Veterinary Science - Theses
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ItemInflammation and endothelial perturbation in canine abdominal surgery: the potential modulatory effect of lidocaine( 2019)Complication rates following emergency laparotomy surgery are high, with organ dysfunction being a commonly encountered post-operative complication. Given the endothelium acts as the interface between the systemic circulation and the organs, its function is vital to maintaining organ health. The endothelium is in a constant state of flux, impacted largely by the local environment of which it is a part. In the presence of wide-spread systemic inflammation, inflammatory mediators precipitate change to the structure of the endothelial glycocalyx. These changes result in shedding of the endothelial glycocalyx and alteration of the endothelial phenotype. The endothelium may, as a result, lose the capacity to regulate vasomotor tone, and shift toward a pro-inflammatory and pro-coagulant state. This predisposes to reduced tissue oxygen delivery, and organ dysfunction may ensue. This thesis aimed to answer two key questions: does surgical trauma induced in canine patients undergoing emergent abdominal surgery invoke a systemic inflammatory response and subsequent endothelial activation? And if so, does lidocaine, a proposed immunomodulatory drug, mitigate this effect when given in the post-operative period? Chapter two provides a detailed review of endothelial structure and function, and current literature pertaining to systemic inflammation and endothelial activation in the context of abdominal surgery. Chapter two also examines the literature regarding the proposed mechanisms through which lidocaine acts as an immunomodulatory drug, and reviews publications that investigate the use of lidocaine as an anti-inflammatory drug in human patients after abdominal surgery. Chapter three is a randomized, blinded clinical trial quantifying the effect of emergency abdominal surgery on the concentration of markers of systemic inflammation and endothelial perturbation in canine patients in the post-operative period. The trial also assessed the potential use of lidocaine as a post-operative immunomodulatory therapy in dogs having undergone laparotomy. Fifty canine patients undergoing abdominal surgery were enrolled in the study. Patients were randomized into two separate groups: a study group receiving lidocaine intravenously, and a control group receiving 0.9% NaCl intravenously for a twelve-hour period following abdominal surgery. Blood samples were gathered prior to surgery, followed by six and twelve hours post-operatively. Concentrations of markers of systemic inflammation (IL-6) and markers of endothelial perturbation (VEGF and HA) were quantified via means of ELISA at each time point. Results revealed a significant increase in the concentration of markers of systemic inflammation and endothelial perturbation in post-operative blood samples. No immunomodulatory or endothelial preserving effect of lidocaine was appreciated.
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ItemEndothelial activation in dogs with severe sepsis( 2018)Two components of endothelial biology – endothelial glycocalyx, endothelial activation – have been explored this two-part, in-depth research project. An extensive literature review discusses the endothelial glycocalyx in health and critical illness. A prospective observational clinical research study then measures the concentration of soluble biomarkers of endothelial activation in severely septic dogs. The study found a significant difference in the concentration of biomarkers between the septic dogs and controls, a result consistent with the presence of endothelial activation in dogs with severe sepsis.
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ItemUltrasound guided versus palpation guided intra-articular injection of the canine hip joint( 2016)Canine hip dysplasia is a common orthopedic condition that results in progressive and often debilitating osteoarthritis. Intra-articular drug therapy holds much promise in the management of this chronic condition but intra-articular injection of the canine hip joint is challenging using a conventional palpation-guided approach. This thesis describes a feasibility and accuracy study to investigate a novel ultrasound guided imaging technique for intra-articular injection of the canine cadaver hip joint. Ultrasound-guided hip injection could be performed using a caudoventrolateral approach and excellent correlation was present between the sonoanatomy and gross anatomy. The results show that ultrasound-guided hip injection using a caudoventrolateral approach has similar to or better accuracy than that of a palpation-guided technique. No iatrogenic damage was noted with the procedure. Ultrasound-guided hip injection using a caudoventrolateral approach is an accurate and minimally invasive technique for injection of the canine cadaver hip joint.
