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Funktionsfähigkeit, Behinderung, Gesundheit und Lebenszufriedenheit von Überlebenden nach Herzkreislaufstillstand und Hypoxisch-Ischämischer Enzephalopathie
Get PDFBackground: The incidence of hypoxic-ischemic encephalopathy (HIE) after cardiac arrest (CA) is increasing. The long-term course of disability, as well as subjective and psychosocial aspects whose understanding is necessary for the establishing of a patient-centered medicine, remains insufficiently researched.
The aim of the present thesis is to describe the levels of functioning, disability, health and life satisfaction of survivors of HIE after CA one year after onset, and to identify factors associated with each.
Methods: Participants: 57 patients (and 39 caregivers) were surveyed one year after onset. Variables of interest: mortality, level of consciousness, sociodemographic and treatment- related factors, global clinical outcome, functional status, functioning and disability, life satisfaction and psychosocial outcome. Instruments: International Classification of Functioning, Disability and Health (ICF), Questionnaire on Life Satisfaction (german: Fragebogen zur Lebenszufriedenheit – Module; FLZ-M) on 33 patients and their dependants. Analysis: Patient ICF data were clustered into three groups based on severity/extent of disability in the domains: body function, body structure, activity and participation and environmental factors. Life satisfaction (LS) data were dichotomized in “satisfied” and “dissatisfied”. These ICF and LS categories were fed into a correlation matrix that included sociodemographic, treatment- and outcome-related variables.
Results: ICF Data: 42.3% (body function) and 29.8% (body structure) of CA survivors could be classified as severely bodily disabled, whereas 47.4% showed capacity and 51% performance impairments related to activity and participation in daily life. LS Data: High life satisfaction was reported by 78.8% of 33 contactable survivors. Significantly associated with high life satisfaction were good functioning, satisfaction with health status and satisfaction with medical care at follow-up. 45% of patients with moderate and severe body function disabilities were nevertheless satisfied with their lives, and 33% of survivors with moderate and severe impairments in their capacity to participate and perform activities of daily living were satisfied with their lives. Compared to dissatisfied survivors, disabled/impaired survivors satisfied with life were significantly more likely to have children as well as better basal motor functions but were paradoxically more likely to show indications of diminished emotional functions.
Conclusion: The results of the present study show that when survivors of CA/HIE regain consciousness, they suffer varying degrees of long-term body function disabilities and impairments in activities of daily living. Furthermore, present data also suggest that, although as expected higher LS levels tend to be significantly associated with lower levels of such disabilities and impairments, there was a group of severely disabled/impaired patients who were nevertheless satisfied with their lives. It could be argued that the “satisfaction paradox” and the “post-traumatic growth theory” could provide a possible theoretical framework for this phenomenon but at present, their explanatory reach seems to be only partial at best. In sum, our findings underline that strengthening the general health status and individual psychosocial resources can lead in most cases to measurable levels of high LS.Hintergrund: Die Inzidenz der Hypoxisch-Ischämischen Enzephalopathie (HIE) durch Herzkreislaufstillstände (HKS) steigt. Der Langzeitverlauf resultierender Behinderungen sowie subjektive und psychosoziale Faktoren, deren Verständnis für die Etablierung einer patientenorientierten Medizin notwendig sind, wurden bislang wenig untersucht.
Ziel der Arbeit ist es, die Grade von Funktionsfähigkeit, Behinderung und Gesundheit sowie die Lebenszufriedenheit von Überlebenden nach HKS und HIE ein Jahr nach dem Ereignis zu beschreiben, und die jeweils mit ihnen im Zusammenhang stehenden Faktoren zu identifizieren.
