Rainfall derived inflow and infiltration (RDII) is a cause of sanitary sewer overflows and sewers exceeding capacity before the end of their design lives, but it is not well understood. Several methods exist to model RDII in existing sanitary sewers. These models are not applicable for design, which is frequently accomplished by applying constant unit rates. Two analytical probabilistic models are developed to estimate the contribution of RDII to peak flow and volume. The analytical models have been tested against computer simulations using long-term rainfall records and parameters calibrated using actual field data. One model relies on calibrated parameters from the RTK method; a commonly used method requiring a time-consuming calibration process. The second model relies on the R-value parameter of the RTK method, and a time of concentration parameter. By providing better information to designers, these analytical models aim to improve engineering decision-making in the design of sewer systems.

Rainfall derived inflow and infiltration (RDII) is a cause of sanitary sewer overflows and sewers exceeding capacity before the end of their design lives, but it is not well understood. Several methods exist to model RDII in existing sanitary sewers. These models are not applicable for design, which is frequently accomplished by applying constant unit rates. Two analytical probabilistic models are developed to estimate the contribution of RDII to peak flow and volume. The analytical models have been tested against computer simulations using long-term rainfall records and parameters calibrated using actual field data. One model relies on calibrated parameters from the RTK method; a commonly used method requiring a time-consuming calibration process. The second model relies on the R-value parameter of the RTK method, and a time of concentration parameter. By providing better information to designers, these analytical models aim to improve engineering decision-making in the design of sewer systems.

Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioural and the psychological symptoms of dementia (BPSD). The objective of this study was to examine the effects of quetiapine on anxiety-like behaviour in the amyloid precursor protein (APP)/ presenilin 1 (PS1) double transgenic mouse model of Alzheimers disease (AD). The mice were treated with quetiapine (0, 2.5, or 5 mg/kg/day) orally in drinking water for 7 or 10 months starting from 2 months of age. Conditioned anxiety was measured using the elevated T-maze (ETM). To measure memory, the Y-maze and the Morris Water maze were employed. After behavioural testing, â-amyloid (Aâ) plaques in the hippocampus and cortex of transgenic mice were stained using Congo Red. Brain-derived neurotrophic factor (BDNF) in the basolateral amygdala (BLA) and the hippocampus of mice was examined using immunohistochemical methods. The statistics revealed an interaction between quetiapine and APP/PS1 double transgenic mice in the avoidance phase of the ETM. Quetiapine modulates anxiety-like behaviours in the ETM. The anxiety-like behaviours were associated with reductions in BDNF levels in the BLA and hippocampus of the transgenic mice. This was reversed by treatment with quetiapine. Furthermore, chronic administration of quetiapine attenuated the memory impairment and decreased the Aâ plaque load in the brain. This study demonstrates that quetiapine normalizes anxiety-like behaviour and up-regulates cerebral BDNF levels in the APP/PS1 mice, suggesting that quetiapine may function as a neuroprotectant as well as an antipsychotic in treating the BPSD associated with AD.

Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, a minute chromosome that leads to the creation of the fusion gene BCR/ABL and the transcription of the fusion protein BCR/ABL in transformed cells. The constitutively active tyrosine kinase BCR/ABL confers enhanced proliferation and survival on leukemic cells. CML has in only a few decades gone from being a disease with very bad prognosis to being a disease that can be effectively treated with oral tyrosine kinase inhibitors (TKIs). TKIs are drugs inhibiting BCR/ABL as well as other tyrosine kinases. In this thesis, the focus has been on the immune system of CML patients, on immune escape mechanisms present in untreated patients and on how these are affected by TKI therapy. We have found that newly diagnosed, untreated CML patients exert different kinds of immune escape mechanisms. Patients belonging to the Sokal high-risk group had higher levels of myeloid-derived suppressor cells (MDSCs) as well as high levels of the programmed death receptor 1 (PD-1)-expressing cytotoxic T cells compared to control subjects. Moreover, CML patients had higher levels of myeloid cells expressing the ligand for PD-1, PD-L1. CML patients as well as patients with B cell malignacies had high levels of soluble CD25 in blood plasma. In B cell malignacies, sCD25 was found to be released from T regulatory cells (Tregs). Treatment with the TKIs imatinib or dasatinib decreased the levels of MDSCs in peripheral blood. Tregs on the other hand increased during TKI therapy. The immunostimulatory molecule CD40 as well as NK cells increased during therapy, indicating an immunostimulatory effect of TKIs. When evaluating immune responses, multiplex techniques for quantification of proteins such as cytokines and chemokines are becoming increasingly popular. With these techniques a lot of information can be gained from a small sample volume and complex networks can be more easily studied than when using for example the singleplex ELISA. When comparing different multiplex platforms we found that the absolute protein concentration measured by one platform rarely correlated with the absolute concentration measured by another platform. However, relative quantification was better correlated.

