Die Belastungsinkontinenz des Mannes ist eine häufige Komplikation der radikalen Prostatovesikulektomie. Abgewandelte Operationstechniken und Rekonstruktions-verfahren führen zu verbesserten postoperativen Kontinenzraten und weisen auf die Bedeutung einzelner Komponenten am urethralen Verschlussmechanismus hin. Im Vergleich zum weiblichen ist der männliche Harnkontinenzmechanismus nur ansatzweise verstanden. In der vorliegenden Arbeit werden die am urethralen Verschluss beteiligten Komponenten und ihre Verbindungen zu angrenzenden Strukturen makroskopisch und mikroskopisch analysiert und auf ihre funktionelle Bedeutung untersucht. Zehn konservierte Leichname wurden für Untersuchungen des männlichen Urogenitaltraktes genutzt, aus drei Becken wurden Organpakete für die Erstellung von mikroskopischen Schnittpräparaten entnommen. Die histologischen Untersuchungen konnten zeigen, dass die Form des Musculus sphincter urethrae externus im Transversalschnitt von der Schnitthöhe abhängig ist. Seine Fasern strahlen in die Faszie des Musculus levator ani ein. Auch die Fasern des Corpus perineale inserieren in die Faszie dieses Muskels. Anhand dieser Ergebnisse wird die zentrale Rolle des Musculus levator ani im männlichen Harnkontinenzapparat deutlich. Der eigentliche Verschlussdruck wird demnach durch den Musculus levator ani aufgebaut und durch das Corpus perineale von dorsal auf die Urethra übertragen. Die Aufgabe des Musculus sphincter urethrae externus wird nicht als primär aktiv, sondern als dynamisches Widerlager für die membranöse Urethra beschrieben. Außerdem geht die Arbeit auf die noch wenig erforschte Mediatorfunktion der glatten Muskulatur im männlichen Urogenitaltrakt ein. Diese Ergebnisse präzisieren die Vorstellung des Kontinenzmechanismus des Mannes als Zusammenspiel von unterschiedlichen Komponenten und geben Anlass, aktuelle Standardtechniken der Beckenchirurgie zu überdenken und den Fokus auf schonende bzw. rekonstruktive Operationsverfahren zu richten.:Inhaltsverzeichnis Seite Bibliographische Beschreibung……………………………….………........…………… 3 Inhaltsverzeichnis………………………………………………………….........………….. 4 Verzeichnis der Abkürzungen…………………………………….…….......…………… 7 Verzeichnis der Abbildungen……………………………………….…….......…………. 8 Verzeichnis der Tabellen…………………………………………….…………........……. 9 1 Einleitung……………………………………………………….………...........………. 10 1.1 Epidemiologie der Harninkontinenz………………………….…...…………… 10 1.2 Stellenwert der radikalen Prostatektomie im Spektrum der operativen Therapieverfahren zur Behandlung des Prostatakarzinoms…............... 11 1.3 Protektion und Rekonstruktion von Kontinenzstrukturen....…..... 13 1.4 Zielstellung der Arbeit……………………………………………………....…...... 15 2 Material und Methoden……………………………………………………........…. 16 2.1 Instrumentarium und Reagenzien…………………………………………….. 16 2.2 Körperspender…………………………………………………………….......…....... 16 2.3 Konservierung…………………………………………………………....….......…... 16 2.4 Makroskopische Darstellung………………………………………………....…... 17 2.5 Gewebeentnahme…………………………….................................…..... 19 2.6 Fixation und Einbettung…...................................………………….... 20 2.7 Färbung………………………………………………………….…………...........……. 21 2.8 Histologische Auswertung…………………………………....…………………... 22 3 Ergebnisse……………………………………………............………………………… 23 3.1 Makroskopie………………………………………………………..........…………….. 23 3.1.1 Musculus sphincter urethrae externus – ein fächerförmiger Muskel mit ausgeprägter Vaskularisierung......................................... 23 3.1.2 Corpus perineale…...........................................…………....... 26 3.1.3 Musculus levator ani – Bestandteil der ventralen Suspension des Harnkontinenzorgans………………………………………...............…………… 26 3.2 Mikroskopie……………………………………………………….........…………....... 28 3.2.1 Musculus sphincter urethrae externus und Corpus perineale inserieren im Musculus levator ani und lateralen Venenplexus…...….… 28 3.2.2 Form und Verlauf des Musculus sphincter urethrae externus........………........................................................................... 32 3.2.3 Glatte Muskulatur als dynamische Verankerung des Harnkontinenzorgans......................................................... 34 4 Diskussion…………………………………………...........………………………….... 37 4.1 Struktur und Form des Musculus sphincter urethrae externus…. 37 4.2 Verankerung des Musculus sphincter urethrae externus …......... 39 4.3 Kontroverse Ansichten zum Corpus perineale und seiner Verankerung….................................................................................. 41 4.4 Glattmuskuläre Komponenten im männlichen Kontinenzsystem.43 4.5 Vorstellungen zum männlichen Harnkontinenzmechanismus…… 44 4.7 Experimentelle Arbeiten zum Harnkontinenzorgan im Vergleich..48 4.8 Auswirkungen der Ergebnisse auf die Praxis…………………......……… 53 5 Zusammenfassung……………………………………………………........…….… 55 Anhang…………………………………………………………………............……………….. 59 Erklärung über die eigenständige Abfassung der Arbeit……….......………. 64 Lebenslauf…………………………………………………………………………...........….... 65 Danksagung………………………………………………………………...........……………. 66 Literaturverzeichnis………………………………………………........………………...... 67

