La dystrophie myotonique de type 1 (DM1) est une maladie dégénérative impliquant des symptômes d’atrophie musculaire et de myotonie. Au niveau moléculaire, elle est caractérisée par une expansion aberrante de CUG dans la région 3’UTR de l’ARNm de DMPK (Dystrophia Myotonica protein kinase). Ces répétitions CUG forment des agrégats toxiques (appelés foci) majoritairement nucléaires dans les cellules de patients DM1 et causent la séquestration anormale de ribonucléoprotéines (RBP), tel que le facteur «Muscleblind-like 1» (MBNL1), qui lieraient normalement les motifs CUG d’autres ARN. Les fonctions normales de ces RBPs seraient alors perturbées. En plus de leur rôle dans l’épissage alternatif, MBNL a récemment été caractérisé pour son implication dans la localisation intracellulaire de ses ARN cibles. Ceci suggèrerait que la pathogénèse de la DM1 pourrait résulter de l’effet perturbateur des répétitions CUG sur la localisation d’ARN précis et de protéines RBPs. À cet effet, un criblage basé sur de la microscopie fluorescente de 322 RBPs dans des myoblastes de patients DM1 a permis d’identifier des nouveaux facteurs qui colocaliseraient avec les expansions pathogéniques CUG. De plus, ces myoblastes DM1 ont été fractionnés et un séquençage-ARN a par la suite permis l’identification de transcrits délocalisés. Les deux banques de données ainsi générées, tant par le criblage que par le fractionnement/séquençage-ARN, pourraient ouvrir des nouvelles avenues de recherches dans la compréhension des anomalies moléculaires associées à la DM1, et potentiellement d’autres maladies à expansions microsatellites. / Myotonic dystrophy of type 1 (DM1) is a degenerative disorder implicating symptoms of muscular atrophy and myotony. In a molecular level, it is caused by the aberrant expansion of CUG repeats in the 3’-UTR region of the DMPK mRNA (Dystrophia Myotonica protein kinase). Excessive CUG repeats then form toxic aggregates (foci) enriched within the nucleus of DM1 patient cells. These RNA foci cause the abnormal sequestration of RNA Binding Proteins (RBP), in particular members of the Muscleblind-like protein 1 (MBNL), that normally bind the CUG motif of other target RNAs, and will hence alter their normal functions. In addition to their role in alternative splicing, MBNL1 has recently been implicated in the intracellular localisation of its RNA targets. It remains elusive whether the pathogenesis of DM1 could result from the deregulating effect of CUG repeats on the localisation of specific RNAs and RBP proteins. In this thesis, a fluorescent imaging-based screening of 322 RBPs in DM1 patient’s myoblasts has been conducted and this had led to the identification of new factors that may colocalize with pathogenic CUG expansions. Moreover, these DM1 myoblasts have been fractionated and subsequent RNA-sequencing has permitted the identification of transcripts that are delocalised between subcellular compartments. From the two large datasets generated from the RBP imaging-based screening and fractionation/RNA-sequencing, new avenues of research can be initiated to further understand not only DM1, but perhaps also other disorders that implicate microsatellite expansions.

The promyelocytic leukemia protein (PML) is a tumour suppressor. It has been reported that PML interaction with the p53 protein is involved in the activation of cell cycle checkpoints and, when persistent, may lead to the premature onset of cellular senescence. Cellular senescence is a state of permanent cell growth arrest that is associated with characteristic morphological and metabolic changes and persistent DNA damage signalling. Importantly, PML nuclear bodies coassociate with persistent DNA damage foci in senescent cells; however, the role of this interaction is still obscure. My goal was to characterize the role of PML in DNA damage response (DDR) and the induction of premature cellular senescence after genotoxic stress, namely X-radiation, using both siRNA-mediated PML knock down (PML KD) and complete PML knock out (PML KO) in human cells. The dynamics of DNA damage foci, levels of various proteins involved in DDR, and proliferation rate were measured in both PML KD and KO cells. No significant changes in the formation of DNA damage foci, activated DDR (p53 and Chk2), activated p21CIP1/WAF1 cyclin-dependent kinase inhibitor, senescent morphology, and SA-β-galactosidase activity in PML KO cells were observed. However, PML KO cells displayed higher levels of retinoblastoma protein (Rb) and...

