Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 15/19

Wed, 16 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16176/ https://edoc.ub.uni-muenchen.de/16176/1/Richter-Hallgarten_Henry_George.pdf Richter-Hallgarten, Henry George

Wed, 16 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16180/ https://edoc.ub.uni-muenchen.de/16180/1/Zaharieva_Magdalena.pdf Zaharieva, Magdalena

Wed, 16 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16186/ https://edoc.ub.uni-muenchen.de/16186/1/Klein_Katharina_Leila.pdf Klein, Katharina Leila

Die Schizophrenie, eine psychiatrische Erkrankung mit stärksten Auswirkungen auf Wahrnehmung, Gedanken und Emotionen der Patienten, tritt weltweit bei etwa einem Prozent aller Menschen auf. Ihre genaue Ursache ist bisher weitgehend ungeklärt. Neben Umweltfaktoren spielt die genetische Komponente eine herausragende Rolle, wobei nicht ein Gen alleine beteiligt ist, sondern ein Zusammenspiel verschiedener Gene als Auslöser vermutet wird.Die Erforschung solcher Suszeptibilitätsgene kann zu besserem Verständnis der Ätiopathogenese der Erkrankung führen und schließlich zu neuen Ansätzen in Diagnose und Therapie. Zahlreiche funktionelle Kandidatengene der Schizophrenie, allen voran der Dopaminrezeptor D2, unterliegen der Regulierung durch Retinoidrezeptoren, welche dadurch selbst zum Gegenstand der Forschung werden. In vorliegender Arbeit wird das Gen des Retinoidrezeptor RXR gamma (RXRG-Gen) untersucht, das sich auf Chromosom 1q22-23 befindet. In einer Fall-Kontroll-Assoziationsstudie mit 287 Schizophrenie¬patienten und 421 gesunden Kontrollpersonen als Probanden werden zwei Einzelbasenaustausch-Polymorphismen – einer ist innerhalb der potentiellen Promotorregion lokalisiert, der andere befindet sich auf Exon 8 –auf einen Zusammenhang mit Schizophrenie untersucht.Bei den Allel- und Genotypfrequenzen der Polymorphismen rs1467664 und rs2134095 zeigte sich keine signifikante Assoziation mit Schizophrenie, bei rs1467664 konnte der homozygote Genotyp des selteneren Allels Guanin im Vergleich zu den zusammengefaßten beiden anderen Genotypen einen Trend in Richtung Assoziation aufweisen. Um eine Beteiligung des RXR gamma bei der Entstehung der Schizophrenie endgültig klären zu können, müßten noch andere Polymorphismen des Gens flächendeckend untersucht und ein stärkeres Augenmerk auf das Wechselspiel mit anderen Genen gelegt werden, da eine isolierte Betrachtung eines Gens innerhalb der Ätiologie einer so komplexen Erkrankung wie die der Schizophrenie zu wenig Aussagekraft hat.

Tue, 15 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/17526/ https://edoc.ub.uni-muenchen.de/17526/1/Leroy_Celine.pdf Leroy, Céline ddc:610, ddc:600, Medizinische Fakultät

Thu, 10 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16178/ https://edoc.ub.uni-muenchen.de/16178/1/Neumann_Carla.pdf Neumann, Carla ddc:610,

