<p>Gonadotropin Releasing Hormone (GnRH) is a hypothalmic decapeptide, which regulates mammalian gonadotropin secretions by binding to specific, high affinity receptors in the pituitary. Two forms of GnRH (GnRH I and GnRH II) are expressed in the brain of human and some primates. Even though primates have been used extensively in a variety of investigations in relation to the role of GnRH in reproduction, there is no evidence of any research to investigate the direct effect of GnRH on primate sperm.</p>

Antral mucosal biopsies were examined microbiologically and histologically for the presence of Campylobacter pylori in 224 patients with upper gastrointestinal symptoms. One hundred and eighty three (83%) patients were found to harbour Campylobacter pylori in their gastric mucosa. Campylobacter pylori was strongly associated with the presence of histological gastritis (93%) and was detected in only 10% of 30 patients whose gastric biopsies showed normal histology. Endoscopically diagnosed duodenal lesions were more strongly associated with the presence of Campylobacter pylori than were gastric lesions (p<0.001). A variety of laboratory methods were evaluated to determine the sensitivity and specificity to detect the presence of Campylobacter pylori. Histology was the most sensitive and specific method to detect the presence of Campylobacter pylori. Although culture was highly specific, it was less sensitive than histology in detecting Campylobacter pylori in gastric antral mucosal specimens. The "conventional" gastric urease assay, although specific, needs be performed under controlled conditions (37°C) for optimal results. The "one-minute" urease assay was more sensitive than the "conventional" gastric urease assays and was highly specific. ELISA to detect specific-IgG antibodies to Campylobacter pylori was a moderately sensitive non-invasive method to detect Campylobacter pylori infection, but was non-specific. / Thesis (M.Med.)-University of Natal, 1988.

Microbiological and molecular epidemiological studies were conducted on 36 multi-resistant Haemophilus influenzae strains, isolated from paediatric patients, over a 26 month period (April 1986 to May 1988). The majority of strains (80,5%) had been isolated from blood and cerebrospinal fluid. More than 80% of isolates tested belonged to biotype II and 90% were of serotype B. Minimal inhibitory concentrations against 6 antibiotics (ampicillin, chloramphenicol, tetracycline, rifampicin, streptomycin and cefotaxime) confirmed the presence of multi-resistant strains. Resistance to rifampicin was confirmed in 6 (16,7%) strains. All strains were susceptible to cefotaxime. Ten transconjugants analysed with respect to their plasmid content were shown to harbour an identical 41 MDa plasmid. Restriction endonuclease digests of these plasmids with Eco R1 and Sst1 revealed almost identical restriction patterns. Outer membrane protein profiles of 19 strains revealed the predominance of one particular subtype. By combining the microbiological and molecular epidemiological findings, it is concluded that one strain of H. influenzae type b is responsible for the nosocomial acquisition of infections amongst paediatric patients. The implifications of these findings are discussed. / Thesis (M.Med.)-University of Natal, Durban, 1988.

Practicing clinical veterinarians in large companion animal practices are often faced with the phenomena of epileptic seizures which occur commonly in dogs. The high incidence of non-responsive cases is often frustrating, and the literature offers incomplete, conflicting and often inaccurate information. The concept of therapeutic anti-epileptic drug concentration monitoring, as applied in man as an aid to treatment, appears attractive in order to provide an improved service to the patient and client. An investigation into the pharmacokinetics of phenobarbitone, particularly at steady state, became necessary in order to interpret the application of drug serum concentration monitoring. The trend of veterinarians to extrapolate human kinetics to dogs is common and unsound. This study was an attempt to identify the similarities and dissimilarities between the pharmacokinetics of dogs and humans. No literature was available, both for man or animal, on the effect of food on the absorption of phenobarbitone. As dog owners frequently have to administer oral medication in food, this was an important factor to examine. The kinetics of the drug was determined in a group of epileptic dogs in order to provide a possible base-line therapeutic regime on commencement of treatment, and the practical application of therapeutic drug monitoring in order to individualize and improve response to treatment was explored. / Thesis (M.Sc.)-University of Durban-Westville, 1990.

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Although there are many laboratory manuals in microbiology for differenct professions (e.g., A General Microbiology Manual for Nurses, Laboratory Manual for Professional Students in the Medical Sciences, etc.), there has been no laboratory manual in this area for Turkish High School Biology Teachers.The author anticipates that the present manual will be successful in accomplishing the objective of better preparing Turkish High School Biology Teachers.In summer courses, teachers from all of Turkey gather to learn new science ideas, and gain new skills by studying in the laboratories. This manual is intended for use as a study guide in these summer courses.The author has conducted all experiments in the laboratory manual and has attempted to assure that fundamental principles of bacteriology and diagnostic microbiology are interwoven in a functional pattern.