Dietary fiber (DF) consumption is related with several healthy benefits such as the decreasing risk of colon cancer development. The DF is not digested by the digestive enzymes and reach to colon where is fermented by the colonic microbiota. The fermentation process releases metabolites as short chain fatty acids (SCFA) such as butyrate, propionate and acetate. Besides the fermentation process, the DF can directly interact with intestinal epithelial cells inducing mechanism that can also be related with the associated DF consumption benefits. The lack of information regarding DF and colon cancer are due to the complexity of both the cancer and the DF structure. The papayas DF are derived from the fruit cell wall, and they are probably naturally modified during ripening through a massive polysaccharide hydrolysis, because papayas show a very fast pulp softening. Due to the lack of information about DF and their beneficial effects to human health as well as the possibility of the natural papaya ripening to modifying the DF presented in the fruit pulp, the present thesis had as the primary objectives: 1) to evaluate how the cell-wall degrading enzymes affect the fruit cell wall solubilization and molecular weight; 2) to investigate the direct effects of the papaya pectin derived from unripe to ripe papayas in cancer cell lines, in galectin-3 interaction and in HEK cells expressing pattern recognition receptors (PRR); 3) to evaluate the human colonic in vitro fermentation using DF from unripe and ripe papayas as substrates; 4) to conduct an in vivo experiment using rats with pre-neoplastic colon lesions while receiving a diet with DF from unripe and ripe papayas. The endopolygalacturonases were the main enzymes acting on the solubilizing papaya cell wall pectin affecting both the papaya firmness and pectin structure. Overall, the papayas DF showed a ripening dependent structureeffects. In the cancer cell lines experiments, the ripe papayas pectin showed a more pronounced effects in inducing cancer cell death, inhibiting cancer cells migration and aggregation, activating PRR as toll-like receptors and inhibiting the pro-metastatic protein galectin-3. The DF from papayas also showed different aspects in colonic in vitro fermentation regarding the DF utilization by the bacteria and the bacteria abundance profile. Lastly, the animals receiving the diet with the DF from ripe papayas had less aberrant crypt foci in colon than the animals that received the DF from unripe papayas or cellulose (AIN-93G DF). Therefore, the study of papaya DF was carried out both during papaya ripening and its biological effects in vitro and in vivo, generating unprecedented results relating the endogenous biochemical changes of the fruits during maturation with the possible beneficial effects of their ingestion for health human. / O consumo de fibras alimentares (FA) está relacionado com vários benefícios à saúde como a diminuição no risco do desenvolvimento de câncer de cólon. A FA não é digerida pelas enzimas digestivas do trato gastrointestinal sendo fermentada pela microbiota intestinal do cólon. Como subproduto do processo de fermentação há a liberação de ácidos graxos de cadeia curta (SCFA) - como o butirato, o propionato e o acetato. Além do processo de fermentação, a FA pode interagir diretamente com as células epiteliais do intestino, induzindo mecanismos que também podem estar relacionados com os benefícios associados ao consumo de FA. A falta de informação sobre a FA e o câncer de cólon é, em partes, devido à complexidade de ambos, tanto do câncer quanto da estrutura da FA. As FA do mamão papaia são derivadas da parede celular da fruta apresentando diferentes estruturas dependendo do ponto de amadurecimento do fruto. Esse fato ocorre, pois, durante o amadurecimento do mamão papaia, existe uma extensa hidrólise dos polissacarídeos presentes na parede celular, diminuindo rapidamente a firmeza da polpa do fruto. Devido à falta de informações sobre FA e seus efeitos benéficos à saúde humana que são dependentes da sua estrutura, bem como a possibilidade do amadurecimento do mamão papaia naturalmente modificar as FA presentes na polpa dos frutos, a presente tese teve como principais objetivos: 1) avaliar como as enzimas que degradam a parede celular do mamão papaia afetam a solubilização e o peso molecular da parede celular do fruto; 2) investigar os efeitos diretos da pectina derivada de mamões verdes e maduros em linhagens de células de câncer, na interação com a galectina-3, e em células do tipo HEK que expressam receptores de reconhecimento de padrões (RRP); 3) avaliar a fermentação colônica humana in vitro utilizando as FA de mamões verdes e maduros; 4) avaliar em ratos com lesões pré-neoplásicas no cólon o efeito do consumo de ração com ou sem FA de mamões papaias verdes e maduros. As endopoligalacturonases foram relacionadas como as principais enzimas que atuam solubilizando a pectina da parede celular do mamão, afetando tanto a firmeza