Veterinary Clinical Sciences - Theses

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    Isocitrate dehydrogenase 1 R132H: epidermal growth factor receptor and Ki-67 expression in canine gliomas
    Fraser, Anne Rosemary ( 2019)
    The diagnosis, histological classification and grading of canine gliomas can be challenging, particularly in the antemortem. In humans, it is essential to accurately diagnose gliomas as the treatment and prognosis vary between tumour histologic type and grade. Numerous biomarkers have been investigated to aid in the diagnosis and classification of human gliomas, including epidermal growth factor receptor (EGFR), Ki-67 and a point mutation in the isocitrate dehydrogenase 1 gene at codon 132 (IDH1 R132H). Only limited studies looking at these biomarkers have been performed in dogs, from which clear conclusion cannot be drawn. The prognosis for canine glial tumours is considered guarded to poor, with the current treatment options having limited success. Consequently, there is a lack of gold standard treatment for canine glioma. In humans, gliomas are being investigated at a molecular level to identify therapeutic targets and to improve responsiveness to treatment. Numerous molecular targets have been identified including EGFR and IDH1 R132H. Canine gliomas share many morphologic, histologic and immunohistochemical characteristics with human gliomas, suggesting a translational approach to the classification, treatment and prognostication of canine gliomas may be possible. The objectives of this research were: (1) to describe the signalment, presenting clinical signs, diagnostic findings, treatment and survival time of a series of dogs with glial tumours, (2) to investigate the series of canine gliomas for the IDH1 R132H mutation, and for EGFR and Ki-67 expression, utilising immunohistochemistry and (3) to determine if immunoreactivity is associated with tumour histologic type and grade. The clinical data of thirty-one dogs with histologically confirmed glial tumours was reviewed retrospectively. The formalin-fixed paraffin-embedded tumour specimens were evaluated for IDH1 R132H, pan-IDH1 (IDH1 wild-type and mutated IDH1), EGFR and Ki-67 expression. IDH1 R132H and pan-IDH1 expression were recorded as positive or negative. EGFR immunoreactivity was evaluated using a semi-quantitative score, and Ki-67 expression was expressed as the Ki-67 labelling index (LI). Patient signalment, clinical presenting signs and diagnostic investigation findings were similar to previous reports. The IDH1 R132H point mutation was not identified in any (0%) of the canine glial tumours, while all 31 (100%) tumours were positive for pan-IDH1 expression. EGFR expression was identified in 16/31 (51.6%) tumours and expression was significantly greater in high grade gliomas when compared to low grade tumours (P = 0.04). Furthermore, EGFR expression was significantly greater in gliomatosis cerebri when compared to oligodendroglioma (P = 0.002), astrocytoma (P = 0.01), and oligoastrocytoma (P = 0.04). Ki-67 expression was identified in 28/31 (90.3%) gliomas, and the Ki-67 LI was significantly higher in high grade tumours (P = 0.02). A significant moderate correlation between the Ki-67 LI and EGFR immunoreactivity (r = 0.47, P = 0.007) was identified. The IDH1 R132H point mutation was not identified in this series of canine gliomas, and may not be an appropriate biomarker to aid in the classification and treatment of these tumours. EGFR, however, may be a suitable therapeutic target, particularly for gliomatosis cerebri. The Ki-67 LI may aid in the development of a grading scheme for canine gliomas.