<p>Preeclampsia and other hypertensive disorders of pregnancy impact 2-8% of pregnancies with often devastating results. Current treatment methods resort to birth, which forces the fetus into the world before they are fully developed but can save the mother’s life. Preeclampsia is broadly considered to be of placental origin and current etiologic understanding focuses on systemic endothelial dysfunction triggered by an imbalance of vasoregulatory factors released by this maternal/fetal organ. This imbalance explains many early-term cases but fails to adequately address later cases where this imbalance is not always seen. Conversely, ischemia-reperfusion of the kidney is known to correlate with endothelial dysfunction, and preeclamptic women are known to have a stenosis in their left renal vein (LRV) in the supine position (on their back). Herein, we suggest that extrinsic compression of the LRV by the gravid uterus, without collaterals, produces a renal injury which can induce systemic endothelial cell dysfunction. We theorize this compression is position dependent and produces renal ischemia through an unchecked cycle of increased intrarenal pressure, subsequent afferent arteriole constriction and decreased glomerular perfusion, and activation of the renin-angiotensin-aldosterone system. We aim to elucidate this through murine studies of a surgically induced LRV stenosis and a retrospective clinical study where the maternal renal veins are measured from magnetic resonance images. Findings from this work suggest partial renal venous outflow obstruction leads to renal injury but could be moderated through alternative maternal resting positions. This potential alternative pathologic mechanism has significant clinical implications for future therapies targeting this condition.</p>

Bakgrund: Att ha en dysfunktionell urinblåsa kräver assisterad blåstömning med hjälp av en kateter. En urinkateter kräver daglig skötsel och kunskap, både kring katetern som hjälpmedel och om komplikationer som kan uppstå. Personcentrerad vård handlar om att se, höra och lyssna på personen som är i behov av vård och är grundstenen för ett individanpassat bemötande. Syftet: Var att belysa patienters upplevelse av att vara beroende av assisterad blåstömning. Metod: En allmän litteraturstudie där åtta kvalitativa artiklar användes. Resultat: Det framkom tre huvudkategorier; Påverkan på livskvalitén, skam och rädsla. Underkategorier som framkom var; Betydelsen av kontroll och betydelsen av stöd. Slutsats: Information om urinkatetrar upplevs bristfällig både gällande som hjälpmedel och vid intima relationer vilket påverkar personens livskvalité. Att vara i behov av assisterad blåstömning påverkar personers självbild och genererar begränsningar i vardagen på grund av skam. Stöd från familj eller vårdpersonal är av betydelse. Den personcentrerade omvården behöver förbättras för personer med assisterad blåstömning för att hanteringen i vardagen ska underlättas. / Background: Having a dysfunctional bladder requires assisted bladder emptying using a catheter. A urinary catheter requires daily care and knowledge, both about the catheter as an aid and about complications that may arise. Person-centred care is about seeing, hearing and listening to the person in need of care and is the cornerstone of an individually tailored treatment. Aim: of the study was to shed light on patients' experience of being dependent on assisted bladder emptying. Method: A general literature study with eight qualitative articles were used. Results: Three main categories emerged; Impact on quality of life, shame and fear. Subcategories that emerged were; Importance of control and the importance of support. Conclusion: Information about urinary catheters is perceived to be insufficient both as an aid and in intimate relationships, which affects the person's quality of life. Living with assisted bladder drainage affects people's self-image and generates limitations in everyday life due to shame. Support from family or healthcare professionals is important. The person-centered care needs to be improved for people with assisted bladder emptying to facilitate handling in everyday life.