da polpa do fruto quanto a solubilização da pectina durante o amadurecimento. De modo geral, as FA dos mamões exerceram um efeito estruturadependente de acordo com a maturação do fruto. Nos experimentos utilizando linhagens de células de câncer, a pectina do mamão papaia maduro apresentou efeitos mais pronunciados na indução da morte e na inibição da migração e da agregação das células, bem como ativando os RRP, como por exemplo, os receptores do tipo toll-like, além de inibir a proteína pró-metastática galectina-3. As FA dos mamões também apresentaram diferentes resultados na fermentação colônica in vitro quanto à utilização das FA pelas bactérias do intestino, e também no perfil de crescimento dessas bactérias. Por fim, os animais que receberam a dieta com as FA dos mamões maduros apresentaram menor incidência de focos de criptas aberrantes do que os animais que receberam as FA provenientes de mamões verdes ou de celulose (FA da ração AIN-93G). Portanto, o estudo das FA dos mamões foi efetuado tanto durante o amadurecimento dos mamões quanto dos seus efeitos biológicos in vitro e in vivo, tendo gerado resultados inéditos relacionando as alterações bioquímicas endógenas dos frutos durante o amadurecimento com os possíveis efeitos benéficos da sua ingestão para a saúde humana.

O composto estudado neste trabalho foi o corante comercial CI Disperse Blue 291 (DB291), que contém o aminoazobenzeno 2-[(2-bromo-4,6-dinitrofenil)azo]-5-(dietilamino)-4-metoxiacetanilida. Esse produto é um azo-corante disperso usado largamente pelas indústrias têxteis para o tingimento de poliéster e pode ser encontrado em ambientes aquáticos oriundo da descarga de efluentes industriais, podendo levar à exposição de humanos por meio da ingestão de água ou alimentos contaminados. Portanto, faz-se importante a avaliação toxicológica do DB291. Este produto apresentou atividade mutagênica para linhagens de Salmonella typhimurium que possuem alta expressão das enzimas nitrorredutase e Ο-acetiltransferase. Tais enzimas também são expressas pelas bactérias da flora intestinal humana e de roedores e, desempenham importante papel na biotransformação de substâncias presentes na luz intestinal. O objetivo deste trabalho foi investigar a atividade do corante DB291 na indução de lesões pré-neoplásicas no cólon de ratos, avaliada pelo teste do cometa e pelo desenvolvimento de focos de criptas aberrantes (FCAs). Resultados com 2, 8, 16 e 24 semanas de tratamento demonstraram que o DB291 não foi capaz de induzir FCAs em ratos tratados por gavage com a dose de 50mg/kg de peso corpóreo, três vezes por semana em dias alternados. Entretanto, resultados com o teste do cometa demonstraram que o corante foi capaz de causar danos ao DNA das células da mucosa do cólon de ratos tratados por via intra-retal. Estes resultados sugerem que o DB291 possui atividade genotóxica in vivo. Considerando a resposta genotóxica para o teste do cometa, a alta atividade mutagênica no teste Salmonella microssoma e o recente relato de que o DP291 causou danos em células de fígado humano (HepG2), faz-se necessário a realização de testes de carcinogênese de longa duração para avaliação segura do seu potencial carcinogênico, não somente em cólon, mas em outros órgãos tais como fígado e bexiga. / The commercial disperse dye product CI Disperse Blue 291 , which contain the aminoazobenzene 2-[(2-bromo-4,6-dinitrophenyl)azo]-5-(diethylamino)-4-methoxyacetanilide (CAS registry no. 56548-64-2) is used for polyester fibers dyeing. It can be released in the aquatic environment through the discharge of industrial effluents. Humans can be exposed through the consumption of water and food contaminated with this product therefore its toxicological properties are important to be evaluated. This product showed elevated mutagenic activity with nitroreductase and Ο-acetyltransferase overproducing Salmonella strains. These enzymes are also expressed by human intestinal microflora, making intestines a possible target organ to the development of cancer after exposure to this product. The aim of this study was to investigate the effects of the commercial disperse dye product containing the CI Disperse Blue 291 on rat colon carcinogenesis, evaluated by the single cell gel assay (comet assay) and by aberrant crypt foci development. Results within different experimental periods showed the DB291 were not able to induce preneoplastic lesions in the colon of rats orally treated with 50mg/kg b.w., three times a week. The DB291 induced damages in the DNA of the rats colon mucosa, evaluated by the comet assay. These data indicate that the OB291 showed genotoxic activity in the colon mucosa cells. Considering these results, the mutagenic activity with Salmonella test and the recent data that the OB291 presents toxicity to human liver cells (HepG2), further long time carcinogenesis assays are needed to security evaluation of its carcinogenic potential, not only in colon, but also another organs like liver and kidney.

