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Beschreibung des Patientenkollektives der Patienten mit familiärem Long-QT-Syndrom der Spezialambulanz für angeborene Arrhythmiesyndrome der LMU München und Identifikation von Prädiktoren für das Auftreten maligner ventrikulärer Arrhythmien
Full text linkWir haben in einem Kollektiv von LQT-Patienten untersucht welche Parameter mit einem erhöhten Risiko für „kardiale Ereignisse“, also akut lebensbedrohliche Ereignisse mit kardialer Genese, wie plötzlicher Herztod und reanimationspflichtige Ereignisse, sowie adäquates Auslösen des Kardioverten-Defibrillators, assoziiert sind.
Dabei haben wir zunächst das Kollektiv beschrieben und dabei erwartungsgemäß Unterschiede in der Krankheitsmanifestation von „Indexpatienten“ und ebenfalls als LQTS diagnostizierten Familienangehörigen darstellen können.
Bei der Betrachtung der LQT-Patienten mit kardialem Ereignis im Vergleich zu den LQT-Patienten ohne kardiales Ereignis haben sich die etablierten Risikoparameter wie Synkopen, Torsades-de-Pointes-Tachykardien, QTc-Zeit-Verlängerung und die genetischen Subtypen LQT-Typ 1-3 bestätigt. Zusätzlich ergeben sich aus unserer retrospektiven Registerstudie Hinweise, dass auch T-Wellen-Alternanzen und LQT-Typ 15 mit einem erhöhten Risiko für kardiale Ereignisse assoziiert sein können.
Um für die seltene Erkrankung LQTS mittel- und langfristig belastbare Aussagen zur Risikostratifizierung für kardiale Ereignisse erheben zu können sind standardisierte Erhebungen retrospektiver Daten ebenso wie ein langfristiges prospektives Follow-up in spezialisierten Zentren unerlässlich. Die einzelnen spezialisierten Zentren müssen sich darüber hinaus auch auf lokaler, nationaler und internationaler Ebene vernetzen, um dieses ambitionierte Ziel zu erreichen und die Patientenversorgung zu verbessern. Seit 2022 beteiligt sich das LMU-Klinikum im Rahmen des European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERNGUARD-Heart) an einer vielversprechenden Initiative
Epigenetische Veränderungen an Genen des WNT/β-Catenin-Signalwegs in Wilms-Tumoren
Full text linkWT represent the most common type of kidney tumors in children. Therefore, it should be given high priority in research. Overall, the prognosis of this disease is favourable, nevertheless most of the affected children suffer from the exhausting therapy, which almost always consists of surgery, neoadjuvant chemotherapy and sometimes even additional radiotherapy. Each of this therapeutic modalities causes different side effects and long-term effects, which, especially in children, should be considered carefully.
This study focused on the WNT/β-Catenin-pathway, which is known to be dysregulated in some of WT and even in higher frequency in other tumors. Up to now, there is a lack of knowledge, regarding whether epigenetic changes are responsible for these dysregulations. As a starting point for this study, an investigation of an irregular activation of the WNT/β-Catenin-pathway was conducted for a cohort of 101 WT. An overexpression of AXIN2 was observed in 31 % of WT through a gene expression analysis, which accounts for a larger portion than previously reported. Thus, the relevance of the research question could be confirmed.
One possible reason for this dysregulation could be the mutation of CTNNB1, which is already known as one of the most common mutations in WT. In the examined cohort, this mutation accounts only for 16 % of WT with activated WNT/β-Catenin-pathway. Therefore, as the next step, the involvement of APC, known to be altered in a lot of different tumors, was investigated as a potential cause of pathway-activation. This could not be confirmed through expression analysis or methylation analysis. Another focus was directed towards the group of SFRP.
It could not be stated that there is a lower expression level for SFRP2,4,5, which could lead to an dysregulated activation of the WNT/β-Catenin-pathway. For SFRP1 the expression was significantly lower than in the control group, but the interpretation of these results is difficult as no connection could be established with the activation of the WNT/β-Catenin-pathway. Very few of WT with an underexpression of SRFP1 also showed an irregular activation of the WNT/β-Catenin-pathway. The cause of this significant underexpression of SFRP1 could not be identified. The methylation analysis in the promoter of SFRP1 did not show any changes compared to the healty kidney tissue. Further investigations are required therefore.
According to previous research especially stromal WT are affected by an irregular activation of the WNT/β-Catenin-pathway in the investigated cohort. Other associations between an activation of the pathway and specific phenotypes, such as metastasis, tumor recurrence, age at diagnosis, gender, survival or bilateral occurrence could not be established.