Methoden: Teilnehmer: 57 Überlebende (und 39 Angehörige) ein Jahr nach HKS und HIE. Untersuchte Variablen: Mortalität, Bewusstseinsniveau, soziodemographische und behandlungsbezogene Faktoren, globales klinisches Outcome, Funktionsstatus, Funktionsfähigkeit und Behinderung, Lebenszufriedenheit und psychosoziales Outcome. Instrumente: International Classification of Functioning, Disability and Health (ICF), Fragebogen zur Lebenszufriedenheit – Module (FLZ-M). Auswertung: mit den ICF-Daten wurde eine Clusterung der Patienten in drei Gruppen je nach Ausmaß/Schweregrad der Behinderung durchgeführt für die vier Komponenten: Körperfunktionen, Körperstrukturen, Aktivitäten und Partizipation und Umweltfaktoren. Die Daten zur Lebenszufriedenheit (LZ) wurden dichotomisiert in „zufrieden“ und „unzufrieden“. Die ICF- und LZ-Kategorien wurden Unabhängigkeitstests unterzogen, welche soziodemographische, behandlungs- und Outcome- bezogene Variablen beinhaltete.
Ergebnisse: ICF-Daten: 42,3% (Körperfunktionen) und 29,8% (Körperstrukturen) Überlebende nach HKS und HIE wurden als schwer körperlich behindert eingestuft, 47,4% zeigten Beeinträchtigungen der Leistungsfähigkeit und 51% der Leistung bei Aktivitäten und Partizipation im täglichen Leben.
LZ-Daten: Eine hohe LZ wurde bei 78,8% von 33 kontaktierbaren Überlebenden beschrieben. Mit einer hohen LZ waren eine gute Funktionsfähigkeit, die Zufriedenheit mit dem Gesundheitszustand und mit der medizinischen Versorgung zum Follow-Up-Zeitpunkt assoziiert. 45% der Patienten mit moderaten und schweren Behinderungen der Körperfunktionen waren trotzdem zufrieden mit ihrem Leben, sowie 33% derer mit moderaten und schweren Beeinträchtigungen von Aktivitäten und Partizipation. Im Vergleich zu unzufriedenen Patienten mit starken Behinderungen hatten die zufriedenen signifikant öfter Kinder, bessere Funktionen der basalen Bewegungsfähigkeit, aber paradoxerweise eher geminderte emotionale Funktionen.
Fazit: Die Ergebnisse der vorliegenden Arbeit zeigen, dass Überlebende nach HKS und HIE unterschiedlich stark unter Schädigungen von Körperfunktionen und Einschränkungen der Alltagsaktivitäten leiden, wenn sie das Bewusstsein wiedererlangen. Die LZ der vorliegenden Stichprobe war, wie zu erwarten, signifikant besser, je weniger Behinderungen vorhanden waren. Weshalb ein beachtlicher Teil der Patienten trotz Behinderungen eine gute LZ angab, kann nur teilweise erklärt werden und sollte Gegenstand weiterer Forschung bleiben, etwa vor dem Hintergrund des „Zufriedenheitsparadox“ und des „post-traumatic growth“. Unsere Ergebnisse unterstreichen, dass Patienten nach HKS und HIE eine besondere Aufmerksamkeit hinsichtlich der Stärkung ihrer Funktionsfähigkeit und ihres Gesundheitszustandes sowie individueller psychosozialer Ressourcen zukommen muss, um eine größtmögliche LZ zu fördern
Epigenetische Reprogrammierung von Pankreaskarzinomzellen zur Aufhebung der molekularen Heterogenität