L’objectif de cette recherche est d’étudier la relation entre les nouvelles carrières et l’engagement organisationnel. La gestion des carrières et l’engagement organisationnel sont importants, à la fois, pour les individus que pour les organisations. Toutefois, les carrières ne sont plus bâties au sein d’une même organisation, elles deviennent des carrières sans frontières. Nous cherchons à comprendre et analyser la nature de l’engagement des ingénieurs consultants en SSII. Les données qualitatives ont été collectées sur le marché de l’emploi français, 47 interviews ont été mené, dans le secteur des SSII. Les résultats montrent que les ingénieurs consultants développent aussi bien un engagement envers la SSII qu’envers l’entreprise cliente. Ils développent aussi un engagement professionnel, un engagement envers l’équipe et un engagement envers le leader. Il s’agit don, d’un engagement multi-cibles. Simplement les carrières de ces ingénieurs ne sont pas nécessairement nomades. Dans ce nouveau contexte, les carrières ne sont plus bâties au sein d’une même organisation, elles deviennent des carrières sans frontières.Elles sont caractérisées par des parcours singuliers et idiosyncrasiques ; des mobilités inter organisationnelles outre celles intra organisationnelles ; une vision plus élargie de la compétence ; une promesse d’employabilité au lieu de la promesse de carrière à vie et la monté de la dimension subjective de la réussite de carrière. D’autre part, au-delà des postulats selon lesquels la question d’implication organisationnelle est devenue une aberration, une telle attitude est encore importante, elle devient même plus cruciale qu’elle l’était auparavant. Suite au désengagement des entreprises et à la responsabilisation des individus en matière de gestion de leurs carrières, la question d’implication devient plus capitale. De ce fait, l’objectif de notre recherche est d’étudier l’impact des carrières individuelles sur l’engagement organisationnel. / The purpose of this paper is to study the relationship between new careers and organizational commitment. Managing careers and organizational commitment are typically important for individuals as organizations. However, careers are no longer bounded in one organization, instead, they become boundaryless. We aim to understand and analyze the nature of commitment of IT professional, in the SSIIs in France.Surveys were collected from French labor market; 47 semi-structured interviews were among French persons working for SSII.The findings reveal that SSII engineers develop commitment to the agency: SSII and to the client. They also develop professional commitment, team commitment and Leader commitment. However, their careers are not necessary boundaryless, traditional careers still exist among these professionals on IT.

The structure, function and accessibility of epidermal skin provide aunique opportunity to study the DNA damage response (DDR) of a normaltissue. The in vivo response can be examined in detail, at a molecularlevel, and further associated to the structural changes, observed at atissue level. We collected an extensive skin biopsy material frompatients undergoing fractionated radiotherapy for 5 to 7 weeks. Several end-points inthe DDR pathways were examined before, during and after the treatment. Quantification of DNA double strand break (DSB) signalling focirevealed a hypersensitivity to doses below 0.3Gy. Furthermore, aconsiderable amount of foci persisted between fractions. The low dosehypersensitivity was observed throughout the treatment and was alsoobserved for several key parameters further downstream in the DDR-pathway, such as p21-associated checkpoint activation, apoptosisinduction and reduction in basal keratinocyte density (BKD).Furthermore, for dose fractions above 1.0 Gy, a distinct acceleration inDDR was observed half way into treatment. This was manifested as anaccelerated loss of basal keratinocytes, mirrored by a simultaneousincrease in DSBs and p21 expression. Quantifications of mitotic events revealed a pronounced suppression ofmitosis throughout the treatment which was clearly low dosehypersensitive. Thus, no evidence of accelerated repopulation could beobserved for fraction doses ranging from 0.05 to 2Gy. Our results suggest that the keratinocyte response primarily isdetermined by checkpoints, which leads to pre-mitotic cell elimination by permanent growth arrest and apoptosis. A comparison between the epidermal and dermal sub-compartments revealsa consistent up-regulation of the DDR response during treatment. Adifference was however observed in the recovery phase after treatment,where miR-34a and p21 remain up-regulated in dermis more persistentlythan in epidermis. Our observations suggest that the recovery phaseafter treatment can provide important clues to understand clinicalobservations such as the early and late effects observed in normaltissues during fractionated radiotherapy.