The hydraulic-mechanical behaviour of swelling clay is examined in this thesis. The study includes laboratory testing and numerical modeling which considers the influence of boundary conditions on the hydraulic-mechanical behaviour of a compacted unsaturated swelling clay soil. The laboratory testing component of this research consists of three (3) series of tests using a newly modified triaxial apparatus on which mechanical and hydraulic boundary conditions are altered during liquid infiltration. Mechanical boundary conditions range from constant volume to constant mean stress and also include constant stiffness which is a spring type boundary consisting of both volume expansion and mean stress increase. Hydraulic boundary conditions include drained and undrained flow into triaxial specimens. The numerical modeling component of this research includes the creation of a new capillary tube model for swelling clay materials and incorporates dynamic changes to the cross-sectional area for flow. Laboratory results are modeled using the capillary tube model, an empirical hydraulic model, D’Arcy’s Law, and in an elastic-plastic context for unsaturated soil. Results of the laboratory and numerical modeling components show that boundary conditions dominate the hydraulic-mechanical behaviour of unsaturated swelling clay soil during liquid infiltration. In particular, a mechanism is shown to explain how hydraulic conductivity of a swelling soil can decrease with increasing water content at constant void ratio. Finally hydraulic and mechanical behaviour cannot be considered separately in swelling materials due to the intimate relationship in their response.

Fundamental to the understanding of how rivers transform and shape our environment is the role of turbulence and complex, three-dimensional flow, such as vorticity, in sediment transport and erosion. However, classical sediment transport models (or formulae) are based, for the most part, on boundary shear stress and do not incorporate these natural phenomena. This is understandable given that the relationship between turbulence generation, intensity and form; the influence of turbulence on mobile sediment; and the magnitude and patterns of deposition and erosion are complex and difficult to quantify. Nevertheless, the failure to incorporate turbulence and complex, three-dimensional flow into existing models means that our understanding of sediment transport remains incomplete. The central hypothesis of this thesis is that vortical motion is the main factor in the development of local scour. To examine this, a comprehensive experimental approach was taken. This approach involved detailed measurements of the unique three-dimensional patterns of velocity, turbulence and bed morphology associated with flow in an open channel with and without the presence of submerged groyne-like structures (stream barbs and wing dikes) at both the laboratory and field scales. Using densely spaced velocity data and new techniques for processing and analyzing these data, it was possible to identify complex features of the flow field at both scales, such as the presence of vortex cores, and correlate these with changes in bed levels. These data provide a unique perspective of the spatial variability of velocity, turbulence and bed morphology in open channels (and in particular in channel bends, where flow is highly three-dimensional). In particular, it was found that, of the flow parameters analyzed, turbulent stresses were most correlated to scour in channel bends without the presence of structures. In contrast, vorticity was found to be the dominant factor in local scour hole development in the vicinity of submerged structures at both the laboratory and field scale. Such data are rare (if non-existent) in existing experimental research, particularly at the scale of a large natural river. This research also examines stream barb design and performance. Stream barbs (also known as submerged groynes or spur dikes) are a relatively novel approach to stream bank protection and are not common in Canada. The design and installation of stream barbs in a creek in Ottawa (Sawmill Creek) was undertaken to serve as a demonstration project for the use of these structures in a semi-alluvial channel, for which no such case studies exist. Three years of monitoring the site and the performance of these structures to reduce bank erosion and improve aquatic habitat have been carried out. Laboratory testing of stream barb performance was also undertaken and showed that with improper design, the outer bank in a channel bend may be more susceptible to erosion due to excessive local scour downstream of the barb. In particular, to avoid bank erosion downstream of the barb, barbs should be small, such that they create minimum flow obstruction, and include a bank key that is wider than the barb itself and extends in the downstream direction.

