The overall aim of this thesis is to evaluate the risk for increased morbidity and mortality due to long-term arsenic exposure via drinking water by use of epidemiological and spatial approaches in studies performed in Matlab, Bangladesh. A total of 166,934 individuals aged 4 years and above were screened for skin lesions in 2002-2003. Another sample of 115,903 adults aged 15 years or more and a third sample of 26,972 pregnancies in 1991-2000 were considered in a historical cohort and an ecological study, respectively, where risk of adult mortality and spatial clusters of foetal loss and infant death were analysed in relation to arsenic exposure. More than 70% of the tube-wells in the study area exceeded the threshold for arsenic contamination according to the WHO guideline (10 µg/L). The prevalence of arsenic-induced skin lesions was 3/1000 and men had significantly higher prevalence of skin lesions (SMR 158, 95% CI: 133-188) compared to women. There was an increased risk for death in adulthood due to all non-accidental causes (hazards ratio = 1.16, [95% CI 1.06-1.26]) even at a low level of arsenic contamination (10-49 µg/L). Slightly lower risks were observed for death in cancers (1.44 [1.06-1.95]) and infectious diseases (1.30 [1.13-1.49]) at 50-149 µg/L, but for cardiovascular diseases, it was evident (1.23 [1.01-1.51]) from the level 150-299 µg/L. A dose-response relationship was observed for each of these causes. We identified high and low risk clusters of foetal loss and infant death that coincided with identified high and low clusters of arsenic exposure. Water arsenic concentration of the reported main water source was significantly correlated with arsenic concentration in urine, which reflects current arsenic intake from all sources (R2=0.41, ρ< 0.0001), and the influence of neighbouring water sources was minimal. The study findings underlines that the ongoing arsenic exposure has resulted in a series of severe public health consequences in Bangladesh that call for reinforcement in the mitigation efforts. Knowledge about the spatial distribution of exposure and health effects may be of value in that process.

Both experimental and numerical investigations of converging shock waves have been performed. In the experiments, a shock tube was used to create and study converging shock waves of various geometrical shapes. Two methods were used to create polygonally shaped shocks. In the first method, the geometry of the outer boundary of the test section of the shock tube was varied. Four different exchangeable shapes of the outer boundary were considered: a circle, a smooth pentagon, a heptagon, and an octagon. In the second method, an initially cylindrical shock wave was perturbed by metal cylinders placed in various patterns and positions inside the test section. For three or more regularly spaced cylinders, the resulting diffracted shock fronts formed polygonal shaped patterns near the point of focus. Regular reflection was observed for the case with three cylinders and Mach refection was observed for cases with four or more cylinders. When the shock wave is close to the center of convergence, light emission is observed. An experimental investigation of the light emission was conducted and results show that the shape of the shock wave close to the center of convergence has a large influence on the amount of emitted light. It was found that a symmetrical polygonal shock front produced more light than an asymmetrical shape. The shock wave focusing was also studied numerically using the Euler equations for a gas obeying the ideal gas law with constant specific heats. Two problems were analyzed; an axisymmetric model of the shock tube used in the experiments and a cylindrical shock wave diffracted by cylinders in a two dimensional test section. The results showed good agreement with the experiments. The temperature field from the numerical simulations was investigated and shows that the triple points behind the shock front are hot spots that increase the temperature at the center as they arrive there. As a practical example of shock wave focusing, converging shocks in an electrohydraulic lithotripter were simulated. The maximum radius of a gas bubble subjected to the pressure field obtained from the lithotripter was calculated and compared for various geometrical shapes and materials of the reflector. Results showed that the shape had a large impact while the material did not influence the maximum radius of the gas bubble. / QC 20100706

