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Transforming growth factor-ß (TGF-ß) reguliert eine Vielzahl zellulärer Funktionen, wie Proliferation, Differenzierung und Apoptose. Über membrangebundene Serin/Threonin-Kinase-Rezeptoren werden TGF-ß Signale durch Phosphorylierung an Smad-Proteine, die intrazellulären Signaltransduktoren, weitergeleitet, die im Kern die Transkription spezifischer Gene modulieren. Obwohl die drei TGF-ß Isoformen, TGF-ß1, -ß2 und -ß3, äußerst homologe Proteine sind, unterscheiden sich die Phänotypen ihrer Genknockouts stark. Variabilität und Spezifität können auf vielerlei Arten und Ebenen der TGF-ß Signalübertragung erreicht werden. In der vorliegenden Arbeit wird eine alternativ gespleißte Variante des TGF-ß Typ II Rezeptors (TßRII), TßRII-B, charakterisiert. Dieser Rezeptor ist, im Gegensatz zum bisher bekannten TßRII, in der Lage alle drei TGF-ß Isoformen hochaffin zu binden und in Abwesenheit eines unterstützenden Typ III Rezeptors (TßRIII) Signale über den Smad-Pathway weiterzuleiten. TßRII-B ist außerdem fähig ligandenabhängig mit den verschiedenen TGF-ß Rezeptortypen zu Oligomerisieren. Erste Hinweise auf Besonderheiten der TGF-ß2 Bindung an TßRII-B wurden mittels verschiedener zellbiologischer Ansätzen gewonnen. Aus Untersuchungen zur gewebespezifischen Expression des Rezeptors geht hervor, daß TßRII-B, im Vergleich zu TßRII, ein distinktes Expressionsmuster aufweist und v.a. in TGF-ß2-beeinflußten Geweben nachgewiesen werden kann. In diesen Erkenntnissen spiegelt sich die Bedeutung dieses Rezeptors für eine TGF-ß Isoform-spezifische Signalübertragung wider. Der zweite Teil der vorliegenden Arbeit beschäftigt sich mit der Rolle von TGF-ß und seinen Rezeptoren bei der Entstehung von Tumoren. B-Zellen einiger Patienten mit chronischer lymphatischer Leukämie (B-CLL), der häufigsten Form adulter Leukämie in westlichen Ländern, zeigen Resistenz gegenüber TGF-ß-vermittelter Wachstumsinhibierung und ein verändertes Expressionsmuster der TGF-ß Rezeptoren an ihrer Zelloberfläche. In dieser Arbeit wird die Identifizierung und Charakterisierung zweier Mutationen innerhalb der putativen Signalpeptidsequenz des TGF-ß Typ I Rezeptors (TßRI) in B-Zellen TGF-ß resistenter CLL-Patienten beschrieben. Hierbei handelt es sich um einen Aminosäure-Austausch (L12Q) und eine ‚in-frame‘ Alanin-Deletion (A8) innerhalb einer aus 9 Alaninen bestehenden Sequenz. Es konnte gezeigt werden, daß diese Mutationen zwar keinen Einfluß auf Oberflächenexpression und Komplexbildungseigenschaften des TßRI haben, jedoch TGF-ß stimulierte Reportergeninduktion verringern, was eine kausale Beziehung bei der Entwicklung TGF-ß resistenter B-CLL-Zellen vermuten läßt. Ein Auftreten von Mutationen innerhalb der 9-Alanin-Sequenz des TßRI korreliert mit TGF-ß Insensitivität von B-CLL Zellen. Obwohl noch weitere Studien benötigt werden, um den präzisen molekularen Mechanismus zu verstehen, der zu TGF-ß Resistenz in B-CLL Zellen führt, kann spekuliert werden, daß TßRI Mutationen das Voranschreiten von B-CLL und evtl. anderen Tumorarten unterstützen. Gezieltes Screenen nach TßRI Signalpeptidsequenz Mutationen könnte demnach als prognostischer Indikator für Tumorprogression eingesetzt werden., Transforming growth factor-ß (TGF-ß) regulates a variety of cellular functions like proliferation, differentiation and apoptosis. It signals through membrane-bound serine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins, the intracellular signaltransducers, and thereby trigger their nuclear translocation and transcriptional activity. Although the three mammalian TGF-ß isoforms, TGF-ß1, -ß2 and –ß3, are highly homologous proteins, the phenotypes of their genknockouts reveal striking differences. Variability and specificity can be achieved on different levels of the TGF-ß signaltransduction. In this work an alternatively spliced variant of the TGF-ß type II receptor (TßRII), TßRII-B, is characterized, which in contrast to TßRII binds and mediates signaling of all TGF-ß isoforms. This signaling occurs via the Smad pathway and is independent of any supporting type III receptor (TßRIII). Therefore interaction and oligomerization of TßRII-B with the TGF-ß isoforms as well as the different TGF-ß receptor types was analyzed in detail. Furthermore we defined the characteristics of TGF-ß2 binding to TßRII-B. Expression studies demonstrate that TßRII-B expression is restricted to cells originating from tissues where the TGF-ß2 isoform has a predominant role. All that reflects the importance of this receptor splice-variant in TGF-ß isoform-specific signaling. The second part of this work focuses on the role of TGF-ß and its receptors in tumor development. B cell chronic lymphocytic leukemia (B-CLL) is the most common lymphoid cancer in Western societies, and is also currently incurable. B-cells from some B-CLL patients are resistant to the growth inhibitory effects of TGF-ß and show a different expression pattern of TGF-ß receptors at their cell surface. In this work the identification and characterization of two mutations within the putative signal sequence of the tßrI gene in B-cells from TGF-ß resistant B-CLL patients is described. Thereby a single aminoacid substitution (L12Q) is accompanied by an ‘in frame’ single alanine deletion within an 9-alanine stretch. It could be shown that this mutations do not mediate the apparent loss of functional TßRI in TGF-ß resistant B-CLL, but they attenuate reporter gene induction stimulated by TGF-ß, suggesting a causal relationship in the development of TGF-ß resistant B-CLL. The appearance of mutations within the 9-alanine stretch of the TßRI correlated with and predicted for B-CLL patient insensitivity to TGF-ß. Although more studies are needed to ascertain the precise molecular mechanism leading to TGF-ß resistance in B-CLL cells, it is tempting to speculate that these TßRI mutations may promote the progression of B-CLL and other cancers from their indolent to active states. This suggests that screening for TßRI signal sequence mutations can be employed as a prognostic indicator of B-CLL patient sensitivity to TGF-ß.

