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Management and Outcomes of Descending Necrotizing Mediastinitis: A 15-Year Experience
No full textBackground/Objectives : Descending necrotising mediastinitis (DNM) is a severe, life-threatening infection that originates from the oropharyngeal or odontogenic regions and spreads to the mediastinum. It poses significant challenges due to its rapid progression and high morbidity. Methods : This monocentric, retrospective study analysed the records of 22 patients treated for DNM between 2008 and 2022. Diagnosis relied on characteristic clinical, radiological, and intraoperative findings linking oropharyngeal or cervical infections to mediastinitis. Contrast-enhanced computed tomography (CT) was used in all cases for diagnosis. Data collected included demographics, comorbidities, surgical interventions, time from diagnosis to surgery, re-operations, and complications. Microbiological analyses targeted aerobic and anaerobic pathogens. Results : The study included 22 patients (mean age 60 ± 9 years, 59% male) with DNM. The primary sources of infection were oropharyngeal (77%) and odontogenic (23%). Hypertension (86%), diabetes (68%), and cardiac arrhythmias (59%) were common comorbidities. Thoracotomy with mediastinal drainage and debridement was performed in 95% of patients, while 45% underwent cervicotomy and 82% required tracheostomy. The median intensive care unit (ICU) and hospital stays were 21 and 30 days, respectively. Delayed surgery (>24 h) significantly prolonged hospital stays (median: 62 vs. 28 days, p = 0.05). Re-operations were required in 82% of patients, with longer ICU stays observed in this group (median: 25 vs. 7 days, p = 0.003). Sepsis occurred in 55% and was associated with a higher tracheostomy rate (100% vs. 60%, p = 0.029). The mortality rate was 9%. Conclusions : Early recognition and prompt aggressive surgical intervention are paramount in managing DNM to mitigate complications and improve survival.This research received no external funding
Real-world smartphone-based point-of-care diagnostics in primary health care to monitor HbA1c levels in people with diabetes
No full textBackgroundThe lack of accurate and affordable monitoring of glycated hemoglobin (HbA1c) is a common issue among patients with diabetes in low- and middle-income countries. We aimed to test a tablet- and smartphone-based point-of-care (TSB POC) device against a local laboratory-based measure of HbA1c for monitoring diabetes under real-world conditions.MethodsFor this cross-sectional clinical method applicability study, capillary and venous blood was collected in duplicate and analyzed at local primary health care centers. For a heterogeneity test, the tests were performed by an expert, and by a team of local nurses. The study was conducted in a multicenter design in rural and urban Aceh, Indonesia in 2019, and included a total of 533 adults. We mainly used Bland-Altman plots to assess the number of readings within the 95%-limits of agreement (LoA) and Deming regressions.ResultsThe results show a mean difference between capillary HbA1c on the test device and the reference method of −0.54 [CI0.95 = −1.6933; 0.6048] with 5.21% of measurements outside the LoA and a Pearson’s r = 0.91 in the Deming Regression. There is no significant difference in test concordance between local nurses and the expert (4.23% versus 5.13% results outside the LoA [CI0.95 = −0.0331; 0.0511]).ConclusionsTSB POC for analysis of HbA1c is an acceptable alternative for accessible monitoring of diabetes patients under these conditions. This method could provide access to high-quality diagnostic decisions through regular and cost-effective HbA1c monitoring directly in healthcare facilities, thus providing better access to essential health services.Plain language summary People with diabetes in low- and middle-income countries often lack access to reliable and affordable tests to monitor their long-term blood sugar levels, known as HbA1c. This study tested a simple tablet- or smartphone-based device to measure HbA1c directly at primary health centers. The study was conducted in urban and rural areas of Indonesia with 533 participants. The results showed that the device’s measurements were almost identical to laboratory tests. There was hardly any difference in the results, regardless of whether the tests were carried out by experienced experts or by nurses in the field. This method could provide a basis for regular and affordable HbA1c testing to improve diabetes care and access to basic health services for patients in these regions.Rhode et al. investigate the applicability of smartphone-based point-of-care diagnostics for monitoring HbA1c levels of diabetes patients under real-world conditions in a lower-middle income setting. They discover that the method offers an acceptable alternative for accessible monitoring under these conditions
Änderung der Dispersionsparameter von Nanopartikeln zur Strukturkontrolle von sprühgetrockneten Suprapartikeln
No full textSupraparticles, which are assemblies of nano/microparticles (building blocks), offer the possibility of incorporating a diverse range of building blocks to form versatile structures. Supraparticles often reveal collective or synergistic properties, such as enhanced optical, magnetic, or catalytic behaviors. Crucially, their functionalities and potential applications are notably dependent on their structures, making structural control of high interest for accessing desired properties.