<p>The translational potential of diagnostic and prognostic platforms developed using expression microarray technology is evident. However, the majority of array-based diagnostics have yet to make their way into the clinical laboratory. Current approaches tend to focus on development of multi-gene classifiers of disease subtypes, but very few studies evaluate the translational potential of these assays. Likewise, only a handful of studies focus on development of approaches to optimize array-based tests for the ultimate goal of clinical utility. Prior to translation into the clinical setting, molecular diagnostic platforms should demonstrate a number of characteristics to ensure optimal and efficient testing and patient care. Assays should be accurate and precise, technically and biologically robust, and should take into account normal sources of biological variance that could ultimately affect test results. The overarching goal of the research presented in this dissertation is to develop methods for evaluating and optimizing the translational potential of molecular diagnostics developed using expression microarray technology.</p><p> </p><p>The first research section of this dissertation is focused on our evaluation of the impact of intratumor heterogeneity on precision in microarray-based assays in breast cancer. We conducted genome-wide expression profiling on 50 needle core biopsies from 18 breast cancer patients. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen (ER) and progesterone receptor (PR) status were compared to immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics were evaluated by interclass correlation. Results demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single gene predictors of ER (intraclass correlation coefficient (ICC)=0.94) and PR expression (ICC=0.90), and in a multi-gene predictor of ER pathway activation (ICC=0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multi-gene signatures of cancer recurrence (ICC=0.71), and chemotherapeutic sensitivity (ICC=0.72 and 0.64). Together, these results demonstrated that intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise micro-array based predictions of tumor behavior or clinical outcome in breast cancer patients.</p><p> </p><p>Leading into the second research section, we observed that in some cancer types, certain genes behave as molecular switches and have either an "on" or "off" expression state. Specifically, we observed these molecular switch genes exist in breast cancer as robust diagnostic and prognostic markers, including ER, PR, and HER2, and define tumor subtypes associated with different treatment and patient survival. We hypothesized that clinically relevant molecular switch (bimodal) genes exist in epithelial ovarian cancer, a type of cancer with no established molecular subgroups. To test this hypothesis, we applied a bimodal discovery algorithm to a publically available ovarian cancer expression microarray dataset (GSE9891:285 tumors; 246 malignant serous (MS), 20 endometrioid (EM), 18 low malignant potential (LMP) ovarian carcinomas). Genes with robust bimodal expression were identified across all ovarian tumor types and within selected subtypes. Of these bimodal genes, 73 demonstrated differential expression between LMP vs. MS and EM, and 22 genes distinguished MS from EM. Fourteen bimodal genes had significant association with survival among MS tumors. When these genes were combined into a single survival score, the median survival for patients with a favorable versus unfavorable score was 65 versus 29 months (p<0.0001, HR=0.4221). Two independent datasets (n=53 high grade, advanced stage serous and n=119 advanced stage ovarian tumors) validated the survival score performance. Taken together, the results of this study revealed that genes with bimodal expression patterns not only define clinically relevant molecular subtypes of ovarian carcinoma, but also provide ideal targets for translation into the clinical laboratory.</p><p> </p><p>Finally, the third research section of this dissertation focuses on development of robust blood-based molecular markers of decompression stress (DS). DS is defined as the pathophysiological response to inert gas coming out of solution in the blood and tissues when a body experiences a reduction in ambient pressure. To date, there are no established molecular markers of DS. We hypothesized that comparing gene expression before and after human decompression exposures by genome-wide expression profiling would identify candidate molecular markers of DS. Peripheral blood was collected 1hr before and 2hr after 93 hyperoxic, heliox experimental dives (n=54). Control arms included samples collected 1 hour before and 2 hours after high pressure oxygen breathing (n= 9) and surface exercise (n=9), and samples collected at 7am and 5pm for time of day (n=11). Pre and post-dive expression data collected from normoxic nitrox experimental dives were utilized for independent validation. Blood samples were collected into PaxGene RNA tubes. RNA was extracted and processed for globin reduction prior to cDNA synthesis and Affymetrix U133A GeneChip hybridization. 746 genes were differentially expressed following hyperoxic, heliox decompression exposures (permutation adjusted p-value cutoff 1.0E-4). After filtering control significant genes, 726 genes remained. Pathway analysis demonstrated a significant portion of genes were associated with innate immune response (p<0.0001). A 362 multi-gene signature of significant, covariant genes was then applied to the independent dataset and demonstrated differentiation between pre and post-dive samples (p=0.0058). There was no significant correlation between signature and venous bubble grade or bottom time in the validation study. Our results showed that expression profiling of peripheral blood following decompression exposures, while controlling for experimental and normal sources of biological variance, identifies a reproducible multi-gene signature of differentially expressed genes, primarily comprising genes associated with innate immune response and independent of venous bubble grade or dive profile. </p><p> </p><p>Taken together, the research and results presented in this dissertation represent considerable advances in the development of approaches to guide microarray-based diagnostics towards the ultimate goal of clinical translation.</p> / Dissertation

No description available.