In summary this study could verify and underline the importance of interest in the WNT/β-Catenin-pathway in the origin of WT. The pathway is aberrant in a large portion of WT. In addition to CTNNB1 mutation, there have to be more mechanisms causing the proven activation of the pathway. Epigenetic changes in the genes investigated could not be attributed as the cause of the aberrant activation. A direct relationship between the underexpression of SFRP1 and the activation needs to be further investigated.
Although WT with activation of the WNT/β-Catenin-pathway belong to the group of WT with favourable histology, it is worth further investigating these approaches. A detailed understanding of the origin of WT could be applied in clinical practice, for example to deescalate therapy or to provide a basis for future pharmacological treatments
Ästhetische Bilder und visuelle Faszination im Physikunterricht
Full text linkBilder im Physikunterricht erfüllen über ihre instruktionalen Funktionen hinaus viele affektive Funktionen, wie z.B. Aufmerksamkeit erregen, Faszination wecken sowie Interesse fördern. Die bisherige Forschung legt nahe, dass eine erhöhte affektive Wahrnehmung die Freude und die Bereitschaft zur Auseinandersetzung mit physikalischen Inhalten verstärken kann. Studien schreiben dabei ästhetischen Bildern eine besonders hohe affektive Komponente zu. Für ein umfassendes Verständnis der Effekte von ästhetischen Bildern im naturwissenschaftlichen Unterricht sind weitere Erkenntnisse nötig.
Dies motiviert die in der vorliegenden Arbeit durchgeführte Untersuchung von Ästhetik und visueller Faszination instruktionaler Bilder im Physikunterricht. Mit dem Ziel, wichtige Komponenten für ästhetische Bilder zu erfassen, wurde ein Katalog mit forschungsbasierten Kriterien zur Auswahl von ästhetischen Bildern für den Physikunterricht zusammengestellt. Dabei wurden unter anderem Erkenntnisse der Psychologie angewendet sowie inhaltsbezogene Kriterien aus der Forschung und Praxis der Physikdidaktik mit einbezogen. In der vorliegenden Arbeit wurden diese Kriterien eingesetzt, um potentiell ästhetische Bilder zu dem Thema geometrische Optik mit dem Kontext Natur auszuwählen. Für eine instruktionale Einbindung wurden die Bilder als Teil von Aufgaben in eine Lernumgebung integriert. Zur Evaluation der subjektiv empfundenen visuellen Ästhetik wurde ein Messinstrument, basierend auch auf Vorarbeiten in der Kunst- und Emotionspsychologie, für Bilder im Physikunterricht zugeschnitten und validiert.
Auf dieser Basis wurde eine Schulstudie mit Schülerinnen und Schülern (N = 118) der Mittelstufe durchgeführt. Die Lernenden bearbeiteten in einem Crossover-Design Aufgaben mit ästhetischen Bildern und mit Bildern, die denselben Lerninhalt mit Bildern von Experimenten im Klassenzimmer zeigen. Anschließend wurden Bilder beider Kategorien nach ihrer ästhetischen und affektiven Bildwahrnehmung bewertet. Auch weitere Faktoren wie Interesse, themenspezifisches Wissen sowie die Bearbeitungszeit der Aufgaben wurden erhoben. Die Ergebnisse zeigen durchwegs eine signifikant bessere Bewertung der ausgewählten ästhetischen Bilder mit hohen Effektstärken für die ästhetische Bildwahrnehmung (Cohen's d = [1,05 - 1,56]) und die affektive Bildwahrnehmung (Cohen's d = [0,85 - 1,48]). Eine einzige punktuelle Ausnahme kann im Rahmen des Forschungshintergrunds gut erklärt werden. Für die Wissenszuwächse und Bearbeitungszeiten konnten bei den vorgegebenen begrenzten Interaktionszeiten keine signifikanten Unterschiede erfasst werden.