Get PDFDas duktale Adenokarzinom des Pankreas ist durch begrenzte Therapiemöglichkeiten und eine hohe Letalität gekennzeichnet. Genexpressionsanalysen konnten molekulare Tumorsubtypen identifizieren, welche unterschiedlich auf vorhandene Behandlungsoptionen reagieren. Der genetische Mutationsstatus der Subtypen ist dabei sehr ähnlich, weshalb epigenetische Mechanismen eine entscheidende Rolle bei der Ausprägung von Tumorzellcharakteristika spielen könnten. Ziel der Arbeit war es, ein epigenetisches Profil der molekularen Subtypen des duktalen Pankreaskarzinoms zu erstellen. Zudem wurden epigenetische Therapiemöglichkeiten untersucht, welche eine Reprogrammierung der Tumorzellen zugunsten eines therapiesensibleren Phänotyps erreichen könnten. Zunächst konnte nachgewiesen werden, dass sowohl für den klassischen als auch den quasimesenchymalen Subtyp spezifische Gene epigenetisch reguliert werden. Darüber hinaus zeigte sich, dass die subtypenklassifizierenden Gene mit bestimmten Acetylierungsmustern an den Transkriptionsstartpunkten korrelieren und Gene des quasimesenchymalen Subtyps mehr von Histonacetylierungen bestimmt sind als Gene des klassischen Subtyps. Passend dazu ergab die Analyse epigenetischer Enzyme, welche für die vielfältigen Modulierungen an DNA- und Chromatinstrukturen verantwortlich sind, ein ähnliches Genexpressionsmuster innerhalb der Tumorsubtypen. Zugleich ließ sich der klassische Subtyp vom quasimesenchymalen Subtyp anhand des epigenetischen Profils unterscheiden. Die Ergebnisse legen nahe, dass epigenetische Mechanismen Einfluss auf die Tumorzellcharakteristika der Subtypen des duktalen Pankreaskarzinoms nehmen. Weiter galt es daher zu überprüfen, ob durch eine Behandlung mit epigenetischen Wirkstoffen eine Veränderung der Tumorzellcharakteristika erreicht werden kann. Zunächst konnte vor allem nach der Behandlung mit Vorinostat und PRT4165 ein Einfluss auf das Überleben der Tumorzellen nachgewiesen werden. Das Ansprechen der Tumorzellen ausgewählter Zelllinien korrelierte dabei mit den molekularen Subtypen des duktalen Pankreaskarzinoms. In der anschließenden Expressionsanalyse verschiedener Histonmodifikationen konnte nach epigenetischer Behandlung bei den Inhibitoren Vorinostat und GSK126 eine gute Wirksamkeit beobachtet werden. In Hinblick auf die epigenetischen Wirkstoffe PRT4165 und LSD1-Inhibitor konnte keine entsprechende Änderung der Histonmodifikationen aufgezeigt werden. Auch eine abschließende Expressionsanalyse subtypendefinierender Gene ergab nach epigenetischer Behandlung keine Änderung des Genexpressionsprofils zugunsten verbesserter Tumorzellcharakteristika. Trotz der begrenzt positiven Ergebnisse hinsichtlich der epigenetischen Monotherapie mit ausgewählten Wirkstoffen sollte weiter auf den vielversprechenden Fortschritten der letzten Jahre im Bereich der Epigenetik und epigenetischer Behandlungsmöglichkeiten zur Umprogrammierung von Tumorzellen aufgebaut werden
Astrophysics of galaxy clusters and groups with eROSITA
Get PDFThis thesis investigates non-gravitational astrophysical phenomena shaping the physical properties of galaxy clusters and groups. The impact of these processes is constrained by measuring the physical properties of galaxy clusters and groups using X-ray observations of eROSITA. The constraints are contextualized by comparing the eROSITA measurements with the predictions of the simple spherical collapse scenario and the predictions of cosmological hydrodynamical simulations. The results presented in this thesis provide a broad view of the population properties of galaxy clusters and groups and serve as a benchmark for unraveling the non-gravitational mechanisms governing cosmic structures.