Stress affects virtually all organisms and can result in both physiological and behavioral changes. Conditioned defeat in Syrian hamsters is a model of stress-induced behavioral plasticity that occurs in a social context. In this model, hamsters are defeated by a larger, more aggressive counterpart. Defeated hamsters subsequently fail to defend their own territory and show striking and long-lasting increases in submissive behavior even when paired with a non-threatening counterpart. The present series of experiments seeks to identify the brain regions and molecular mediators that contribute to this behavioral plasticity. One brain region that has been overlooked by our laboratory is the hippocampus. The results of the first study suggested that the ventral, but not dorsal, hippocampus is important for the acquisition of conditioned defeat as temporary inactivation of the ventral hippocampus prior to defeat training significantly reduced submissive and defensive behaviors when hamsters were tested with a non-aggressive intruder. Next, we sought to identify a potential molecular mediator of social stress-induced behavioral plasticity in hamsters identified as winners or losers after a fight. Using in situ hybridization for brain-derived neurotrophic factor (BDNF) mRNA, we showed that winning and losing hamsters exhibited differences in BDNF mRNA in several regions including the basolateral and medial amygdala as well as the dentate gyrus of the dorsal hippocampus and CA1 of the ventral hippocampus. We next showed that neurotrophic activity in the basolateral amygdala is important for the acquisition of conditioned defeat because K252a infused into the basolateral amygdala prior to defeat training by an aggressive counterpart, significantly decreased submissive and defensive behavior during subsequent testing. Finally, existing data suggest that the amygdala and hippocampus interact to modulate the formation of emotional memories. To test the hypothesis that the basolateral amygdala and ventral hippocampus interact to mediate the behavioral plasticity observed in conditioned defeat, we simultaneously inactivated these regions either contralaterally or ipsilaterally prior to social defeat. Our results suggest that BLA and VHPC interact to mediate the acquisition of conditioned defeat, however, the nature of this interaction remains to be determined.

One of today’s most widely spread health problems is urinary incontinence, affecting 60-80% of the US population from age 15 and up. Treatment based on the possibility to implant a scaffold seeded with the patients’ own urine-derived stem cells, hUSC, to regenerate the damaged muscle tissue, would prove effective. A main challenge in regenerating new tissue from cell-seeded scaffolds is the limited cell survival due to insufficient oxygen diffusion to the center of the scaffold. Ways of enhancing cell survival, and thereby, proliferation and differentiation, is by hypoxic preconditioning of the cells or implantation in an oxygen-release material. Hypoxic preconditioning has shown to enhance proliferation as well as the expression of vascular endothelial growth factor, VEGF, in for example human bone marrow derived stem cells, hBMSC. VEGF is involved in the establishment of vasculature structures and an upregulation of its expression may therefore help promote quicker angeogenisis, increasing the oxygen supply and the cell survival. Oxygen-release materials have shown to enhance cell survival and growth both in vitro and in vivo. This study aims to investigate the effect of hypoxia on hUSC, during 9 days of hypoxic culturing (2.0% ± 0.1% O2) with and without oxygen-release material (PLGA 75:25 with 5 w% CPO) in vitro. hBMSC, and human smooth muscle cells, hSMC, have been used as control groups. Cell proliferation, morphology, differentiation, production of VEGF, and expression of hypoxia inducible factor HIF-1α have been studied. According to the results, combining hypoxic preconditioning of hUSC with implantation in oxygen-release material could be an effective way to regenerate muscular tissue. Hypoxic preconditioning enhanced cell proliferation, production of VEGF, and HIF-1α expression. The increase of VEGF and HIF-1α would promote vascularization when implanted. The oxygen-release material showed possible promotion of cell differentiation, which would augment the hUSCs’ myogenic differentiation, while supplying oxygen until the tissue’s vascular structure has been established.