One year after a nonspecific trauma and with a history of pain of four weeks only, an osteoid osteoma of the first phalanx of the left thumb was diagnosed in a 31-year-old man. The radiologic appearance as well as a bone scan were suggestive for an osteoid osteoma. The diagnosis was confirmed histologically after resection of the tumor. As indicated in the literature, osteoid osteoma of the hand is relatively rare. The symptoms and radiologic features (osteolytic nidus and sclerosis) of osteoid osteomas are independent of the tumor location. Surgery with resection of the nidus is the only known curative therapy. The etiological role of trauma is discussed and a review of the literature is done with 15 other cases of posttraumatic osteoid osteoma having been reported.

Principally driven by economic necessity, i.e. reduction of health care personnel and beds, a significant increase in number of major operations for in-patients and a general attempt to reduce costs, a day-surgery unit was established for the Surgical Department at the Kantonsspital St. Gallen. Several requirements have to be met: Standardized techniques have to be applied by experienced surgeons and strict selection criteria for patients as well as intensive preoperative patient information and consenting have to be observed. During a two year period (September 1992 to August 1994) 389 patients were evaluated for ambulatory surgery. 106 patients (27.2%) had to be rejected for social, medical and financial reasons. Eventually operations were carried out on 283 patients. The majority of procedures performed were for herniae (37.8%) followed by varicose vein-surgery (22.6%). Only 8 patients had to be admitted for observation as in-patients, this was mainly due to difficulties in postoperative mobilisation and micturition problems. To monitor our quality of care, questionnaires were sent to patients and general practitioners (GP's). 98% of patients were satisfied with the preoperative information standards. Difficulties in adapting to a postoperative daily routine was stated by 13% of patients. 80% of patients would again opt for surgery on a day-care basis in future. 81% of GP's reported a positive benefit for their patients from ambulatory surgery. All GP's were prepared to undertake preoperative patient evaluation according to standardized selection criteria. A significant reduction in costs can be expected. With the current health-insurance system this is unfortunately achieved with an increased financial burdening for the patient.

During a 6-year period from 1986 to 1991, 119 patients with lung cancer underwent thoracotomy. 112 underwent surgical resection with lymphadenectomy. The mean age of the 97 male patients was 62.7 years, and of the 15 female patients was 62.7 years, and of the 15 female patients 57.1 years. 54 patients were in stage I, 23 stage II, 21 stage IIIa, 8 stage IIIb and 6 stage IV. Pneumonectomy was performed in 20 cases, bilobectomy in 2, lobectomy in 81, segmentectomy in 3 and sleeve lobectomy in 6. Perioperative death occurred in 2.7% of all patients, 5% of patients who underwent pneumonectomy and 2.2% of patients who underwent lobectomy. Serious complications occurred in 19% of all thoracotomy patients. The re-thoracotomy rate was 6% and mortality 0.8%. The cumulative 5-year survival rate in all 112 patients with surgical resection was 54.6%, and for the 54 patients with radical resection 60.3%.

During a 19-month period 549 patients (278 women, 271 men) suffering from abdominal pain unrelated to trauma (mean age 48.2 years) entered the emergency room of the Department of Surgery of the University Hospital Zürich. 43% presented during business hours, whereas 57% were admitted during nighttime and/or weekends. Clinical examination, abdominal roentgenograms (upright and supine) as well as sonography were the most commonly used diagnostic tools. 40% suffered from abdominal pain of unknown cause. The most common diagnosis on admission was appendicitis. Only half of these cases really proved to be an appendicitis. In 36% the diagnosis on admission corresponds both to the initial diagnosis made by a member of staff during his first visit, as well as to the final diagnosis. The initial diagnosis agrees in 57% with the final diagnosis. In 10% of the patients the cause of pain was not elucidated despite extensive diagnostic procedures. High technology and sophisticated diagnostics are less important than the clinical evaluation. The decision between operative or nonoperative treatment was mainly based on clinical findings.

During an 11-year period from 1978 to 1988, 720 cadaver kidneys were transplanted at the University Hospital of Zurich. 103 of the kidney grafts were from donors 16 years old or younger. The mean age of these donors was 11 years (range 2 1/3 to 16 years). There were 3 donors under 5 years, where we preserved and transplanted both kidneys en bloc. Only 3 recipients were less than 16 years old. After 1 year, 67 out of 103 recipients had a functioning pediatric graft. In the cyclosporine-treated group, the 1-year graft survival was even 80%, similar to kidney transplants from adult donors. Graft loss was observed in 48 cases. 33 patients rejected the transplant and 10 grafts were lost after recurrence of the primary renal disease. Only 5 grafts had a vascular complication. We conclude that kidneys from pediatric donors can successfully be transplanted into adults.