Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

While much research has been conducted on the experiences of individuals with inflammatory bowel diseases, there remains a dearth of research conducted on those affected by polyposis conditions. As a result, little is known about the lived experiences of those with polyposis conditions, especially in the cases of parents of pediatric patients with these conditions. This study qualitatively explored the lived experiences of parents of children with polyposis conditions, specifically Juvenile Polyposis Syndrome and Peutz-Jeghers Syndrome. Hermeneutic phenomenology was used to explore the lived experiences of seven parents of children diagnosed with polyposis conditions through semi-structured interviews. Collected data was analysed using Lindseth and Norberg (2004)’s Phenomenological Hermeneutical Method for Researching Lived Experience. In total, four major themes comprising of twelve sub-themes were revealed. Parents discussed feeling grateful for the use of family-centred approaches by their children’s physicians as well as access to medical care for their children, which encouraged them to demonstrate a proactive approach towards their children’s health maintenance. Furthermore, they explained that while seeking information concerning their children’s conditions was anxiety-inducing, discussing their experiences with others with situations similar to theirs was validating and informative. The participants described the importance of advocating for their children within and outside of the medical system, and the responsibility they feel in teaching their children to undertake the advocating process for themselves. Lastly, the parents reflected on the impact their children’s diagnoses have had on their relationships with themselves, their families and their support networks. Overall, the findings from this study are in-line with findings from prior research, except in the case of the ‘Teaching the children to speak for themselves’ theme which proves to be a novel contribution to the literature. The shared key aspects of the phenomenon indicate that focus should be placed on the utilization of family-centred care by physicians, the development of support groups for parents, and on educating physicians on how to best facilitate parents as they model advocating behaviours to pediatric patients. This study provides insight into the lived experiences of parents of children with polyposis syndromes, informing the medical community of how the needs of this group can be better met. Furthermore, the qualitative nature of this research will provide the polyposis, chronic illness and rare illness literatures with information it has been lacking, using a valuable methodological perspective.

Afscheidsrede Universiteit Maastricht. / Met bibliogr.

Proefschrift Universiteit Maastricht. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Die vorliegende Arbeit ist eine qualitative und semiquantitative lichtmikroskopische Auswertung Hämalaun-Eosin gefärbter histologischer Serienschnitte von 1991 bis 1993 operierter Patienten mit Erstauftreten von Polyposis nasi. Hierzu wurde die Einteilung nach Kakoi und Hiraide herangezogen, wodurch sich Nasenpolypen in einen ödematösen, glandulär-zystischen und fibrösen Polypentypen unterteilen lassen. Von insgesamt 92 Patienten hatten 58,7% einen ödematösen und 41,3% einen glandulär-zystischen Polypentypen entwickelt. Kein Patient konnte eindeutig einem fibrösen Nasenpolypentypen zugeordnet werden. Aufgrund der doch eindeutigen Aufteilungsmöglichkeit wird entgegen der Vorstellung von Kakoi und Hiraide, dass es sich hierbei nur um Stadien einer Krankheitsentität handelt, eine Subtypisierung von Polyposis nasi postuliert. Zahlreiche Einteilungskonzepte existieren bereits in der gegenwärtigen Literatur, die allerdings unterschiedliche Ansatzpunkte zum Gegenstand ihrer Einteilung machen. Die Ätiopathogenese von Polyposis nasi ist allerdings immer noch nicht genau geklärt. Erfolgsversprechende Ansätze könnten die Erforschung der Interaktion der inflammatorischen Zellen über Zytokine und die Bedeutung verschiedener Enzymsyteme sein. Aber auch schon häufiger diskutierte Ansatzpunkte wie die Bedeutung bakterieller, mykotischer Infektionen und Analgetikaintoleranz werden sicher noch Gegenstand zukünftiger Untersuchungen sein. Eine Einteilung in unterschiedliche Subtypen ist sicherlich eine neue Möglichkeit zur differenzierteren Untersuchung der Ursache von Polyposis nasi. Hierbei kann die ursprüngliche Einteilung nach Kakoi und Hiraide auch weiterhin als Grundlage dienen. Welche klinische Bedeutung die Subtypisierung hat, sollte allerdings in einer prospektiven Studie weiter geprüft werden. / No abstract available