Die sichere präoperative Abgrenzung maligner Befunde ist ein essentieller Schritt zur optimalen Therapie des Ovarialkarzinoms. Mit dem Ziel, die präoperative Diagnostik um einen zuverlässigen, wenig invasiven Test zu ergänzen, wurden in 92 Serumproben von Patientinnen mit Ovarialkarzinomen und benignen Raumforderungen im Adnexbereich die Spiegel des in der Diagnostik etablierten Markers CA 125 sowie der potentiellen neuen Biomarker HE4, CA 72-4, Galektin-1 und Galektin-3 bestimmt. Um mehr über die Rolle der Galektine in der Biologie maligner Ovarialtumore zu erfahren, wurden 111 histologische Präparate, ebenfalls von an malignen und benignen Adnextumoren erkrankten Patientinnen, auf die Expression von Galektin-1 und -3 hin untersucht. Bei den Untersuchungen des Serums war CA 125 der beste Einzelmarker und zeigte mit einer Fläche unter der Kurve (AUC) von 0,944 eine gute Diskriminationsfähigkeit zwischen Karzinomen und benignen Erkrankungen. Besonders gute Ergebnisse erzielten wir mit einer AUC von 0,897 auch mit dem neuen Marker HE4. Das Glykoprotein hat sich jedoch nicht nur bei unseren Untersuchungen, sondern auch in zahlreichen anderen Studien gegenüber dem etablierten Marker CA 125 als ebenbürtig erwiesen. CA 72-4 zeigte mit einer AUC von 0,726 eine mittlere Genauigkeit bei der Bestimmung der Tumordignität. Es zeichnete sich aber durch eine hervorragende Spezifität von maximal 98,2 % aus, so dass bei positivem CA 72-4 mit hoher Wahrscheinlichkeit von einem malignen Tumor ausgegangen werden muss. Galektin-1 (AUC 0,609) und Galektin-3 (AUC 0,71) sind dem etablierten Marker CA 125 in der Diagnostik des Ovarialkarzinoms weit unterlegen und daher allenfalls als ergänzende Marker geeignet. Um zusätzliches Differenzierungspotential zu erhalten haben wir unter Einbeziehung der in einer bereits veröffentlichten Arbeit unserer Forschungsgruppe untersuchten Marker jeweils zwei Biomarker miteinander kombiniert. Tatsächlich konnte die Vorhersagefähigkeit durch mehrere Kombinationen gegenüber der von CA 125 verbessert werden. Unsere beste Kombination war, mit einer AUC von 0,961, die aus CA 125 und HE4. Das entspricht einem Zuwachs von immerhin 1,7 % gegenüber dem besten Einzelmarker CA 125 (AUC 0,944). Bei auffälligem Sonographiebefund könnte die Bestimmung dieser beiden Marker in Zukunft helfen, Patientinnen mit hohem Risiko für ein Ovarialkarzinom präoperativ frühzeitig zu identifizieren. Hinsichtlich der Expression der Galektine 1 und 3 im Gewebe fiel eine besonders starke Akkumulation von Galektin-1 im karzinomassoziierten Stroma auf. Dieses Expressionsmuster wird auch von anderen Arbeitsgruppen im Zusammenhang mit verschiedenen Malignomen beschrieben und oftmals als Zeichen maligner Progression gewertet. Wir hoffen, dass die durch unsere Untersuchungen gewonnen Erkenntnisse über das Expressionsmuster der Galektine in Ovarialkarzinomen zur Durchführung weiterführender Studien anregen, da das Potential dieser Proteine gerade in einer möglichen Entwicklung neuer therapeutischer Ansätze und der Gewinnung neuer Erkenntnisse über das Wechselspiel zwischen malignen Zellen und dem Immunsystem groß zu sein scheint.

Thu, 10 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16231/ https://edoc.ub.uni-muenchen.de/16231/1/Held_Hanns-Christoph.pdf Held, Hanns-Christoph ddc:610, ddc:600, Medizinische F

Thu, 10 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16162/ https://edoc.ub.uni-muenchen.de/16162/1/Avila_Ferrufino_Alejandro.pdf Avila Ferrufino, Alejandro

Thu, 10 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16376/ https://edoc.ub.uni-muenchen.de/16376/1/Mack_Ines.pdf Mack, Ines ddc:610, ddc:600, Medizinische Fakult

Thu, 10 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16174/ https://edoc.ub.uni-muenchen.de/16174/1/Le_Bras_Emmanuelle.pdf Le Bras, Emanuelle

Wed, 9 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16390/ https://edoc.ub.uni-muenchen.de/16390/1/Autenrieth_Christine_S.pdf Autenrieth, Christine S. ddc:610, ddc:600, Medizinische Fakultät

Wed, 2 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16168/ https://edoc.ub.uni-muenchen.de/16168/1/Petersen_Ann-Kristin.pdf Petersen, Ann-Kristin ddc:610, ddc:600, Medi

Thu, 26 Sep 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/17494/ https://edoc.ub.uni-muenchen.de/17494/1/Aronshtam_Yulia.pdf Aronshtam, Yulia ddc:610, ddc:600, Medizinisch

Mon, 23 Sep 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16685/ https://edoc.ub.uni-muenchen.de/16685/1/Priller_Markus.pdf Priller, Markus ddc:610, ddc:600, Medi

Astrocytes present a major population of glial cells in the adult mammalian brain. The heterogeneity of astrocytes in different regions of the healthy central nervous system (CNS) and their physiological functions are well understood. In contrast, rather little is known about the diversity of astrocyte reactions under pathological conditions. After CNS injury the reaction of astrocytes, also termed ‘reactive astrogliosis’, is characterized by morphological and molecular changes such as hypertrophy, polarization, migration and up-regulation of intermediate filaments. So far, it was unknown whether all astrocytes undergo these changes, or whether only specific subpopulations of reactive astrocytes possess special plasticity. Since some quiescent, postmitotic astrocytes in the cortical gray matter apparently de-differentiate and re-enter the cell cycle upon injury, reactive astrocytes have the ability to acquire restrictive stem cell potential. However, the mechanisms leading to increased astrocyte numbers after acute injury, e.g. proliferation and migration, had not been investigated live in vivo. For the first time, recently established in vivo imaging using 2-photon laser scanning microscopy (2pLSM) allowed to follow single GFP-labeled astrocytes for days and weeks after cortical stab wound injury. Tracing morphological changes during the transition from a quiescent to reactive state, these live observations revealed a heterogeneous behavior of reactive astrocytes depending on the lesion size. Different subsets of astrocytes either became hypertrophic, polarized and/ or divided, but never migrated towards the injury. Intriguingly, the lack of astrocyte migration was not only contradictory to what had been predicted based on in vitro and in situ studies, but was also in stark contrast to the motility of other glial cells. Additionally, live imaging provided first evidence that only a small subset of reactive astrocytes in juxtavascular positions re-gains proliferative capacity after injury. While astrocyte proliferation was affected by conditional deletion of RhoGTPase Cdc42 – a key regulator of cell polarity –, the vascular niche was preserved, indicating that juxtavascular astrocytes are uniquely suited for proliferation after injury. Following the behavior of cdc42-deficient astrocytes by live imaging using an in vitro scratch wound assay, cell-autonomous effects including disturbed polarity and impaired directional migration confirmed a crucial role of Cdc42 signaling in reactive astrocytes after acute injury in vitro and in vivo. These novel insights revise current concepts of reactive astrocytes involved in glial scar formation by assigning regenerative potential to a minor pool of proliferative, juxtavascular astrocytes, and suggesting specific functions of different astrocyte subsets after CNS trauma.