Self-compacting concrete (SCC) offers rational and fast casting process since it merely has to be poured, or pumped, into the formwork without any compaction work needed. But this can be at the cost of high form pressure. However, reported results show that SCC can act thixotropically, i.e., build up a structure at rest, and this can reduce the form pressure considerably. Thus, in order to utilise the favourable possibilities to increase effectiveness without risking form collapses, the need arises for deeper and broader understanding of the mechanisms behind this thixotropic behaviour. Methodologies have been developed for the characterisation and measurement of the structural build-up at rest, both for the fluid (micro mortar) phase and the concrete itself. Hypotheses state that thixotropic mechanisms originate within the colloidal domain and, thus, motivate studies on the fluid phase comprising this domain. The stress-strain methodology is based on the hypothesis stating that the magnitude of the structure is represented by the maximum elastic stress the fresh material can withstand before the structure breaks. An instrumented steel tube is used to simulate various casting heights and rates. Results show that both micro mortar and SCC are thixotropic and this behaviour is influenced by every measure taken influencing the interparticle colloidal forces. The time-dependent structural build-up of SCC is a function of an irreversible structure (slump-loss) and a reversible, thixotropic structure. There is apparently a threshold value of the structural build-up necessary to reach before obtaining any significant form pressure reduction. Housing SCC´s, with W/C = 0.58, show low degree of structural build-up and pressure decrease while civil engineering SCC´s can show the opposite, but this often at the cost of slump-loss. Recommendations are presented and for the nearest future, suggesting a conservatism regarding design of formwork systems when SCC is used. If the behaviour of a SCC is known it should be used to optimise the formwork. If not, calculating with hydrostatic pressure should be done or the knowledge missing should be gained by using this methodology. A third option is given and this is to monitor the form pressure in real time using sensors. / QC 20100812

Mitigation of the blast risk associated with terrorist attacks and accidental explosions threatening critical infrastructure has become a topic of great interest in the civil engineering community, both in Canada and abroad. One method of mitigating blast risk is to retrofit vulnerable structures to resist the impulsive effects of blast loading. A comprehensive re-search program has been undertaken to develop fibre reinforced polymer (FRP) retrofit methodologies for structural and non-structural elements, specifically reinforced concrete slabs and walls, subjected to blast loading. The results of this investigation are equally valid for flexure dominant reinforced concrete beams subject to blast effects. The objective of the research program was to generate a large volume of research data for the development of blast-resistant design guidelines for externally bonded FRP retrofit systems. A combined experimental and analytical investigation was performed to achieve the objectives of the program. The experimental program involved the construction and simulated blast testing of a total of thirteen reinforced concrete wall and slab specimens divided into five companion sets. These specimens were subjected to a total of sixty simulated explosions generated at the University of Ottawa Shock Tube Testing Facility. Companion sets were designed to study one- and two-way bending, as well as the performance of specimens with simply-supported and fully-fixed boundary conditions. The majority of the specimens were retrofitted with externally bonded carbon fibre reinforced polymer (CFRP) sheets to improve overall load-deformation characteristics. Specimens within each companion set were subjected to progressively increasing pressure-impulse combinations to study component behaviour from elastic response up to inelastic component failure. The blast performance of companion as-built and retrofitted specimens was quantified in terms of measured load-deformation characteristics, and observed member behaviour throughout all stages of response. The results show that externally bonded FRP retrofits are an effective retrofit technique to improve the blast resistance of reinforced concrete structures, provided that debonding of the composite from the concrete substrate is prevented. The test results also indicate that FRP retrofitted reinforced concrete structures may survive initial inbound displacements, only to failure by moment reversals during the negative displacement phase. The experimental test data was used to verify analytical techniques to model the behaviour of reinforced concrete walls and slabs subjected to blast loading. The force-deformation characteristics of one-way wall strips were established using inelastic sectional and member analyses. The force-deformation characteristics of two-way slab plates were established using commonly accepted design approximations. The response of all specimens was computed by explicit solution of the single degree of freedom dynamic equation of motion. An equivalent static force procedure was used to analyze the response of CFRP retrofitted specimens which remained elastic after testing. The predicted maximum displacements and time-to-maximum displacements were compared against experimental results. The analysis indicates that the modelling procedures accurately describe the response characteristics of both retrofitted and unretrofitted specimens observed during the experiment.