Purpose The purpose of this study was to quantify the number of surgical programs currently training osteopathic residents and to solicit advice for current osteopathic medical students who are interested in pursuing a surgical residency. Methods A questionnaire was sent to all listed Electronic Residency Application Service® (ERAS®) email contacts for the following specialties: General Surgery, Neurological Surgery, Orthopedic Surgery, Otolaryngology, Urology, Integrated Vascular Surgery, Integrated Plastic Surgery, and Integrated Thoracic Surgery. The questionnaire was sent a total of three times. Results Two hundred sixty-four of the 1,040 surgical residency programs responded to the questionnaire. Of these responses, 19% were formerly American Osteopathic Association (AOA) accredited programs. About 47.3% of responding programs indicated they are not currently training an osteopathic physician. One hundred thirteen programs provided additional comments on how osteopathic medical students may improve the competitiveness of their residency applications. These comments included increasing volumes of research activities, performing well on the United States Medical Licensing Exam (USMLE), and completing a sub-internship in the desired field or at a specific institution. Conclusion Osteopathic students still face many barriers to matching into surgical residencies. This study provides concrete steps students may take to increase the competitiveness of their application.

Muscle mechanical behavior potentially plays an important role in some of the most common bladder disorders. These include overactive bladder, which can involve involuntary contractions during bladder filling, and impaired contractility or underactive bladder, which may involve weak or incomplete contractions during voiding. Actin-myosin cross-bridges in detrusor smooth muscle (DSM) are responsible for contracting and emptying the bladder. The total tension produced by muscle is the sum of its preload and active tensions. Studies suggest that actin-myosin cross-links are involved in adjustable preload stiffness (APS), which is characterized by a preload tension curve that can be shifted along the length axis as a function of strain history and activation history. DSM also exhibits length adaptation in which the active tension curve can exhibit a similar shift. Actin-myosin cross-bridges are also responsible for myogenic contractions in response to quick stretch of DSM strips and spontaneous rhythmic contractions (SRC) that may occur during bladder filling. Studies show that SRC may participate in the mechanical regulation of both APS and length adaptation. However, the mechanical mechanisms by which actin-myosin interactions enable this interrelated combination of behaviors remain to be determined and were the primary focus of this dissertation. The objectives of this study were to: 1) provide evidence to support the hypothesis that a common mechanism is responsible for SRC and myogenic contraction, 2) develop a sensor-based mechanical model to demonstrate that SRC in one cell is sufficient to trigger stretch-induced myogenic contraction in surrounding cells and propagate the contraction, and 3) develop a conceptual model with actin-myosin cross-bridges and cross-links that produces the coupled mechanical behaviors of APS, SRC, and length adaptation in DSM. Improved understanding of bladder biomechanics may enable the identification of specific targets for the development of new treatments for overactive and underactive bladder.

