UPTAKE OF THE PERIODIC HEALTH EXAM AMONG ADULTS WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES FROM 2003 TO 2015

Background: Over the past decade, annual heath exams have been de-emphasized for the general population but emphasized for adults with intellectual and developmental disabilities (IDD). The purpose of this project was to determine if there has been an increase in the uptake of the health exam among adults with IDD in Ontario, to what extent, and the effect on the quality of preventive care provided. Methods: Using administrative health data, the proportion of adults (18-64 years old) with IDD who received a health exam (long appointment, general assessment, and “true” health exam), a high value on the primary care quality composite score (PCQS), and a health exam or high PCQS each year was compared to the proportion in a propensity score matched sample of the general population. Negative binomial and segmented negative binomial regression controlling for age and sex were used to determine the relative risk of having a health exam/high PCQS/health exam or PCQS over time. Results: Pre joinpoint, the long appointment and general assessment health exam definitions saw a decrease and the “true” health exam saw an increase in the likelihood of adults having a health exam. Post joinpoint, all health exam definitions saw a decrease in the likelihood of adults having a health exam. Pre joinpoint, all PCQS measures (high PCQS, long appointment or high PCQS, “true” health exam or high PCQS) saw an increase in the likelihood for adults to achieve a high PCQS or high PCQS/have a health exam. Post joinpoint, all PCQS measures saw a decrease in the likelihood for adults to achieve a high PCQS or high PCQS/have a health exam. Achieving a high PCQS was strongly associated with having a health exam regardless of health exam definition or IDD status. Conclusions: Despite the publication of guidelines, only a small proportion of adults with IDD are receiving health exams. This indicates that the publication of guidelines alone was not sufficient to change practice. More targeted measures, such as the implementation of an IDD-specific health exam fee code, should be considered to increase the uptake of the health exam among adults with IDD.

The differential impact of oxytocin receptor (OXTR) genotypes on the risk of autism spectrum disorder (ASD) and resulting social communication deficits

Background: Autism spectrum disorder (ASD) is multifactorial and is likely the result of complex interactions between multiple environmental and genetic factors. Recently, it has been suggested that each symptom cluster of the disorder, such as poor social communication, may be mediated by different genetic influences. Genes in the oxytocin pathway, which mediates social behaviours in humans, have been studied with single nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) being implicated in ASD. This thesis examines the presence of different oxytocin receptor genotypes, and their associations with ASD and resulting social communication deficits. Methods: The relationship between four OXTR variants and ASD was evaluated in 607 ASD simplex (SPX) families. Cases were compared to their unaffected siblings using a conditional logistic approach. Odds ratios and associated 95 percent confidence intervals were obtained. A second sample of 235 individuals with a diagnosis of ASD was examined to evaluate whether these four OXTR variants were associated with social communication scores on the Autism Diagnostic Interview – Revised (ADI-R). Parameter estimates and associated 95 percent confidence intervals were generated using a linear regression approach. Multiple testing issues were addressed using false discovery adjustments. Results: The rs53576 AG genotype was significantly associated with a lower risk of ASD (OR = 0.707, 95% CI: 0.512-0.975). A single genotype (AG) provided by the rs2254298 marker was found to be significantly associated with higher social communication scores (Parameter estimate = 1.833, SE = 0.762, p = 0.0171). This association was also seen in a Caucasian only and mothers as the respondent samples. No association was significant following false discovery rate adjustments. Conclusion: The findings from these studies provide limited support for the role of OXTR SNPs in ASD, especially in social communication skills. The clinical significance of these associations remains unknown, however, it is likely that these associations do not play a role in the severity of symptoms associated with ASD. Rather, they may be important in the appearance of social deficits due to the rs2254298 markers association with enlarged amygdalas.