In this thesis, we first focus on the X-ray scaling relations of galaxy clusters and groups. We calibrate seven X-ray scaling relations, accounting for selection effects and the halo mass function, using eROSITA observations of 265 galaxy clusters and groups detected in the eFEDS field. The sample is obtained by applying selection procedures that are reproducible in eROSITA simulations such that the resulting sample has a well-defined selection function. A Bayesian framework is employed to fit the relations, incorporating a custom selection function and a canonical halo mass function to account for selection effects and the mass distribution of halos. Our results show significant deviations from the self-similar model, aligning well with simulations that include prescriptions for non-gravitational mechanisms and recent studies considering selection effects. Our findings suggest that non-gravitational processes significantly influence the physical state of clusters and groups. Our study extends scaling relations to low-mass, low-luminosity parameter space using eFEDS observations. It demonstrates eROSITA's capability to measure intracluster/intragroup medium emission out to r500c with survey-depth exposures and constrain scaling relations across a broad mass-luminosity-redshift range.
Second, we focus on the effects of AGN feedback on the entropy and characteristic temperature of galaxy groups detected in SRG/eROSITA's first All-Sky Survey (eRASS1). We analyze eRASS:4 observations of 1178 galaxy groups from the eRASS1 galaxy clusters and groups catalog. We divide the sample into 271 subsamples based on the physical and statistical properties of the groups and jointly analyze their X-ray observations following a Bayesian approach. Through this procedure, we extract average thermodynamic properties, including electron number density, temperature, and entropy, at three characteristic radii (from cores to outskirts) as well as the average integrated temperature within r500c for the 271 group bins. We achieve the tightest constraints with unparalleled statistical precision on the impact of AGN feedback by measuring the average entropy and characteristic temperature of the largest group sample used in X-ray studies. We also quantify the impact of various systematics on our measurements and include their impact to their total error budget. We find that entropy increases with temperature following a power-law relation at higher intra-group medium (IGrM) temperatures, while a slight flattening is observed in cooler (T<1.44 keV) IGrM temperatures. We compare our results with cosmological hydrodynamic simulations (MillenniumTNG, Magneticum, OWL), and find that our entropy measurements at the core lie below the predictions of simulations. At mid-region and outskirts, we find that our measurements align well with the predictions of the Magneticum simulations. Our measurements will facilitate more accurate AGN feedback implementations in numerical simulations. Future eROSITA surveys will extend entropy measurements to even cooler IGrM temperatures, enabling the testing of AGN feedback implementations in this parameter space.
Lastly, in this thesis, we explore the thermodynamic property profiles of eROSITA-selected galaxy groups. Previous studies suggest significant differences between the profiles of thermodynamic properties of groups and clusters due to groups having shallower potential wells and, therefore, being more sensitive to non-gravitational processes. In our study, we measure the density, temperature, entropy, and pressure profiles of 1178 galaxy groups using eROSITA observations. The sample used in this study is identical to the one employed in our second study and, therefore, has a well-defined selection function. We obtain tight constraints on the average scaled thermodynamic profiles of X-ray bright groups by normalizing thermodynamic profiles with the self-similar model predictions. Comparing scaled profiles with previous cluster and group measurements, we find that the scaled density profiles of groups are significantly below the scaled density profiles of clusters. Our finding confirms previous studies suggesting groups to be baryon depleted within r500c. We also find that the scaled entropy profiles of groups are considerably higher than clusters at all radii, highlighting AGN's more significant impact on the IGrM compared to the ICM. We compare our measurements with predictions of the non-radiative hydrodynamical simulations, which serve as baselines, and found that the non-gravitational processes decrease groups' scaled density and pressure profiles while increasing the scaled entropy and temperature profiles. Furthermore, we apply our selection function to simulations (Magneticum, MillenniumTNG) that include different AGN feedback models and compare our results with their predictions. We find that Magneticum reproduces our measurements the best at the intermediate radii and outskirts, while our measurements at the core agree better with MillenniumTNG. We further find that our entropy measurements lie below the predictions of simulation at the core and above their prediction at the outskirts, suggesting the excess entropy introduced by the central AGN at the core cannot be efficiently carried to larger radii in the current AGN feedback implementations
Final liberation
Get PDFThis thesis investigates the specific context in which vāsanās cause bījas to manifest from the ālayavijñāna. The Indian Yogācāra school employs the concepts of bījas and vāsanās to elucidate the process of conceptualization in the mundane world, the continuity of rebirth in the repetitive behavioural circle (saṃsāra), and the potential for obtaining final liberation (nirvāṇa).