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    Associations between the radiographic appearance of vascular channels in proximal sesamoid bones, their microstructural characteristics and past racing performance in thoroughbreds
    Lloyd, Kristen Amy ( 2019)
    Reasons for performing the study: ‘Sesamoiditis’ is classically defined by equine practitioners as the presence of and abnormalities in vascular channel appearance within the proximal sesamoid bones (PSB). It is the most common finding in Thoroughbred yearling presale radiographs, as well as often being evaluated on radiographs of adult racehorses with lameness and poor performance. Despite this, the pathogenesis and clinical significance of changes in vascular channel morphology are poorly understood, and the association of ‘sesamoiditis’ with racing performance is inconsistently reported. Objectives: To determine the microstructural characteristics of the PSB associated with the radiographic appearance of vascular channels in Thoroughbred racehorses using micro-computed tomography (µCT), and to determine whether the presence, number and size of vascular channels has an association with past racing performance. Methods: Study design was cross-sectional. One pair of PSB were isolated from a randomly selected forelimb of 59 Thoroughbred racehorses presenting for post-mortem examination over the study period. Each PSB (n=118) was radiographed, assigned a vascular channel grade using previously published and novel radiographic grading systems, then imaged using µCT and similarly assessed. Racing history for each horse was collected. Uni- and multi-variable generalized linear models accounting for clustering at the horse level were generated to investigate associations between radiographic, µCT and performance variables. Results: All PSB had vascular channels observed on µCT originating from the abaxial border (mean 3.6, s.d 0.89), yet in only 63.6% (75/118) were channels observed radiographically. PSB with a higher bone volume fraction (OR 1.08; P=0.031) and wider channel diameter on µCT (OR 20.67; P=0.001) were more likely to have vascular channels identified on radiographs. Radiographic channel number (OR 0.96; P=0.043) and channel size (OR 0.96; P=0.049) were negatively associated with career placings. Main Limitations: Only the forelimb proximal sesamoid bones were collected, radiographs of isolated bones avoided normal superimposition of soft tissue encountered in the live horse, and a cross-sectional study design meant changes in sesamoid vasculature over time and work load could not be assessed. Conclusions: The ability to identify vascular channels radiographically indicates widening of channels and densification of the bone. Increased radiographic channel number and size is associated with poorer measures of past performance suggesting that these changes are not desirable.
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    Inflammation and endothelial perturbation in canine abdominal surgery: the potential modulatory effect of lidocaine
    Donaldson, Liam Robert ( 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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    Update on clinicopathological assessment of renal health in non-racing greyhounds
    Liffman, Rebekah ( 2019)
    Background: Serum creatinine concentrations differ in greyhounds compared with non-sighthounds, but it is not known whether urine creatinine concentrations also differ and whether any difference would influence the interpretation of the urine protein to creatinine ratio (UPC). Additionally, there is some evidence for greyhounds having higher serum symmetric dimethylarginine (SDMA) than non-sighthounds, but this has yet to be confirmed in healthy non-racing greyhounds. Objectives: The objectives of this study were fourfold: (1) to compare the urine creatinine concentrations in healthy greyhounds and a control group of healthy non-sighthounds, (2) to determine the UPC reference interval in healthy greyhounds and to compare this with the UPC reference interval in a control group of healthy non-sighthounds, (3) to determine the serum SDMA concentration reference interval in healthy greyhounds and to compare this with the serum SDMA concentration reference interval in a control group of healthy non-sighthounds and with a previously established canine serum SDMA concentration reference interval, and (4) to establish whether lean body mass is correlated with serum creatinine and urine creatinine concentrations in greyhounds. Methods: The study used an observational cross-sectional design and included 98 clinically healthy non-racing greyhounds and 24 non-sighthound dogs with similar weight, age and sex distributions, as determined by t-test and chi-squared tests. SDMA, urine creatinine concentration and UPC values were measured from blood and urine samples. Linear regression was used to compare the greyhound and non-sighthound groups. Greyhound reference intervals were determined for SDMA and UPC using non-parametric methods. These were compared with the reference intervals for the non-sighthound group and with current International Renal Interest Society guidelines. In the greyhound sample, the association of urine creatinine with thigh circumference, height and weight was estimated using Pearson correlation. Statistical significance was set at P < 0.05 for all analyses. Results: Mean urine creatinine was approximately 22% higher in greyhounds than non-sighthounds after adjusting for urine concentration (P < 0.05). The upper limit of the greyhound UPC reference interval was 0.20 or 0.42, depending on whether strict or moderate exclusion criteria, respectively, were applied. The mean UPC was 29% lower in greyhounds than non-sighthounds, but this difference was not statistically significant (P = 0.1). The serum SDMA reference interval for greyhounds was 6.3–19.7 µg/dL (0.31–0.98 µmol/L). The upper end of this interval was higher than the upper limit of the published canine reference interval (6–13 µg/dL), and the mean concentration was statistically significantly higher in greyhounds (13.0 µg/dL) than non-sighthounds (10.2 µg/dL, P < 0.001). In greyhounds, there were weak correlations between the three morphometric measurements and both serum creatinine and urine creatinine after adjusting for urine concentration. Conclusions and clinical importance: These findings provide further evidence that greyhounds require several breed-specific reference intervals when evaluating renal function. Apart from having higher serum creatinine, greyhounds also have higher SDMA and higher urine creatinine when compared to non-sighthounds. Although UPC trended slightly lower in greyhounds, this finding was not significant, and therefore the threshold for non-proteinuria set by IRIS guidelines appears to be appropriate for greyhounds based on the calculated reference interval.