Thu, 19 Sep 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16806/ https://edoc.ub.uni-muenchen.de/16806/1/Chachage_Mkunde.pdf Chachage, Mkunde ddc:610, ddc:600, Medizinische Fakultät

Background: Asthma and allergies are world-wide common chronic diseases among children and young people. Little is known about prevalence and environmental and dietary risk factors of asthma and allergies among rural and urban school children in Bolivia. The aim of this study was to describe the prevalence, severity and risk factors associated with asthma, rhinoconjunctivitis, and eczema symptoms in children of school age in Oropeza Province – Bolivia. Methods: Overall, 2584 children (response 91%) attending fifth elementary grade in Oropeza province answered the written and the video questionnaire of the International Study on Asthma and Allergies in Childhood. Lifetime, 12 months and severity prevalence were determined for asthma, rhinoconjunctivitis and eczema symptoms. The associations between: environmental and dietary factors and symptoms of asthma, rhinoconjuctivitis and eczema symptoms were analysed using logistic regression analysis with adjustment for age, sex and place of living. Results: Median age of children was 11 years, 52% were female and 26% lived in rural areas. The prevalence of asthma symptoms was higher in the written (18%) than in the video questionnaire (6%). 22% of children reported symptoms of rhinoconjunctivitis and 9% eczema symptoms. Overall, rural children reported more frequently symptoms of asthma and allergies than urban children. Parental smoking (adjusted OR 1.3; 95%IC 1.0-1.6), presence of disease vectors at home (fourth quartile vs. first quartile: 1.5; 1.1-2.2) and farm animals (1.3; 1.0-1.6) were statistically significant predictors of asthma symptoms detected by the written questionnaire. The associations were similar for symptoms of rhinoconjunctivitis and eczema. A greater adherence to the Mediterranean Diet (MD) was inversely related with asthma symptoms in the video questionnaire (reference category: 1st quartile; second quartile 0.6; 0.3-0.9, third quartile 0.7; 0.4-1.2, fourth quartile 0.6; 0.3-1.0) Conclusion: Our results suggest that promoting a healthy diet and reducing exposure to modifiable risk factors like environmental tobacco smoke, precarious housing conditions and certain disease vectors would have a significant positive impact on asthma and allergies morbidity in children in this region.

Tue, 17 Sep 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/17493/ https://edoc.ub.uni-muenchen.de/17493/1/Nicoli_Francesco.pdf Nicoli, Francesco ddc:610, ddc:600, Medizinische Fakultät

Mon, 16 Sep 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16821/ https://edoc.ub.uni-muenchen.de/16821/1/Nji_Akindeh_Mbuh.pdf Nji, Akindeh Mbuh ddc:610,

Mon, 16 Sep 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16830/ https://edoc.ub.uni-muenchen.de/16830/1/Paudel_Deepak.pdf Paudel, Deepak ddc:610, ddc:6

Thu, 12 Sep 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16823/ https://edoc.ub.uni-muenchen.de/16823/1/Zhao_Yue.pdf Zhao, Yue

Tue, 10 Sep 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16109/ https://edoc.ub.uni-muenchen.de/16109/1/Stawarczyk_Bogna.pdf Stawarczyk, Bogna ddc:610, ddc:600, Medizinische Fakultät

Tue, 10 Sep 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16126/ https://edoc.ub.uni-muenchen.de/16126/1/Scherl_Andre.pdf Scherl, Andre ddc:610, ddc:600, Medizinische Fakultät

