Operative Therapie des gastrooesophagealen Refluxes im Kindesalter unter besonderer Berücksichtigung von Kindern mit Behinderung

Ein pathologischer Gastrooesophagealer Reflux (GÖR) tritt häufig bei Kindern mitBehinderung und nach einer Operation am Oesophagus auf wie zum Beispiel nach Korrektureiner Oesophagusatresie. Bei diesen Kindern ist eine medikamentöse Therapie überwiegendzum Scheitern verurteilt und eine Therapie wie die der Antirefluxoperation wird notwendig.In der vorliegenden Arbeit werden die 100 Kinder beschrieben, die mit derVerdachtsdiagnose GÖR in den Jahren 1983 bis 1998 vorgestellt wurden. 68 Kinderbenötigten eine Antirefluxoperation. Schwerpunktmäßig werden neurologisch behinderteKinder (85%), bei denen erwartungsgemäß häufig ein GÖR vorliegt, untersucht. Mitbesonderem Interesse werden dabei das Vorliegen und Zusammentreffen mehrerer GÖRprädisponierenderErkrankungen (Behinderung und Zustand nach Korrektur einerOesophagusatresie) untersucht, um Hinweise für eine mögliche Differenzierung prae- undpostoperativer Bilder des GÖR und seine Komplikationen zu gewinnen.Weiterhin werden Aussagen gewonnen bezüglich des Alters der Kinder zum Zeitpunkt desAuftretens der Symptome und zum Zeitpunkt der Operation. Diese werden ebenso wie dieZeiträume zwischen dem Auftreten der Symptome und der Diagnosenstellung, bzw. demOperationszeitpunkt mit den Aussagen in der Literatur verglichen.Ferner wird überprüft, ob sich für die einzelnen Personengruppen (Kinder mit cerebralen undmotorischen Retardierungen (85%), Kinder mit angeborener Oesophagusatresie (4%), Kindermit beiderlei GÖR-prädisponierender Erkrankungen (3%) und Kinder ohne prädisponierendeErkrankungen (8%)) differenzierte Aussagen finden.A pathological gastroesophageal reflux (GER) is often found in handicapped children andafter surgical treatment at the esophagus e. g. after correction of esophagusatresia. Here,medical treatment is often ineffective and an antireflux plasty is needed.In this study 100 children are examined, who had the suspected diagnosis of GER in the years1983 – 1998. 68 children needed a surgical treatment. The majority form the neurologicalhandicapped children (85%), who are predisposed to GER as expected.A special interest of the study is on the existence and coincidence of several GERpredisposingdiseases (disability and esophagusatresia), in order to get an indication forpossible differentiations of pre- and postoperative symptoms and complications of GER.Furthermore evidence is obtained on the age of the children, when the symptoms appearedfirst and when the operation took place. These data and the period of time between theappearence of symptoms and the time of diagnosis and operation are compared with theinformation given in the literature.Moreover the different evidences between the four groups (children with cerebral andmotorial retardation (85%), children with congenital esophagusatresia (4%), children withboth (3%) and children without GER-predisposing diseases (8%)) are analysed.

Transgenic mice as a tool for depression research: examples from the endocannabinoid and the corticotropin-releasing hormone system

Major depression belongs to the most serious and widespread psychiatric disorders in today’s society. There is a great need for the delineation of the underlying molecular mechanisms as well as for the identification of novel targets for its treatment. In this thesis, transgenic mice of the endocannabinoid and the corticotropin-releasing hormone (CRH) system were investigated to determine the putative role of these systems for depression-like phenotypes in mice. In the first part of the thesis, we found that the endocannabinoid system was prominently involved in a brain region-specific and temporally controlled manner in acute as well as in chronic stress processing. Genetic deletion in combination with pharmacological intervention revealed the importance of a fully functional endocannabinoid system for efficient neuroendocrine and behavioral stress coping. Accordingly, cannabinoid type 1 (CB1) receptor-deficient mice displayed several depression-like symptoms and molecular alterations, including “behavioral despair”, stress hormone hypersecretion and decreased glucocorticoid receptor and brain-derived neurotrophic factor expression in the hippocampus. However, the endocannabinoid system was dispensable for the efficacy of currently used antidepressant drugs. To facilitate future endocannabinoid research, a transgenic mouse was generated, which overexpressed the CB1 receptor protein fused to a fluorescent protein. In the second part of the thesis, conditional brain region-specific CRH overexpressing mice were evaluated as a model for pathological chronic CRH hyperactivation. Mutant mice showed aberrant neuroendocrine and behavioral stress coping and hyperarousal due to CRH-induced activation of the noradrenergic system in the brain. Mutant mice appeared to share similarities with naturally occurring endogenous CRH activation in wild-type mice and were sensitive to acute pharmacological blockade of CRH receptor type 1 (CRH-R1). Thus, CRH overexpressing mice serve as an ideal in vivo tool to evaluate the efficacy of novel CRH-R1 antagonists. Together, these findings highlight the potential of transgenic mice for the understanding of certain endo-phenotypes (isolated symptoms) of depression and their molecular correlates.