In the Yogācāra school, bīja refers to the latent potency within one’s mental continuum, whereas vāsanā represents a dynamic force generated by karman or manifested dharma. The works attributed to Sthiramati reveal a diminishing emphasis on bīja while increasing the prominence of vāsanā. Although both bīja and vāsanā are considered defilements, the latter exerts a stronger influence on subsequent mental moments. Accordingly, the Mahāyānasaṃgraha (MSg) introduces the concept of the “vāsanā of hearing [Buddhist teachings]” as a mechanism for transmitting the Buddha’s teachings to ordinary beings, thereby facilitating the path to liberation.
The Yogācāra school employs bījas and vāsanās to elucidate not only conceptualization and rebirth but also the attainment of liberation, thereby structuring the mental continuum across past, present, and future. By articulating the relationship between ālayavijñāna, bījas, and vāsanās, Yogācāra establishes its soteriology: vāsanā serves as the link between the mundane and supramundane realms, while bīja functions as the underlying cause of liberation
Plasmacytoid dendritic cells contribute to the spatio-temporal distribution of megakaryocytes in the bone marrow
Get PDFMegakaryopoiesis describes the maturation from haematopoietic stem cells (HSCs) to megakaryocytes (MKs). Megakaryocytes are large and scarce cells in the bone marrow which produce platelets. The production of platelets is achieved by fragmentation of the MK cytoplasm, which ultimately leads to MK apoptosis. Multiple studies have studied megakaryopoiesis, all trying to elucidate responsible factors for the differentiation and maturation of HSCs. This works aims to investigate the role of plasmacytoid dendritic cells (pDCs) in the regulation of megakaryopoiesis.
Cell quantification of pDCs, megakaryocytes and megakaryocyte progenitors (MKPs) in the bone marrow was performed by confocal microscopy and fluorescence-activated cell sorting (FACS). Confocal microscopy was also used to characterize the cell-to-cell interactions between pDCs and MKs or MKPs, as well as the spatial distribution of these cells in the bone marrow.
We observed a high number of pDC-MK interactions in the bone marrow of untreated mice. Next, pDCs were ablated in genetically modified mice, pDC-DTR, using the diphtheria toxin. Here, the number of MKs and MKPs significantly decreased after 3 days of pDC depletion. In addition, the recruitment of MKs and MKPs towards the vasculature – which is necessary for platelet production – was impaired and the remaining population of MKs showed an increased ploidy, suggesting that they were older than the MKs in steady state. Together, these results indicate that pDCs may influence the maturation and migration of MKs and MKPs towards the vascular niche.
We hypothesize that pDCs can sense the apoptotic MKs at the end of their plateletproducing life and induce MKP proliferation in order to replace the dying MKs. Since pDCs are the major producer of interferon α (IFNα), treatment with IFNα was used to investigate its possible role in the signaling between pDCs and MKPs. In our experiment, this treatment showed no effect on the number and the distribution of MKs and MKPs in our experiment. However, due to the limitations os our setup, the role of IFNα in megakaryopoiesis remains to be clarified
Klinische und genetische Analysen von rezidivierten akuten Leukämien nach allogener Stammzelltransplantation
Get PDFSimulation of critical biomechanical loads on the lumbar spine in crash situations for automated driving
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Neuronal and behavioral mechanisms of pro-environmental behavior
Get PDFPro-environmental decisions, which involve balancing personal benefits with environmental considerations, are ubiquitous in our daily lives. While systemic, organizational, and technological structures are crucial for mitigating climate change, these efforts ultimately require changing individual behavior (Ray, Franz, Jarrett, & Pickett, 2021; Schultz & Kaiser, 2012). Therefore, understanding the factors driving individuals to engage in pro-environmental behaviors is critical, especially given the substantial investments in interventions and policies whose success is not guaranteed (Wamsler, Osberg, Osika, Herndersson, & Mundaca, 2021). A significant challenge in this field is the attitude-behavior gap, where pro-environmental attitudes rarely translate into pro-environmental behavior (Kollmuss & Agyeman, 2002). To create more effective interventions and policies, it is essential to gain deeper insights into the mechanisms underlying pro-environmental behavior (and the attitude-behavior gap)—not just theoretically, but empirically and ideally neurobiologically. This thesis aims to elucidate the mechanisms underlying pro-environmental behavior using a multidisciplinary approach that integrates behavioral and neuroscientific methods. For this purpose, the dissertation (i) investigates a potential contributor to pro-environmental behavior: mindfulness; (ii) studies the intricate relationship between pro-environmental, prosocial and future-oriented behavior at a behavioral and neuronal level; and lastly (iii) investigates the neuronal mechanism of the attitude-behavior gap.