Chromosomal translocations are common in human leukemias. Detailed studies of chromosomal translocation have been useful in understanding the pathogenesis and identifying therapeutic targets in hematologic malignancies. Some translocations result in the formation of fusion genes. These fusion proteins play an important role in leukemogenesis. The t(10;11)(p12;q14) translocation is rare but recurring and results in the formation of the CALM/AF10 fusion protein. Patients with this translocation have a bad prognosis. To understand how CALM/AF10 leads to leukemia, various mouse models have been established. In a murine bone marrow retroviral transduction and transplantation model Deshpande et al. (2006) showed that mice expressing CALM/AF10 in their bone marrow cells developed an acute myeloid leukemia with a penetrance of 100% and a short latency period of 110 days. Using a transgenic mouse model, in which CALM/AF10 was under the control of Vav promoter, Peter Aplan and colleagues demonstrated that only 40% to 50% of mice developed leukemia after a long latency of 10 to 12 months. Two classical transgenic CALM/AF10 models were established in our group using the immunoglobulin heavy chain enhancer/promoter (IgH-CALM/AF10) and proximal murine LcK promoter (pLck-CALM/AF10) to drive CALM/AF10 expression. These transgenic mice did not show any leukemic phenotype even after an observation period of 15 months. Taken together these studies strongly suggest that additional collaborating factors are required for the CALM/AF10 fusion gene to induce leukemia. Meis1, a Hox cofactor, is known to collaborate with several Hox genes and Hox fusion genes such as HOXA9 and NUP98-HOXD13. In these studies, Meis1 played a critical role in accelerating the development of leukemia. It could also be shown that MEIS1 is highly expressed in CALM/AF10 positive human leukemia cells. Therefore, I sought to determine whether the homeobox gene Meis1 collaborates with CALM/AF10 in inducing leukemia. In order to achieve this goal, lethally irradiated non-transgenic mice were transplanted with IgH-CALM/AF10 transgenic bone marrow cells transduced with a Meis1 expressing retrovirus. The transplanted mice developed an acute leukemia with a penetrance of 100% and a median latency period of 187 days. The leukemia showed predominantly myeloid features such as the presence of myeloid marker positive cells. The myeloid blast cells infiltrated in multiple hematopoietic as well as non-hematopoietic organs. The leukemic cells were also positive for the B-cell marker B220. Cells that were positive for both lymphoid and myeloid markers, a characteristic feature of CALM/AF10-induced leukemia, were also detected in all the mice. The leukemic cells had clonal DJH rearrangements. Overall, these data suggest that the transformed cell might be an early progenitor cell capable of lymphoid as well as myeloid differentiation or that the leukemia was initiated by a B220+ IgH DJ rearranged cell with blocked lymphoid differentiation, which started a default myeloid differentiation program. By performing serial secondary and tertiary transplantations the leukemic nature of the disease could be confirmed. Colony forming cell assays showed that CALM/AF10 in collaboration with Meis1 failed to induce the transformation of hematopoietic progenitors in vitro. This could either be due to the lack of required growth factors and conditions necessary for the proliferation of the transformable cell or lack of additional events essential for progression towards leukemia development. In conclusion, I have demonstrated that Meis1 collaborates with CALM/AF10 in inducing acute myeloid leukemia. Additional, detailed analyses of the leukemia initiating cell in these models would help to better understand the pathogenesis of CALM/AF10-induced leukemia.

Background: Childhood overweight has become a growing public health challenge. It has been suggested that inadequate or excessive gestational weight gain (GWG) may result in permanent metabolic and neuronal changes in the developing fetus. Although effects of GWG on birth weight are established, less is known about its effects on the long-term weight status of the child. In 2009, the Institute of Medicine (IOM) and the National Research Council (NRC) published recommendations for trimester-specific and total GWG depending on maternal pre-pregnancy body mass index (BMI). It is unknown, however, how well the trimester-specific IOM/NRC recommendations for GWG identify women at risk of total GWG outside those recommendations. It is also unknown, whether a reverse from excessive GWG in early or mid-pregnancy reduces the risk of childhood overweight. Aims: Contribute to the existing knowledge on the association between GWG and childhood overweight (study 1). Examine whether and to what extent inadequate or excessive total GWG can be predicted in the first, second and third trimester, based on trimester-specific GWG cut-off values (study 2). Investigate whether a reverse from excessive GWG before the third trimester is associated with a risk reduction of childhood overweight (study 3). Methods: A retrospective cohort study was conducted. The sample was recruited prior to the school entry health examinations in 2009 and 2010. Data on maternal weight was derived from medical records and child’s anthropometric data were measured. From 11,730 mother-child pairs available, 6,837 were included in study 1, 7,962 in study 2 and 6,767 in study 3. To investigate the effect of total GWG, overall and stratified by maternal pre-pregnancy BMI, and reverse from excessive GWG in early or mid-pregnancy, multivariate logistic regression analyses were conducted including a large number of potential confounders. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. The prognostic values of lower and upper trimester-specific GWG cut-off values were examined by calculating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and positive diagnostic likelihood ratio (DLR+). Results: 1) Overall, the risk of childhood overweight increased by 4% per additional kg GWG (OR: 1.04, 95% CI: 1.02, 1.05). Excessive total GWG was associated with a 57 % higher risk of childhood overweight (OR: 1.57, 95% CI: 1.30, 1.91). Stratified by maternal pre-pregnancy BMI, significant associations between excessive GWG and childhood overweight found among normal weight mothers (OR: 1.29, 95% CI: 1.01, 1.66) and overweight mothers (OR: 1.64, 95% CI: 1.06, 2.63). 2) Prediction of total GWG within the IOM/NRC recommendations increased with gestational age and was related to the maternal BMI category and outcome. In trimester two, inadequate total GWG could be predicted with a sensitivity of 49% and 60.2% and a PPV of 72.1% and 68.3% in underweight and normal-weight mothers, respectively. Excessive GWG could be predicted with a sensitivity of 72.7% and 70.4% and a PPV of 94.3% and 93.3% in overweight and obese mothers, respectively. 3) Compared to mothers who always gained below the excessive GWG cut-off values (reference category), children of mothers with excessive GWG in the third and any previous trimester had a 42% higher risk of overweight at school entry (OR: 1.42, 95% CI: 1.17, 1.72). There was a 39% higher risk if mothers gained excessively in the third trimester only (OR: 1.39, 95% CI: 1.06, 1.82). No higher risk was observed for mothers who reversed from excessive GWG before the third trimester compared to reference category. Conclusions: Excessive total GWG appears to be a risk factor for childhood overweight. It can be well predicted from the second trimester on, in particular in overweight and obese women. Reverse from excessive GWG before the third trimester may reduce the risk of childhood overweight. More research is required to further establish the strength of association between GWG and childhood overweight. It appears possible to identify women at risk of gaining outside the recommendations as early as the second trimester. Those women should be allocated to appropriate weight modifying measures. The long-term benefit of GWG modifying measures on childhood overweight, especially a reverse from excessive GWG in the first or second trimester, should be investigated in randomised controlled studies.