<p>This thesis deals with problem solving of general practitioners (GPs), which is explored with different methods and from different perspectives. The general aim was to explore and describe rules of thumb and to analyse the management of respiratory and urinary tract infections (RTI and UTI) in general practice in Sweden. The results are based upon focus group interviews concerning rules of thumb and a prospective diagnosis-prescription study concerning the management of patients allocated a diagnosis of RTI or UTI. In addition unpublished data are given from structured telephone interviews concerning specific rules of thumb in acute sinusitis and prevailing cough.</p><p>GPs were able to verbalize their rules of thumb, which could be called tacit knowledge. A specific set of rules of thumb was used for rapid assessment when emergency and psychosocial problems were identified. Somatic problems seemed to be the expected, normal state. In the further consultation the rules of thumb seemed to be used in an act of balance between the individual and the general perspective. There was considerable variation between the rules of thumb of different GPs for patients with acute sinusitis and prevailing cough. In their rules of thumb the GPs seemed to integrate their medical knowledge and practical experience of the consultation. A high number of near-patient antigen tests to probe Streptococcus pyogenes (Strep A tests) and C-reactive protein (CRP) tests were performed in patients, where testing was not recommended. There was only a slight decrease in antibiotic prescribing in patients allocated a diagnosis of RTI examined with CRP in comparison with patients not tested. In general, the GPs in Sweden adhered to current guidelines for antibiotic prescribing. Phenoxymethylpenicillin (PcV) was the preferred antibiotic for most patients allocated a diagnosis of respiratory tract infection.</p><p>In conclusion, the use of rules of thumb might explain why current practices prevail in spite of educational efforts. One way to change practice could be to identify and evaluate rules of thumb used by GPs and disseminate well adapted rules. The use of diagnostic tests in patients with infectious illnesses in general practice needs critical appraisal before introduction as well as continuing surveillance. The use of rules of thumb by GPs might be one explanation for variation in practice and irrational prescribing of antibiotics in patients with infectious conditions.</p> / On the day of the public defence the status of the articles IV and V was: Accepted.

<p>The natural history of localized prostate cancer is not fully understood. In most patients the tumor will never progress to a lethal disease, while a subset of patients will ultimately die of the disease. Efficient tools to separate indolent from lethal disease is currently lacking which means that many patients will be offered treatment without any benefit, but still be at risk of experiencing treatment related side effects.</p><p>The aims of these studies were to get more insight into the natural history of untreated localized prostate cancer, to assess the prognostic value of established clinical parameters such as Gleason score, nuclear grade and tumor volume and, moreover, some new prognostic markers Ki-67, AMACR and MUC-1. We also aimed to study time trends in the detection of incidental tumors in Sweden.</p><p>Patients with localized disease (n=223) and no initial treatment were followed for 21 years. Most patients had a favorable outcome. However, a subset of patients developed lethal disease even beyond 15 years of follow-up and these patients define the group that may benefit most from treatment with curative intent. Patients with poorly differentiated tumors experienced a 9 time higher risk of dying in prostate cancer.</p><p>The studies on prognostic markers are based on a cohort of patients (n=253) with incidental prostate cancer detected by transurethral resection for presumed benign hyperplasia. All patients were left without initial treatment. Gleason grade, nuclear grade and tumor volume turned all out to be independent prognostic factors. MUC-1, AMACR and Ki-67 also carried prognostic information. However, after adjustment for Gleason grade, nuclear grade and tumor volume only MUC-1 and AMACR remained as statistically significant prognostic factors. When tested for sensitivity and specificity they all failed and, consequently, they seem to be of less value in daily practice for cancelling an individual patient regarding the choice of treatment.</p><p>Time trends in incidental prostate tumors in Sweden were analyzed in a cohort of patients with prostate tumors detected by transurethral resection (TUR-P). Through linkage of the national registration number (NRN) with several registers, e.g. the Swedish Cancer Registry, the National Inpatient registry and the Cause of Death Registry we identified, during the period 1970 through 2003, in total 23288 patients with incidental prostate cancer, who constituted the study group. As comparison group we choose all patients diagnosed with prostate cancer between 1970-2003 excluding those with incidental cancer, in total 112204 patients. Our result confirms earlier findings that there has been a dramatic change over time in incidence of incidental prostate cancers in Sweden, which parallels the introduction of prostate specific antigen. We also found that the cumulative incidence of prostate cancer death is high in the incidental group, opposing earlier findings that incidental tumours are a non-lethal disease.</p> / issn 1642-4063

