Medicine & Health

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  • (2009) Boyle, Patrick; Grimm, Michael; Scicluna, Helen; McNeil, H. Patrick
    The UNSW Medical Student Experience Questionnaire was designed to establish a database of student response both for monitoring aspects of students’ experience and for developing strategic improvements to the UNSW MBBS Program to improve that experience. In its effectiveness as a measurement tool for these purposes, interest has been piqued in other quarters, prompting the development of an accompaniment to the questionnaire, synopsising its development, features and utility, to contextualise appropriate reading of the instrument and to cite as required. The context provided includes the principles guiding the development of the questionnaire; the methods of its trial and application; the properties of the questionnaire in terms of validity and utility; and its projected future use, both internal to UNSW Medicine, but also, as a guiding principle of form and content for development of similar tools in other contexts.

  • (2007) Song, Emma Yanjun
    Purpose: Control of micrometastatic ovarian cancer in the peritoneal cavity remains a major objective in post-surgical treatment. The purpose of this project was to investigate the efficacy and toxicity of targeted alpha therapy (TAT) for ovarian cancer in vitro and in vivo in animal models and to select the optimal targeting vector for an ovarian cancer clinical trial. Animal models of ovarian, breast and prostate cancer were developed and for further TAT; a phase I melanoma clinical trial was supported, paving the way for an ovarian cancer clinical trial. Methods: The expression of the turnor-associated antigens (Her2, MUC1, uPAfuPAR) on cancer cell line, animal model xenografts and human ovarian cancer tissue was tested by immunostaining. MTS and TUNEL assays were used to evaluate cell killing of alpha conjugates in monolayer and spheroids. Toxicity and maximum tolerance doses for different vectors were tested and determined in vivo. Pharmacokinetics was studied for different time points and different parameters. The antiproliferative effect of 213Bi-C595 and 213Bi-PAI2 was tested at 9 days post-peritoneal cell inoculation of the ovarian cancer cell line OVCAR3. The treatment efficacy of 213Bi-Herceptin was tested at a 2 days post-subcutaneous breast cancer cell BT474 inoculation. Mice were injected (i.p) with various concentrations of alpha conjugates (AC). Changes in cancer progression were assessed by girth size and tumor size. Results: uPA/uPAR and MUCI are expressed on ovarian cancer cell lines and more than 45% ovarian cancer tissue, while HER2 was only positive in one cell line and was positive in less than 15% of ovarian cancer tissues. The ACs can target and kill cancer cells in vitro in a dose dependent fashion. TUNEL positive cells were found after incubation with the different ACs. PAI2 and C595 vectors were selected for in vivo ascites model study of OVCARJ cell with high expression. Delayed and acute toxicity in animal models showed that radiation nephropathy was the cause of body weight loss. Biodistribution studies showed that kidney was the major uptake organ. L-lysine can reduce kidney uptake for 213Bi-PAI2, but no significant differences were found. A single ip injection of 213Bi-C595 or 213Bi-PAI2 can inhibit ascites growth, whereas, 213Bi-Herceptin can inhibit breast cancer growth in a nude mice model. Conclusion: 213Bi labelled targeting vectors can specifically target ovarian cancer cells in vitro and inhibit tumor growth in vivo. These ACs may be useful agents for the treatment of ovarian cancer at the minimum residual disease stage.

  • (2007) Chu, Stephanie Wai Ling
    Paclitaxel (PTX) is an effective anti-mitotic drug. It stops cancer from spreading by interfering with the microtubule dynamics which in turn leads to cell cycle arrest and eventually cell death. Despite the clinical success in treating different types of cancers, resistance to PTX remains a major hurdle for successful treatment in relapse patients. Albendazole (ABZ) is a popular anthelmintic used world-wide for the treatment of various types of helmintic infections. In helminthes, ABZ binds to β-tubulin and inhibits microtubule polymerisation. It was subsequently found that ABZ has anti-cancer activity. This study was carried out to study the effects of ABZ on PTX sensitive and PTX resistant human ovarian carcinoma cells. Cell growth assays revealed that the anti-proliferative activity of ABZ was not only effective on the PTX-sensitive human ovarian carcinoma cell line lA9, but also on its PTX-resistant sub-line, lA9PTX22. The ICso values of ABZ in lA9 and lA9PTX22 were 205 nM and 322 nM, respectively. Confocal images demonstrated that ABZ disrupted the microtubule network and caused formation of short microtubule bundles in both cell lines. Further analysis using tubulin polymerisation assay showed that the percentage of polymerised tubulin in lA9 and lA9PTX22 was increased by 58.9 % and 20.6 % respectively. Together, these results revealed for the first time that ABZ interacts with microtubules in human cancer cells and causes their polymerisation. It was also demonstrated that ABZ increased the release of cytochrome c, an important component of the intrinsic pathway in apoptosis. It was found that the expression of Bim, a BH-3 only pro-apoptotic protein was not elevated after ABZ treatment. The results presented in this study provide some information on the effect of ABZ on the microtubule network which could relate to its apoptotic effect in human ovarian carcinoma cells.