Spray-drying is a popular forced-assembly technique to synthesize supraparticles, offering numerous advantages, including chemical versatility, simplicity, rapid operation, continuous processing, scalability, and highly reproducible results. In this thesis, it is demonstrated that supraparticles can be designed via spray-drying to achieve versatile structures by tuning the nanoparticle parameters of the feeding dispersions, including size, weight concentration, size ratio, weight ratio, and colloidal stability.
To systematically explore these parameters, silica (SiO2) nanoparticles are used as model materials in the first three sections of this thesis, due to their easy synthesis of monodisperse dispersions with varied sizes, and the simplicity of its surface (only hydroxyl groups). Section 3.1 demonstrates the simultaneous influence of the nanoparticle size and weight concentration on the final supraparticle structure. Monomodal dispersions were spray-dried to mushroom-cup-like, spherical, and colloidal cluster-like supraparticles and non-connected nanoparticles. Depending on the nanoparticle size, the buckling of supraparticles is increased with decreasing nanoparticle diameter. The supraparticle sizes are increased with an increased particle weight concentration. The bimodal and trimodal dispersions are found to form core-shell, colloidal cluster-like, and well-mixed structures with either spherical or non-spherical morphology, depending on the size combination and concentration. Fragmented particles, resulting from mechanical breakage during the spray-drying process, were characterized to reveal their internal structures. The mechanism behind the formation of distinct structures is proposed: The buckling of supraparticles is a result of the collapse of the flexible shell of small nanoparticles and the size difference of nanoparticles leads to their size segregation within supraparticles because of thermophoretic effects influencing the mobility of nanoparticles.
Based on the findings about the size segregation and mechanical breakage from Section 3.1, Section 3.2 presents a one-step method to achieve platelet-shaped Janus supraparticles. These Janus supraparticles feature two distinct regions with different chemical or physical properties, similar to the concept of Janus particles. To successfully form a Janus structure, the size ratio and weight ratio of the two types of building blocks were optimized, and the device parameters such as cyclone types were adjusted. Crucially, the stability of nanoparticles is found to be essential for forming a core-shell structure, a prerequisite to producing Janus supraparticles. In contrast, the introduction of salt is suboptimal in the formation of Janus supraparticles, as it causes pre-agglomeration of nanoparticles and hinders segregation. Furthermore, this section shows the transferability of this Janus supraparticle fabrication method to a wide range of other metal oxide materials.
In Section 3.3, the influence of the salt addition on the colloidal stability of nanoparticles in bimodal dispersions and the resulting supraparticulate structures is shown. While the use of salts is a well-studied approach to manipulating the colloidal stability of nanoparticles, studies about the influence of salt on the structure formation of supraparticles, especially those formed from bimodal dispersions, remain rare. Section 3.3 demonstrates that the addition of salts can induce nanoparticle instability, leading to the formation of pre-agglomeration, which significantly influences the resulting supraparticulate structures. Different salts such as NaCl, CaCl2, and AlCl3, were introduced to the feeding dispersions before spray-drying. Depending on the cation valency and concentration, the degree of pre-agglomeration can be varied, producing distinct supraparticle structures, including core-shell, Janus-like, and well-mixed types. These variations also lead to corresponding changes in the textural properties, such as surface roughness and pore systems.
Building on the method of adding salt to control the structure of supraparticles, Section 3.4 focuses on the adjustability of a functional property in a structure-controlled supraparticle. Instead of using bare SiO2 nanoparticles as building blocks, superparamagnetic iron oxide nanoparticles (SPIONs) were added to provide magnetic functionality. A structural variety of supraparticles was produced, and the relationship between the SPION cluster distance and magnetic interaction was explored. It is shown that the method of adding salt to alter the supraparticulate structure can be applied not only to tune the structure but also to the magnetic properties of supraparticles. The magnetic interaction is shown to depend on the distance between SPION clusters, as detected by magnetic particle spectroscopy.