The dissertation's first study investigated mindfulness training's effects on pro-environmental behavior. In addition, building on the theoretical link between pro-environmental, prosocial, and future-oriented behavior, we investigated how their baseline preferences are related at a behavioral level (Pfattheicher, Sassenrath, & Schindler, 2016; Weber, 2017). Lastly, given that mindfulness is also associated with these behaviors we examined the roles of prosociality and future orientation as mediators of the mindfulness-environmental link. Contrary to previous correlational and theoretical accounts, mindfulness training decreased, instead of increased, environmental and prosocial choices, and no significant effects were found for future orientation (Ericson, Kjønstad, & Barstad, 2014; Geiger, Grossman, & Schrader, 2019). Although prosocial and environmental choices were correlated, prosocial decisions did not moderate the link between mindfulness and pro-environmental behavior. Therefore, while pro-environmental and prosocial behaviors are related, prosocial behavior alone does not fully explain the connection between mindfulness and pro-environmental behavior. These findings challenge previous theoretical accounts suggesting a positive effect of mindfulness on pro-environmental and prosocial behavior (Ericson et al., 2014).
The second project investigated the neuronal underpinnings of pro-environmental behavior. To test whether the hypothesized link between pro-environmental, prosocial, and future-oriented behavior is mirrored at the neuronal level, we compared their neuronal correlates in a single study testing their shared neuronal mechanisms, a novel approach in the literature (Gladwin, Krause, & Kennelly, 1995; Weber, 2017). We also examined whether these mechanisms play a role in bridging the attitude-behavior gap. Our study found that pro-environmental behavior exhibited higher brain activation in the dorsomedial prefrontal cortex (DMPFC), precuneus, and temporoparietal junction (TPJ). The TPJ was also activated during the neuronal overlap of pro-environmental and prosocial behavior, and it modulated the attitude-behavior gap. These findings are in line with previous neuroscientific studies demonstrating the causal role of the TPJ (Langenbach, Savic, Baumgartner, Wyss, & Knoch, 2022). Our results contribute to the existing literature on TPJ and pro-environmental behavior by showing that TPJ activation is associated with both environmental and prosocial decisions and highlighting its role in the major challenge of this field, namely the attitude-behavior gap.
Taken together, our findings challenge previous theoretical accounts by suggesting potential reverse effects of mindfulness on pro-environmental behavior (Ericson et al., 2014). However, they do not imply a general negative impact of mindfulness on pro-environmental and prosocial behaviors. Instead, they underscore the nuanced nature of pro-environmental behavior and the need for future research. Moreover, our research highlights a closer relationship between pro-environmental and prosocial decisions compared to future-oriented preferences, both at behavioral and neuronal levels. This relationship is further supported by the involvement of the TPJ, known for its association with prosocial behavior (Van Overwalle, 2009), in bridging the attitude-behavior gap. These findings might have broader implications for public interventions and policies, advocating for the integration of prosocial aspects alongside environmental elements in their development