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    Viscoelastic coagulation changes in dogs with tiger snake envenomation
    Stanley, Monique Kirstie ( 2018)
    Snake venom induced consumption coagulopathy (SVICC) is an important yet poorly described clinical syndrome in the field of veterinary medicine. Publications referencing humans, on the other hand, are numerous in comparison, especially since the establishment of the Australian Snakebite Project. Since the introduction of Australian snake-specific antivenoms, SVICC has become the most common underlying reason for human fatality from snake envenomation in Australia.1 The annual canine snakebite caseload in Australia alone is vast and could be established as a model for the human condition. The overall objective of this study is to extend the scientific literature on SVICC in veterinary medicine, namely the role of thromboelastography (TEG) in tiger snake envenomed dogs. The study assessed the changing clot kinetics of canine whole blood after natural tiger snake envenomation using an established technique called thromboelastography (TEG). Specifically, we will be determining the TEG changes in dogs at several time points: T0 = time of presentation; T1 = 1 hour after antivenom administration; T18 = 18 hours after antivenom administration; and, finally, T24 = 24 hours after antivenom administration. Tiger snake venom caused alterations in TEG parameters, specifically the prolongation of R time (time to initiation of clot formation) during the first 24 hours of envenomation.2 No clinical benefit exists in using TEG over classical coagulation parameters in the identification of SVICC in tiger snake envenomed dogs. Hypercoagulability occurs for 24 hours after envenomation and VetSVICC appears to resolve 18–24 hours after antivenom, which is suggestive of a shorter period to apparent clinical recovery compared to humans, suggesting that VetSVICC may be a unique clinical syndrome. This project is a stepping stone to future research into both SVICC and tiger snake envenomation in veterinary medicine, including establishing an accessible and reliable diagnostic test for SVICC and further delineation of its importance regarding the severity of illness and outcome.
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    Investigation into the relationship between scrotal circumference, body weight, semen characteristics, daughter fertility and genomic breeding values, as well as monitoring behaviour in commercial pasture-based dairy breed natural-service sires
    Waite, Rosemary ( 2018)
    Use of natural-service sires in the pasture-based dairy industry of south-eastern Australia is common, however, research into their selection and management is sparse. This investigation included a cross-sectional study of the genetic merit of pasture-raised natural-service dairy breed sires and quantified the association between natural-service sire scrotal circumference and their daughter fertility breeding value. Additionally, investigations into the association within breeds between scrotal circumference (as an explanatory variable) and daughter fertility breeding value as the outcome variable in a linear regression model were conducted. And finally, this investigation aimed to monitor bull behaviour, including mounting and serving behaviour, as well as tracking distanced walked. Deoxyribose nucleic acid was submitted for genotyping from two groups of Tasmanian Holstein (n=124) and Jersey (n=85) bull calves to get a set of genomic breeding values. Scrotal circumference and body weight measurements and semen characteristics were recorded at 8 weekly intervals from the age of 6 months to 18 months of age. In addition, an observational study was conducted using collar mounted tri-axial accelerometers and global positioning systems on bulls (n=10) on a commercial pasture-based dairy farm in Tasmania, Australia. The genomic information from natural-service sires was compared to contemporary artificial insemination sires, however a clearly defined association between scrotal circumference and the daughter fertility breeding value could not be elucidated, despite the link in beef breeds. Linear regression quantified the relationship between scrotal circumference and body weight and classification and regression tree analyses were determined the predictive value of scrotal circumference and body weight on semen characteristics. Linear regression showed that 50 kg increase in a Holstein bull’s body weight was associated with a 2.9 (95% CI 2.8 to 3.0) centimetre change in scrotal circumference (P= <0.001). For Jerseys, 50 kg increase in body weight was associated with a 2.4 (95% CI 2.3 to 2.5) centimetre change in scrotal circumference (P= <0.001). Classification and regression tree analysis for Holsteins and Jerseys combined showed that 95% of animals that weighed greater had a scrotal circumference of at least 27 cm had a percent normal sperm score greater than 70%. Using learning algorithms bull behaviour was monitored including grazing (F = 0.86) and walking (F = 0.91) compared with ruminating (F = 0.19) and resting (F = 0.38). However, due to the short, yet explosive nature of the mounting and serving signatures, the algorithm was not able to detect them. Mean distance travelled per day ranged from 12.0km to 6.5km and maximum distance travelled per day of 28.0km to the least maximum distance of 14.6km. This study provides information about the genomic merit of natural-service sires and the relationship between scrotal circumference and daughter fertility, augments information on scrotal circumference and body weight relationships in pasture-raised Holstein and Jersey breed bulls and supports the use of the bull breeding soundness exam to manage the risk for sub-fertility in the dairy industry. Additionally, it was found that walking long distances may contribute to the lameness in dairy natural-service sires.