This thesis demonstrates that the structure of spray-dried supraparticles can be systematically designed by altering the nanoparticle parameters of the feeding dispersions. These adjustments enable control over the morphology and textural properties of the supraparticles to achieve specific structures. Notably, the one-step method to fabricate platelet-shaped Janus supraparticles and the approach of adding salt to tune the supraparticulate structures are shown to be transferable to other materials beyond SiO2
Interactive Surgical Liver Phantom for Cholecystectomy Training
No full textTraining and prototype development in robotassisted surgery requires appropriate and safe environments for the execution of surgical procedures. Current dry lab laparoscopy phantoms often lack the ability to mimic complex, interactive surgical tasks. This work presents an interactive surgical phantom for the cholecystectomy. The phantom enables the removal of the gallbladder during cholecystectomy by allowing manipulations and cutting interactions with the synthetic tissue. The force-displacement behavior of the gallbladder is modelled based on retraction demonstrations. The force model is compared to the force model of ex-vivo porcine gallbladders and evaluated on its ability to estimate retraction forces
Analyzing tree-growth response, past hydroclimate variability and related geohazard activities in the Western Himalayas using dendroecological and dendrogeomorphological approaches
No full textThe inevitable climate change will have significant long-term impact on the Earth’s natural ecosystem and human civilization over the world. The unprecedented global warming observed since the last century and warming trend predicted by climate models, alarms the future availability of fresh water and other ecosystem services for human livelihood. The Himalayan arc, which hosts diverse ecosystems under different hydroclimatic regimes, is highly susceptible to climate change with a warming rate higher than the global average. The impact of temperature rise in the Himalayan region is evident by the monitored high rates of glacier retreats, tree-line shifts, changes in vegetation composition, phenology, species distribution, and in addition by a significant rise in extreme weather events and related geohazard episodes. The western Himalayan climate exhibits a complex interplay of western disturbances (WDs) and south Asian summer monsoon (SASM) controlling the hydrology, ecosystem and livelihood over the region. Meteorological records show an inverse relationship between WD and SASM circulation intensity, and their connectivity with other climatic circulations operating in the north Atlantic, the tropical Pacific and the Indian Ocean regions. However, the limited geographical coverage of meteorological stations with instrumental data not before the 20th century restricts our understanding of the behaviour of these interconnected climatic circulations beyond the meteorological records. The long-term quantification of these climatic processes is thus needed to extend the present meteorological records for a robust understanding of climate processes on regional to local level, and their impact on biodiversity. Although a number of climate reconstructions are available from the Himalayan region, large knowledge gaps still exist on the annually to intra-annually resolved climate in time and space. Tree-rings are the best archives preserving the evidences of ongoing climatic and non-climatic processes of regional and local scale. This dissertation presents the contribution and interconnection of three independent studies on the tree-growth dynamics, climate reconstructions, and geohazard activity analysis in relation to climate from sites located in different hydroclimatic regimes of the western Himalayas.
The first study in chapter 2 entitled “Tree-ring oxygen isotope variations in subalpine Firs from the Western Himalaya capture spring season temperature signals” focuses on the growth response of Abies spectabilis (Fir) at subalpine altitudes in the SASM dominated region of the western Himalayas. Here, a developed 60 year-long (1960–2019 CE) tree-ring δ18O chronology was found to be strongly sensitive to temperatures, snow-cover, soil-moisture and relative humidity of late winter and spring months (February to April). The spatial correlation with sea surface temperatures (SSTs) and climate indices identified an influence of the North Atlantic Oscillation (NAO) with subdued effects of tropical Pacific circulations. At the subalpine site, the winter snow fed soil-moisture and spring months’ temperature modulates the 18O fractionation in the trees during photosynthesis. Moreover, the “amount effect” of summer precipitation is found to be too weak to override the spring temperature signals at the subalpine altitudes.
Chapter 3 entitled “Himalayan silver fir reveals moist phase during Little Ice Age in the Kashmir region of the western Himalayas” focusses on the region under the influence of winter precipitation by WD circulations. A 461 year-long (1555-2016 CE) tree-ring width chronology (TRWC) of Abies pindrow (silver Fir) covers the time span of Little Ice Age (LIA) climate anomaly. The tree growth-climate relationship revealed a coupled response of temperature and moisture of spring and summer months (April-June) significant for Fir radial growth. The moisture reconstruction using the self-calibrated Palmer drought severity index (scPDSI) for the period 1643-2016 CE was able to identify wet and dry phases corresponding to the respective LIA and post-LIA periods. Further analysis showed the significant impact of the Atlantic Multi-decadal Oscillation (AMO) and NAO with a strong westerly circulation pattern for the wet LIA phase, and a subsequent weakening of WD strength during the 19th and 20th century.
The third study in chapter 4 put forth “Past drought reconstruction and related dendrogeomorphic time-series analysis from Kinnaur region of western Himalayas”. This study site located in the WD and SASM transient region also presents a 463 year-long (1558-2021 CE) Tree ring width chronology of Cedrus deodara (Deodar or Cedar) covering the LIA period. The late winter and spring months (FMA) moisture are important for deodar growth in the region. The 364 years reconstruction of the standardized precipitation evapotranspiration index (SPEI04) revealed a phase of high moisture variability corresponding to the LIA and a subsequent dry post-LIA phase. The climate modes AMO and NAO show a strong influence during the 18th century, whereas El Niño-Southern Oscillation (ENSO) and Pacific Decadal Oscillation (PDO) impacted the study area during the 19th and 20th century. In a pioneer attempt, past geohazard episodes are reconstructed for the Himalayan region using dendrogeomorphological approach. Reconstructed rockfall activities correspond with years of dry spring and summer months.