Time-dependency of Rocks and Implications Associated with Tunnelling

The formulation of a geotechnical model and the associated prediction of the mechanical behaviour is a challenge engineers need to overcome in order to optimize tunnel design and meet project requirements. Special challenges arise in cases where rocks and rockmasses are susceptible to time-effects and time-dependent processes govern. Progressive rockmass deformation and instability, time-dependent overloading of support and delayed failures are commonly the result of time-dependent phenomena. The research work presented in this thesis serves as an attempt to provide more insight into the time-dependent behaviour of rocks. Emphasis is given on investigating and analyzing creep deformation and time-dependent stress relaxation phenomenon at the laboratory scale and in-depth analyses are presented. This thesis further develops the understanding of these phenomena and practical yet scientific tools for estimating and predicting the long-term strength and the maximum stress relaxation of rock materials are proposed. The identification of the existence of three distinct behavioural stages during stress relaxation is presented and discussed. The main observations associated with time-dependent behaviour are employed in numerical analyses and applied at the tunnel scale. A new approach for simulating and capturing the time-dependent behaviour coupled with the tunnel advancement effect is also developed and analyzed. Guidance is provided to increase the understanding of the support-rockmass interaction and the main implications and significance of time-dependent behaviour associated with rock tunnelling are discussed. The work presented in this thesis advances the scientific understanding of time-dependent rock and rockmass behaviour, increases the awareness of how such phenomena are captured numerically, and lays out a framework for dealing with such deformations when predicting tunnel deformations. Practical aspects of this thesis are also presented, which will increase their usage in the associated industries and close the gap between the scientific and industry communities.

RELIBILITY ANALYSIS OF SIMPLE SLOPES AND SOIL-STRUCTURES WITH LINEAR LIMIT STATES

The first objective of this research was to develop closed-form and numerical probabilistic methods of analysis that can be applied to otherwise conventional methods of unreinforced and geosynthetic reinforced slopes and walls. These probabilistic methods explicitly include random variability of soil and reinforcement, spatial variability of the soil, and cross-correlation between soil input parameters on probability of failure. The quantitative impact of simultaneously considering the influence of random and/or spatial variability in soil properties in combination with cross-correlation in soil properties is investigated for the first time in the research literature. Depending on the magnitude of these statistical descriptors, margins of safety based on conventional notions of safety may be very different from margins of safety expressed in terms of probability of failure (or reliability index). The thesis work also shows that intuitive notions of margin of safety using conventional factor of safety and probability of failure can be brought into alignment when cross-correlation between soil properties is considered in a rigorous manner. The second objective of this thesis work was to develop a general closed-form solution to compute the true probability of failure (or reliability index) of a simple linear limit state function with one load term and one resistance term expressed first in general probabilistic terms and then migrated to a LRFD format for the purpose of LRFD calibration. The formulation considers contributions to probability of failure due to model type, uncertainty in bias values, bias dependencies, uncertainty in estimates of nominal values for correlated and uncorrelated load and resistance terms, and average margin of safety expressed as the operational factor of safety (OFS). Bias is defined as the ratio of measured to predicted value. Parametric analyses were carried out to show that ignoring possible correlations between random variables can lead to conservative (safe) values of resistance factor in some cases and in other cases to non-conservative (unsafe) values. Example LRFD calibrations were carried out using different load and resistance models for the pullout internal stability limit state of steel strip and geosynthetic reinforced soil walls together with matching bias data reported in the literature.

CHARACTERIZATION AND THERMAL-HYDRAULIC MODELING OF ENGINEERED BARRIERS FOR A CANADIAN DEEP GEOLOGICAL REPOSITORY FOR USED NUCLEAR FUEL

Within Canada there are more than 2.5 million bundles of spent nuclear fuel with another approximately 2 million bundles to be generated in the future. Canada, and every country around the world that has taken a decision on management of spent nuclear fuel, has decided on long-term containment and isolation of the fuel within a deep geological repository. At depth, a deep geological repository consists of a network of placement rooms where the bundles will be located within a multi-layered system that incorporates engineered and natural barriers. The barriers will be placed in a complex thermal-hydraulic-mechanical-chemical-biological (THMCB) environment. A large database of material properties for all components in the repository are required to construct representative models. Within the repository, the sealing materials will experience elevated temperatures due to the thermal gradient produced by radioactive decay heat from the waste inside the container. Furthermore, high porewater pressure due to the depth of repository along with possibility of elevated salinity of groundwater would cause the bentonite-based materials to be under transient hydraulic conditions. Therefore it is crucial to characterize the sealing materials over a wide range of thermal-hydraulic conditions. A comprehensive experimental program has been conducted to measure properties (mainly focused on thermal properties) of all sealing materials involved in Mark II concept at plausible thermal-hydraulic conditions. The thermal response of Canada’s concept for a deep geological repository has been modelled using experimentally measured thermal properties. Plausible scenarios are defined and the effects of these scenarios are examined on the container surface temperature as well as the surrounding geosphere to assess whether they meet design criteria for the cases studied. The thermal response shows that if all the materials even being at dried condition, repository still performs acceptably as long as sealing materials remain in contact.