by Keung Wing Ying. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 115-128). / Abstract also in Chinese. / Abstract --- p.I / Acknowledgments --- p.IV / Abbreviations --- p.V / List of Tables --- p.VII / List of Figures --- p.VIII / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Familial Adenomatous Polyposis (FAP) --- p.1 / Chapter 1.1.1 --- Occurrence and prevalence --- p.1 / Chapter 1.1.2 --- Clinical features --- p.2 / Chapter 1.1.3 --- Laboratory studies --- p.5 / Chapter 1.1.4 --- Diagnosis --- p.6 / Chapter 1.1.5 --- Management --- p.8 / Chapter 1.2 --- Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) --- p.8 / Chapter 1.2.1 --- Clinical features --- p.9 / Chapter 1.2.2 --- Pathogenesis --- p.11 / Chapter 1.2.3 --- Histology --- p.12 / Chapter 1.2.4 --- Differential diagnosis --- p.13 / Chapter 1.2.5 --- CHRPE as an early clinical marker for FAP --- p.14 / Chapter 1.3 --- The Adenomatous Polyposis Coli (APC) Gene --- p.16 / Chapter 1.3.1 --- Discovery --- p.16 / Chapter 1.3.2 --- Structure and function --- p.17 / Chapter 1.3.3 --- Sequence alterations in the APC gene --- p.18 / Chapter 1.3.4 --- APC mutations associated with specific clinical features --- p.21 / Chapter 1.3.5 --- APC gene mutations in Chinese --- p.22 / Chapter 1.3.6 --- Methods for detecting mutation in the APC gene and linkage analysis --- p.23 / Chapter Chapter 2 --- Study Objectives --- p.44 / Chapter Chapter 3 --- Methodology --- p.45 / Chapter 3.1 --- Subjects --- p.45 / Chapter 3.2 --- CHRPE analysis --- p.45 / Chapter 3.2.1 --- Ophthalmoscopic examination --- p.45 / Chapter 3.2.2 --- Diagnostic criteria of CHRPE --- p.45 / Chapter 3.3 --- Materials and Equipment --- p.46 / Chapter 3.3.1 --- Enzymes --- p.46 / Chapter 3.3.2 --- DNA markers --- p.46 / Chapter 3.3.3 --- Reagent kits --- p.46 / Chapter 3.3.4 --- Primers for PCR --- p.46 / Chapter 3.3.5 --- Chemicals and reagents --- p.47 / Chapter 3.3.6 --- Radioisotopes --- p.47 / Chapter 3.3.7 --- Solutions and buffers --- p.47 / Chapter 3.3.8 --- Equipment --- p.48 / Chapter 3.4 --- Methods --- p.49 / Chapter 3.4.1 --- Blood collection --- p.49 / Chapter 3.4.2 --- DNA extraction --- p.49 / Chapter 3.4.3 --- DNA quantitation --- p.50 / Chapter 3.4.4 --- Polymerase Chain Reaction (PCR) --- p.50 / Chapter 3.4.5 --- Agarose gel electrophoresis --- p.51 / Chapter 3.4.6 --- Single Strand Conformation Polymorphism (SSCP) --- p.52 / Chapter 3.4.7 --- Direct DNA sequencing --- p.52 / Chapter 3.4.8 --- Analysis of microsatellite markers --- p.54 / Chapter Chapter 4 --- Results --- p.59 / Chapter 4.1 --- Study subjects --- p.59 / Chapter 4.1.1 --- FAP index patients --- p.59 / Chapter 4.1.2 --- FAP families --- p.59 / Chapter 4.1.3 --- Control subjects with CHRPE only --- p.60 / Chapter 4.1.4 --- Normal control subjects --- p.60 / Chapter 4.2 --- CHRPE analysis --- p.60 / Chapter 4.2.1 --- CHRPE in FAP index patients --- p.60 / Chapter 4.2.2 --- CHRPE in family members --- p.61 / Chapter 4.2.3 --- CHRPE in controls subjects --- p.61 / Chapter 4.2.4 --- Statistical analysis --- p.61 / Chapter 4.3 --- PCR optimization --- p.62 / Chapter 4.4 --- SSCP analysis of the APC gene --- p.62 / Chapter 4.5 --- Direct DNA sequencing analysis --- p.63 / Chapter 4.5.1 --- Nonsense mutations --- p.63 / Chapter 4.5.2 --- Novel silent mutations --- p.64 / Chapter 4.5.3 --- Polymorphisms --- p.65 / Chapter 4.6 --- Haplotype analysis --- p.67 / Chapter 4.7 --- Family studies --- p.67 / Chapter 4.7.1 --- Family A --- p.67 / Chapter 4.7.2 --- Family B --- p.68 / Chapter 4.7.3 --- Family C --- p.68 / Chapter 4.7.4 --- Family D --- p.69 / Chapter 4.7.5 --- Family E --- p.70 / Chapter 4.7.6 --- Family F --- p.70 / Chapter Chapter 5 --- Discussion --- p.104 / Chapter 5.1 --- The predictive value of CHRPE in FAP patients and family members --- p.104 / Chapter 5.2 --- The laboratory techniques in this study --- p.105 / Chapter 5.2.1 --- PCR optimization --- p.105 / Chapter 5.2.2 --- Single Strand Conformation Polymorphism (SSCP) --- p.106 / Chapter 5.2.3 --- Direct DNA sequencing --- p.107 / Chapter 5.3 --- Novel mutation in the APC gene --- p.108 / Chapter 5.4 --- Reported mutations in the APC gene --- p.108 / Chapter 5.4.1 --- 3183del5 --- p.108 / Chapter 5.4.2 --- R216X and R283X --- p.109 / Chapter 5.5 --- Novel silent mutations and polymorphisms in the APC gene --- p.109 / Chapter 5.5.1 --- Novel silent mutations --- p.109 / Chapter 5.5.2 --- Polymorphisms --- p.110 / Chapter 5.6 --- The relationship between APC gene mutations and CHRPE --- p.111 / Chapter 5.7 --- Haplotype analysis --- p.112 / Chapter Chapter 6 --- Conclusion --- p.114 / Chapter Chapter 7 --- References --- p.115