This PhD dissertation synthesizes the outcomes of studies from three sites discussing on the established tree-ring width and tree-ring δ18O chronologies, tree-growth response, long-term hydroclimatic trend and their driving mechanisms on a regional perspective over the western Himalayas. The studies captured the variability in the tree-growth sensitivity to climate showing influence of geographical position and elevation. Importantly, this endeavor presents two TRWC based hydroclimate reconstruction covering the LIA time frame which is still less understood for its inter- and intra-annual hydroclimate dynamics over the Himalayas. The correlation amongst the reconstructed long-term hydroclimatic trends from two sites reflects the dynamics of WD and SASM circulations at regional and local spatial scale. Moreover, the pioneer attempt of geohazard analysis using tree-rings at one study site has provided insight on the relationship between climate and geohazard activities. The generated datasets will help append the available proxy records and also complements the meteorological stations to fill the spatial climate data gaps in the region. Moreover, the research findings could help managers and decision-makers in sustainable management of forests, land-use, water resources, and towards geohazard risk management and mitigation.Der nachweisliche Prozess des Klimawandels hat in langfristiger Perspektive erhebliche Auswirkungen auf die natürlichen Ökosysteme der Erde und die menschliche Zivilisation. Die seit dem letzten Jahrhundert zu beobachtende beispiellose globale Erwärmung und die von Klimamodellen vorhergesagte Erwärmungstendenz bedrohen die zukünftige Verfügbarkeit von Süßwasser und anderen Ökosystemdienstleistungen. Der Himalaya mit seinen unterschiedlichen hydroklimatischen Verhältnissen und vielfältigen Ökosystemen ist aufgrund der im globalen Vergleich hohen Erwärmungsraten hochgradig gegenüber dem Klimawandel anfällig. Die Auswirkungen des Temperaturanstiegs im Himalaya äußern sich dabei in einem beobachteten, starken Gletscherrückgang, einer Verschiebung der Baumgrenze, an Veränderungen in der Vegetationszusammensetzung, der Phänologie und der Artenverteilung sowie in einer signifikanten Zunahme extremer Wetterereignisse und damit verbundener Naturereignisse.
Das Klima der westlichen Himalaya-Region weist ein komplexes Zusammenspiel von westlichen Störungen (WD) und dem südasiatischen Sommermonsun (SASM) auf, der die Hydrologie, das Ökosystem und die Lebensgrundlagen in der Region kontrolliert. Meteorologische Aufzeichnungen zeigen eine umgekehrte Beziehung zwischen der Zirkulationsintensität der WD und des SASM sowie deren Verbindung mit anderen klimatischen Zirkulationsmustern im Nordatlantik, im tropischen Pazifik und im Indischen Ozean. Die begrenzte Verfügbarkeit von meteorologischen Stationen und dort aufgezeichneter Klimadaten, die zudem nicht vor dem 20. Jahrhundert zur Verfügung stehen, schränkt jedoch das Verständnis für die Konnektionen dieser miteinander verbundenen Klimazirkulationen signifikant ein.
Eine langfristige Quantifizierung von Klimaprozessen ist daher notwendig, um sie mit meteorologischen Aufzeichnungen zu erweitern und dadurch ein solides Verständnis der Klimadynamik auf regionaler bis lokaler Ebene sowie der damit verbundenen Auswirkungen auf die biologische Vielfalt zu erlangen. Obwohl einige Klimarekonstruktionen aus der Himalaya-Region zur Verfügung stehen, gibt es nach wie vor große Wissenslücken bezüglich des jährlichen bis intra-jährlichen Klimas in Zeit und Raum. Jahrringe sind das bestgeeignete Klima-Archiv, das nachweislich Informationen zu aktuellen und vergangenen klimatischen und nichtklimatischen Prozessen auf regionaler und lokaler Ebene beinhalten. Diese Dissertation stellt den Beitrag und die Verbindung dreier unabhängiger Studien über die Dynamik des Baumwachstums, Klimarekonstruktionen und die Analyse von Naturgefahren im Zusammenhang mit der Klimadynamik an Standorten mit unterschiedlichen hydroklimatischen Regimen des westlichen Himalaya vor.
Die erste Studie in Kapitel 2 mit dem Titel „Tree-ring oxygen isotope variations in subalpine Firs from the Western Himalaya capture spring season temperature signals“ konzentriert sich auf die Wachstumsreaktion von Abies spectabilis (Tanne) in subalpinen Höhenlagen in der SASM-dominierten Region des westlichen Himalaya. Es wurde festgestellt, dass eine über 60 Jahre (1960-2019 n. Chr.) lange δ18O-Chronologie von Baumringen stark auf die Temperaturen, die Schneedecke, die Bodenfeuchtigkeit und die relative Luftfeuchtigkeit der späten Winter- und Frühlingsmonate (Februar bis April) reagiert. Die räumliche Korrelation mit den Meeresoberflächentemperaturen (SST) und den Klimaindizes zeigt den Einfluss der Nordatlantischen Oszillation (NAO) mit einer gedämpften Wirkung der tropischen pazifischen Zirkulationen. In den subalpinen Regionen, modulieren die durch Schnee gespeiste Bodenfeuchtigkeit im Winter und die Temperatur in den Frühlingsmonaten die 18O-Fraktionierung in den Bäumen während der Photosynthese. Darüber hinaus wurde festgestellt, dass der „Mengeneffekt“ des Sommerniederschlags zu schwach ist um die Temperatursignale des Frühjahrs in den subalpinen Höhenlagen zu überlagern.