Accommodating Muslim Minorities in Secular Societies: Public Education in England, Scotland, Ontario, and Quebec

Abstract This thesis examines one of the most sensitive challenges facing contemporary democracies: the accommodation of Muslim minorities in public institutions and services. It focuses on the field of education, and on two particular issues: the public funding of Islamic schools and the accommodation of Muslim needs in public secular schools. The analysis is based on an examination of outcomes in four jurisdictions that differ significantly in the level of accommodation that has emerged: England, Scotland, Ontario, and Quebec. I seek to explain why such variation in outcomes exists among these four cases. I draw on four bodies of literature to underpin the theoretical framework: historical institutionalism, political mobilization by civil society, political parties, and ideationalism. My argument can be summarized simply; historic church-state settlements, unique in each case, are the most important factor explaining the variation in outcomes in England, Scotland, Ontario, and Quebec. In some cases, the historic church-state template is incrementally adapted to accommodate Muslim minorities. In other cases, relatively little accommodation occurs and the path-dependent trajectory of church-state relations remains entrenched. While the historic church-state template is a necessary factor in the explanation, it does not fully account for the variation. For a more complete picture, I demonstrate that there are several additional key factors that also shape the outcomes: first, national identity and public attitudes towards immigration and immigrants; second, the extent of mobilization by political agents, such as civil society organizations and historic churches; and third, the response of political parties to demands by Muslims for institutional accommodation. Ultimately, I conclude that Muslims in these jurisdictions are receiving some accommodation, but the process is slow and partial. This thesis makes important theoretical and empirical contributions to the discussion of Muslim integration in liberal democratic states. First, a framework has yet to be developed that considers the theoretical implications of institutional accommodation of Muslims; I address this gap. Second, this research demonstrates the utility of historical institutionalism in explaining the adaptation of church-state templates to accommodate Muslims’ demands. Last, this study makes an original contribution by comparing the cases of England, Scotland, Ontario, and Quebec in the accommodation of Muslims in education. A comparison of Canada with the United Kingdom has not yet been done.  

Reversibly Photo-Crosslinkable Polycarbonate-Based Polymersomes for Drug Encapsulation and Delivery

This thesis describes the preparation of polymersomes from poly(ethylene glycol)-block-polycarbonate (PEG-PC) copolymers functionalized with pendant coumarin groups. Coumarin groups undergo photo-reversible dimerization when irradiated with specific ultraviolet wavelengths, so they can be used to prepare polymers with photo-responsive properties. In this case, the pendant coumarin groups enable stabilization of the polymersome membrane through photo-crosslinking of the hydrophobic block. Initially, several novel cinnamoyl and coumarin functionalized cyclic carbonate monomers were synthesized using ester, ether, or amide linkages. While the homopolymerization of these functionalized monomers proved challenging due to their high melting points, both cinnamoyl and coumarin functionalized monomers were successfully copolymerized with trimethylene carbonate (TMC) at 100 ℃ using a catalyst-free melt polymerization process where the TMC doubled as a solvent for the higher melting point monomer. Using this system, polycarbonate copolymers with up to 33% incorporation of the functionalized monomers were prepared. In addition, an investigation of some anomalous polymerization results identified previously unreported triethylamine-based catalysts for the melt polymerization of carbonate monomers. These studies also demonstrated that the catalyst-free polymerization of TMC occurs faster and at lower temperatures than previously reported. Subsequently, the photo-crosslinking of cinnamoyl and coumarin functionalized polycarbonates was compared and coumarin was identified as the more effective crosslinking agent when using 300-400 nm UV. An investigation of the photo-reversibility of the coumarin dimerization revealed no discernible change in the properties of crosslinked networks, but rapid photo-reversion in dilute solutions. The photo-crosslinking and photo-reversion kinetics of the coumarin functionalized polycarbonates were determined to be second-order in both cases. Finally, the self-assembly of PEG-PC diblock copolymers functionalized with coumarin was examined and both reverse solvent evaporation and solvent displacement were found to induce self-assembly, with hydrophilic mass fractions (f-factors) of 12-28% resulting in the formation of solid microparticles and nanoparticles and f-factors of 33-43% resulting in the formation of polymersomes. The stabilization of these polymersome membranes through photo-initiator-free photo-crosslinking was demonstrated with the crosslinking allowing polymersomes to withstand centrifugation at 12,000 x g. In addition, the encapsulation of calcein, as a model small molecule drug, in the stabilized polymersomes was successfully demonstrated using confocal microscopy.