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 94-105).

Mutations in the tumour suppressor gene Adenomatous polyposis coli (APC) are found in 80 % of sporadic colorectal cancer (CRC) tumours and are also responsible for the inherited form of CRC, Familial adenomatous polyposis (FAP). In order to identify novel therapeutic targets for the treatment of APC mutated CRC, we have generated an in vitro model of APC mutant CRC using CRISPR-cas9 gene editing. Using the APC wildtype colorectal carcinoma cell line RKO, we targeted the cells with guide RNA (gRNA) targeting exon 2 or exon 15 (encodes 80 % of APC) of the APC gene. We generated isogenic cell lines which differed in the expression of APC, the controls were APC wildtype and the APC mutant (APC Lys736fs) cell lines expressed a truncated ~80 kDa APC protein. We used these cell lines to perform an siRNA screen against 720 kinases and kinase-related genes. We selected seven genes to investigate further, unfortunately none of the potential hits validated. Additionally, we performed an FDA-approved compound screen targeting over 1000 compounds. From this, we identified a group of HMG-CoA reductase (HMGCR) inhibitors known as statins, which selectively cause a greater loss in cell viability in the APC mutated cell lines, compared to the APC wildtype cells. Mechanistically, our data suggests this synthetic lethal relationship is due to a greater decrease in the anti-apoptotic protein survivin. We propose this is due to statins altering the localisation of Rac1, reducing Pak1 activation and reducing the level of Wnt signalling. This results in the reduction of the Wnt target gene survivin. We have successfully identified an FDA-approved family of compounds, which show synthetic lethality with the APC mutation in our in vitro model.