Kapitel 3 mit dem Titel „Himalayan silver fir reveals moist phase during Little Ice Age in the Kashmir region of the western Himalayas“ dar, die sich auf die Region unter dem Einfluss von Winterniederschlägen durch WD-Zirkulationen konzentriert. Eine 461 Jahre lange (1555-2016 n. Chr.) Baumring-Breiten-Chronologie (TRWC) basierend auf Abies pindrow (Weißtanne) deckt die Zeitspanne der Klimaanomalie der Kleinen Eiszeit (LIA) ab. Die Beziehung zwischen Baumwachstum und Klima zeigte eine gekoppelte Reaktion von Temperatur und Feuchtigkeit in den Frühlings- und Sommermonaten (April-Juni), die für das radiale Wachstum der Tanne von Bedeutung ist. Die Feuchtigkeitsrekonstruktion unter Verwendung des selbstkalibrierten Palmer-Dürre-Schwere-Index (scPDSI) für den Zeitraum 1643-2016 n. Chr. konnte feuchte und trockene Phasen identifizieren, die den jeweiligen LIA- und Post-LIA-Zeiträumen entsprechen. Weitere Analysen zeigten, den straken Einfluss der Atlantischen Multidekadischen Oszillation (AMO) und die NAO mit starken WD-Zirkulationen für die feuchte LIA-Phase und eine anschließende Abschwächung der WD-Stärke während des 19. und 20.
Die dritte Studie in Kapitel 4 befasst sich mit der Rekonstruktion der Trockenheit und der damit verbundenen dendrogeomorphen Zeitreihenanalyse in der Region Kinnaur im westlichen Himalaya. An diesem Studienort, der in der gemeinsamen WD- und SASM-Region liegt, wurde eine 463 Jahre (1558-2021 n. Chr.) dauernde Jahrringbreitenchronologie aus Cedrus deodara Bäumen (Deodar-Zeder) generiert, die damit den Zeitraum der LIA abdeckt. Die Feuchtigkeit in den späten Winter- und Frühlingsmonaten (FMA) ist hierbei von hoher Bedeutung für das Wachstum der Deodar-Zeder in der Region. Die 364-jahre umfassende Rekonstruktion mit Hilfe des standardisierten Niederschlags-Evapotranspirations-Index (SPEI04) zeigt ebenfalls eine Phase hoher Feuchtigkeitsvariabilität, die der LIA und einer daran anschließenden trockeneren Klima-Phase entspricht. Im 18. Jahrhundert beeinflussen die Klimamodi AMO und NAO und im 19. und 20 Jahrhundert die El Niño-Southern Oscillation (ENSO) und Pacific Decadal Oscillation (PDO) die Region nachhaltig. In einem Pionierversuch wurden darauf aufbauend vergangene Geohazard-Episoden in der Himalaya-Region mithilfe eines dendrogeomorphologischen Ansatzes rekonstruiert. Die darin rekonstruierten Steinschlagaktivitäten stimmen dabei mit Jahren mit eher trockenen Frühlings- und Sommerbedingungen überein.
Die Dissertation beinhaltet somit zusammenfassend die Ergebnisse von drei thematisch individuellen Studien von drei verschiedenen Regionen im westlichen Himalaya, in denen etablierten Jahrringbreiten und δ18O-Chronologien, die Reaktion des Baumwachstums, der langfristige hydroklimatische Trend und ihre Antriebsmechanismen aus regionaler Sicht erörtert wurden. In den Studien wurde die Variabilität der Empfindlichkeit des Baumwachstums gegenüber dem Klima erfasst, wobei der Einfluss der geografischen Lage und der Höhenlage deutlich wurde. In diesem Projekt werden zwei TRW-basierte Rekonstruktionen des Hydroklimas vorgestellt, die den LIA-Zeitraum abdecken, dessen inter- und intra-annuelle Hydroklimadynamik über dem Himalaya noch wenig verstanden ist. Die Korrelation zwischen den rekonstruierten langfristigen hydroklimatischen Trends von zwei Standorten zeigt die Dynamik der WD- und SASM-Zirkulationen auf regionaler und lokaler räumlicher Ebene. Darüber hinaus hat der Pionierversuch einer Georisikoanalyse mit Hilfe von Baumringen an einem Studienstandort einen Einblick in die Beziehung zwischen Klima und Georisikoaktivitäten gegeben. Die erzeugten Datensätze werden dazu beitragen, die verfügbaren Proxy-Datensätze zu ergänzen und die meteorologischen Stationen zu vervollständigen, um die räumlichen Klimadatenlücken in der Region zu schließen. Darüber hinaus könnten die Forschungsergebnisse den Managern und Entscheidungsträgern bei der nachhaltigen Bewirtschaftung von Wäldern, Landnutzung und Wasserressourcen sowie beim Risikomanagement und der Risikominderung von Georisiken helfen
Mechanismen der Abnahme des L-Typ-Ca2+-Stroms linksventrikulärer Kardiomyozyten der Ratte in Primärkultur