The application of PCA as a movement pattern recognition technique: A proof of principle

Quantitative methods can help us understand how underlying attributes contribute to movement patterns. Applying principal components analysis (PCA) to whole-body motion data may provide an objective data-driven method to identify unique and statistically important movement patterns. Therefore, the primary purpose of this study was to determine if athletes’ movement patterns can be differentiated based on skill level or sport played using PCA. Motion capture data from 542 athletes performing three sport-screening movements (i.e. bird-dog, drop jump, T-balance) were analyzed. A PCA-based pattern recognition technique was used to analyze the data. Prior to analyzing the effects of skill level or sport on movement patterns, methodological considerations related to motion analysis reference coordinate system were assessed. All analyses were addressed as case-studies. For the first case study, referencing motion data to a global (lab-based) coordinate system compared to a local (segment-based) coordinate system affected the ability to interpret important movement features. Furthermore, for the second case study, where the interpretability of PCs was assessed when data were referenced to a stationary versus a moving segment-based coordinate system, PCs were more interpretable when data were referenced to a stationary coordinate system for both the bird-dog and T-balance task. As a result of the findings from case study 1 and 2, only stationary segment-based coordinate systems were used in cases 3 and 4. During the bird-dog task, elite athletes had significantly lower scores compared to recreational athletes for principal component (PC) 1. For the T-balance movement, elite athletes had significantly lower scores compared to recreational athletes for PC 2. In both analyses the lower scores in elite athletes represented a greater range of motion. Finally, case study 4 reported differences in athletes’ movement patterns who competed in different sports, and significant differences in technique were detected during the bird-dog task. Through these case studies, this thesis highlights the feasibility of applying PCA as a movement pattern recognition technique in athletes. Future research can build on this proof-of-principle work to develop robust quantitative methods to help us better understand how underlying attributes (e.g. height, sex, ability, injury history, training type) contribute to performance.

Paternalism and Competent Patient Choice in the Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People

In 2016 physicians in Ontario will be granted the authority to refer patients with gender dysphoria for sex reassignment surgery. In order to be granted this authority physicians must be trained in the World Professional Association for Transgender Health’s Standards of Care, which outlines healthcare procedures for the treatment of gender dysphoria and provides background information concerning transgender health. The Standards of Care require that patients undergo a process of 12 months of continuous living in a gender role that is congruent with their gender identity prior to being given access to sex reassignment surgery. While this requirement can sometimes be helpful it can also cause more harm than benefit. This paper argues that the requirement is strongly paternalistic in its current form and should no longer be mandatory in most cases.

MARKERS OF CARDIOVASCULAR DYSFUNCTION AFTER PREGNANCIES COMPLICATED BY PRE-ECLAMPSIA

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy characterized by maternal systemic endothelial dysfunction. While the clinical manifestations resolve soon after delivery, a large body of epidemiological evidence indicates significant long-term maternal risk for cardiovascular disease (CVD) after PE. The mechanisms by which PE and future CVD are associated are unclear, although shared constitutional risk factors likely contribute to the features of endothelial dysfunction characteristic to both. We postulate that PE offers a window of opportunity for the identification of unique markers of dysfunction in the earliest stages of disease that may be used to validate cardiovascular risk screening in the early postpartum period. The studies presented in this thesis provide evidence of changes in circulating factors in women with a recent history of PE. Using blood samples collected within the first year of pregnancy, unique patterns of microRNA expression, enrichment of coagulation system proteins and endothelial progenitor cell dysfunction were described. Many of the described changes appear to be independent of cardiovascular risk. In addition to alterations in circulating factors however, longitudinal postpartum assessments demonstrated that microvascular and cardiac abnormalities were evident in the early periods postpartum after a pre-eclamptic pregnancy. Collectively, the data presented in this thesis reveal that physiological alterations in women with a recent history of PE are not necessarily dependent on clinical parameters of cardiovascular risk, and that resulting dysfunction may be demonstrated within the first year postpartum. Importantly, the biomarkers presented herein are all demonstrated elsewhere in the literature to benefit from lifestyle modification and risk reduction. In closing, the findings of this thesis support a need for cardiovascular risk screening based on obstetrical history, namely after pregnancies complicated by PE.