This thesis deals with problem solving of general practitioners (GPs), which is explored with different methods and from different perspectives. The general aim was to explore and describe rules of thumb and to analyse the management of respiratory and urinary tract infections (RTI and UTI) in general practice in Sweden. The results are based upon focus group interviews concerning rules of thumb and a prospective diagnosis-prescription study concerning the management of patients allocated a diagnosis of RTI or UTI. In addition unpublished data are given from structured telephone interviews concerning specific rules of thumb in acute sinusitis and prevailing cough. GPs were able to verbalize their rules of thumb, which could be called tacit knowledge. A specific set of rules of thumb was used for rapid assessment when emergency and psychosocial problems were identified. Somatic problems seemed to be the expected, normal state. In the further consultation the rules of thumb seemed to be used in an act of balance between the individual and the general perspective. There was considerable variation between the rules of thumb of different GPs for patients with acute sinusitis and prevailing cough. In their rules of thumb the GPs seemed to integrate their medical knowledge and practical experience of the consultation. A high number of near-patient antigen tests to probe Streptococcus pyogenes (Strep A tests) and C-reactive protein (CRP) tests were performed in patients, where testing was not recommended. There was only a slight decrease in antibiotic prescribing in patients allocated a diagnosis of RTI examined with CRP in comparison with patients not tested. In general, the GPs in Sweden adhered to current guidelines for antibiotic prescribing. Phenoxymethylpenicillin (PcV) was the preferred antibiotic for most patients allocated a diagnosis of respiratory tract infection. In conclusion, the use of rules of thumb might explain why current practices prevail in spite of educational efforts. One way to change practice could be to identify and evaluate rules of thumb used by GPs and disseminate well adapted rules. The use of diagnostic tests in patients with infectious illnesses in general practice needs critical appraisal before introduction as well as continuing surveillance. The use of rules of thumb by GPs might be one explanation for variation in practice and irrational prescribing of antibiotics in patients with infectious conditions. / On the day of the public defence the status of the articles IV and V was: Accepted.

Hypoxia Inducible Factor-1α in Renal Cell Carcinoma Departments of Surgical and Perioperative Sciences, Urology and Andrology; Radiation Sciences, Oncology; Medical Biosciences, Pathology; and Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden Background: Renal cell carcinoma (RCC) accounts for approximately 2-3% of all human cancers. A distinguished feature of RCC is vascularisation and among the three dominating RCC types conventional RCC (cRCC) generally is more vascularised than papillary RCC (pRCC) and chromophobe RCC (chRCC). Angiogenesis is a critical step in tumour progression controlled by a balance involving molecules that have positive and negative regulatory activity. A balance distorted by metabolic stress such as hypoxia, acidosis, and inflammation. Hypoxia-Inducible Factor 1α (HIF-1α) is a key transcription factor in angiogenesis and tumour progression, targeting more than a 100 genes involved in vascular growth and regulation, iron metabolism and erythropoesis, collagen matrix formation, regulation of extracellular pH, glucose uptake and metabolism, proliferation, apoptosis, differentiation, and cell viability. Methods: Tumour tissue and corresponding kidney cortex from nephrectomised RCC patients was used in order to characterize HIF-1α expression and one of its target genes, Glucose Transporter 1 (GLUT-1). All tumour samples were thoroughly described regarding tumour type, TNM stage, nuclear grade, tumour size, vein invasion, and patient survival. Utilizing RT-PCR, Westen Blot and Tissue micro array (TMA) we studied HIF-1α mRNA and protein expression as well as GLUT-1 protein expression, correlating them to each other and clinicopathological parameters. Results: Using Western Blot, HIF-1α protein expression differed significantly between the different RCC types and kidney cortex. In cRCC, high expression of HIF-1α was an independent prognostic factor for favourable prognosis. TMA is a useful method to analyze HIF-1α protein expression in RCC. HIF-1α levels were significantly lower in locally aggressive cRCC and patients with high levels of HIF-1 tended to have a better prognosis. GLUT-1 levels were higher in cRCC than in other RCC types and for cRCC a correlation to HIF-1α was seen. HIF-1α mRNA levels were significantly lower in cRCC compared to other RCC types and kidney cortex. An inverse correlation between HIF-1α protein expression and mRNA levels was observed. Summary: These results demonstrate a discrepancy between RCC types, highlighting the need to separately evaluate biological events in different RCC types. Overexpression of HIF-1α protein is not necessarily all bad and translational regulation appears more critical than anticipated. Further studies are encouraged to clarify angiogenic pathways in RCC.