No full textHintergrund und Ziele: Kardiomyozyten in primärer Zellkultur sind ein wesentliches und gut etabliertes Modell für verschiedenste elektrophysiologische und molekularbiologische Untersuchungen zur Erforschung kardialer (Patho-)Physiologie. Im Verlauf der Kultur kommt es zu Veränderungen der Morphologie und elektrophysiologischer Eigenschaften der Kardiomyozyten. Die Mechanismen dieser Veränderungen sind bisher nur unzureichend verstanden. Der L-Typ-Ca2+-Strom spielt eine entscheidende Rolle in der Physiologie der ventrikulären Kontraktion und ist daher untrennbar in die Pathogenese einer Vielzahl von Herzerkrankungen involviert. Seine Regulation erfolgt über ein komplexes Zusammenspiel verschiedener intrazellulärer Signalwege. In dieser Arbeit wurden die Veränderungen des L Typ-Ca2+-Stroms sowie der Zellkapazität als Maß für die Zelloberfläche linksventrikulärer Kardiomyozyten in Primärkultur charakterisiert und auf eine Beteiligung der mTOR- und GR-Signalwege, des Zytoskelettes sowie Veränderungen der Proteinsynthese untersucht.
Methoden: Nach Isolation linksventrikulärer Kardiomyozyten adulter Wistar Ratten wurden die Zellen in Primärkultur überführt und nach 24, 48 und 72 Stunden Inkubation mit entsprechenden Pharmaka bzw. unter Kontrollbedingungen mittels der Patch-Clamp-Technik in der whole-cell Konfiguration untersucht.
Ergebnisse und Beobachtungen: Zunächst konnte gezeigt werden, dass sich unter Kontrollbedingungen im zeitlichen Verlauf der Zellkultur eine signifikante Abnahme des L-Typ-Ca2+-Stroms sowie Veränderungen einiger kinetischer Eigenschaften einstellen. Die Zellkapazität zeigte sich ebenfalls reduziert. In den Inkubationsversuchen konnten diese Veränderungen durch den Proteinsyntheseinhibitor Cycloheximid antagonisiert werden. Dexamethason führte darüber hinaus noch zu einer Zunahme des L-Typ-Ca2+-Stroms über das Niveau frisch isolierter Kardiomyozyten, wobei dieser Effekt durch den GR-Antagonist Mifepriston aufgehoben werden konnte. Unter Inkubation mit Colchicin, einem Tubulindisruptor, zeigte sich eine beschleunigte Abnahme des L-Typ-Ca2+-Stroms sowie der Zellkapazität verglichen zu Kontrollbedingungen. Für den mTOR-Inhibitor Rapamycin zeigte sich kein wesentlicher Effekt.
Schlussfolgerungen und Diskussion: In der vorliegenden Dissertation konnte gezeigt werden, dass die Veränderungen des L-Typ-Ca2+-Stroms in Primärkultur entsprechend der komplexen Regulation des L-Typ-Ca2+-Kanals am ehesten multifaktoriell bedingt sind. Eine wichtige Rolle scheint unter anderem die unter Kulturbedingungen fehlende GR-Stimulation zu spielen. Somit bekräftigen die vorliegenden Ergebnisse die Hypothese, dass der GR-Signalweg nicht nur bei der Entwicklung kardialer Erkrankungen beteiligt, sondern auch für die Aufrechterhaltung der physiologischen kardialen Funktion elementar ist. Zudem scheinen Veränderungen der Proteinsynthese die Grundlage der beobachteten Abnahme des L-Typ-Ca2+-Stroms zu sein, da diese durch Inhibition der Translation mit Cycloheximid gänzlich antagonisiert werden konnten. Da unter Tubulindisruption eine Beschleunigung der unter Kontrollbedingungen beschriebenen elektrophysiologischen Veränderungen festgestellt werden konnte, lässt dies die Vermutung zu, dass Mikrotubuli am intrazellulären Transport und somit der Aufrechterhaltung der L-Typ-Ca2+-Kanal-Dichte beteiligt sind und möglicherweise daher ein progredienter Verlust dieses Systems in mehrtägiger Kultur auftritt. Eine Beteiligung des mTOR-Signalweges konnte nicht sicher objektiviert werden.Objectives: Cardiomyocytes in primary cell culture are an essential and well-established model for a broad variety of electrophysiological and molecular biological studies to investigate cardiac (patho-)physiology. Circumscribed changes in cardiomyocyte morphology and electrophysiological properties are known to occur over time in culture. To this date, the mechanisms of these changes are poorly understood. The L-type Ca2+ current plays a crucial role in the physiology of ventricular contraction and is therefore involved in the pathogenesis of various cardiac diseases. Its regulation occurs through a complex interplay of different intracellular signaling pathways. In this work, the changes in L-type Ca2+ current as well as cell capacity as a marker of cell surface area of left ventricular cardiomyocytes were characterized in primary culture. Incubation experiments were used to investigate the involvement of the mTOR and GR signaling pathways, the cytoskeleton, and changes in protein synthesis.
