Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 17/19 Archiv

Recent epidemiologic studies suggest that patients with diabetes mellitus suffer from increased hospital mortality after myocardial infarction and stroke. The aim of our analysis was to compare the hospital outcome of diabetic and non-diabetic patients with cardiovascular events and to analyse the relevant risk predictors. Therefore data of the Schwabing Myocardial Infarction Registry from 1999 to 2004, the Schwabing stroke register from 2003/2004, and the Pasing stroke register from 2007/2008 were assessed. Overall, these are 3171 recorded patients, of which 1087 were diabetic patients (34.3%) and 2084 non-diabetic patients (65.7%). Diabetic patients showed, apart from CRP, comparable risk predictors (GFR OR 4.2, CI 1.7-10.6, p

Myelin Oligodendrocyte Glycoprotein (MOG) is one of the few proteins known to be localized on the outermost sheath of central nervous system (CNS) myelin. Due to this localization, MOG is accessible to antibodies. Anti-MOG antibodies are demyelinating and enhance clinical symptoms in a number of animal models of CNS inflammation. Autoantibodies recognizing conformationally intact MOG are found in different inflammatory diseases of the CNS, but their antigenic epitopes had not been mapped. In this work, 9 variants of MOG with an intracellular enhanced green fluorescent protein (EGFP) tag were expressed on the cell surface of human HeLa cells and used to analyze sera from 111 patients (104 children, 7 adults), who had antibodies recognizing cell-bound human MOG. These patients had different diseases, namely acute disseminated encephalomyelitis (ADEM), one episode of transverse myelitis or optic neuritis, multiple sclerosis (MS), anti-aquaporin-4 (AQP4)–negative neuromyelitis optica (NMO), and chronic relapsing inflammatory optic neuritis (CRION). The expression levels of the mutants were comparable and cells with a defined expression level (fluorescence intensity in the EGFP channel of 102-103) were gated. Each MOG-mutant was recognized by at least one MOG-specific mAb. This allowed the comparison of binding to the different mutants. In order to assess the reproducibility of the system, binding of the 111 sera to the mutants was analyzed up to three times in independent experiments, yielding a very good reproducibility of the binding percentage with an absolute SD of 7.8% in the case of low recognition of a mutant and a relative SD of 20% in the case of high recognition of a mutant. The applied variants of MOG gave insight into epitope recognition of 98 patients. All epitopes identified in this work were located at loops connecting the ß-strands of MOG. The immunodominant epitope of human anti-MOG antibodies was at the membrane-proximal CC’-loop containing aa42, which is not present in rodent MOG. This loop was recognized by about half of all patients. Overall, seven epitope patterns were distinguished, including the one mainly recognized by mouse mAbs at the FG-loop around aa104. Evidence from mouse models of CNS inflammation shows that anti-MOG antibodies recognizing different epitopes can be demyelinating and thus pathogenic. This suggests that not only those antibodies recognizing the same epitope of MOG as the pathogenic mAbs (i.e. the FG-loop), but also the ones recognizing the CC'-loop are pathogenic in humans, as both epitopes allow for the recognition of cell-bound MOG. In half of the patients, the anti-MOG response was directed to a single epitope. To analyze the effect of glycosylation on the recognition of MOG by human autoantibodies, a “non-glycosylation mutant” N31D was made. Digestion with PNGaseF and Western blot analysis confirmed that N31 was the only used N-glycosylation site of the MOG constructs in HeLa cells. Glycosylation of MOG was not needed for antibody binding, but 8% of the patients recognized deglycosylated MOG at least two-fold better. The epitope specificity was not linked to certain disease entities. The individual epitope recognition patterns stayed constant in 11 analyzed patients over an observation period of up to 5 years without evidence for intramolecular epitope spreading. Some patients with acute syndromes had anti-MOG IgG at disease onset, but rapidly lost their anti-MOG IgG reactivity. These patients were able to generate a long-lasting IgG response to measles and rubella virus vaccine indicating that the loss of anti-MOG reactivity was not reflective of a lack of capacity for longstanding IgG responses. Human anti-MOG antibodies are mainly of the IgG1 isotype, which can activate complement and antibody dependent cellular cytotoxicity. Upon binding to MOG in the CNS, human anti-MOG antibodies are hence expected to cause demyelination. Transfer experiments with purified human anti-MOG antibodies have not been performed yet. The fact that the majority of human anti-MOG antibodies did not recognize rodent MOG has implications for animal studies. Using the described assay will help to identify patient samples appropriate for these transfer experiments and finally lead to the formal proof of the pathogenicity of human anti-MOG antibodies. This work also gives important information for future detection of potential mimotopes and the development of anti-MOG antibody detection assays and might pave the way to antigen-specific depletion.

