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CBL proteins are E3 ubiquitin ligases and adaptor proteins. The mammalian homologs – CBL, CBL-B and CBL-3 show broad tissue expression; accordingly, the CBL proteins play roles in multiple cell types. We have investigated the function of the CBL-B protein in hematopoietic cells and fibroblasts. The causative agent of chronic myeloid leukemia (CML) is BCR-ABL. This oncogenic fusion down-modulates CBL-B protein levels, suggesting that CBL-B regulates either the development or progression of CML. To assess the involvement of CBL-B in CML, bone marrow transduction and transplantation (BMT) studies were performed. Recipients of BCR-ABL-infected CBL-B(-/-) cells succumbed to a CML-like myeloproliferative disease with a longer latency than the wild-type recipients. Peripheral blood white blood cell numbers were reduced, as were splenic weights. Yet despite the reduced leukemic burden, granulocyte numbers were amplified throughout the animals. As well, CBLB(-/-) bone marrow (BM) cells possessed defective BM homing capabilities. From these results we concluded that CBL-B negatively regulates granulopoiesis and that prolonged latency in our CBL-B(-/-) BMT animals was a function of perturbed homing.To develop an in vitro model to study CBL-B function we established mouse embryonic fibroblasts (MEFs) deficient in CBL-B expression. Transduction of the wild-type and CBL-B-deficient MEFs with BCR-ABL did not confer transformation; nevertheless, the role of CBL-B in fibroblasts was evaluated. The CBL-B(-/-) MEFs showed enhanced chemotactic migration toward serum in both Transwell migration and time-lapse video microscopy studies. The biochemical response to serum was extensively evaluated leading to the development of a model. We predict that CBL-B deficiency either: (a) augments GRB2-associated binding protein 2 (GAB2) phosphorylation leading to enhanced extracellular signal-regulated kinase (ERK) and protein kinase B (PKB / Akt) signaling, or (b) alleviates negative control of Vav3 resulting in stimulation of Rho effectors. In either case, our results reveal a negative regulatory role for CBL-B in fibroblast migration. The two studies detailed herein expand our knowledge of CBL-B function. They strongly suggest that CBL-B can modulate granulocyte proliferation and point toward a role for CBL-B in the motility of numerous cell types.

Enligt Patientdatalagen (SFS 2008:355), 3 kap, 1 § har fastställts att sjuksköterskan är skyldig att föra journal. I varje patientjournal ska upprättas en omvårdnadsplan vilken ska vara utformad enligt omvårdnadsprocessens fem faser: bedömning, diagnos, mål, planering, genomförande och utvärdering. Omvårdnadsdokumentationen har som syfte att beskriva den vård som patienten erhållit genom att den beskriver vilka beslut som tagits, vilka åtgärder som gjorts samt vilka resultat som uppnåtts. Patienter som genomgår allogen stamcellstransplantation (SCT) upplever ofta en hög psykologisk påfrestning och själva transplantationstillfället är i sig komplext med många behandlingsrelaterade biverkningar som påverkar hela den transplanterades tillvaro både fysiskt och psykiskt. Syftet med uppsatsen var att undersöka sjuksköterskans  omvårdnadsdokumentation avseende omvårdnadsprocessen gällande patienters emotionella hälsa (EH) från utskrivningsdatum för SCT och ett år framåt. Totalt granskades 40 patientjournaler på en hematologmottagning, vilket är en mottagning som har ansvar för uppföljning och eftervård av de patienter som genomgått allogen SCT. Av dessa 40 patienter hade 73% minst en journalanteckning dokumenterad av en sjuksköterska som handlade om EH. 81% av det som var dokumenterat handlade om negativa upplevelser. Ingen patient hade upprättad omvårdnadsplan byggd enligt omvårdnadsprocessen gällande sin EH och patientens EH beskrevs i 86% under sökordet välbefinnande. Utifrån dessa resultat är författarens upplevelse att sjuksköterskorna på den här mottagningen i stor utsträckning dokumenterar patienters EH någonstans i omvårdnadsjournalen men att det saknas en planering av patientens EH som följer omvårdnadsprocessen i dess helhet. Med utgångspunkt av detta anser författaren till uppsatsen att alla sjuksköterskor borde ges möjlighet till kontinuerlig utbildning i omvårdnadsdokumentation för att upprätthålla och bättra på sin kunskap. / According to the Patient Act (SFS 2008:355), Chapter 3, § 1 has been determined that the nurse is required to keep records. Each health record shall contain a care plan which will be designed according to nursing process, five phases: assessment, diagnosis, goals, planning, implementation and evaluation. Nursing documentation is intended to describe the given care, what decisions and actions that have been taken and the results achieved. Patients undergoing allogeneic stem cell transplantation (SCT) often experience a high psychological distress and the time of transplantation is in itself complex, with many treatment- related side effects, both physically and mentally. The aim of the study was to investigate the nurse´s nursing documentation on nursing process to patient emotional health (EH) from the discharge date for SCT and one year ahead. 40 patient records were reviewed at a haematological reception, which is the reception which has responsibility for monitoring and follow-up care of patients undergoing allogeneic SCT. 73% of these 40 patients had at least one entry recorded in the journal about EH. 81% of documented records is about negative experiences. No patient had an established care plan, built according to nursing process known their EH and EH patients were described in 86% over the keyword welfare. Based on these results the author´s experience that the nurses at this clinic extensively documenting patients´ EH somewhere in the nursing journal, but that there is no planning of patient EH arising nursing process as a whole. Based on the result in the study, the author´s view is that all nurses should be given the opportunity to get training in nursing documentation in order to maintain and improve their knowledge.