Design & Methods: After isolation of left ventricular cardiomyocytes from adult Wistar rats, the cells were transferred to primary culture. Incubation with colchicine, rapamycin, cycloheximide, and dexamethasone/dexamethasone & mifepristone or a control solution was performed. Immediately after as well as 24, 48 and 72 hours after isolation, L-type Ca2+ current and cell capacity were examined by patch-clamp technique in whole-cell configuration.
Observations & Results: First, it was shown that under control conditions, there is a significant decrease in L-type Ca2+ current and changes in some kinetic properties over time in cell culture. Cell capacity was also shown to be reduced. In the incubation experiments, these changes could be antagonized by the protein synthesis inhibitor cycloheximide. Dexamethasone further induced an increase in L-type Ca2+ current above the level of freshly isolated cardiomyocytes, although this effect could be abolished by the GR antagonist mifepristone. Incubation with colchicine, a tubulin disruptor, showed an accelerated decrease in L-type Ca2+ current as well as cell capacity compared to control conditions. No significant effect was seen for the mTOR inhibitor rapamycin.
Conclusions: In the present study, we show that the changes in L-type Ca2+ current in primary culture are most likely multifactorial, in accordance with the complex regulation of the L-type Ca2+ channel. Among other factors, the lack of GR stimulation under culture conditions appears to play an important role. Thus, the present results reinforce the hypothesis that the GR signaling pathway is not only involved in the development of cardiac disease but is also elementary for the maintenance of physiological cardiac function. Moreover, changes in protein synthesis appear to be the basis of the observed decrease in L-type Ca2+ current, as these could be antagonized entirely by inhibition of translation with cycloheximide. Since an acceleration of the electrophysiological changes described under control conditions was observed under tubulin disruption, this suggests that microtubules are involved in intracellular transport and thus maintenance of L-type Ca2+ density and possibly a progressive loss of this system occurs in multi-day culture. Involvement of the mTOR signaling pathway could not be objectified with certainty
The Segment Anything foundation model achieves favorable brain tumor auto-segmentation accuracy in MRI to support radiotherapy treatment planning
No full textBackground Promptable foundation auto-segmentation models like Segment Anything (SA, Meta AI, New York, USA) represent a novel class of universal deep learning auto-segmentation models that could be employed for interactive tumor auto-contouring in RT treatment planning. Methods Segment Anything was evaluated in an interactive point-to-mask auto-segmentation task for glioma brain tumor auto-contouring in 16,744 transverse slices from 369 MRI datasets (BraTS 2020 dataset). Up to nine interactive point prompts were automatically placed per slice. Tumor boundaries were auto-segmented on contrast-enhanced T1w sequences. Out of the three auto-contours predicted by SA, accuracy was evaluated for the contour with the highest calculated IoU (Intersection over Union, “oracle mask,” simulating interactive model use with selection of the best tumor contour) and for the tumor contour with the highest model confidence (“suggested mask”). Results Mean best IoU (mbIoU) using the best predicted tumor contour (oracle mask) in full MRI slices was 0.762 (IQR 0.713–0.917). The best 2D mask was achieved after a mean of 6.6 interactive point prompts (IQR 5–9). Segmentation accuracy was significantly better for high- compared to low-grade glioma cases (mbIoU 0.789 vs. 0.668). Accuracy was worse using the suggested mask (0.572). Stacking best tumor segmentations from transverse MRI slices, mean 3D Dice score for tumor auto-contouring was 0.872, which was improved to 0.919 by combining axial, sagittal, and coronal contours. Conclusion The Segment Anything foundation segmentation model can achieve high accuracy for glioma brain tumor segmentation in MRI datasets. The results suggest that foundation segmentation models could facilitate RT treatment planning when properly integrated in a clinical application.Open Access funding enabled and organized by Projekt DEAL.Universitätsklinikum Erlangen (8546
Bayerns Dialekte Online: Ein dynamisches Sprachinformationssystem zu den Dialektwörterbüchern Bayerisches Wörterbuch, Dialektologisches Informationssystem von Bayerisch-Schwaben und Fränkisches Wörterbuch.