Βασισμένη στην «κοινωνικό- πολιτισμική, ιστορική προσέγγιση» η παρούσα έρευνα συνιστά μια προσπάθεια αξιοποίησης θεωρητικών εργαλείων και μεθοδολογικών αρχών από το συγκεκριμένο θεωρητικό πλαίσιο κατά την ερευνητική διαδικασία της ανίχνευσης παραστάσεων παιδιών νηπιαγωγείου σε σχέση με τα σύννεφα. Τα επιμέρους ερευνητικά ερωτήματα που τίθενται αφορούν στο πώς αντιλαμβάνονται τα παιδιά του νηπιαγωγείου τα σύννεφα, πώς συγκροτούν τις σχετικές νοητικές τους παραστάσεις και πώς διαχειρίζονται, αναδομούν, μετασχηματίζουν τις παραστάσεις αυτές σε διαφορετικές κοινωνικές περιστάσεις. Δείγμα της έρευνας αποτέλεσαν δέκα έξι (16) μαθητές δημόσιου νηπιαγωγείου αστικής περιοχής της περιφέρειας Δυτικής Ελλάδας. Η συλλογή των δεδομένων έγινε μέσω διευρυμένων ανοικτού τύπου συζητήσεων ανά δύο παιδιών του δείγματος και της ερευνήτριας. Η παρατήρηση, ανάλυση και παρουσίαση των αποτελεσμάτων έγινε με άξονα τη «μέθοδο τριπλής εστίασης» της Rogoff (προσωπική εστίαση, διαπροσωπική, πλαισίου). Τα αποτελέσματα που προκύπτουν αφήνουν να διαφανεί, πέραν από τις νοητικές παραστάσεις των παιδιών, ο τρόπος με τον οποίο κοινωνικά- πολιτισμικά και ιστορικά στοιχεία και εργαλεία διαμεσολαβούν στη σκέψη τους και στις διαδικασίες συγκρότησής της. Συμπεραίνεται επομένως πως, μέσω της οπτικής που μελετάται, οδηγούμαστε σε μια διευρυμένη και ολιστική προσέγγιση της παιδικής σκέψης αποκεντρωμένη από την αυστηρά εννοιολογική προοπτική του πιαζετικού προτύπου. Η έρευνα καταλήγει με την ανάδειξη σημαντικών ερευνητικών προοπτικών σε θεωρητικό, εμπειρικό και διδακτικό επίπεδο. / This Master Thesis, based on the “sociocultural-historical” approach on child thought development, constitutes an attempt of exploiting the theoretical tools and methodology principles from this particular theoretical field during research procedures of tracing kinder-garden children views on clouds. The various raised research questions are related to how kinder-garden children comprehend clouds, how they construct cloud-related conceptual schemes and how they manage, restructure and transform these schemes in different social circumstances. The research sample consisted of sixteen (16) public urban-area kinder-garden students in the vicinity of Western Greece. The data collection has been done using expanded, open type, conversations between the sample’s children in pairs and the researcher. The observation, analysis and presentation of results has been done using Rogoff’s “three foci approach” (personal, interpersonal, contextual or cultural-institutional focus of analysis). Through those results, beyond conceptual schemes, the way that socio-cultural and historical elements and tools intercede in children thinking and the process of structuring it, is highlighted. It can be concluded that, through the studied perspective, we are led to an expanded and holistic approach of the sample’s children thinking, which is detached from the strictly conceptual viewpoint. The outcome of the Master Thesis research results has highlighted the important research potentials of the sociocultural approach in theoretical, empirical and didactic level.