Thu, 25 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16094/ https://edoc.ub.uni-muenchen.de/16094/1/Scholtz_Jan-Erik.pdf Scholtz, Jan-Erik ddc:610, ddc:600, Medizinisch

Thu, 25 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16165/ https://edoc.ub.uni-muenchen.de/16165/1/Zeller_Judith.pdf Zeller, Judith

Thu, 25 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15986/ https://edoc.ub.uni-muenchen.de/15986/1/Rainer_Sophie.pdf Rainer, Sophie ddc:610, ddc:600, Medizinische Fakultät

Purpose The aim of this study was to establish a method to examine acute ischemic pain in humans using the example of adenosine. Materials and Methods 11 patients with unilateral peripheral arterial disease (PAD) performed a treadmill exercise until intolerable exercise-induced ischemic pain. Blood gas analysis (BGA) and blood samples were taken before treadmill examination (baseline), directly after treadmill examination and after recovery. The ankle-brachial index (ABI) and systemic blood pressure was measured at the same time. The ABI was measured via conventional Doppler method. High-performance liquid chromatography (HPLC) was used to determine the purine adenosine and its metabolite inosine. S100B-serum levels were detected via Elecsys® S100B Immunoassay (Roche Diagnostics, Penzberg Deutschland). Results Treadmill exercise lead to intolerable exercise-induced ischemic pain in the PAD affected leg. ABI decreased to pathological values. BGA and blood samples showed typical ischemic changes. A systemic increase in adenosine levels was measured, whereas no local increase in the PAD affected leg could be found. A correlation between S100B and peripheral nerve damage could not be found. Conclusion The established method is an effective model to examine acute ischemic pain in humans.

Thu, 25 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16002/ https://edoc.ub.uni-muenchen.de/16002/1/Gloning_Anna.pdf Gloning, Anna

Thu, 25 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16067/ https://edoc.ub.uni-muenchen.de/16067/1/Hauer_Johannes_S.pdf Hauer, Johannes Sebastian ddc:610, ddc:600, Medizinische Fakultät 0

Die Rolle, die die hydrophoben Surfactantproteine SP-A und SP-D welche in den oberflächlichen Atemwegsflüssigkeiten zu finden sind spielen lässt sich wie folgt zusammenfassen. Zum einen, eine wichtige immunologische Funktion, indem sie zur Abwehr von Erregern beitragen. Zum anderen, bei der Regulation allergischer Reaktionen, bei welcher der eosinophile Granulozyt mit den von ihm freigesetzten Entzündungsmediatoren als wichtigste Effektorzelle zu nennen ist. Ziel dieser Arbeit war es den Einfluss der Surfactantproteine A und D auf eosinophile Granulozyten in Bezug auf ihre ECP-Degranulation zu untersuchen. In verschiedenen Versuchsreihen wurde die Freisetzung von Eosinophilem kationischem Protein (ECP) ohne (native Zellen) und nach Stimulation der Zellen mittels Fluoreszenzassay gemessen. Als Stimulanzien kamen Ca-Ionophore A23187 als eine potenter, wenn auch unphysiologischer Zellstimulus und die Immunglobuline A und G, sowie das Serum eines Allergikers als physiologische Stimuli zum Einsatz. Die Ergebnisse zeigten, dass durch die Surfactantproteine selbst keine Aktivierung der ECP-Freisetzung aus nativen eosinophilen Zellen ausgelöst werden kann. Die Degranulation stimulierter Zellen hingegen kann durch natürliches SP-A, SP-D und rekombinantes SP-D reduziert werden. Die wirksamen SP-D Konzentrationen lagen zwischen 0,05 und 5000ng/ml, wenn die Zellen mit Ca-Ionophore stimuliert wurden. Wurden IgA und IgG als Stimuli verwendet, konnte die ECP-Degranulation durch SP-A, SP-D und rekombinantes SP-D ebenfalls gehemmt werden, zeigte sich jedoch in keiner Konzentration signifikant. Bei der Stimulation mit Allergikerserum zeigten sowohl SP-A, SP-D als auch rekombinantes SP-D eine hemmende Wirkung. Zusammenfassend zeigen unsere In-vitro-Ergebnisse eine inhibitorische Wirkung von SP-A und D auf die ECP-Degranulation aus stimulierten eosinophilen Granulozyten. Dies ist mit der Hypothese einer protektiven Wirkung dieser Surfactantproteine bei Erkrankung aus dem allergischen Formenkreis vereinbar.

