/progression, patients had been treated with a median of three (range 1-10) lines of therapy. Six (25\%) patients showed FDG avid extramedullary disease without adjacency to bone. We observed significantly higher maximum standardized uptake values (SUV\(_{max}\)) in patients harboring del(17p) compared with those without del(17p) (p = 0.025). Moreover, a high SUV\(_{max}\) of >15 indicated significantly shortened progression-free survival (PFS) (p = 0.01) and overall survival (OS) (p = 0.0002). One female patient exhibited biallelic TP53 alteration, i.e., deletion and mutation, in whom an extremely high SUV\(_{max}\) of 37.88 was observed. In summary, this pilot study suggested a link between del(17p)/TP53 alteration and high SUV\(_{max}\) on 18F-FDG PET/CT in RRMM patients. Further investigations are highly warranted at this point.}, language = {en} } @article{BruneckerMuessigArrowsmithetal.2020, author = {Brunecker, Carina and M{\"u}ssig, Jonas H. and Arrowsmith, Merle and Fantuzzi, Felipe and Stoy, Andreas and B{\"o}hnke, Julian and Hofmann, Alexander and Bertermann, R{\"u}diger and Engels, Bernd and Braunschweig, Holger}, title = {Boranediyl- and Diborane(4)-1,2-diyl-Bridged Platinum A-Frame Complexes}, series = {Chemistry - A European Journal}, volume = {26}, journal = {Chemistry - A European Journal}, number = {39}, doi = {10.1002/chem.202001168}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214707}, pages = {8518 -- 8523}, year = {2020}, abstract = {Diplatinum A-frame complexes with a bridging (di)boron unit in the apex position were synthesized in a single step by the double oxidative addition of dihalo(di)borane precursors at a bis(diphosphine)-bridged Pt\(^{0}\)\(_{2}\) complex. While structurally analogous to well-known μ-borylene complexes, in which delocalized dative three-center-two-electron M-B-M bonding prevails, theoretical investigations into the nature of Pt-B bonding in these A-frame complexes show them to be rare dimetalla(di)boranes displaying two electron-sharing Pt-B σ-bonds. This is experimentally reflected in the low kinetic stability of these compounds, which are prone to loss of the (di)boron bridgehead unit.}, language = {en} } @article{MuessigLisinetskayaDewhurstetal.2020, author = {Muessig, Jonas H. and Lisinetskaya, Polina and Dewhurst, Rian D. and Bertermann, R{\"u}diger and Thaler, Melanie and Mitric, Roland and Braunschweig, Holger}, title = {Dibortetraiodid (B\(_2\)I\(_4\)) ist im Festk{\"o}rper ein Polymer aus sp3-hybridisiertem Bor}, series = {Angewandte Chemie}, volume = {132}, journal = {Angewandte Chemie}, number = {14}, doi = {10.1002/ange.201913590}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219653}, pages = {5574-5579}, year = {2020}, abstract = {Anhand der ersten Festk{\"o}rperstrukturen von Dibortetraiodid (B\(_2\)I\(_4\)) wird gezeigt, dass dieses nicht, wie lange angenommen, analog zu den leichteren Dibortetrahalogeniden B\(_2\)F\(_4\), B\(_2\)Cl\(_4\) und B\(_2\)Br\(_4\) in allen Aggregatzust{\"a}nden in Form diskreter Molek{\"u}le mit planaren, dreifach koordinierten Boratomen vorliegt. R{\"o}ntgenstrukturanalysen, Festk{\"o}rper-NMR- und IR-Messungen zeigen, dass B\(_2\)I\(_4\) im Festk{\"o}rper in zwei polymeren Konformeren vorkommt, die tetraedrisch koordinierte Boratome enthalten. Anhand von DFT-Rechnungen werden die IR-Spektren in L{\"o}sung und im Festk{\"o}rper simuliert und mit den experimentellen Daten verglichen.