Background: Renal cell carcinoma (RCC) is most lethal of the urological cancers, with more than 40% dying of the disease. About 30% of the patients have metastases at initial diagnosis and up to 40% undergoing nephrectomy for localized RCC develop metastasis. A follow-up protocol based on accurate prognostic variables allows identification of low and high risk patients and selection of those most likely to benefit from adjuvant therapy. I have studied a number of prognostic patient-related factors, including tumour stage and grade, angiogenetic factors and tumour markers, in order to improve follow-up guideline as well as to try to predict prognosis and clinical outcome for individual patients. Material and Methods: The studies are based on patients treated for RCC between 1982 and 2002. All patients eligible for surgery with or without metastasis were treated with nephrectomy and were followed according to a scheduled follow-up programme. Serum samples were collected after obtained informed consent. Multiple clinicopathological, laboratory variables and preoperative radiological examinations were analyzed. Results: Study I- After nephrectomy in 187 patients with non-metastatic RCC, 30% developed metastases during the follow-up. The risk for metastases was greater for more advanced stage and was adjusted by size and DNA ploidy. The median time to the diagnosis of metastases was 14.5 months. Metastases occurred in 43% of the patients within one year, within 2 years in 70% and 80% in 3 years. Patients with tumours less than 5 cm and diploid pT1&gt;5cm and pT2 tumours survived longer than those with larger and aneuploid tumours. The 5-years survival rate for pT1, pT2, pT3 tumours were 95%, 87%, and 37% respectively. In pT3 tumours DNA ploidy had no relation to survival time. Study II and IV- The median survival time for patients with metastatic RCC was 7 months. Cytoreductive nephrectomy was associated with longer survival time. Factors including performance status (PS), number of metastatic sites, erythrocyte sedimentation rate (ESR), calcium in serum, vein invasion, capsule invasion had independent prognostic value with Cox multivariate analysis. Study III- The incidence of adrenal tumour involvement was 5.3 %, unaffected of RCC type, tumour location or side. Gender (male) and locally advanced tumours (pT3 &gt; 5cm) were factors predicting adrenal involvement. The presence of adrenal involvement was a significant adverse prognostic variable, indicating a significantly shorter survival in patients both with and without distant metastases. Conclusion: Optimal follow-up guidelines are important from both medical and economic perspectives. The risk for progression depends mainly on stage, which in combination with other prognostic factors may allow more individualized and cost effective follow-up, in some cases by avoiding unnecessary examinations in a third of the patients. Cytoreductive nephrectomy in patients with good PS, metastases limited to one organ, low ESR, normal calcium and no vein invasion were factors associated to long survival time. Soluble angiogenic factors in serum gave no prognostic information. Ipsilateral adrenalectomy in conjunction with radical nephrectomy should be performed if an adrenal lesion cannot be cleared of suspicion during preoperative work up. Ipsilateral adrenal involvement is a highly adverse prognostic factor and should be staged as M1a in the TNM staging system.