http://hdl.handle.net/2440/14759 2021-01-24T23:19:10Z http://hdl.handle.net/2440/129639 Title: Triglyceride rich lipoproteins and Apolipoprotein C-III in Atherosclerosis Author: Pan, Wenru Abstract: While the causal role of low-density lipoprotein cholesterol (LDL-C) in atherosclerosis and the clinical benefit of lipid lowering with statins are well established, the impact of triglyceride rich lipoproteins (TRL) in cardiovascular disease is less well understood. Given the important association between hypertriglyceridaemia and both obesity and type 2 diabetes, mechanistic studies are required to further understand the role of TRL as both a causal factor and potential target for therapeutic modification. This thesis aims to investigate the impact of both TRL and Apolipoprotein C-III (ApoC-III), an important factor that regulates TRL metabolism, in atherosclerosis. It demonstrated the adverse effect of oxidised TRL on endothelial cells following co-incubation studies in vitro. It also described the presence of ApoC-III within atherosclerotic lesions in an animal model of diabetes and dyslipidaemia, with evidence of a direct correlation between plaque levels of ApoC-III with both the burden and inflammatory composition of plaques. Additional studies demonstrated inverse correlations between hepatic levels of triglyceride and ApoC-III with expression of factors involved in the generation of high-density liporptoeins (HDL) and the promotion of reverse cholesterol transport. Modification of LDL by myeloperoxidase (MPO), a peroxidase enzyme secreted by leukocytes, has been established to promote vascular inflammation and cholesterol uptake by macrophages, a critical step in foam cell formation. In cell studies, we demonstrated that MPO modified TRL (MPO-TRL) exerted an adverse effect in human umbilical vein endothelial cells (HUVEC), as evidenced by an upregulation of mRNA expression of pro-inflammatory adhesion molecules. MPO-TRL co-incubation also resulted in a reduction in endothelial cell proliferation which can be restored by co-incubation with HDL. Cells treated with MPO-TRL also demonstrated an increase in expression of proteins involved in responses to hypoxia (HIF1ɑ) and in angiogenesis (VEGF) and a reduced expression of the cholesterol transporter ABCG1. We are further interested in whether triglyceride mediator ApoC-III exerts similar adverse effect in atherosclerosis in the settings of mouse models with dyslipidaemia and diabetes. We demonstrated that ApoC-III was present within plaque and the presence was positively associated with lesion size and inflammatory marker CD68. ApoC-III has been well characterised to induce endothelial cell inflammation, whether ApoC-III will induce inflammation in other vascular cells will be of additional interest in future studies. We have also found that using patients’ serum stratified with different levels of triglyceride, ApoC-III levels inversely correlated with HepG2 expression of both PPARɑ and cholesterol transporter ABCA1, important factors which involved in the synthesis of both ApoAI and HDL and subsequent effects on lipid transport. Further experiments are needed to demonstrate the correlation of ApoC-III in HDL metabolism in large, prospective cohorts. In summary, these observations described potential adverse effects of triglycerides and ApoC-III on vascular cells, atherosclerosis and lipid metabolism. The findings support potential causal effets and novel targets for therapeutic targeting to prevent atherosclerotic disease. 2020-01-01T00:00:00Z http://hdl.handle.net/2440/129638 Title: Clinico-Chemical Parameters of Fetal Fluids and Maternal Blood in the Bovine Model: Effects of Genetics and Sex and Relationships with Feto-Placental Phenotype Author: Shuaib, Entesar Saleh Moh Abstract: Prenatal growth is influenced by bidirectional exchange between the fetal and maternal systems that programme birth weight and postnatal phenotype. Fetal fluids are essential but unexplored areas for prenatal growth. This study examined allantoic and amniotic fluids and maternal blood in a Bos taurus, Bos indicus bovine model to provide fundamental information that is lacking regarding (i) changes in clinico-chemical parameters of maternal blood in early and midgestation and their relationships with placental-embryo/fetal weights (ii) differences in clinico-chemical parameters of allantoic and amniotic fluids of bovine concepti in early and midgestation, (iii) effects of genetics and sex on clinico-chemical parameters of fetal fluids and their relationships with feto-placental phenotype, and (iv) the effects of conceptus sex and genetics on maternal blood parameters. Purebred and reciprocal cross Bos taurus, (Bt) and Bos taurus indicus, (Bi) concepti were recovered in early gestation (Day 48, n = 60), and midgestation (Day 153, n = 72), (term ~ 280 days). Fetal fluids and maternal blood were sampled and analysed for clinico-chemical parameters. Insulin-like growth factors and thyroid hormones were assessed in maternal blood. Effects of genetics and sex on the measured parameters were determined using general linear models, and relationships with feto-placental phenotype assessed by linear regression. Breed effects on maternal electrolytes, metabolites and enzymes and their relationships with placental-embryo/fetal weights provide evidence of differences in maternal mineral metabolism, liver and kidney functions that influence conceptus growth. Stage- and genetic-specific differences were seen in clinico-chemical parameters of fetal fluids, which likely reflect differences in feto-placental phenotype. Greater maternal genome effects on fetal fluid in early gestation reflect the significance of placenta and maternal environment and represent maternal-offspring coadaptation. Paternal genome and maternal by paternal genome interactions exert stronger effects on amniotic fluid suggesting greater fetal influence and (epi)genetic regulation in line with the conflict-of-interest hypothesis. Conceptus sex had strong effects on fetal fluid metabolites in early gestation, while parental genome by sex effects influence amniotic fluid parameters at both stages. Furthermore, paternal genome and sex interacted with non-genetic maternal effects to affect fetal fluid parameters at both stages. Significant relationships between maternally controlled allantoic fluid parameters and embryo-placental weights suggest a critical role of allantoic fluid for embryonic development. In midgestation, paternally controlled amniotic fluid Na/K ratio showed significant relationships with fetal weight and fetal fluid volume, suggesting a paternal influence on amniotic fluid water and nutrient transfer. Conceptus sex and genetics affected maternal physiology in a maternal genetics dependent manner by influencing key parameters of maternal mineral metabolism, liver function and thyroid status. In conclusion, this study provides reference values for clinico-chemical parameters of fetal fluids and maternal serum in Bt and Bi concepti in early and midgestation. Results support the hypothesis that fetal fluid parameters are affected by genetics and sex, and are related to feto-placental phenotype, demonstrating their critical role in prenatal growth. This study highlights the importance of considering conceptus sex, genetics and maternal genetics as factors that impact maternal physiology and demonstrates the need for genetic background-specific maternal assessment. 