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    The effects of intravenous fluids on thromboelastrographic variables in dogs
    Chan, Adelina ( 2018)
    Intravenous fluid resuscitation plays a fundamental role in treating dogs in haemorrhagic shock, as it can rapidly replenish lost intravascular volume and improve tissue perfusion. However, a consequence of intravenous fluid therapy is interference with haemostasis, which has a detrimental effect to trauma patients that are already haemostatically compromised. In people, intravenous fluid therapy can effect haemostasis and subsequently can increase haemorrhage, transfusion needs and mortality. The effects of intravenous fluids on haemostasis in dogs have not been widely established. More recently, viscoelastic devices like thromboelastography have been used to examine haemostasis. Compared to conventional coagulation testing, viscoelastic devices have the advantages to be able to assess the speed and kinetics of clot formation, clot strength and even the breakdown of the clot. The aim of our study was to determine the effects of intravenous fluids on coagulation in dogs with the use of thromboelastography. The objective of our study was to determine the effect of dilution of canine whole blood with clinically relevant doses of common intravenous fluids on thrombelastographic variables. Our hypothesis was that in vitro dilution of canine whole blood from healthy dogs with intravenous fluids will induce dose-dependent changes in thromboelastographic variables consistent with hypocoagulability. Further, we hypothesized that the characteristics of the fluids, such as its ionic strength and osmolality, will effect thromboelastographic variables in addition to those of dilution alone. The results of our study showed that in vitro dilution of canine whole blood with commonly used intravenous fluids lead to thromboelastographic changes consistent with hypocoagulability in a dose dependent manner. Besides dilution percentage, viscoelastic changes were influenced by fluid characteristics, specifically ionic strength, osmolality and colloidal properties. In our study, 7% hypertonic saline had the most severe effects on coagulation, followed by 20% Mannitol then 3.4% hypertonic saline. Hydroxyethyl starch 130/0.4 had minimal effects on coagulation besides a dilutional effect. The differential effect of fluid characteristics should be taken into consideration when resuscitating dogs with large fluid volumes, but clinical studies are still required to further delineate the importance of different resuscitation fluids and volumes on haemostasis in dogs.
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    A pilot study of the seroprevalence of Q fever in cattle, sheep and goats in Victoria
    Tan, Tabita ( 2018)
    Q fever is an important public health concern throughout the world and infection can result in debilitating and lifelong illness in some people. It is caused by the bacterium Coxiella burnetii and the most frequent source of infection for humans are domestic ruminants. Over a quarter of human Q fever cases in Victoria, 192 out of 659 (29%) analysed from 1994 to 2013 (Bond et al., 2018), are locally acquired indicating that it is endemic in the state. In addition, outbreaks of human Q fever in Victoria associated with local livestock is causing concern that the incidence of disease is increasing. However, information regarding the amount of infection present in the animal reservoir are lacking in Victoria. The aim of this pilot study was to survey cattle, sheep and goats in Victoria to estimate the individual animal-level, herd-prevalence and within-herd-prevalence of Coxiella burnetii infection. This survey was carried out from February 2015 to May 2017 in Victoria, Australia. Over 1500 blood samples were collected using a two-stage sampling process from farms and abattoirs. Sera were screened using a commercial Q fever ELISA kit for ruminants. True prevalence and intra-class correlation coefficient for each species was estimated using a Bayesian approach to account for known test imperfections. Post-hoc sample size estimates were calculated based on survey results to inform future study planning. Q fever is endemic in domestic ruminants in Victoria at low levels and may even be absent in some parts of the state. Of the herds and flocks that were sampled, 8% (95% confidence interval, 5 to 13%) had at least one animal seropositive for Q fever. Herd-level seropositivity rates were 0% (0, 4.7%) and 8.7% (2.4, 26.8%) for Goulburn Valley and Gippsland cattle respectively, 17.6% (9.6, 30.2%) for sheep and 8.0% (0.2, 25.0%) for goats. The overall pooled true animal-level prevalence was 1.3% (95% HPD, 0.9 to 2%). This was based on true animal-level prevalence of 0% (0, 0%) and 0.4% (0, 3.5%) for cattle in Goulburn Valley and Gippsland respectively, 2.1% (0, 3.7%) for sheep and 1.6% (0, 2.8%) for goats. Although the overall herd- and animal-level prevalence estimates were very low, the individual animal-level prevalence within infected herds (within-herd prevalence) was much higher, ranging from 12 to 19%, by species. Finding a small number of groups of animals with elevated levels of within-herd seroprevalence, whilst not detecting positive results in the rest of the sampled population, indicates that the prevalence of exposure to Coxiella burnetii was geographically uneven, being highly clustered within a small number of farms in Victoria. Post-hoc sample size estimates based on survey results indicate large numbers of farms and animals are required for further studies to confirm this very low rate or the absence of infection in some areas of Victoria. However, a greater priority and more cost-effective approach would be to establish why some farms are at higher risk, and this could be efficiently investigated using a case-control study. The findings of this pilot study present a step forward in understanding the epidemiology of Coxiella burnetii in this region of Australia and point to further areas of investigation and how to conduct such studies.