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ItemStudies of the pathogenesis of canine pyometra( 2011)Pyometra, a prevalent uterine infection that most commonly affects intact-middle aged to aged bitches, is typically associated with the bacterial pathogen Escherichia coli (E. coli) bacteria. Dogs are particularly susceptible to infection during dioestrus, when uterine tissues are under the influence of progesterone. The pathogenesis of pyometra is not thoroughly understood. Many host factors, such as age of the bitch, ovarian hormones, breed and parity seem to play a role, as well as bacterial factors. Pathogenic E. coli strains carry different uropathogenic virulence factors (UVF), which facilitate infection in the urogenital tract. Adhesive proteins, at the tip of bacterial pili (fimbriae), bind to receptors on epithelial cells of the urogenital tract. Three different types of adhesins (FimH, PapGIII and Sfa) have been identified in E. coli strains isolated from bitches with pyometra. The objectives of the studies in this thesis were to investigate the role of bacterial adhesins in the disease process and to investigate differences in host immune defences during different stages of the oestrous cycle. The primary objective of the first study was to investigate whether the adhesin FimH, which can be found in all E. coli pyometra isolates, facilitates the binding of E. coli to the canine endometrial epithelium. An E. coli strain (strain P4), isolated from the uterus of a bitch with pyometra, that only carried the adhesin gene fimH was used. In order to study the effect of the adhesin FimH, a mutant knock-out strain of P4 (P4-∆fimH::kan) was generated from the P4-wildtype strain (P4-wt) by insertionally inactivating fimH. An in vitro assay that provided quantitative and qualitative assessment of bacterial binding was developed and used to assess the binding properties of the mutant and wildtype strains. The second objective was to examine the role of different stages of the canine oestrous cycle on bacterial binding. The stages of the canine oestrous cycle were simulated in ovariectomised greyhound bitches using a previously established protocol and uterine biopsies from these bitches were used to examine the effect of the stage of the oestrous cycle on bacterial binding. The amount of bacterial binding did not vary significantly with the stage of simulated oestrous cycle. The objective of the second study, described in Chapter 4, was to investigate the role of each adhesin gene product, acting alone or expressed in combination, in the bacterial binding of a strain (P3) carrying all three known adhesin genes to the canine endometrium. Knockout (KO) mutants of this wildtype (P3-wt) strain were generated using insertional inactivation. Single (P3-∆fimH::Kan; P3-∆pap::Cm; P3-∆sfa::Kan), double (P3-∆fimH::Kan-∆pap::Cm; P3-∆fimH::Kan-∆sfa::Kan; P3-∆pap::Cm-∆sfa::Kan), and triple (P3-∆fimH::Kan-∆pap::Cm-∆sfa::Kan) mutants were produced. Adhesion assay were conducted on anoestrous uteri of three post-pubertal bitches. Overall, the number of bacteria adhering to canine endometrial biopsies was comparable and no significant difference in the number of bound bacteria was found between the P3-wt strain and the single or double KO-strains. However, the triple knockout strain (P3-∆fimH::Kan-∆pap::Cm-∆sfa::Kan) displayed less binding to the canine endometrium compared with the P3-wt strain. This study showed that a pathogenic E. coli strain (P3) isolated from the uterus of a bitch with pyometra was able to fully compensate for the loss of two of its three known adhesin genes. It was necessary to inactivate all three known adhesin genes in order to see a significant decrease in binding to canine endometrium. However, the triple knockout mutant still retained 42% of its binding capacity compared with the P3-wt strain. This retained binding contrasted with the analyses of strain P4, in which functional loss of a single adhesin gene (fimH) eliminated >99% of bacterial binding. These combined studies suggest that pathogenicity varies between E. coli strains and that there may be additional adhesions in some E. coli strains that play a role in the pathogenesis of pyometra. The objective of the final study was to investigate if differences in innate immunity account for the differential susceptibility to pyometra during different stages of the oestrous cycle. The expression of the antimicrobial peptide β-defensin 1 was assessed during different stages of the simulated oestrous cycle and in response to pathogenic E. coli (P4 strain). A 100-fold increase in canine β-defensin 1 mRNA expression was seen during dioestrus when compared to anoestrus or oestrus. Canine β-defensin 1 mRNA expression remained unchanged during incubation with or without bacteria over 3 or 8 hours, suggesting constitutive expression. In summary, the studies presented in this thesis illustrate the interaction of bacterial virulence and host immunity. The novel in vitro model developed will allow future research in this area in order to further elucidate the pathogenesis of canine pyometra.