Les recherches exposées dans ce document portent sur l'étude du rôle de HSF2 au cours du développement du système nerveux central. Les Heat Shock Factors (HSF) sont impliqués dans la réponse au choc thermique et également au cours du développement embryonnaire. Mes travaux ont démontré que HSF2 est requis au cours de la formation du cortex cérébral pour la migration de certains neurones en régulant directement l'expression de p35, sous unité activatrice de CDK5. D'autres cibles ont été identifiées NudE, Dclk, Dab1 nécessaires à la migration des neurones en participant à la dynamique du cytosquelette. De plus, ces travaux montrent que HSF2 module la prolifération et la différenciation des cellules souches neurales (NSC) et des progéniteurs (NP) car i) par électroporation in ovo chez le poulet, la surexpression de HSF2 provoque une augmentation de la prolifération des NP; ii) les NSC Hsf2−/− en culture présentent un retard de prolifération, de survie et de différenciation. Ainsi, HSF2 pourrait assister la décision cellulaire des NSC/NP vers la prolifération ou la différenciation et la migration, tel un aiguilleur de destin cellulaire

Studies of prophylactic salpingectomy specimens from BRCA1/2 mutation carriers, at risk for tubal and ovarian high-grade serous carcinoma (SerCa), have consistently revealed occult carcinomas and putative histological cancer precursors in the distal fallopian tube epithelium (FTE), supporting the FTE as the source of SerCa. In this thesis I molecularly characterized and compared non-malignant FTE from mutation carriers (FTEb) and control patients (FTEn) to identify alterations that may predispose to malignant transformation. Gene expression profiling of laser capture microdissected FTEn, FTEb and SerCa indicated that SerCa have similar molecular profiles whether of presumed ovarian or tubal origin, supporting the notion they share a common cell of origin within the FTE. Furthermore, FTEb samples obtained during the post-ovulatory luteal phase showed gene expression profiles closely resembling SerCa samples, suggesting that the luteal phase milieu may contribute to serous carcinogenesis. An initial hypothesis was that FTEb may respond differently to luteal progesterone compared to FTEn, via differential expression of progesterone receptor (PR) isoforms. However, similar relative isoform expression in FTEn and FTEb samples suggested that a luteal phase-associated factor other than progesterone directs gene expression changes in FTEb. The possibility that FTEb respond differently to ovulation-associated inflammatory cytokines that are locally elevated during the luteal phase was next investigated. Importantly, FTEb specimens previously found to cluster with SerCa based on their global gene expression profiles showed evidence of increased nuclear factor-κB (NFκB)-dependent (pro-inflammatory) signalling and diminished glucocorticoid receptor (GR)-dependent (anti-inflammatory) signalling. Furthermore, I demonstrate that disabled homolog 2 (DAB2), an adaptor molecule decreased in SerCa and FTE luteal samples, enhances both GR-mediated transactivation and suppression of NFκB signalling, implicating DAB2 as a crucial determinant of inflammatory signalling and ovarian cancer risk. Altogether, this thesis identifies gene expression changes in FTE from BRCA mutation carriers during the post-ovulatory luteal phase that parallel those detected in SerCa. The data support a proposed novel testable model for predisposing events contributing to SerCa that centres on an altered ability to quickly resolve the pro-inflammatory environment created by the ovulatory event.

Benzodiazepines are widely abused by anxious individuals. Consequently, this thesis modeled anxiety in a mouse model in order to investigate benzodiazepine motivation within this sub-population. Using the Tube test of Social Dominance and the Resident/Intruder Paradigm I investigated whether animals identified as dominant or submissive/defeated would differentially display a preference for 0.25 mg/kg midazolam in a conditioned place preference paradigm. Consistent with my hypotheses, benzodiazepine preference was mediated by negative reinforcement as submissive but not dominant mice displayed a preference for midazolam. Furthermore, different neural systems mediated benzodiazepine preference dependent on the stress status of the animal (acute vs. chronic stress) such that, acutely stressed animals experienced benzodiazepine preference through a dopamine-independent pathway whereas chronically stressed animals experienced benzodiazepine preference through a dopamine-dependent pathway. Within chronically stressed mice, blockade of either D1 or D2 receptors attenuated benzodiazepine preference.