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    The role of diagnostic imaging in small animal endocrine disease
    Rose, Anne Marie ( 2018)
    The work reported in this thesis aimed to investigate the role of diagnostic imaging in small animal endocrine disease: adrenal gland ultrasound in dogs and thyroid scintigraphy in severely hyperthyroid cats. A prospective study evaluated the effect of the patient’s recumbency position on ultrasound derived adrenal gland measurements in dogs with non-adrenal illness. This research determined that the measurement with the best agreement between lateral and dorsal recumbency position was the caudal pole thickness from a longitudinal image plane. Whereas the measurements from the transverse image plane and the length of the adrenal gland had poorer agreement between recumbency positions. A retrospective review of thyroid scintigraphy findings in severely hyperthyroid cats was compared with the general population of hyperthyroid cats. A greater proportion of the severely hyperthyroid cats demonstrated ectopic thyroid tissue and features which increase the suspicion of thyroid carcinoma. These findings suggest that thyroid scintigraphy is useful in severely hyperthyroid cats and assist with treatment decisions. This work also evaluated the role of thyroid scintigraphy in the calculation of an individualised compared to a standard radioiodine dose. The treatment outcome was assessed by the initial post treatment total T4 and found fewer cats receiving a standard radioiodine dose had a total T4 below the reference range. This finding indicates that further evaluation of radioiodine dosing regime is warranted in severely hyperthyroid cats. Thus, the ultrasound assessment of dogs with non-adrenal gland illness has been simplified for all veterinarians including those with less ultrasound experience as the current reference ranges of ultrasound derived adrenal gland measurements were validated and there is flexibility of patient recumbency during the ultrasound examination. Also, this work has contributed to the knowledge of the role of thyroid scintigraphy in both the diagnosis and treatment of severely hyperthyroid cats.
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    Evaluation of tibiotarsal transarticular immobilization techniques and kinematic study of the gastrocnemius muscle-tendon unit in dogs
    Sugiyama, Takanori ( 2018)
    The common calcaneal tendon is a complex muscle-tendon system that regulates flexion/extension of the tibiotarsal joint motion as well as the phalanges. Common calcaneal tendon injury is not uncommon, and two types of injuries are recognized: acute or chronic. Acute injuries are usually related to trauma by a sharp object, transecting skin and underlying structures, including tendons. No definitive causes of chronic injury have been identified, but middle age, large-breed dogs are more predisposed to be affected. The treatment of common calcaneal tendon injury consists of debridement, anastomosis and temporary tibiotarsal joint immobilization during tendon healing. Acute traumatic common calcaneal tendon injury is managed in a very similar way for each patient. Several types of immobilization technique have been described, however, no optimal immobilization technique that neutralizes tension in the common calcaneal tendon has been identified. Numerous biomechanical studies of common calcaneal tendon repairs are reported in human and animal models. In human patients, early controlled motion minimizes various complications, resulting in better outcomes. However, there is no gold standard postoperative protocol for veterinary patients. It can be problematic in veterinary patients to control patient activity and have good client and patient compliance. In this research project, six tibiotarsal transarticular fixation methods were evaluated, and a kinematic evaluation of the gastrocnemius tendon was performed at various femorotibial and tibiotarsal joint angle combinations. These data will help inform development of an optimal immobilization method during healing of common calcaneal tendon injury in dogs.