In dieser Arbeit wurden ästhetische Bilder im Kontext Natur sowohl dekorativ als auch instruktional durch Aufgaben in eine Lernumgebung integriert. Mit den in dieser Arbeit durchgeführten Studien konnte nachgewiesen werden, dass der hier entwickelte Kriterienkatalog nützlich für die Auswahl von ästhetischen Bildern ist, welche bei Lernenden eine signifikante positive ästhetische und affektive Wahrnehmung hervorrufen. Dieser Katalog kann auch Lehrkräften praktische Hinweise für die Auswahl ästhetischer Bilder liefern. Somit ist eine Grundlage für die weitere Nutzung des pädagogischen Potenzials von ästhetischen Bildern im Physikunterricht gelegt. Darüber hinaus bildet diese Arbeit eine Grundlage für zukünftige Untersuchungen von Ästhetik im naturwissenschaftlichen Unterricht
The differential effects of trauma-focused interventions on voluntary and involuntary retrieval of distressing memories
Full text linkPost-Traumatic Stress Disorder (PTSD) is marked by recurrent, distressing memories of traumatic events. Trauma-focused psychological interventions aim to alleviate the distress caused by intrusive memories, but their objective is not to erase the traumatic memory entirely. For instance, a police officer might need to recall details of a past operation to improve future risk assessments, or a survivor of physical assault may require accurate memory recall to pursue legal action against their perpetrator. The effectiveness of trauma-focused interventions in alleviating intrusive memories is well-documented; however, their impact on voluntary memory remains poorly understood. Clinical theories propose that these interventions should selectively reduce intrusive memories, but preserve – or even enhance – the voluntary recall of event details, leading to more coherent and organized memory reports. In contrast, experts in legal psychology raise concerns that these interventions might unintentionally compromise the factual accuracy of voluntary memories. Interventions incorporating imagery-based techniques, such as Imaginal Exposure (IE), Eye Movement Desensitization and Reprocessing (EMDR), and Imagery Rescripting (ImRs), have been at the center of this debate. The primary aim of this thesis was to bridge these contrasting perspectives by systematically examining the effects of IE, EMDR and ImRs on both involuntary and voluntary retrieval of distressing memories across three analogue studies conducted with healthy participants.
Study I and II assessed the effects of these interventions on experimentally induced memories, allowing for experimental control over memory content and assessment of memory accuracy. In Study I, a distressing memory was induced in N = 265 participants, using the Trier Social Stress Test (TSST). The following day, participants received IE, EMDR, ImRs, or no intervention (NIC). One week later, the accuracy of voluntary memory for the TSST was assessed using a cued recall task. Involuntary memories of the TSST were assessed via an app-based intrusion diary. Results indicated no group differences in memory accuracy, suggesting that none of the interventions impaired or enhanced memory accuracy compared to NIC. Regarding involuntary memory, none of the interventions significantly reduced intrusion frequency; however EMDR and IE reduced intrusion load (intrusion frequency weighted by distress). Although these findings are encouraging from a clinical perspective, they leave open the possibility that certain factors in the clinical application of these interventions might still increase the risk of memory distortions.
Study II examined potential risk conditions under which ImRs might lead to memory distortions, focusing on whether instructions encouraging vivid and detailed imagination of changes to a memory increase this risk, and whether unclear or incomplete memories are particularly vulnerable. In a three-day online trauma film paradigm, a distressing memory was induced in N = 267 participants through an aversive film clip. To manipulate memory clarity and completeness, half of the participants viewed the original version of the film (with all sensory information clearly identifiable), while the other half viewed a version where visual and auditory blur filters obscured parts of the image and dialogue. The following day, participants were assigned to one of three conditions: ImRs with instructions to imagine and rescript the scene in as much sensory detail as possible; ImRs without such instructions; or a no-intervention control condition (NIC). On the third day, memory accuracy for the film clip was assessed using a cued recall task. Intrusive memories were assessed with a retrospective intrusion diary. Results showed no adverse effects of ImRs on memory accuracy. In fact, participants who received detailed sensory imagination instructions during ImRs exhibited greater memory accuracy compared to both those who did not receive these instructions and those in the control group, regardless of the initial clarity and completeness of the memory. No significant group differences were found in the frequency of intrusive memories.
Building on these findings, Study III extended the investigation to autobiographical memories. A total of 182 participants provided a detailed verbal report of an aversive life event in a free recall task. They were then randomly assigned to one of four conditions: IE, EMDR, ImRs, or NIC. One week later, participants repeated the free recall task, and independent raters evaluated changes in memory consistency, disorganization, and coherence. Involuntary memory was assessed via an app-based intrusion diary the week before and after the intervention. Additionally, psychophysiological reactivity to intrusive memories was measured during an intrusion-sampling period in both experimental sessions. None of the interventions increased contradictions or omissions in memory reports compared to NIC, suggesting that they do not impair the ability to recall specific memory details or distort their content. IE, however, was associated with more additions to memory reports, though the accuracy of these added details remains unclear. Regarding memory disorganization and coherence, the findings were mixed. IE led to improvements in structural organization by reducing disorganized thoughts, while EMDR and ImRs enhanced contextual memory coherence, reflecting improved spatial and temporal orientation of the memory. In terms of involuntary memory, all interventions reduced intrusion load. However, only ImRs reduced the number of intrusive memories relative to NIC. No group differences were observed in psychophysiological responses to intrusions.