A Study of the Development of the Ability of the Archives Department of the Hudson's Bay Company to Carry Out Document Repairs

The objective of this thesis was to determine whether the establishment and operation of an archives services by the Hudson's Bay Company had an effect on the company's ability to carry out document repairs. Data collection methods included reviews of published material, archival records of the Hudson's Bay Company, and semi-structured interviews. The study found that the Hudson's Bay Company's commitment to operating a modern archives service in accordance with accepted archive administration practices had a substantial effect on its ability to carry out document repairs. The principled approach to repair, as practiced by the Public Record Office, was a major influence. A review of secondary sources placed this development squarely within the context of archival developments in 20th century England. Overall, the thesis findings add to the growing conversation about conservation history in England, in particular, archive conservation history as it occurred outside of the Public Record Office in the 20th century, by discussing how some methods of repair that were devised, adopted and extended by the Public Record Office in the 19th and 20th centuries were adopted and applied in the 20th century by a well-established business corporation.

The PD-1/PD-L1 Axis: An Immune-Mediated Mechanism of Chemoresistance in Cancer

The ability of tumour cells to avoid immune destruction (immune escape) and their acquired resistance to anti-cancer drugs constitute important barriers to the successful management of cancer. The interaction between specific molecules on the surface of tumour cells with their corresponding receptors on immune effector cells can result in inhibition of these effector cells, consequently allowing tumour cells to evade the host’s anti-tumour immune response. The interaction of the Programmed Death Ligand 1 (PD-L1) on the surface of tumour cells with the Programmed Death-1 (PD-1) receptor on cytotoxic T lymphocytes leads to inactivation of these immune effectors, and is a specific example of an immune escape mechanism tumour cells use to avoid immune destruction. Clinically, antibodies capable of blocking the PD-1/PD-L1 interaction have demonstrated significant therapeutic benefit, and are currently being used to help bolster patients’ immune response against malignant cells in a variety of cancer types. Here we show that the PD-1/PD-L1 interaction also leads to tumour cell resistance to conventional chemotherapeutic agents. Incubation of PD-L1-expressing human and mouse tumour cells with PD-1-expressing Jurkat T cells or purified recombinant PD-1 resulted in tumour cell resistance to doxorubicin and docetaxel. Interference with the PD-1/PD-L1 interaction using blocking anti-PD-1 or anti-PD-L1 antibody or shRNA-mediated gene silencing resulted in attenuation of PD-1/PD-L1-mediated drug resistance. Moreover, inhibition of the PD-1/PD-L1 signalling axis using anti-PD-1 antibody enhanced the effect of doxorubicin chemotherapy to inhibit 4T1 tumour cell metastasis in an in vivo mouse model of mammary carcinoma. These findings indicate that blockade of the PD-1/PD-L1 axis may be a useful approach to immunosensitize and chemosensitize tumours in cancer patients and provide a rationale for the use of anti-PD-1/PD-L1 antibodies as adjuvants to chemotherapy.

Glycemic State Regulates Brain-Derived Neurotrophic Factor Responsiveness of Neurons in the Paraventricular Nucleus of the Hypothalamus

Brain derived neurotrophic factor (BDNF) is a member of the family of neurotrophins and binds to the tropomyosin-related kinase B (TrkB) receptor. Like other neurotrophic factors, BDNF is involved in the development and differentiation of neurons. Recently, studies have suggested important roles for BDNF in the regulation of energy homeostasis. The paraventricular nucleus (PVN) is critical for normal energy balance contains high levels of both BDNF and TrkB mRNA. Studies have shown that microinjections of BDNF into the PVN increase energy expenditure, suggesting BDNF plays a role in energy homeostasis through direct actions in this hypothalamic nucleus. We used male Sprague-Dawley rats to perform whole-cell current-clamp experiments from PVN neurons in slice preparation. BDNF was bath applied at a concentration of 2nM and caused depolarizations in 54% of neurons (n = 25; mean change in membrane potential: 8.9 ± 1.2 mV), hyperpolarizations in 23% (n = 11; mean change in membrane potential: -6.7 ± 1.4 mV), while the remaining cells tested were unaffected. Previous studies showing effects of BDNF on γ-aminobutyric acid type A (GABAA) mediated neurotransmission in PVN led us to examine if these BDNF-mediated changes in membrane potential were maintained in the presence of tetrodotoxin (TTX) sodium channel blocker (N = 9; 56% depolarized, 22% hyperpolarized, 22% non-responders) and bicuculline (GABAA antagonist) (N = 12; 42% depolarized, 17% hyperpolarized, 41% non-responders), supporting the conclusion that these effects on membrane potential were postsynaptic. We also evaluated the effects of BDNF on these neurons across varying physiologically relevant extracellular glucose concentrations. At 10 mM 23% (n = 11; mean: -6.7 ± 1.4 mV) of PVN neurons hyperpolarized in response to BDNF treatment, whereas at 0.2 mM glucose, 71% showed hyperpolarizing effects (n = 12; mean: -6.3 ± 2.8 mV). Our findings reveal that BDNF has direct impacts on PVN neurons and that these neurons are capable of integrating multiple sources of metabolically relevant input. Our analysis regarding glucose concentrations and their effects on these neurons’ response to other metabolic signals emphasizes the importance of using physiologically relevant conditions for study of central pathways involved in the regulation of energy homeostasis.