Neuroendocrine tumors are a heterogeneous group of malignancies with an increasing prevalence. Since there is not much progress in therapy, model systems are urgently needed. We have a CEA424-SV40 TAg transgenic mouse model which develops spontaneous tumors in the antral region of the stomach. In addition, several cell lines derived from the tumor were established. Gene expression analysis of the tumor tissue as well as cell lines revealed neuroendocrine markers. Therefore we further characterized this model with special emphasis on the cells of origin and used it for testing new targeted treatment protocols. To analyze CEA424-SV40 TAg mouse model in more detail, tumor tissue as well as the cell lines derived from the primary tumor were investigated by immunohistochemistry, immunofluorescence, western blot, and ELISA. Antibodies used were directed at SV40 TAg, Ki-67, chromogranin A, chromogranin B, secretin, H+-K+-ATPase, glucagon, and transcription factors NeuroD1 and Nkx2.2. Plasma hormone levels of serotonin and secretin were measured by ELISA. Immunostainings of SV40 TAg and Ki-67 revealed highly proliferative tumors cells. The tumors stained intensively for the neuroendocrine markers chromogranin A, chromogranin B, secretin and glucagon. The tumor tissue as well as the cell lines expressed transcription factors NeuroD and Nkx2.2, which are involved in the differentiation of the neuroendocrine lineage. Hormone levels of serotonin and secretin in the plasma of the transgenic mice were dramatically elevated when compared with normal littermates, thus supporting the neuroendocrine phenotype. As the neuroendocrine phenotype of CEA424-SV40 TAg transgenic mouse was confirmed, molecularly targeted therapies were tested in this model system both in vitro and in vivo. Cell lines were tested for drug sensitivity with mTOR inhibitors (RAD001, NVP-BEZ235), paclitaxel, E2F inhibitor, HSP90 inhibitor, and p53 stabilizer Nutlin-3a. All the drugs tested in vitro could efficiently inhibit cell proliferation in a dose dependent manner. From these drugs the mTOR inhibitor RAD001 was chosen for the in vivo experiment. Daily feeding of 10 mg/kg RAD001 inhibited the tumor development and prolonged the survival time of the CEA424-SV40 TAg transgenic mice dramatically. The effects of the RAD001 treatment on tumor cells were achieved mainly through inactivating mTOR-p70S6K and mTOR-4EBP1 signaling as proven by western blot and immunohistochemistry. Still, some cells must develop escape mechanisms, since the tumor tend to grow. To gain a better understanding of the T antigen transforming mechanisms as well as the possible escape mechanisms, some efforts were made on the tumor originating cells in the CEA424-SV40 Tag transgenic mouse model. Possible candidates for these tumor originating cells in the stomach are the newly described epithelial as well as mesenchymal stem cells. In a first attempt, the expression feature of epithelial and mesenchymal stem cell markers were analyzed. Established cell lines as well as tumor tissue from the tumor bearing mice were investigated by reverse transcription PCR (RT-PCR), immunohistochemistry, immunofluorescence, western blot, and microarray analysis. From several markers analyzed, the tumor cell lines showed a high expression level of the potential epithelial stem cell marker Bmi1 in RT-PCR and cDNA expression array. This could be further substantiated by western-blotting and immunostaining. Consequently, Bmi1 message could also be found in the growing tumors both in mRNA and protein levels. Experiments using siRNA to knock down the SV40-TAg expression showed that the Bmi1 expression went down in the cell lines thus showing the interrelationship. On the other hand, the mesenchymal stem cell marker Etv1 was also found to be expressed in the tumor tissue and cell lines derived from the tumor. More interestingly, Etv1 expression level was up-regulated over the time course of the tumor development. From these, an Etv1 positive mesenchymal cell could be a possible candidate for transformation. Since the CEA-promoter used for the generation of the T-antigen transgenic animals contains Etv1 binding sites, it is tempting to speculate, that this may drive the transcription of the T antigen. In conclusion, our data provide convincing evidence that CEA424-SV40 TAg mice are a clinically relevant model for neuroendocrine tumor. Testing of molecularly targeted therapies both in vitro and in vivo offered promising candidates for further clinical evaluation. Thus, this new model system could be of great value not only for studies on the mechanisms of how SV40 TAg induces neuroendocrine tumors but also for exploring novel targeted therapy in a preclinical setting.