Ziel der Arbeit war der Einfluss verschiedener Belichtungskonzepte (16 verschiedene Belichtungsmodi) auf die Eigenschaften moderner Bulk-fill Komposite zu eruieren. Material und Methode: Sieben Bulk-Fill Materialien wurden nach Belichtung mit einer blau/violett LED Polymerisationslampe untersucht. Hierbei wurde das Inkrement unter direkten Kontakt der Lampe (Abstand 0mm) und im Abstand von 7mm ausgehärtet. Der Abstand von 7mm sollte die klinische Situation simulieren, in welcher eine direkte Platzierung der Polymerisationslampe am Inkrement nicht möglich ist. Außerdem wurde die Polymerisationszeit variiert. Die Aushärtung erfolgte bei einer Lichtintensität von 1.000mW/cm² („Standard“) für eine kurze Polymerisationszeit von 5s und eine längere Polymerisationszeit von 20s sowie 40s. Des Weiteren bei Intensität von 1.400mW/cm² („High“) für 3s, 4s, 8s und bei Intensität von 3.200/cm² („Plasma“) für eine Polymerisationszeit von 3s sowie 6s. Die Analyse wurde in einer individuellen, speziell für diese Studie angefertigten, zylindrischen Matrize, deren Kern aus einem trepanierten Molar bestand, vorgenommen. Die Polymerisation der Proben (n=5) erfolgte dabei in einen Spektrometer, was die real-time Variation der Irradianz an der Unterseite der Probe erlaubte. Die so gewonnenen Proben (n=5) der Inkrementstärke von 6mm wurden für 24 Stunden in destilliertem Wasser bei 37°C gelagert, aufbereitet und in einem Universalhärtemessverfahren in axialer Richtung hinsichtlich der Vickershärte, Intendierungsmodul, Kiechen und elastische Arbeit (Messpunktabstand 200µm) vermessen. Ergebnisse: Mit dem höheren Abstand der Polymerisationslampe (7mm) von dem Inkrement halbierte sich die einwirkende Lichtleistung sowie Gesamtenergie. Bei der Auswertung der max. Inkrementdicke zeigte sich, dass sich eine lange Polymerisationszeit (20s, 40s) bei der Lichtintensität „Standard“ (1.000mW/cm²) unter direktem Kontakt der Polymerisationslampe am günstigsten auf die Aushärtetiefe auswirkte Schlussfolgerungen: Es zeigte sich eine gute Polymerisationsgüte an der Probenoberfläche, welche in der Tiefe des Materials, besonders bei einer niedrigen applizierten Gesamtenergie, stärker abnahm. Die vom Hersteller vorgegebene max. Inkrementdicke von 4mm konnte in den Versuchen unter Einwirkung einer hohen Gesamtenergie auf die Probe zu meist übertroffen werden. Eine hohe Gesamtenergie wird durch eine lange Polymerisationszeit, hohe Lichtleistung sowie inkrementnahe Positionierung der Lampe erzielt. Im Allgemeinen können die untersuchten Bulk-Fill Komposite in einer Schichtstärke von 4mm bei einer Polymerisationszeit von 20s und einer Lichtintensität von 1.000mW/cm² suffizient gehärtet werden. Eine längere Polymerisationszeit wirkt sich günstiger auf die Aushärtetiefe aus. Aufgrund der Reziprozität zwischen Bestrahlungsdauer und Bestrahlungsstärke kann bei einer höheren Lichtintensität die Polymerisationszeit entsprechend reduziert werden.

Chronic fatigue syndrome is not a sleep apnoe syndrome subgroup