An immune modulatory role for the fes proto-oncogene

The Fes protein tyrosine kinase is abundantly expressed in phagocytic immune cells, including tumor associated macrophages. Fes knockout mice (fes-/-) display enhanced sensitivity to LPS, and this was shown to be associated with increased NF-κB signaling and TNFα production from fes-/- macrophages. Interestingly, tumor onset in the mouse mammary tumor virus (MMTV-Neu) transgenic mouse model of breast cancer is significantly delayed in fes-/- mice, and this was associated with increased frequency of CD11b+ myeloid and CD3+ T cells in the premalignant mammary glands. Recent studies have also implicated Fes in cross-talk between MHC-I and the NF-κB and IRF-3 pathways in macrophages. Signal 3, the production of inflammatory cytokines and Type I interferons downstream of NF-κB and IRF-3 pathways in antigen presenting cells, is considered an important component of T-cell activation, after engagement of T cell receptor by MHC presented antigen (Signal 1) and co-receptors by their ligands (Signal 2). Using a lymphocytic choriomeningitis virus (LCMV) model of immune activation, I show that LPS stimulated fes-/- macrophages promote more robust activation of LCMV antigenspecific CD8+ T cells than wild type macrophages (fes+/+). Furthermore, LPS stimulated fes-/- macrophages showed increased phosphorylation of NF-B and IRF-3. I also showed that Fes colocalizes with MHC-I in dynamic vesicular structures within macrophages. These observations are consistent with a model where Fes regulates Signal 3 in antigen presenting cells through roles in cross-talk between MHC-I and the NF-kB and IRF-3 signaling pathways. This suggests that Fes plays an immune checkpoint role at the level of Signal 3, and that Fes inhibition could promote tumor immunity through increased Signal 3 driven T cell activation.

Identification and Development of Enzymes Associated With the Sperm Inner Acrosomal Membrane and Their Function during Fertilization

In order for mammalian fertilization to transpire, spermatozoa must transit through the female reproductive tract and penetrate the outer investments of the oocyte: the cumulus oophorus and the zona pellucida. In order to penetrate the oocyte, spermatozoa must undergo the acrosome reaction. The acrosome reaction results in the exposure of the inner acrosomal membrane (IAM) and proteins that coat it to the extracellular environment. After the acrosome reaction, the IAM becomes the leading edge of spermatozoa undergoing progressive movement. Thus the enzymes which effect lysis of the oocyte investments ought to be located on the IAM. An objective of this study was to identify and characterize enzymatic activity detected on the IAM and provide evidence that they play a role in fertilization. This study also describes procedures for fractionating spermatozoa and isolating the IAM and proteins on its intra- and extra-vesicular surfaces, and describes their development during male gametogenesis. Since the IAM is exposed to the extracellular environment and oviductal milieu after the acrosome reaction, this study also sought to characterize interactions and relationships between factors in the oviductal environment and the enzymes identified on the IAM. The data presented provide evidence that MMP2 and acrosin are co-localized on the IAM, originate from the Golgi apparatus in gametogenesis, and suggest they cooperate in their function. Their localization and results of in vitro fertilization suggests they have a function in zona pellucida penetration. The data also provide evidence that plasminogen, originating from the oviductal epithelium and/or cumulus-oocyte complex, is present in the immediate environment of sperm-egg initial contact and penetration. Additionally, plasminogen interacts with MMP2 and enhances its enzymatic action on the IAM. The data also provide evidence that MMP2 has an important function in penetration of the cumulus oophorus. Holistically, this thesis provides evidence that enzymes on the IAM, originating from the Golgi apparatus in development, have an important function in penetration of the outer investments of the oocyte, and are aided in penetration by plasminogen in the female reproductive tract.