O composto estudado neste trabalho foi o corante comercial CI Disperse Blue 291 (DB291), que contém o aminoazobenzeno 2-[(2-bromo-4,6-dinitrofenil)azo]-5-(dietilamino)-4-metoxiacetanilida. Esse produto é um azo-corante disperso usado largamente pelas indústrias têxteis para o tingimento de poliéster e pode ser encontrado em ambientes aquáticos oriundo da descarga de efluentes industriais, podendo levar à exposição de humanos por meio da ingestão de água ou alimentos contaminados. Portanto, faz-se importante a avaliação toxicológica do DB291. Este produto apresentou atividade mutagênica para linhagens de Salmonella typhimurium que possuem alta expressão das enzimas nitrorredutase e Ο-acetiltransferase. Tais enzimas também são expressas pelas bactérias da flora intestinal humana e de roedores e, desempenham importante papel na biotransformação de substâncias presentes na luz intestinal. O objetivo deste trabalho foi investigar a atividade do corante DB291 na indução de lesões pré-neoplásicas no cólon de ratos, avaliada pelo teste do cometa e pelo desenvolvimento de focos de criptas aberrantes (FCAs). Resultados com 2, 8, 16 e 24 semanas de tratamento demonstraram que o DB291 não foi capaz de induzir FCAs em ratos tratados por gavage com a dose de 50mg/kg de peso corpóreo, três vezes por semana em dias alternados. Entretanto, resultados com o teste do cometa demonstraram que o corante foi capaz de causar danos ao DNA das células da mucosa do cólon de ratos tratados por via intra-retal. Estes resultados sugerem que o DB291 possui atividade genotóxica in vivo. Considerando a resposta genotóxica para o teste do cometa, a alta atividade mutagênica no teste Salmonella microssoma e o recente relato de que o DP291 causou danos em células de fígado humano (HepG2), faz-se necessário a realização de testes de carcinogênese de longa duração para avaliação segura do seu potencial carcinogênico, não somente em cólon, mas em outros órgãos tais como fígado e bexiga. / The commercial disperse dye product CI Disperse Blue 291 , which contain the aminoazobenzene 2-[(2-bromo-4,6-dinitrophenyl)azo]-5-(diethylamino)-4-methoxyacetanilide (CAS registry no. 56548-64-2) is used for polyester fibers dyeing. It can be released in the aquatic environment through the discharge of industrial effluents. Humans can be exposed through the consumption of water and food contaminated with this product therefore its toxicological properties are important to be evaluated. This product showed elevated mutagenic activity with nitroreductase and Ο-acetyltransferase overproducing Salmonella strains. These enzymes are also expressed by human intestinal microflora, making intestines a possible target organ to the development of cancer after exposure to this product. The aim of this study was to investigate the effects of the commercial disperse dye product containing the CI Disperse Blue 291 on rat colon carcinogenesis, evaluated by the single cell gel assay (comet assay) and by aberrant crypt foci development. Results within different experimental periods showed the DB291 were not able to induce preneoplastic lesions in the colon of rats orally treated with 50mg/kg b.w., three times a week. The DB291 induced damages in the DNA of the rats colon mucosa, evaluated by the comet assay. These data indicate that the OB291 showed genotoxic activity in the colon mucosa cells. Considering these results, the mutagenic activity with Salmonella test and the recent data that the OB291 presents toxicity to human liver cells (HepG2), further long time carcinogenesis assays are needed to security evaluation of its carcinogenic potential, not only in colon, but also another organs like liver and kidney.

No description available.

