Veterinary Science - Theses
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ItemInvestigating the inflammatory pathways involved in placental detachment in the mare( 2018)The mechanism of placental detachment in the mare has not been investigated in detail and as such remains poorly understood. Research in other species provides strong evidence that parturition and fetal membrane detachment from the endometrium requires involvement of the immune response. Research in horses has also suggested that movement of leukocytes in the umbilical vessels, and their attraction to fetal membranes at parturition, contribute to placental detachment. The aims of this study were to 1) confirm whether a leukocyte “concentration gradient” exists between the equine neonatal umbilical artery and vein, and whether this gradient was associated with fetal membrane retention time 2) to investigate the expression of pro-inflammatory cytokines in the equine endometrium and fetal membranes at parturition using quantitative real time polymerase chain reaction (RT-qPCR) and 3) to localise pro-inflammatory cytokine proteins within the equine endometrial and fetal membrane tissues using immunohistochemistry to correlate with gene expression. Data was collected from 33 spontaneously foaling mares and their foals on a single Thoroughbred stud farm in New Zealand. Umbilical artery and vein blood, fetal membrane and endometrial biopsy tissue samples were obtained. The average fetal membrane retention time was 92 (+/-130) minutes. The median fatal membrane retention time was 47 minutes (IQR 30). There was a significantly higher number of total leukocytes, lymphocytes and neutrophils in the equine neonatal umbilical artery than the umbilical vein at parturition (p <0.001). Fetal membrane retention time tended to decrease with an increase in umbilical leukocyte concentration gradient but did not reach statistical significance (p = 0.098). The mRNA expression of IL-1, IL-6 and IL-8 was significantly greater in the endometrium of foaling mares compared to control mares (p < 0.001). The mRNA expression of IL-8 was significantly higher in the fetal membranes of foaling compared to control mares (p < 0.001) whereas mRNA expression of IL-6 in fetal membranes was significantly lower between the two groups (p< 0.001). Whilst mRNA expression for IL-1 was lower in the fetal membranes of foaling mares compared to controls, the difference was not significant (p = 0.16). This study has demonstrated the presence of an innate inflammatory immune response in the placenta of spontaneously foaling mares, suggesting the role of inflammation in the detachment of the fetal membranes from the endometrium. The results from this study have highlighted the need to further investigate the mechanism of placental detachment in the mare and also understand the pathophysiology behind abnormal fetal membrane retention.
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ItemBiomechanical testing of the calcified metacarpal articular surface and its association with subchondral bone microstructure in Thoroughbred racehorses( 2018)Subchondral bone adaptation and fatigue likely alter joint surface mechanical properties. The aim of this study was to evaluate the relationship of calcified articular surface biomechanical properties in the distal palmar metacarpal condyle of Thoroughbred racehorses with subchondral bone microstructure and training history. Subchondral bone microstructure was evaluated using both micro- and clinical-computed tomography. Biomechanical properties of the calcified articular surface were tested with reference point indentation at the micron level. Articular surface toughness increased with commencement of race training, and was lower in horses that died as a result of musculoskeletal fatigue injury, had evidence of palmar osteochondral disease, had higher subchondral bone connectivity with more concave surfaces, and higher subchondral bone volume fraction. Further investigation of bone microstructural properties is warranted based on bone connectivity and surface shape findings. At clinically applicable imaging resolution, evidence of subchondral bone modelling may be an important indicator of articular surface biomechanical properties.
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ItemAnti-inflammatory effects of clenbuterol hydrochloride on leukocyte activation in the horse( 2013)The work reported in this thesis aimed to investigate the potential anti-inflammatory effects of clenbuterol hydrochloride in the treatment of equine endotoxaemia. Beta adrenergic agonists, such as clenbuterol hydrochloride reduce leukocyte activation and cytokine production through the up regulation of cyclic adenosine monophosphate. Investigations measured pro-inflammatory cytokine production (IL-1β and TNFα) by equine leukocytes, following stimulation with endotoxin, peptidoglycan and lipoteichoic acid and treatment with clenbuterol hydrochloride during in vitro and in vivo studies. The study also aimed to develop a model enabling correlation of pharmacokinetic and pharmacodynamic drug properties in order to predict an optimum dosing regimen for novel anti-inflammatory agents. The results of the study indicated that clenbuterol hydrochloride has significant anti-inflammatory effects on equine leukocytes challenged with Gram negative and Gram positive bacterial toxins in in vitro assays. Clenbuterol hydrochloride was most potent at inhibiting TNFα production in response to endotoxin, with the effects on peptidoglycan and lipoteichoic acid only being significantly inhibited at much higher clenbuterol hydrochloride concentrations (>10-6 M). Also a marked reduction in lipopolysaccharide stimulated IL-1β cytokine production following treatment with clenbuterol hydrochloride was recognised. In in vivo models of equine endotoxaemia, pre-treatment with oral clenbuterol hydrochloride caused a significant reduction in the peak rectal temperature and peak plasma TNFα concentrations. A model correlating clenbuterol hydrochloride pharmacodynamics and pharmacokinetics was developed. Clenbuterol may have a beneficial role alongside non-steroidal anti-inflammatory drugs and other previously investigated therapies in the treatment of inflammation associated with sepsis in horses. Further investigations in clinical cases of equine endotoxaemia are essential prior to the recommendation of clenbuterol hydrochloride as an adjuvant anti-inflammatory agent in the treatment of systemic inflammation.