}, language = {de} } @article{MuessigLisinetskayaDewhurstetal.2020, author = {Muessig, Jonas H. and Lisinetskaya, Polina and Dewhurst, Rian D. and Bertermann, R{\"u}diger and Thaler, Melanie and Mitric, Roland and Braunschweig, Holger}, title = {Tetraiododiborane(4) (B\(_2\)I\(_4\)) is a Polymer based on sp\(^3\) Boron in the Solid State}, series = {Angewandte Chemie International Edition}, volume = {59}, journal = {Angewandte Chemie International Edition}, doi = {10.1002/anie.201913590}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209428}, pages = {5531-5535}, year = {2020}, abstract = {Herein we present the first solid-state structures of tetraiododiborane(4) (B\(_2\)I\(_4\)), which was long believed to exist in all phases as discrete molecules with planar, tricoordinate boron atoms, like the lighter tetrahalodiboranes(4) B\(_2\)F\(_4\), B\(_2\)Cl\(_4\), and B\(_2\)Br\(_4\). Single-crystal X-ray diffraction, solid-state NMR, and IR measurements indicate that B\(_2\)I\(_4\) in fact exists as two different polymeric forms in the solid state, both of which feature boron atoms in tetrahedral environments. DFT calculations are used to simulate the IR spectra of the solution and solid-state structures, and these are compared with the experimental spectra.}, language = {en} } @article{StichPfaffWechetal.2020, author = {Stich, Manuel and Pfaff, Christiane and Wech, Tobias and Slawig, Anne and Ruyters, Gudrun and Dewdney, Andrew and Ringler, Ralf and K{\"o}stler, Herbert}, title = {The temperature dependence of gradient system response characteristics}, series = {Magnetic Resonance in Medicine}, volume = {83}, journal = {Magnetic Resonance in Medicine}, doi = {10.1002/mrm.28013}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206212}, pages = {1519-1527}, year = {2020}, abstract = {Purpose: The gradient system transfer function (GSTF) characterizes the frequency transfer behavior of a dynamic gradient system and can be used to correct non-Cartesian k-space trajectories. This study analyzes the impact of the gradient coil temperature of a 3T scanner on the GSTF. Methods: GSTF self- and B\(_0\)-cross-terms were acquired for a 3T Siemens scanner (Siemens Healthcare, Erlangen, Germany) using a phantom-based measurement technique. The GSTF terms were measured for various temperature states up to 45°C. The gradient coil temperatures were measured continuously utilizing 12 temperature sensors which are integrated by the vendor. Different modeling approaches were applied and compared. Results: The self-terms depend linearly on temperature, whereas the B0-cross-term does not. Effects induced by thermal variation are negligible for the phase response. The self-terms are best represented by a linear model including the three gradient coil sensors that showed the maximum temperature dependence for the three axes. The use of time derivatives of the temperature did not lead to an improvement of the model. The B\(_0\)-cross-terms can be modeled by a convolution model which considers coil-specific heat transportation. Conclusion: The temperature dependency of the GSTF was analyzed for a 3T Siemens scanner. The self- and B0-cross-terms can be modeled using a linear and convolution modeling approach based on the three main temperature sensor elements.}, language = {en} } @article{WeberGlutschGeissingeretal.2020, author = {Weber, J. and Glutsch, V. and Geissinger, E. and Haug, L. and Lock, J.F. and Schneider, F. and Kneitz, H. and Goebeler, M. and Schilling, B. and Gesierich, A.}, title = {Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease}, series = {British Journal of Dermatology}, volume = {183}, journal = {British Journal of Dermatology}, number = {3}, doi = {10.1111/bjd.18739}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213520}, pages = {559-563}, year = {2020}, abstract = {The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti-programmed death-1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long-term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose-optimized ipilimumab (1 mg kg-1) combined with nivolumab (3 mg kg-1), pathological responses were observed in 77\% of patients, while only 20\% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN-neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far.}, language = {en} }