Background The conventional ileostomy can be avoided. Many attempts have been performed. The first successful solution was the continent ileostomy- Kock pouch. The high rate of complications and revisions some experienced forced surgeon to try to restore the continence by the mechanism of the anus involving an ileal pouch. Both procedures afterwards documented excellent functional outcome, but the complication rates were not negligible and the long-term failure rate were increasing. Different surgical refinements were done and the risk factors for complications and failures were investigated as experience and materials increased. Restoring of the integrity of anal function and the succsess of the ileal pouch-anal anastomosis shadowed the practise of the forerunner: the continent ileostomy reservoir. This latter procedure was more demanding and seemed in the first year of ileal pouchanal anastomosis era to have significant more complications and revisional surgery. The worldwide adoption of the pelvic pouch decreased the need for the continent ileostomy and a vicious circle evolved. Today only few centres perform the procedure. Patients who are not suitable for ileal anal-pouch anastomosis are seldom offered the possibility of having a continent ileostomy. Aims The aims of the study was to investigate surgical load, complications and long-term functional outcome and to define factors which affect these subjects in patients operated with ileal pouch-anal anastomosis, continent ileostomy or both in one single surgical department during the same period and without any institutional learning curve, and furthermore, to compare and contrast the two options. Material and methods From 1984 to 2005(7) 304 (315) patients were operated with IPAA at St. Olavs Hospital (earlier: Regional Hospital of Trondheim). From 1983 to 2002(7) 50 (65) patients had a continent ileostomy constructed. This was an observational study in the scope of surveillance and quality assurance. All patients were offered a planed regularly annual outpatient clinic follow up programme including a prospective standardised interview on clinical outcome. This was a supplement to clinical investigation with endoscopy and consecutive documentation of complications and other factors affecting the patients’ health. Data were recorded in the medical chart. In this system, all patients had recorded dataset. However, the intervals between data recordings differ and the intervals increased by time. All inpatients data were included. Standard descriptive statistical analysis and simple associations were undertaken. Handling longitudinal data with limited cases, varying time intervals was done in a Times Series Cross Sectional data model, analysed, and adjusted for several factors affecting functional outcome. Multivariable analysis was done. Results The estimated failure rate at 20 years was 11.4% for ileal pouch-anal anastomosis and 11.6% for continent ileostomy. Salvage procedures rates were 31% vs. 38%, respectively (p=0.06). The salvage procedures in IPAA included local procedures and redoes with laparotomy. Salvage procedures in CI were related to the function of the nipple valve, mainly nipple valve sliding and less frequent stenosis or fistulas. Complications rates were high. In pelvic pouch surgery, half of the patients would need re-operations in 20 years. Ten percentages had early anastomotic separation without septic complications. Four percentages had early pelvic septic complications. Fistulas and sepsis at the anastomotic site were the main severe complications, often leading to pouch failure. Closing of the loop ileostomy was accompanied with complications in six percentages. In the patients (48) who did not have a covering stoma the overall complications rate did not differ from those with a loop ileostomy, although nine needed a secondary stoma. Covering stoma seems to postpone anastomotic complications. Handsewn anastomosis had more strictures, but otherwise the complications rates were similar to stapled anastomosis. Patients having the diagnosis changed to Crohn`s diseases had more complications and higher failure rate. Early anastomotic complications were associated with long-term complications. In patients with continent ileostomy the nipple valve sliding is the main cause of revision. One third needed revision once or several times. At 20 years follow-up, half of the patients would need surgery due to complications. Although many patients with CI need several revisions, all patients were continent at the last follow up with a stable intubation frequency of 3 – 5 per 24 hour. The failure of the pelvic pouch is the end of severe complications. Two third of the failures had the pouch excision or permanent ileostomy with the pouch in situ. One third underwent a conversion to CI, with equal surgical and functional outcome as other patients with CI. In IPAA, bowel movements at day were between 5-6 at day and 0-1 at night. The rates of more or less frequent incontinence were about 10%, and 41% and 55% had reported soling at day and night respectively. The long-term functional outcome did not deteriorate with time: ie. observational time, as an independent factor did not influence outcome. Factors influencing the outcome were found but the impact of gender, age, protective stoma, hand-sewn anastomosis and early complications were negligible. Pouchitis did significantly influence functional outcome negatively, but did not create deterioration over time. Estimated pouchitis rate in IPAA was 43% for more than 20 years. The onset of the first pouchitis appears mostly in the 5-6 first years after surgery. The crude rate was 35% and 6% of the patients had chronic pouchitis. Severe/chronic pouchitis was associated with primary sclerosing cholangitis, but not with pyoderma gangrenousum or diagnosed joint affections. Idiopathic pouchitis were absent among patients with familial adenomatous polyposis. In continent ileostomy the rate of pouchitis was 26%. Conclusion The complications in both the pelvic pouch surgery and the surgery of continent ileostomy are considerable. Although not similar the surgical load are in the same order of magnitude. For the continent ileostomy revisional surgery are to be expected. The failure rate of both procedures are high and in long-term similar. The long-term functional outcome are however stabile and excellent. The failed pelvic pouch can be converted to a continent ileostomy in selected and motivated patients. The entity of pouchitis is conflicting and has to be divided into several different entities both on clinical, constitutional and other differentiating features. Patients with PSC should be informed of a possible higher risk of severe and chronic pouchitis after IPAA.

No description available.