2020-01-01T00:00:00Z http://hdl.handle.net/2440/129637 Title: Using drones to improve wildlife monitoring in a changing climate Author: Hodgson, Jarrod Christopher Abstract: This thesis advances knowledge of wildlife monitoring techniques and demonstrates the potential of high-resolution, remotely sensed data to inform species conservation, improve ecosystem management and assess mitigation strategies for biodiversity loss. Drones can easily collect systematic, high spatial and temporal resolution data to detect fluctuations in key parameters such as abundance, range and condition of some species. Advances in drone-facilitated wildlife monitoring of sentinel species will provide rapid, efficient insights into ecosystem-level changes. This thesis focused on resolving knowledge gaps within three key areas of wildlife drone-ecology: disturbance, population monitoring and body condition. From the outset, we recognised drones might have undesirable or unforeseen behavioural and physiological effects on wildlife. To address this, I led a time-critical publication that advocated researchers adopt a precautionary approach given the limited understanding of the impacts. It also provided recommendations for conducting drone-facilitated research around wildlife as the basis for a code of best practice. Then, using colonial birds as a study group, we tested the utility of drone-derived data for population monitoring. First, life-sized, replica seabird colonies containing a known number of fake birds were used to robustly assess the accuracy of our intended approach compared to the traditional ground-based counting method. Drone-derived abundance data were, on average, between 43% and 96% more accurate, as well as more precise, than estimates from the traditional approach. Our open-source, semi-automated detection algorithm estimated abundance 94% similar to manual counts from the remotely sensed imagery. To apply this in the field, we collected drone-derived abundance data by repeatedly surveying representative, wild colonial birds (a tern, cormorant and pelican species). We used these data to develop a transferable technique requiring minimal user-input for adaptable and high spatiotemporal population monitoring. Finally, to investigate the use of drone-facilitated photogrammetry, we used a representative pinniped species to test if non-invasively acquired, morphometric data could infer body condition. Drone-derived measurements of endangered Australian sea lions (Neophoca cinerea) of known size and mass were precise and without bias. These two- and three-dimensional measurements from orthomosaics and digital elevation models were highly correlated with animal mass and body condition indices and not significantly different to those generated from ground-collected data. This work addresses and informs a range of issues arising from human activity in the Anthropocene, including rapid habitat loss, species extinctions and an altered climate. We have shown that using technology for wildlife monitoring enables timely, proactive environmental and conservation management. 2020-01-01T00:00:00Z http://hdl.handle.net/2440/129624 Title: Sebaceous Carcinoma Author: Wu, Albert Abstract: Sebaceous carcinoma (SC) is a rare skin cancer which usually occurs on the head and neck, and has a propensity for metastasis. It is easily mistaken for benign conditions, resulting in inappropriate management. Thus, it is important to maintain a high index of suspicion for SC, to avoid delay in diagnosis and worsening of prognosis. Due to its poor prognosis and tendency to occur on cosmetically sensitive areas, the primary treatment of SC should be margin control surgery, preferably Mohs micrographic surgery. Chapter 1 is a comprehensive review on cutaneous SC, discussing its epidemiology, clinical features, histologic features, pathogenesis and management. There has been significant uncertainty about the demographics and anatomical distribution of SC. Of particular note, it has frequently been assumed that SC occur more commonly in Asians than whites; however, data to support this are limited. Chapter 2 investigates these uncertainties by comparing the previously published incidence rates of SC in various countries. However, the incidence rates could not be compared accurately as different studies focused on different anatomical sites, and adjusted to different standard populations. To facilitate a more accurate comparison of incidence rates and further clarify the uncertainties about the epidemiology of SC, Chapter 3 presents new data obtained from cancer registries of the United States, England, Norway and Taiwan, and calculates incidence rates with uniform age-adjustment. Chapter 4 reports a case of eyelid SC in situ that presented atypically as a haemorrhagic cyst. Chapter 5 describes an unusual case of SC with lacrimal sac involvement, presenting with clinical features of nasolacrimal duct obstruction. The optimal management of SC remains uncertain, due to its rarity and thus limited data on which to base recommendations. Areas of uncertainty include whether to investigate for subclinical metastasis and other malignancies of Muir-Torre Syndrome, whether to perform sentinel lymph node biopsy and conjunctival map biopsies, and whether to use intraoperative histologic margin control and if so which method (e.g. frozen section, paraffin section, or Mohs). In Chapter 6, the management preferences of different groups of clinicians in different countries are surveyed (Australian Mohs surgeons, and Australian, New Zealand, and Japanese oculoplastic surgeons). This may provide a foundation to develop Asia-Pacific consensus guidelines. 2020-01-01T00:00:00Z