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Stress-related tissue-specific regulation of DNA methylation in non-coding elements of FKBP5 in brain and blood of mice, humanized mice and humans
Get PDFAnalyse und Bewertung der ökonomischen Krankheitslast durch Charcot-Marie-Tooth-Neuropathie in Deutschland
Get PDFDie vorliegende Querschnitts-Beobachtungsstudie untersucht die Identifizierung und Analyse des krankheitsbedingten medizinischen und nicht-medizinischen Ressourcenverbrauchs unter Berücksichtigung der direkten und indirekten medizinischen Kosten bei Patienten mit CMT, die sich im CMT-Patientenregister selbst registriert haben. 397 Teilnehmer mit verschiedenen, genetisch bestätigten CMT-Subtypen konnten eingeschlossen werden. Bewertet wurden die tatsächlichen direkten und indirekten Kosten der CMT-Neuropathie auf nationaler Ebene.
Die jährlichen Gesamtkosten (COI) beliefen sich auf 17.427 € (95 % CI: 15.169-20.047) pro Patient und Jahr, 67,3 % davon betreffen direkte Kosten. Höchster einzelner Kostenfaktor wa-ren die Kosten für informelle Pflege. Für Deutschland konnten die Gesamtkosten für CMT auf 572,8 (498,6-658,9) Millionen Euro hochgerechnet werden. Die multivariate Regressionsanaly-se zeigte den Zusammenhang der Zunahme der Gesamtkosten mit dem Schwergrad der Er-krankung (CMTNS2). Alter, CMT-Subtyp, Komorbiditäten, BMI und Beschäftigungsstatus wa-ren ebenfalls wesentliche Prädiktoren für eine Veränderung der Kosten (p<0,05). Weiterhin wurden bedeutsame Unterschiede in den Gesamtkosten in Abhängigkeit von Familienstand, subjektiv bewerteten Beeinträchtigungen, der Abhängigkeit von anderen Personen, der Pfle-gestufe, dem Bildungsstand und der Krankheitsdauer gefunden.
Es zeigten sich zum Teil erhebliche wirtschaftliche Auswirkungen: Im Vergleich zur Normalbe-völkerung bestand häufigerer Kontakt mit allen Bereichen des Gesundheitssystems. Dies be-trifft sowohl die Konsultation von Hausärzten und Spezialambulanzen wie auch stationäre Auf-enthalte, die Einnahme von Medikamenten und die Inanspruchnahme von Heil- und Hilfsmit-teln.
Es bestätigte sich, dass CMT sehr heterogen ist, Symptome bereits im Kindesalter oder auch erst nach dem 20. Lebensjahr auftreten können und der Verlauf innerhalb einer Familie sehr unterschiedlich sein kann.
Die Schätzung der Kosten von 17.427 € (95 % CI: 15.169-20.047) pro Patient und Jahr zeigte deutlich geringere Krankheitskosten im Vergleich zu anderen hereditären neuromuskulären Erkrankungen wie Muskeldystrophie Duchenne/DMD (€ 78.913) oder Spinaler Muskelatro-phie/SMA (€ 70.566) (1),(2). Aufgrund der höheren Prävalenzschätzungen liegen die für Deutschland hochgerechneten, jährlichen Gesamtkosten für CMT jedoch bei 572,8 (498,6-658,9) Mio. €, was aufgrund der Häufigkeit der Erkrankung 3,8- bzw. 5,4-mal höher ist als für DMD bzw. SMA.
Die Ergebnisse zeigen zentrale Patientenbedürfnisse und potenzielle Lücken in der Gesund-heitsversorgung. Die geringere Inanspruchnahme von psychologischer Unterstützung in die-ser Studie weist möglicherweise auf einen ungedeckten Bedarf hin. Erklärungen, warum CMT-Patienten vermeintlich hilfreiche Angebote wie Ergotherapie nicht nutzen, wurden kürzlich ana-lysiert. Die wichtigsten prominentesten Gründe für die Nichtnutzung waren mangelnde Bera-tung durch den behandelnden Arzt und geringes Wissen über die Krankheit auf Seiten der Therapeuten (3). Aufklärungs- und Sensibilisierungskampagnen könnten sinnvoll sein - sowohl für medizinisches Fachpersonal als auch für betroffene Patienten.
Zusammenfassend zeigen die Ergebnisse, dass CMT-Neuropathien mit einer erheblichen wirt-schaftlichen Belastung für die Patienten und die Gesellschaft verbunden sind. Die Bewertung der Krankheitskosten zeigt die ökonomische Relevanz der Erkrankung und kann damit Ent-scheidungsträger bei der Allokation von knappen sozio-ökonomischen Ressourcen unterstüt-zen (4,5). Zusätzlich ermöglicht die Kostenschätzung spätere Kosten-Effektivitäts-Studien für zukünftige, neue Therapiestrategien. In Anbetracht möglicher Therapieverfahren können diese Ergebnisse äußerst relevant sein.