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ItemDetection of subchondral bone pathology in the fetlock joint of Thoroughbred racehorses( 2013)REASONS FOR PERFORMING STUDY: Two common subchondral bone injuries occur within the fetlock joint; palmar osteochondral disease and condylar fracture of the distal metacarpus. Both result in lameness, whereas condylar fracture can potentially be life threatening. Pre-existing pathology is commonly identified in horses with condylar fractures, detection of which prior to fracture would have both welfare and economic benefits for the racing industry. However the close spatial association of these two conditions complicates imaging of the distal metacarpus/metatarsus. AIMS: To describe patterns of radiopharmaceutical uptake in fetlock joints of Thoroughbred racehorses and to evaluate racing performance post-scintigraphy and to assess the potential of high-resolution peripheral quantitative computed tomography to predict condylar fracture in Thoroughbred racehorses by imaging the subchondral bone of the distal palmar metacarpus and the cortical bone of the mid diaphysis. HYPOTHESES: Increased radiopharmaceutical uptake (IRU) in the metacarpal (MC) and metatarsal (MT) condyles is more common than IRU in the parasagittal grooves and is associated with poorer post-diagnosis performance than controls. Horses with lateral condylar fracture would have greater bone volume fraction, greater localised subchondral bone thickness at the fracture site and that articular surface fissures would be more prominent in the contralateral limb than controls. METHODS: Scintigraphic evaluation of the fetlock region - A retrospective, case control study was performed using horses undergoing scintigraphy for the investigation of lameness or poor performance. Location of IRU within the fetlock region was identified and graded in Thoroughbred (TB) racehorses presenting for scintigraphic examination. Performance variables were determined from race records for horses with moderate/marked MC/MT condylar IRU (cases), all other horses undergoing scintigraphy (scintigraphy controls), and age/sex matched controls from the last race in which a case participated (controls). Statistical analysis included quantile regression, Fisher’s exact test, Kaplan-Meier survival curves, log-rank test and Cox regression. High resolution peripheral quantitative computed tomography as a predictor of condylar fracture - A prospective, cross-sectional, case control study was performed using limbs from all TB racehorses that died or were euthanased on Victorian metropolitan racetracks between June 2007 and June 2009 (n=37). Groups were assigned as follows: horses with MC fractures with a condylar component (cases, n=13); horses with no limb fracture (controls, n=8); horses with fracture in other bones or disruption of suspensory apparatus (other fatal musculoskeletal injuries, n=16). The palmar distal aspect was removed and a 5cm length of midshaft of MC created and stored in 70% ethanol. The palmar condyles of MC and midshaft examined with high resolution peripheral quantitative computed tomography (HR-pQCT) and morphometric parameters computed. Statistical analysis included logistic regression and Spearman’s correlations. RESULTS: Scintigraphic evaluation of the fetlock region - Metacarpal/MT condylar IRU was identified in 103/220 horses with only 3/220 having parasagittal IRU. Moderate/marked IRU was identified in the forelimb MC and hindlimb MT condylar regions in 62 and 48 horses respectively with palmaromedial and plantarolateral IRU most common. Forelimb cases had fewer starts (P<0.001), reduced earnings (P<0.001), fewer wins (P=0.03) and fewer overall places (P<0.001) than controls. Hindlimb cases had fewer starts (P=0.003) and reduced earnings (P=0.01) than controls. Cases were more likely to return to racing later than controls following a rest period (P=0.003). Cases were older than scintigraphy controls (P<0.001). High resolution peripheral quantitative computed tomography as a predictor of condylar fracture - No significant differences were identified in HR-pQCT variables of distal MC and midshafts between cases and controls. Epiphyseal BV/TV was greater in injured limbs of horses with any fatal limb injury compared to controls (OR 1.20, 95% CI 1.01-1.42, P=0.034). An epiphyseal BV/TV >0.74 resulted in a sensitivity of 82.8% and specificity of 62.5% in identifying horses with fatal limb injury. In horses without condylar fracture, increased subchondral bone thickness was associated with POD lesions in the adjacent condyle (rs=0.65, P<0.001). CONCLUSIONS: The identification of condylar fractures prior to catastrophic injury remains challenging. Condylar fractures are rarely identified using bone phase scintigraphy and this may be because lameness is not observed by owners and trainers prior to fracture. Even with high resolution imaging of the distal metacarpus, early condylar fracture detection is challenging although increased BV/TV of the distal metacarpus may be useful for determining horses at risk of any fatal breakdown injury. HR-pQCT of the third metacarpal bone midshaft appears to be of no value for predicting fatal injury. Racehorses with moderate/marked condylar IRU have a shortened racing career, are less successful than age/sex matched controls and are older than other racehorses presented for scintigraphy. POTENTIAL RELEVANCE: Effective screening for condylar fractures prior to catastrophic breakdown would require imaging of horses that are not showing clinical signs of lameness or poor performance. Applying advanced imaging to all horses at regular intervals is not only cost prohibitive but the current evidence suggests it is unlikely to be highly effective. POD appears to be performance limiting in Thoroughbred racehorses.