Benzodiazepines are widely abused by anxious individuals. Consequently, this thesis modeled anxiety in a mouse model in order to investigate benzodiazepine motivation within this sub-population. Using the Tube test of Social Dominance and the Resident/Intruder Paradigm I investigated whether animals identified as dominant or submissive/defeated would differentially display a preference for 0.25 mg/kg midazolam in a conditioned place preference paradigm. Consistent with my hypotheses, benzodiazepine preference was mediated by negative reinforcement as submissive but not dominant mice displayed a preference for midazolam. Furthermore, different neural systems mediated benzodiazepine preference dependent on the stress status of the animal (acute vs. chronic stress) such that, acutely stressed animals experienced benzodiazepine preference through a dopamine-independent pathway whereas chronically stressed animals experienced benzodiazepine preference through a dopamine-dependent pathway. Within chronically stressed mice, blockade of either D1 or D2 receptors attenuated benzodiazepine preference.

Rotary draw bending, which has very good flexibility and easy tooling, is one of the most preferred bending types for tubular profiles. Cross-section distortion and the spring-back phenomena are commonly faced problems in bending processes. Spring-back is the inevitable problem that is to be solved by manufacturer, generally by overbending. For hollow tubes cross-section distortion is another difficulty since using hollow tubes results in higher strain rates and distortions. During the process the thickness of the hollow tube at the inner surface, which is contacting with the die, increases and the thickness of the tube at the outer surface decreases. Wrinkling is another important defect that occurs at the inner surface of the tube in large diameter thin walled tube bendings. This research compares the experimental results with the finite element analysis of the rotary draw bending process. The aim is to obtain bending characteristics of the two material types, SS304 and St37 and so, to reduce the number of the bending in manufacturing. The main parameters in rotary draw bending process are the bending angle, bend radius, material properties and the geometry of the tube that is to be bent. In this study, to deal with the process, two different materials, three different bending angles and three different tube geometries are used in experiments as well as in finite element analysis. In finite element analysis explicit method is used. It is seen that the experimental results are in good agreement with the numerical results.

Studies of prophylactic salpingectomy specimens from BRCA1/2 mutation carriers, at risk for tubal and ovarian high-grade serous carcinoma (SerCa), have consistently revealed occult carcinomas and putative histological cancer precursors in the distal fallopian tube epithelium (FTE), supporting the FTE as the source of SerCa. In this thesis I molecularly characterized and compared non-malignant FTE from mutation carriers (FTEb) and control patients (FTEn) to identify alterations that may predispose to malignant transformation. Gene expression profiling of laser capture microdissected FTEn, FTEb and SerCa indicated that SerCa have similar molecular profiles whether of presumed ovarian or tubal origin, supporting the notion they share a common cell of origin within the FTE. Furthermore, FTEb samples obtained during the post-ovulatory luteal phase showed gene expression profiles closely resembling SerCa samples, suggesting that the luteal phase milieu may contribute to serous carcinogenesis. An initial hypothesis was that FTEb may respond differently to luteal progesterone compared to FTEn, via differential expression of progesterone receptor (PR) isoforms. However, similar relative isoform expression in FTEn and FTEb samples suggested that a luteal phase-associated factor other than progesterone directs gene expression changes in FTEb. The possibility that FTEb respond differently to ovulation-associated inflammatory cytokines that are locally elevated during the luteal phase was next investigated. Importantly, FTEb specimens previously found to cluster with SerCa based on their global gene expression profiles showed evidence of increased nuclear factor-κB (NFκB)-dependent (pro-inflammatory) signalling and diminished glucocorticoid receptor (GR)-dependent (anti-inflammatory) signalling. Furthermore, I demonstrate that disabled homolog 2 (DAB2), an adaptor molecule decreased in SerCa and FTE luteal samples, enhances both GR-mediated transactivation and suppression of NFκB signalling, implicating DAB2 as a crucial determinant of inflammatory signalling and ovarian cancer risk. Altogether, this thesis identifies gene expression changes in FTE from BRCA mutation carriers during the post-ovulatory luteal phase that parallel those detected in SerCa. The data support a proposed novel testable model for predisposing events contributing to SerCa that centres on an altered ability to quickly resolve the pro-inflammatory environment created by the ovulatory event.