In der Anwendungsbegleitung können Patientenregister valide Informationen über Zusammen-hänge im natürlichen Verlauf einer Krankheit liefern. Verifizierte und über einen längeren Zeit-raum gesammelte Daten ermöglichen neben einer verlässlichen Probandenzahlplanung für die Durchführung von Studien auch die Bestimmung der aussagekräftigsten Kriterien für den Er-folg einer Intervention. Sie können Alleinstellungsmerkmale von Biomarkern für eine Diagnose aufzeigen und dadurch ggf. auch auf mögliche neue Therapieansätze hinweisen.
Die Bewertung der Krankheitskosten zeigt die ökonomische Relevanz von seltenen Erkran-kungen wie CMT und kann damit die Zuteilung von knappen sozio-ökonomischen Ressourcen für betroffene Patienten erleichtern.This cross-sectional observational study investigates the identification and analysis of dis-ease-related medical and non-medical resource use, considering direct and indirect medical costs, in patients with CMT who have self-registered in the CMT patient registry. 397 partici-pants with different, genetically confirmed CMT subtypes were included. The actual direct and indirect costs of CMT neuropathy at national level were assessed.
The total annual costs (COI) amounted to € 17,427 (95 % CI: 15,169-20,047) per patient per year, with 67.3 % of the costs being direct costs. The highest single cost factor was the cost of informal care. For Germany, the total costs for CMT could be extrapolated to 572.8 (498.6-658.9) million euros. The multivariate regression analysis showed the correlation of the in-crease in total costs with the severity of the disease (CMTNS2). Age, CMT subtype, comor-bidities, BMI and employment status were also significant predictors of a change in costs (p<0.05). In addition, significant differences in total costs were found depending on marital status, subjectively assessed impairments, dependence on other people, care level, education level and duration of illness.
In some cases, there were considerable economic effects: Compared to the normal population, there was more frequent contact with all areas of the healthcare system. This applies to con-sultations with general practitioners and specialized outpatient clinics as well as inpatient stays, the use of medication and the use of remedies and aids.
It was confirmed that CMT is very heterogeneous, that symptoms can appear as early as childhood or as late as after the age of 20 and that the course of the disease can vary greatly within a family.
The cost estimate of €17,427 (95% CI: €15,169-20,047) per patient per year shows that the medical costs are significantly lower compared to other hereditary neuro-muscular diseases such as Duchenne muscular dystrophy/DMD (€78,913) or spinal muscular atrophy/SMA (€70,566) (1,2). However, due to the higher prevalence estimates, the total annual costs for CMT extrapolated for Germany amount to €572.8 (498.6-658.9) million, which is 3.8 and 5.4 times higher than for DMD and SMA, respectively, due to the frequency of the disease.
The results show the most important needs of patients and possible gaps in healthcare provi-sion. The lower utilization of psychological support in this study may indicate an unmet need. Explanations for why CMT patients do not use supposedly helpful services such as occupa-tional therapy have recently been analysed. The main reasons for non-utilizations were lack of advice from the treating physician and lack of knowledge about the disease on the part of the therapists (3). Education and awareness-raising campaigns could be useful - both for healthcare professionals and affected patients.
In summary, the results show that CMT neuropathies are associated with a considerable eco-nomic burden for patients and society. The assessment of disease costs shows the economic relevance of the disease and can thus support decision-makers in the allocation of scarce socioeconomic resources (4,5). In addition, cost estimation enables subsequent cost-effectiveness studies for future new therapeutic strategies. Regarding possible therapeutic procedures, these results can be of great importance.
In observational studies, patient registries can provide valid information about correlations in the natural course of a disease. Verified data collected over a longer period enables reliable planning of the number of test subjects for conducting studies and the determination of the most meaningful criteria for the success of an intervention. They can reveal the unique fea-tures of biomarkers for a diagnosis and thus possibly also provide indications of possible new therapeutic approaches.
The evaluation of disease costs shows the economic relevance of rare diseases such as CMT and can thus facilitate the allocation of scarce socio-economic resources for affected patients
Integration and interaction of cardiac progenitor cells with human failing myocardium
Get PDFBackground: Regenerative therapy is currently getting attention as one of the most promising treatments for heart failure. However, the survival and quality of integration of stem cell-derived cardiomyocytes with human failing myocardium is still unclear. Human cardiac progenitor cells (CPCs) have the potential to differentiate into ventricular myocytes, and their engraftment in the human fail-ing myocardium may contribute to the enhancement of myocardial contractility and improve myocardial plasticity.