Aβ oligomer-induced neurotoxicity has become an important area of therapeutic development in treating Alzheimer’s disease. Platelet-derived growth factor (PDGF) has been shown to be able to protect neurons against several neuronal insults such as ischemia and HIV1 toxin induced cytotoxicity. These neuroprotective effects correlate well with our previous results that demonstrate the neuroprotective effects of PDGF-BB, one of the PDGF receptor ligand subtypes, against NR2B containing NMDA receptor induced excitotoxicity, a possible underlying cause of Aβ oligomer induced synaptic dysfunction and neuronal death. This project examines the neuroprotective effect of PDGF-BB against Aβ1-42 oligomer induced cytotoxicity in both SH-SY5Y cells and primary hippocampal neurons. Cell viability was monitored by MTT assay and the affected signaling pathways were examined using pharmacological methods and Western blotting. The results demonstrated that Aβ1-42 oligomer elicited a dose-dependent toxicity with a sign of saturation at higher dosages, PDGF-BB failed to protect neurons against Aβ1-42 oligomer induced cytotoxicity. In contrast, Aβ1-42 oligomers strongly inhibit PDGF-BB induced mitogenesis in both SH-SY5Y cells and primary neurons. Further investigation using Western blotting to measure PDGF receptor expression and phosphorylation in SH-SY5Y cells showed that Aβ1-42 oligomer can inhibit PDGF-BB induced phosphorylation of PDGF β-receptor on Tyr1021, a site that is crucial for PLCγ mediated mitogenesis. These findings not only explained the poor neuroprotective effect elicited by PDGF-BB against Aβ1-42 oligomers, but also led to a novel hypothesis that Aβ1-42 oligomer may interfere with neurotrophic factor induced neuronal survival, either selectively or perhaps globally. Further exploration on this hypothesis will be able to shed light on this potentially novel mechanism of pathogenesis in Alzheimer’s disease.

At present two options are available that can lead to a determination of how moral education may be possible in practice. One takes its formulation from the work of Kant, the other stands in the tradition of Aristotle. Kant emphasizes the importance of duty mid obligation. In contrast, Aristotle attempts to construct a theory of moral life on the practice of virtue. Both theoretical perspectives have debilitating deficiencies. A spectrum of moral experience is presented that represents the wood opportunities available to the agent in life experience. The polarities of this spectrum pull most naturally towards either an Aristotelian or a Kantian perspective, although neither perspective is capable of addressing the requirements of the entire spectrum. The Aristotelian perspective is associated with the life of non-dilemmic virtue, undertaken in community, where relational realities and the contextual contingency of moral life is emphasized. The Kantian perspective is associated with dilemmic situations to be resolved by a process of moral The central problem of the dissertation acknowledges the antithetical nature of these perspectives, and the dichotomous nature of their philosophical roots. The central task of the dissertation is the establishment of a dialogic process that has the potential to reconcile this dichotomy, and to allow these perspectives to mutually inform and reinforce each other. This task is accomplished by providing responses to a central research question that is accompanied by a series of subsidiary questions. From an analysis of various theories of moral education, Kohlberg's theory of structural developmentalism is chosen for reformulation as it is informed by the exploration of the requirements of the dialogic process. To address the research questions, additional Spectra are offered to provide an epistemological and ontological basis for a five-step dialogic treatment that combines, through a developmental climacteric, the Magistral dialogue of Vvgotsky Socratic dialogue of Bakhtin. The five-step model is comprised of a recursive loop through the four steps of the Magistral dialogue prior to an entrance into a Socratic dialogue. (Abstract shortened by UMI.)