Thu, 18 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15939/ https://edoc.ub.uni-muenchen.de/15939/1/Guertler_Verena.pdf Gürtler, Verena

In this prospective study we investigated the impact of the proton pump inhibitor (PPI) pantoprazole on the bioavailability of mycophenolic acid (MPA) after oral administration of enteric-coated mycophenolate sodium (EC-MPS; Myfortic) in heart or lung transplant recipients. Previously we demonstrated that pantoprazole reduces the MPA exposure of mycophenolate mofetil (MMF; CellCept) by 34% in area under the concentration-time curve (AUC). Because gastrointestinal side-effects are common after organ transplantation, we investigated the effect of PPI on MPA levels in patients receiving EC-MPS. MPA plasma concentrations and inosine monophosphate dehydrogenase (IMPDH) activity at baseline, 30 minutes and 1, 2, 3 and 4 hours were obtained from 21 patients. These patients were treated with pantoprazole 40 mg once daily and EC-MPS twice daily at a mean dose of 960 mg. Measurements were repeated after pantoprazole withdrawal. MPA concentrations and IMPDH activities did not reveal any significant difference during PPI treatment and after withdrawal. MPA AUC, MPA C(max) (maximal MPA concentration), the time until C(max) was reached (T(max)) and IMPDH activity AUC all showed no significant difference. We did not find an influence of pantoprazole on EC-MPS pharmacokinetics such as we did for MMF in our previous investigation. A further prospective, large, cross-over study is planned to support these preliminary results. Given that MPA exposure by AUC correlates with the incidence of acute rejection episodes and transplant vasculopathy, the present findings may have clinical implications.

Xenotransplantation is thought to have the potential to solve the critical shortage of donor’s hearts with the development of genetically modified organ-source pigs and improvement of immunosuppressive strategies. As an appropriate preclinical animal model, the pig-to-baboon cardiac xenotransplantation model has been widely adopted. Traditionally, the evaluation of cardiac xenograft function in a pig-to-baboon model has been accomplished by means of palpation, ultrasound and biopsy. However, those methods pose increased risk of complications such as bleeding, infection, and apnea, leading to increased morbidity and mortality. Telemetric monitoring systems have been widely applied in the life science research involving a wide variety of animal models. These systems enable non-invasive, reliable and continuous measurements of cardiac xenograft function and provide information valuable for the improved understanding of transplantation pathophysiology. Importantly, these systems do not only avoid repeated anesthesia of the animals but also allow measurements independent from the effects of anesthetics. In preclinical pig-to-baboon xenotransplantations, telemetry systems have only been used in the heterotopic abdominal experiments. The aim of this study was the evaluation of a telemetry system for the monitoring of cardiac xenograft function after heterotopic thoracic cardiac xenotransplantation. Seven baboons underwent heterotopic thoracic cardiac xenotransplantation, for which double or triple transgenic pigs were used as donors. Hemodynamic parameters such as left ventricular peak systolic pressure (LVPSP), left ventricular end diastolic pressure (LVEDP), heart rate (HR), maximal rate of rise or decline of left ventricular pressure (±dP/dtmax), deviation of S-T segment, and the duration and amplitude of QRS complex in electrocardiogram (QRSA) were continuously monitored, using a telemetry system (DSI, St. Paul, MN, USA). Postoperatively, the serum levels of anti-pig antibodies (APA) were analyzed using a hemolytic assay with pig erythrocytes and the serum level of troponin was determined by the clinical laboratory on a daily basis. Based on the changes of troponin levels and APA levels, the baboons were grouped into elevated and unelevated. All parameters were compared between groups and between days. During the last two days of their survival, LVPSP, HR, +dP/dtmax, -dP/dtmax and QRSA were significantly lower in the baboons with elevated troponin compared to the group with unelevated troponin. Regarding specifically the group of baboons with elevation of troponin, the following observation was made: LVPSP, HR, -dP/dtmax, and QRSA decreased significantly on the day elevation of troponin was observed and the next day. In addition, The decrease of the parameter +dP/dtmax was significant one day after troponin increased. In contrast, the analysis of the group of baboons with elevated anti-pig antibodies revealed no significant changes in hemodynamic or electrocardiographic parameters before and after the rise of antibodies. In conclusion, this study demonstrates the ability of the telemetry system to assess changes in xenograft function in the heterotopic thoracic pig-to-baboon cardiac xenotransplant model. In particular, the parameters LVPSP, HR, ±dP/dtmax and QRSA are perceived to be reliable indicators of myocardial damage associated with graft rejection at an early stage following cardiac xenotransplantation. The use of the telemetry system might help to guide immunosuppressive therapy and further improve graft survival in future experiments.

In der vorliegenden Studie wurde mit standardisierten Interviews und Selbstbeurteilungsfragebögen untersucht, ob Unterschiede in der Persönlichkeit bestehen zwischen Patienten, die wegen ihrer Alkoholabhängigkeit und solchen, die wegen ihres multiplen Substanzgebrauchs stationär behandelt werden, um damit einen weiteren Bestandteil der Abhängigkeit zu identifizieren.