Methods: CPCs were derived from embryonic stem cells with a cardiac directed differentiation protocol and were purified with magnetic-activated cell sorting (MACS) to remove potentially remaining undifferentiated stem cells. Human myocardium was acquired from explanted hearts of transplant recipients, and was cultured as living thin slices under biomimetic conditions, enabling con-tinuous stimulation and force measurements. CPCs were seeded on the sur-face of myocardial slices and were cocultured for 5 weeks. Real-time contrac-tility was monitored and cardiac functional assessments were performed daily. Morphological maturation and integration of CPCs were characterized by no-stain labeling (eGFP and second-harmonic generation) and immunohistology. Cell-to-cell interaction and CPCs maturation in cocultured myocardial slices were investigated by single-nucleus RNA sequencing.
Results: After 5 weeks of coculture, we observed that CPCs have autonomous-ly migrated, and were uniformly distributed into deep layers of the myocardium. They expressed morphological characteristics of cardiomyocytes (elongated and t-tubule-like structure, α-actinin positive myofibrils) during coculture. Tis-sue connective proteins (connexin-43 and N-cadherin) have been formed be-tween CPC-derived cardiomyocytes and host failing cardiomyocytes. In com-parison to plain myocardial slices, functional changes were detected in cocul-ture, including enhanced force development, synchronized kinetics of contrac-tion and intracellular calcium, more positive response to rapid pacing, and tight electrical coupling. Single-nucleus RNA sequencing demonstrates dedifferen-tiation-redifferentiation of host failing cardiomyocytes and advanced matura-tion of CPC-derived cardiomyocytes during coculture. Cell-cell communication and interaction were identified between CPC-derived and host failing cardio-myocytes, which are associated with improved contractility and cardiac devel-opment of the failing cardiomyocytes in coculture.
Conclusion: CPCs differentiate into cardiomyocytes and self-integrate with human failing myocardium during long-term coculture. Integration promotes contractility and affects excitation-contraction coupling. Moreover, cross-talk between CPCs and host failing myocardium develops, leading to mutual adap-tation and functional synchronization
Untersuchungen zu Epidemiologie und Charakterisierung von häufigen immunmediierten neurologischen Erkrankungen bei Hunden und Katzen
Get PDFImmunmediierte neurologische Erkrankungen spielen auch in der Tiermedizin eine bedeutende Rolle.
Ziel der Studie war es, epidemiologische und klinische Daten zu zwei häufigen immunmediierten neurologischen Erkrankungen an europäischen Hunde- und Katzenpopulationen zu erheben und weitere Einblicke in die Ätiologie der Krankheiten zu bekommen
On the ground state energy of large Coulomb systems
Get PDFThis thesis is concerned with two different Coulomb systems in the many-particle limit. First of all, the liquid drop model for nuclei interacting with a neutralizing homogeneous background of electrons is considered. The regime that is of interest is when the fraction between the electron and the nucleon charge density is small. In three dimensions, it is shown that in this dilute limit the thermodynamic ground state energy is given to leading order by that of an isolated nucleus. In two dimensions, it is proven how the leading order coefficient of the thermodynamic ground state energy is in the dilute limit and error estimates are shown that reproduce the second order of a conjectured asymptotics.
Furthermore, a result is derived on the uniform distribution of energy in any dimension which is based on a method Armstrong and Serfaty used to prove uniform distribution of energy for the jellium model.
The second Coulomb system that is considered is the "neutral'' case of the many-polaron system in the Pekar-Tomasevich approximation. In 2015, Benguria, Frank and Lieb showed that in this case the ground state energy goes as -N7/5 for large N. They proved an upper bound for the coefficient and conjectured it to be the correct one. Here, it is established that this is indeed true by proving the corresponding lower bound. To do so, a one-component charged Bose gas with Coulomb interaction and a background with variable charge distribution is studied. Adapting methods of Lieb and Solovej one can justify Bogolubov theory for this model.In dieser Doktorarbeit werden zwei verschiedene Coulomb-Systeme im Vielteilchen-Limes betrachtet. Zuerst wird das Tröpfchenmodell für die Wechselwirkung von Nukleonen mit einem Hintergrund von Elektronen untersucht. Dabei wird der Grenzwert betrachtet bei dem das Verhältnis der Elektronen- zur Neukleonenladungsdichte klein ist. In drei Dimensionen wird gezeigt, dass der thermodynamische Limes der Grundzustandsenergie zur führenden Ordnung der eines einzelnen Atomkernes entspricht wenn die Ladungsdichte klein ist. In zwei Dimensionen wird der Koeffizient der führenden Ordnung hergeleitet und es werden Fehlerschranken bewiesen, die die Größenordnung einer vermuteten Asymptotik der zweiten Ordnung haben. Außerdem wird ein Resultat bewiesen zur gleichmäßigen Verteilung der Energie im Raum mithilfe einer Methode, die Armstrong und Serfaty verwendeten um die gleichmäßige Verteilung der Energie im Jellium Modell zu beweisen.