In summary, this thesis makes an important contribution to the current literature by directly testing contrasting predictions regarding the memory effects of trauma-focused interventions. The findings challenge concerns that these interventions inherently risk distorting factual memory content, which has important implications for trauma survivors whose credibility might be questioned in legal contexts due to their treatment history. While the studies extend prior research by better modeling the complexity of memories typically addressed in clinical practice (Studies I and II) and examining autobiographical memories (Study III), their generalizability to traumatic memories and clinical populations remains limited. It is important to replicate the findings in these populations. Furthermore, the mixed results concerning intrusive memories and memory disorganization highlight the need to refine both experimental paradigms and theoretical frameworks to better account for the nuanced effects of trauma-focused interventions. Practical implications and directions for future research are discussed
Interpretable approaches for cellular organisation and molecular profiles using (spatial) omics data in health and disease
Full text linkDeciphering cellular organisation and how molecular expression patterns vary across tissues is fundamental to gaining insights into biological processes and disease mechanisms. Advances in omics technologies, particularly spatial omics, have revolutionised our ability to investigate these patterns at unprecedented resolution and dimensionality. While various statistical and machine-learning approaches have emerged to analyse these complex data sets, critical gaps remain in our understanding of the differential cellular organisation and tissue characteristics across different conditions. Furthermore, the field typically lacks robust tools for a three-dimensional, holistic view of tissues, which is crucial for comprehending disease dynamics. In this thesis, I present a suite of mathematical approaches to analyse diverse omics data,
focusing on spatial omics, with various resolutions, throughputs, and dimensionalities to reveal crucial insights into differential changes in molecular expression and cellular organisation across conditions. First, as part of a large multimodal comprehensive study, I expanded on our understanding of cell heterogeneity, the distinctive proteome signatures in the skull bone marrow, and its role in immunological responses to neurological disorders. Second, increasing the complexity and advancing into the spatial omics domain, I advanced the current approaches to quantitatively analyse the cellular organisation across multiple scales, from individual cell types and tissue niches to whole tissue revealing condition-specific tissue changes. Third, I
proposed graph models and comprehensive multimodal ablation studies to understand the tissue traits contributing to patient outcomes and associate them with tissue architecture motifs to enhance our understanding of disease progression. Fourth, moving into three-dimensional space, I used our new technology, DISCO-MS, to explore the proteome changes in amyloid-beta plaques in Alzheimer’s disease to capture very early (6 weeks) and late-stage dynamics and region-specific variations, providing a holistic view of the plaques’ microenvironment. Collectively, these approaches represent a comprehensive effort and advancement in our ability to study the differential changes in molecular expression, cellular organisation, and tissue traits across different physiological and pathological conditions while further extending into three-dimensional volumes for a more holistic understanding of biological systems
Immune cell composition in thrombosis: insights into arterial disease, infection, and tumor metastasis
Full text linkThe present thesis, the multifaceted roles of immune cells, especially of CD4+ T cells in atherothrombosis as well as in thrombosis in infection, infection and tumor metastasis have been investigated.
The morphological and structural characterization of large thrombi from carotid and femoral arteries highlighted distinct regional differences in fibrin density and immune cell distribution. CD4+ T cells, particularly activated subsets, were predominantly located in fibrin and platelet-rich regions, potentially modulating fibrinolysis through fibrinolysis regulators such as uPA and TAFI. In pulmonary thrombi from COVID-19 patients, CD4+ T cells negatively correlated with the extent of microvascular thrombosis. This correlation was stronger in COVID-19 than in influenza virus infection, highlighting the unique inflammatory and thrombotic interplay in COVID-19 pathophysiology.
In chronic arterial thrombosis, neovascularization occurred with microthrombi embedded in microvessels that often contained T helper cells. This could suggest that CD4+ T cells are long-term regulators of thrombosis, potentially contributing to contributing to the maintenance of blood flow through organized thrombotic tissue.
In experimental infection with E. coli, CD4+ T cells were found to be engaged in fibrinolysis by means of the binding the fibrinolysis inhibitor (TAFI). CD4+ T cells counteracted TAFI-mediated fibrinolysis inhibition in particular by preventing binding of TAFI to fibrin. Moreover, in a murine model of S. pneumoniae infection, activated Th17 cells were identified as potent attractors of tPA in microvascular thrombosis within liver sinusoids, suggesting a specialized role for this T cell subtype in fibrinolysis during infection.
In animal models of pancreatic metastasis, microvascular thrombosis influenced tumor cell extravasation. While rivaroxaban reduced extravasation in poorly pro-coagulant tumor cell lines, it increased extravasation in highly pro-coagulant tumor cell lines, suggesting that under specific conditions, microvascular thrombosis might potentially accelerate early metastasis by influencing vessel permeability.
This thesis provides significant insights into the intricate roles of thrombosis and CD4+ T cells across different pathological settings, paving the way for targeted therapeutic strategies in thrombosis and related diseases