Thu, 18 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16080/ https://edoc.ub.uni-muenchen.de/16080/1/Luig_Tatjana.pdf Luig, Tatjana

Thu, 18 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16081/ https://edoc.ub.uni-muenchen.de/16081/1/Pertl_Cordula.pdf Pertl, Cordula ddc:610, ddc:600, Medizinische Fakult

Thu, 18 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16140/ https://edoc.ub.uni-muenchen.de/16140/1/Zhao_Xue.pdf Zhao, Xue d

Zielsetzung und Fragestellung: Goldstandard in der Therapie des fortgeschrittenen Morbus Dupuytren ist nach wie vor die partielle Aponeurektomie mit allen bekannten Nebenwirkungen. Mit dem Ziel, neue therapeutische Strategien zu entwickeln, haben wir Zellen aus gesunder Palmaraponeurose (Kon) isoliert, molekularbiologisch charakterisiert und mit Zellisolaten der Palmaraponeurose von Patienten mit einer Erstmanifestation von Morbus Dupuytren (PrimDup) sowie von Patienten mit Morbus-Dupuytren-Rezidiv (RezDup) verglichen. Da Zellen der Palmaraponeurose von Morbus-Dupuytren-Patienten Merkmale von Stammzellen wie z.B. die Fähigkeit von Fibroblasten zu Myofibroblasten zu transdifferenzieren haben, wurde neben der Zellmorphologie und dem Integrinprofil der Zellen auf RNA-Ebene insbesondere das Wachstumsverhalten und der Stammzellcharakter untersucht.

Thu, 11 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15895/ https://edoc.ub.uni-muenchen.de/15895/1/Tremel_Christina.pdf Tremel, Christina

Thu, 11 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15919/ https://edoc.ub.uni-muenchen.de/15919/1/Orban_Mathias.pdf Orban, Mathias ddc:610, ddc:600, Medizinische Fakultä

Thu, 11 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15925/ https://edoc.ub.uni-muenchen.de/15925/1/Elster_Astrid.pdf Elster, Astrid ddc:610, dd

Thu, 11 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15932/ https://edoc.ub.uni-muenchen.de/15932/1/Schmidt_Sarah.pdf Schmidt, Sarah ddc:610, ddc:600, Medizinische Fakultät

Thu, 11 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15948/ https://edoc.ub.uni-muenchen.de/15948/1/Kunkel_Thomas.pdf Kunkel, Thomas

Die Korrektur einer angeborenen, indirekten Leistenhernie ist eine der häufigsten Operationen im Kindesalter. Zunehmend rückt hier die minimal-invasive Versorgung in den Vordergrund. In der vorliegenden Arbeit wurden retrospektiv die Daten von den 144 Patientinnen in der Klinik für Kinderchirurgie im Klinikum Dritter Orden erfasst, bei denen im Zeitraum von 1. Januar 2003 bis 31. Dezember 2010 eine minimal-invasive Korrektur bei angeborener Leistenhernie durchgeführt wurde. Bei den 144 Mädchen lagen präoperativ signifikant mehr rechtsseitige (67%) als linksseitige (21%) Leistenhernien vor. Bei 12% war eine beidseitige Leistenhernie die präoperative Diagnose. Intraoperativ fand sich bei einem Drittel der Patientinnen ein kontralateraler Processus vaginalis peritonei. Es traten zwei Rezidive im postoperativen Beobachtungszeitraum auf. Die Laparoskopie stellt ein ausgezeichnetes diagnostisches Werkzeug dar, um zum einen die klinisch unauffällige Gegenseite zu beurteilen und ggf. auch zu versorgen und zum anderen Fehlbildungen im Bereich der inneren Genitalorgane wie beispielsweise bei der testikulären Feminisierung zu erkennen. Die in dieser Arbeit aufgeführte Methode bietet eine gute Alternative zu den in der Literatur bisher beschriebenen minimal-invasiven Techniken. Ein großer Vorteil zu einigen anderen laparoskopischen Techniken liegt vor allem in der Möglichkeit des extrakorporalen Knüpfens, was auch für den Anfänger leicht durchführbar ist. Die Rezidivquote aus dieser Arbeit ist mit 1.55% sowohl vergleichbar mit der bei der konventionellen Herniotomie als auch mit den Rezidivraten anderer veröffentlichter laparoskopischer Techniken. Im Vergleich zu den meisten in der Literatur bisher publizierten Techniken ist das in dieser Arbeit beschriebene Verfahren durch perkutane Nähte ohne Präparation noch weniger traumati¬sierend und bei Mädchen problemlos durchführbar.

Thu, 11 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16015/ https://edoc.ub.uni-muenchen.de/16015/1/Waidhauser_Georg_K.pdf Waidhauser, Georg Korbinian ddc:610, ddc:600, Medizinische Fakultät

Mon, 8 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15870/ https://edoc.ub.uni-muenchen.de/15870/1/Standl_Marie.pdf Standl, Marie ddc:610, ddc:600, Medizinische Fakultä

Thu, 4 Jul 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15864/ https://edoc.ub.uni-muenchen.de/15864/1/Stephan_Nicolas.pdf Stephan, Nicolas ddc:610, ddc:600, Medizinische Fakultät