This thesis develops a balanced scorecard model based on the attributes of Kaplan and Nortons Balanced Scorecard (1992, 1996, 2001). The model is then operationalized using a survey that is administered to CMAs (Certified Management Accountants) employed by for profit, Canadian companies with greater than 51 employees. One hundred and forty nine usable responses were received. The thesis attempts to answer two research questions: (1) What attributes of a Kaplan & Norton (hereafter K&N) Balanced Scorecard (BSC) are present in the performance measurement systems of Canadian organizations? and (2) What are the differences between organizations with different levels of K&N Balanced Scorecard adoption? <p>Of the 149 responses, 110 (73.8%) organizations were classified as BSC firms (Levels 1 to 4) and 39 (26.2%) were classified as non-BSC firms. The 110 BSC firms were further classified as follows: 15 (13.6%) as Level 1 BSC firms, 14 (12.7%) as Level 2A BSC firms, 20 (18.2%) as Level 2B BSC firms, 25 (22.7%) as Level 3 BSC firms and 36 (32.7%) as Level 4 BSC firms. Thus, based on our conceptual model, we can say that 32.7% of the BSC firms (24.2% of the total respondents) had a fully developed K&N BSC. <p>The study found several differences between Level 4 and Level 1 BSC organizations. For example, respondents in 83% of the Level 4 organizations, versus in 67% of the Level 1 organizations, indicated that their organizations reviewed their performance measures when their strategy changed. <p>This study adds to academic research by conceptualizing Kaplan and Nortons (1996, 2001) Balanced Scorecard and comparing this to the performance measurement systems of Canadian companies. Although there are numerous academic studies on the balanced scorecard (e.g., Chan & Ho 2000; Hoque & James 2000; Lipe & Salterio 2000, 2002; Malina & Selto 2001; Ittner & Larcker 2003; Speckbacher et al. 2003; Stemsrudhagen 2004), only the Speckbacker et al. 2003 study has developed a conceptual model of Kaplan and Nortons (1992, 1996, 2001) Balanced Scorecard and used it to examine the extent of its adoption. Our study mirrors theirs, with two notable exceptions: we have a different and noteworthy conceptualization of Kaplan and Nortons Balanced Scorecard and we apply this to a Canadian setting.

Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioural and the psychological symptoms of dementia (BPSD). The objective of this study was to examine the effects of quetiapine on anxiety-like behaviour in the amyloid precursor protein (APP)/ presenilin 1 (PS1) double transgenic mouse model of Alzheimers disease (AD). The mice were treated with quetiapine (0, 2.5, or 5 mg/kg/day) orally in drinking water for 7 or 10 months starting from 2 months of age. Conditioned anxiety was measured using the elevated T-maze (ETM). To measure memory, the Y-maze and the Morris Water maze were employed. After behavioural testing, â-amyloid (Aâ) plaques in the hippocampus and cortex of transgenic mice were stained using Congo Red. Brain-derived neurotrophic factor (BDNF) in the basolateral amygdala (BLA) and the hippocampus of mice was examined using immunohistochemical methods. The statistics revealed an interaction between quetiapine and APP/PS1 double transgenic mice in the avoidance phase of the ETM. Quetiapine modulates anxiety-like behaviours in the ETM. The anxiety-like behaviours were associated with reductions in BDNF levels in the BLA and hippocampus of the transgenic mice. This was reversed by treatment with quetiapine. Furthermore, chronic administration of quetiapine attenuated the memory impairment and decreased the Aâ plaque load in the brain. This study demonstrates that quetiapine normalizes anxiety-like behaviour and up-regulates cerebral BDNF levels in the APP/PS1 mice, suggesting that quetiapine may function as a neuroprotectant as well as an antipsychotic in treating the BPSD associated with AD.