The signalling cascade induced by the binding of neurotrophins (NGF, BDNF, NT3 and NT4) to their high-affinity tyrosine kinase receptors (TrkA, B and C) is well documented to be important for neuronal cell survival, proliferation and differentiation. Evidence has accumulated demonstrating the importance of these signalling pathways in nonneuronal tissues, including the ovary where all neurotrophins and their receptors are expressed. In the mouse, effects on ovulation have been demonstrated but the role of Trk signalling in neonatal ovary development is less clear. Previous work had found that TrkB expression is upregulated at the time of follicle formation in the mouse and transgenic mice null for the TrkB receptor demonstrate significant loss of oocytes neonatally (TrkB knockouts, KO, die shortly after birth). This thesis examines the phenotype of the TrkB KO using morphological, histological and surgical techniques with the aim being to further investigate the role of TrkB signalling in oocyte survival, and to contribute to our understanding of neonatal ovary development. The main questions addressed are: 1) what developmental defects are occurring on a morphological level that result in the phenotype of the TrkB KO; 2) can these defects be quantified; and 3) what are the longterm survival prospects for TrkB KO oocytes. Morphological assessment revealed that TrkB KO ovaries exhibit poorer follicle health than their Controls and this was confirmed by assessment of basement membrane (BM) composition. TrkB KO brain and kidney were also assessed and found to have similarly affected BM. It is well known that cells require contact with the BM to maintain survival, thus it is postulated that TrkB signalling contributes to oocyte survival through regulation of the BM. Due to the postnatal lethality of the mutation, TrkB KO ovaries were transplanted to ascertain long-term oocyte survival. Unexpectedly it was found that TrkB KO oocytes are able to survive and follicles grow as well as they do in the Control transplants. Consequently, the in vivo effect has to be indirect. It is known that oocytes in the neonatal ovary undergo an increased rate of cell death but it is not known how the cell debris is removed. A novel observation of a neonatal ovarian immune response has been made in this thesis and is postulated to be a physiological mechanism for cell debris clearance. In conclusion, this thesis has demonstrated that signalling through TrkB has an effect on regulating BM in the ovary and other organs, but that surprisingly it has an indirect effect on oocyte survival.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Cardiac transplantation is the treatment of choice for eligible patients with advanced heart failure; however, it is limited by a critical shortage of suitable organs from traditional brain-dead donors. Organs donated following circulatory death (DCD) have been used to successfully expand the pool of organs available for kidney, liver, and lung transplantation; however, concerns regarding the severity of injury sustained by the heart following withdrawal of life sustaining therapy have deterred the clinical transplantation of DCD hearts. Investigations aiming to optimize the resuscitation, preservation, and evaluation of DCD hearts may facilitate the development of an evidence based protocol for DCD heart transplantation that can be translated to the clinical area and expand the donor pool. Therefore, the objectives of this thesis are to develop a clinically relevant large animal model of DCD and gain a greater understanding regarding the physiologic impact of donor extubation on the DCD heart, demonstrate as a ‘proof-of-concept’ that utilizing an approach to donor heart resuscitation, preservation, and evaluation that is tailored to the DCD context can facilitate successful transplantation, and finally to investigate ways to optimize the resuscitation, preservation, and evaluation of DCD hearts for transplantation. The results of this thesis may then be used to inform the development of an evidence-based protocol for DCD heart transplantation that can be translated to the clinical area. The clinical adoption of such a protocol has the potential to expand the donor pool and improve outcomes for patients with end-stage heart failure. / May 2017

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Background: Aim of this single center cross-sectional study was to investigate oral behavior, dental, periodontal and microbiological findings in patients undergoing hemodialysis (HD) and after kidney transplantation (KT). Methods: Patients undergoing HD for end-stage renal failure and after KT were investigated. Oral health behavior was recorded using a standardized questionnaire, e.g. dental behavior, tooth brushing, oral hygiene aids. Oral investigation included screening of oral mucosa, dental findings (DMF-T) and periodontal situation (Papilla bleeding index [PBI] periodontal probing depth [PPD] and clinical attachment loss [CAL]). Additionally, microbiological analysis of subgingival biofilm samples (PCR) was performed. Statistical analysis: Student’s t-test or Mann–Whitney-U-test, Fisher’s exact test (α = 5 %). Results: A total of 70 patients (HD: n = 35, KT: n = 35) with a mean age of 56.4 ± 11.1 (HD) and 55.8 ± 10.9 (KT) years were included. Lack in use of additional oral hygiene (dental floss, inter-dental brush) was found. KT group presented significantly more gingivial overgrowth (p = 0.01). DMF-T was 19.47 ± 5.84 (HD) and 17.61 ± 5.81 (KT; p = 0. 21). Majority of patients had clinically moderate and severe periodontitis; showing a need for periodontal treatment of 57 % (HD) and 71 % (KT; p = 0.30). Significantly higher prevalence of Parvimonas micra and Capnocytophaga species in the HD group were found (p < 0.01). Conclusion: Periodontal treatment need and lack in oral behavior for both groups indicate the necessity of an improved early treatment and prevention of dental and periodontal disease, e.g. in form of special care programs. Regarding microbiological findings, no major differences between KT and HD patients were found.