Das zweite Coulomb-System behandelt viele Polaronen in der Pekar-Tomasevich Näherung. Benguria, Frank und Lieb bewiesen 2015, dass die entsprechende Grundzustandsenergie propotional ist zu -N7/5 für große N. Sie bewiesen eine obere Schranke für den Koeffizienten und formulierten die Vermutung, dass diese scharf ist. In dieser Doktorarbeit wird bewiesen, dass die Vermutung korrekt ist indem die entsprechende untere Schranke hergleitet wird. Dabei wird ein geladenes Bose-Gas mit Coulomb-Wechselwirkung und einem Hintergrund entgegengesetzter Ladung betrachtet. Mithilfe von Methoden von Lieb und Solovej kann Bogolubov Theorie verwendet werden
Investigating the role of adipocyte expressed A disintegrin and metalloprotease 17 (ADAM17) in energy expenditure and metabolic health
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Enhancing fluorophore performance for single-molecule applications and super-resolution imaging
Get PDFTo see the world, we need to see the small things. And so, science has made great efforts to observe the details of biological systems. Sophisticated microscopes have been developed to visualize structures and interactions at the dimension of proteins and other biomolecules. In fluorescence microscopy these nanometer-sized features are revealed through photon-emitting labels, attached to the molecule of interest. High performance of these dyes in terms of stability, specificity and brightness is a prerequisite for any successful experiment. At the same time, in order to observe the system in its innate state, interference of the observation method with the specimen should be minimal. Once this is ensured, it can be applied to observe biomolecules in their inherently complex environment and detect disease markers reliably.
The first section of this thesis is focused on increasing fluorophore photostability. To improve the signal-to-background ratio, fluorescence microscopy is often performed at the highest possible illumination power and for as long as possible before sample and fluorescent labels degrade (photobleaching). Aside from desired cycling between singlet excited and ground state (fluorescence), fluorophores can also enter other states such as the triplet state from where photobleaching is likely to originate. Systems to prevent this pathway commonly employ oxygen removing enzymes in combination with triplet state quenchers (TSQ), which ensure a fast return to the singlet state. Sensitive biological systems, however, can be disrupted by these additives and the required concentrations. In this work a minimally-invasive strategy that adresses this issue by attaching the TSQ to single stranded DNA (ssDNA) is introduced. An extended sequence (docking site) on the molecule of interest enables the hybridization and exchange of both the label and the photostabilization strand. This approach improves the TSQ soluability and increases the local concentration near the label. By performing hour-long measurements of an otherwise photolabile dye without oxygen removal, we demonstrate enhanced fluorophore performance at 10^7 less additive concentration. This DNA-mediated stabilization is not restricted to one type of TSQ. The modularity of the technique allows for exploration of several stabilizers to match other fluorophores. Due to its adaptability and efficacy at low concentrations, our method can be applied to challenging imaging modalities such as multi-target visualization in complex biological systems.
The next section explores key factors for fluorescence-based disease detection, namely specificity and brightness of fluorescent labels. Reliable diagnosis of Malaria tropica in early stages of infection is necessary to begin treatment as soon as possible. While healthy red blood cells (RBC) do not contain cellular organelles, the Plasmodium falciparum parasite introduces them upon invasion. A silicon rhodamine dye equipped with a glibenclamide moiety is first used in this study to specifically target the endoplasmic reticulum. This allows for detection and distinction of infected over uninfected RBC in two different strains. The potential for application in the field is demonstrated by experiments on a low-cost portable smartphone microscope.
State-of-the-art methods for DNA detection rely on up-concentration of low-abun-dance target sequences over the background. A promising alternative is the detection of individual dye-labeled DNA molecules, which can be achieved through signal amplification using DNA origami nanoantennas. These plasmonic nanostructures bind two metallic nanoparticles (NP) and enhance fluorescence signal in the plamonic hotspot between. Fluorescently labeled disease markers can be directed towards this position by including ssDNA capture strands in the DNA origami. Two design generations for disease detection are included in this work. The chosen target sequence is responsible for an antibiotic resistant Klebsiella pneumoniae infection.
The first generation introduces a cleared region in the hotspot of the DNA nanostructure to provide space for the DNA detection element and two NPs. By optimizing the target DNA hybridization with label and capture strand (sandwich assay), efficient detection and amplification is achieved and a home-built smartphone microscope can be used to detect individual disease markers.
The second design (Trident) includes a more accessible hotspot to host even larger biomolecules. In comparison to the previous generation, detection speed of a 151 nucleotide ssDNA is tripled and the fraction of multiple captured molecules is doubled. Simultaneously, high fluorescence amplification is ensured.
This thesis demonstrates how photostabilization improves the performance of fluorophores in state-of-the art fluorescence microscopy. Through specific labeling and fluorescence enhancement, disease detection can be performed even on low-tech microscopes