Ziel der vorliegenden Arbeit war es, 1. die Einflüsse von Alter bzw. Parität auf Prävalenz und Entwicklung endometrialer Alterationen beim Rind zu untersuchen, 2. einen repräsentativen Überblick über die mittels Endometriumbiopsie erfassbaren Erkrankungen bei klinisch gesunden Kühen zu schaffen 3. die Entwicklung der histopathologischen Befunde nach einer weiteren Trächtigkeit zu dokumentieren. Grundlage dieser Arbeit sind sechs Endometriumbioptate von klinisch (inklusive rektaler Untersuchung) gesunden Färsen (Gruppe A), 165 Bioptate von klinisch gesunden Kühen (Gruppe B) sowie Bioptat-Paare (Gruppe C) von 46 Tieren, die im Abstand einer Trächtigkeit entnommen wurden. Die Proben der Gruppe A dienten als Kontrollgruppe, wobei die Gefäße als Grundlage für die Normalstruktur vor der ersten Trächtigkeit herangezogen wurden. Innerhalb der Endometriumbioptate der Färsen (Gruppe A) waren keine pathologischen Veränderungen (Endometritis, Endometrose, Angiosklerose) und keine Lymphfollikel nachweisbar. Bezüglich der Endometritis-Prävalenz, die bei 23,6 % lag, ließ sich in Gruppe B keine Abhängigkeit von der Parität oder dem Entnahmezeitpunkt nachweisen. Eine Endometrose trat überwiegend bei Erstkalbinnen (24,4 %) und Tieren mit fünf Abkalbungen (41,6 %) auf. Eine Korrelation mit dem Alter lag nicht vor. Auffällig war die signifikant höhere Endometrose-Prävalenz innerhalb der ersten acht Wochen p.p. (20,1 %), im Vergleich zu später entnommenen Proben (3,2 %). Für das Auftreten von Lymphfollikel, die im Mittel bei 53,3 % der Kühe auftraten, konnten keine Korrelationen mit der Parität oder dem Zeitpunkt der Bioptatentnahme ermittelt werden. Auch scheint weder das Vorliegen einer Endometritis die Entwicklung von Lymphfollikeln zu begünstigen, noch schützen Lymphfollikel im Endometrium vor einer Entzündung des Uterus. Mit steigender Parität war eine Zunahme der Angiosklerose-Prävalenz zu verzeichnen, allerdings konnte keine statistisch signifikante Korrelation zum Grad der Gefäßveränderungen (anhand der H.E.-Färbung) nachgewiesen werden. Innerhalb der Karunkel lagen signifikant höhergradige Veränderungen vor als in interkarunkulären Gefäßen. Da das Alter der Tiere eng mit der Anzahl der Abkalbungen korreliert, war eine gesonderte Betrachtung der altersassoziierten Einflüsse anhand des untersuchten Materials nicht möglich. Mittels der durchgeführten Untersuchungen ließ sich kein negativer Einfluss der vorwiegend geringgradigen histopathologischen Veränderungen im Endometrium (Endometritis, Endometrose, Angiosklerose, Lymphfollikel) auf die Fertilität (Erstbesamungserfolg, Rastzeit, Güstzeit, Gesamtträchtigkeitsrate) nachweisen. Innerhalb der Gruppe C konnte nach einer weiteren Trächtigkeit ein signifikanter Anstieg der Endometrose-Prävalenz von 7,0 % auf 25,6 % nachgewiesen werden, während der Anteil der Tiere mit einer Endometritis bzw. Angioskerose nahezu unverändert blieb. Bei einigen Tieren wurde allerdings in der ersten Probe, jedoch nicht im Folgebioptat, eine Endometrose diagnostiziert. Bei einer Kuh lag dabei sogar zuerst eine mittelgradige periglanduläre Fibrose vor, die im zweiten Bioptat nicht mehr nachweisbar war. Im Hinblick auf die Entwicklung vaskulärer Alterationen konnte nach einer weiteren Trächtigkeit eine signifikante Zunahme der Faserzubildungen (Pikrosiriusrot-Färbung) in der Tunica media interkarunkulärer arterieller Gefäße und karunkulärer Arterien sowie in der Tunica adventitia von interkarunkulären Arteriolen nachgewiesen werden. Weiterhin wurden im Zweitbioptat anhand der Pikrosiriusrot-Färbung signifikant höhergradigere Veränderungen (Gesamtschädigung) der karunkulären Arterien und Arteriolen diagnostiziert. Für alle übrigen Gefäßtypen lag zwar eine Zunahme der Gesamtschädigung im zweiten Bioptat vor, diese war jedoch nicht statistisch signifikant. Zu beiden Untersuchungszeitpunkten konnten innerhalb des untersuchten Materials vor allem Elastosen und Elastofibrosen nachgewiesen werden. Dabei lagen bezüglich der Art der zugebildeten Fasern keine signifikanten Unterschiede zwischen beiden Proben vor. Insgesamt konnten anhand des untersuchten Materials von klinisch gesunden Kühen zahlreiche pathologische Befunde im Endometrium diagnostiziert werden. Allerdings ist die Interpretation der Befunde bislang schwierig, da keine Einflüsse auf die Fertilität nachweisbar waren. Jedoch lagen besonders im Hinblick auf die Endometritis und Endometrose meist nur geringgradige Veränderungen vor, so dass sich diese vermutlich nicht negativ auf die Fruchtbarkeit auswirken. Weiterhin ist anhand der vorliegenden Ergebnisse fraglich, ob eine Endometrose beim Rind als irreversible Erkrankung angesehen werden muss. Hierzu sind weitere Studien erforderlich.