Full text linkDie vorliegende Arbeit dokumentiert die Planung und Realisierung der Online-Plattform „Bayerns Dialekte Online“, die die drei großlandschaftlichen Dialektwörterbücher der Bayerischen Akademie der Wissenschaften auch digital unter einem Dach vereint: das Bayerische Wörterbuch, das Dialektologische Informationssystem von Bayerisch-Schwaben und das Fränkische Wörterbuch. Die beiden primären Forschungsfragen, die es zu bearbeiten galt, betreffen die Datenintegration und die Benutzerfreundlichkeit. In Bezug auf erstere Frage wird erläutert, wie die Homogenisierung und die anschließende Integration der heterogenen Datenbestände der drei Wörterbücher durchgeführt werden können und welche Aufwände damit verbunden sind. Zur zweiten Forschungsfrage liefert die Arbeit Auskunft darüber, welche Eigenschaften ein System wie „Bayerns Dialekte Online“ haben muss, um eine hohe Benutzerfreundlichkeit sowohl für die interessierte Öffentlichkeit als auch für die Fachwissenschaft zu gewährleisten. Von besonderer Bedeutung war hierbei, beiden Nutzer:innengruppen einen niedrigschwelligen Zugang zu den Ressourcen zu ermöglichen, ohne dabei die Bedürfnisse der Fachwissenschaft nach granularen Suchoptionen und Visualisierungen zu vernachlässigen. Da der Themenkomplex zur Benutzerfreundlichkeit (Usability) und Nutzerzufriedenheit (User Experience) innerhalb der Domäne der elektronischen Lexikographie bisher wenig Beachtung gefunden hat, wird er detailliert beschrieben. Inwiefern der Ansatz des sogenannten „nutzerorientierten Designs“ zur Durchführung des Projekts zielführend war, wird ebenfalls erläutert. Die Anforderungen an die Online-Plattform, die im Rahmen dieses Ansatzes erhoben wurden, werden ausführlich beschrieben und durch eine umfangreiche Nutzerstudie positiv evaluiert. Die Studie bestätigt zudem das gesamte Konzept zur Umsetzung des Projekts als zielführend. Des Weiteren ergibt sich aus ihr die Erkenntnis, dass wenige direkte, persönlich durchgeführte Nutzungstests und Befragungen qualitativ weitaus höhere Einblicke ermöglichen als indirekte Erhebungen mittels Fragebögen. Als vollständige Dokumentation zur Entstehung von „Bayerns Dialekte Online“ kann die Arbeit darüber hinaus als Leitfaden für ähnliche Vorhaben dienen.This thesis documents the planning and realisation of the online platform “Bayerns Dialekte Online” (Bavaria’s Dialects Online), which digitally unites the three dialect dictionaries of the Bavarian Academy of Sciences and Humanities: the Bavarian Dictionary, the Dialectological Information System of Bavarian Swabia, and the Franconian Dictionary. The two main research questions that had to be addressed concern the topics of data integration and usability. With regard to the first, the thesis explains how the homogenisation and subsequent integration of the heterogeneous databases of the three dictionaries can be carried out, as well as the required effort. For the second research question on usability, the work provides information on which characteristics a system such as “Bayerns Dialekte Online” should have in order to provide a high level of usability for laypeople as well as for scientists. To provide both user groups with simple, low-threshold access to the resources without neglecting the needs of scientists for detailed search options and visualisations was of particular importance in this context. As the issues of usability and user experience have received little attention within the domain of electronic lexicography so far, they will be presented in detail. The success of the so-called “user-centered design” approach in realising the project and the requirements for the platform, which were gathered as part of this approach, are explained in particular. They were positively evaluated by a comprehensive user study, which thus also confirms the effectiveness of the project implementation concept. Furthermore, the study revealed that a few direct, face-to-face user tests and surveys provide far greater insights in terms of quality than indirect surveys using questionnaires. Hence, as a complete documentation of the creation of “Bayerns Dialekte Online”, the work can also serve as a guide for similar projects
Electrostatic All-Passive Force Clamping of Charged Nanoparticles
Full text linkIn the past decades, many techniques have been explored for trapping microscopic and nanoscopic objects, but the investigation of nano-objects under arbitrary forces and conditions remains nontrivial. One fundamental case concerns the motion of a particle under a constant force, known as force clamping . Here, we employ metallic nanoribbons embedded in a glass substrate in a capacitor configuration to generate a constant electric field on a charged nanoparticle in a water-filled glass nanochannel. We estimate the force fields from Brownian trajectories over several micrometers and confirm the constant behavior of the forces both numerically and experimentally. Furthermore, we manipulate the diffusion and relaxation times of the nanoparticles by tuning the charge density on the electrode. Our highly compact and controllable setting allows for the trapping and force-clamping of charged nanoparticles in a solution, providing a platform for investigating nanoscopic diffusion phenomena.Alexander von Humboldt-Stiftung 10.13039/100005156Max-Planck-Gesellschaft 10.13039/501100004189International Max Planck Research School N