  • (2007) Yan, Tristan Dongbo
    In the past, patients with peritoneal surface malignancy were considered incurable and were only offered palliative treatments. However, in a substantial number of patients, disease progression that is isolated to peritoneum may occur. It has been realised that elimination of peritoneal surface tumours may have an impact on the survival of these cancer patients, in whom a prominent cause of death is peritoneal carcinomatosis. The focus of this PhD. thesis is on the combined treatment of cytoreductive surgery and perioperative intrapersonal chemotherapy for diffuse malignant peritoneal mesothelioma, pseudomyxoma peritonei, colorectal peritoneal carcinomatosis and resectable gastric cancer. Section one describes the major principles of management for peritoneal surface malignancy, covering the historical perspectives, the treatment rationales and the learning curve associated with the combined procedure. Section two is devoted to peritoneal mesothelioma, in trying to examine this disease from its clinical, radiologic and histopathologic aspects. A radiologic classification and a histopathologic staging system for this disease are proposed. In section three, the results of the combined treatment for pseudomyxoma peritonei are presented, including a systematic review of the literature, a case series of 50 patients from our Australian centre and a treatment failure analysis of 402 patients from the Washington Cancer Institute. These studies suggest that a disease-free state is important for long-term survival for patients with pseudomyxoma peritonei. In section four, the current evidence on the combined treatment for colorectaI peritoneal carcinomatosis is demonstrated by conducting a systematic review of the literature and survival and perioperative outcome analyses of two separate patient cohorts. These results suggest that the combined treatment is associated with an improved survival, as compared with historical controls. In the last section, a metaanalysis of the randomised controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer shows that a significant improvement in survival is associated with hyperthermic intraoperative intraperitoneal chemotherapy alone or in combination with early postoperative intraperitoneal chemotherapy.

  • (2008) Szczesniak, Michal Marcin
    The work presented in this thesis concerns neurophysiology and pharmacology of the oesophageal afferent pathways involved in oesophago-pharyngeal reflexes and oesophageal nociception. Disturbances of reflexes governing contractile and relaxation responses of the upper oesophageal sphincter (DOS) are likely to be implicated in the pathophysiology of conditions involving excessive oesophago-pharyngeal regurgitation, impaired oesophageal clearance, and an abnormal belch reflex. Visceral hypersensitivity, a heightened perception of gastrointestinal sensation is frequently observed in functional gastrointestinal disorders and provides compelling evidence that it plays an important role in the pathogenesis of functional heartburn and non-erosive reflux disease. The work in this thesis explores the neurophysiology, pharmacology and pathophysiology of oesophago-DOS reflexes in humans by experimentally inducing DOS relaxations in healthy controls and patients with reflux laryngitis, and by recording DOS motor responses during spontaneous oesophago-pharyngeal regurgitation. Nociception was assessed by measuring oesophageal sensitivity to electrical stimulation and oesophageal acid perfusion in healthy controls, which was then compared with several heartburn populations (functional heartburn, erosive and non-erosive reflux disease). Additional studies were performed to evaluate the potential role of intraluminal impedance in defining antegrade bolus flow through the pharyngo-oesophageal segment during swallowing as a prelude to the adaptation of the technique to find a more accurate method for the detection of oesophago-pharyngeal regurgitation. The main findings from this work are as follows. 1) Mucosal lignocaine-sensitive afferents mediate the distension-induced oesophago-DOS relaxation reflex and lignocaine insensitive, presumably muscular mechanoceptors, mediate the distension-induced oesophago-DOS contractile reflex. The latter reflex is also upregulated by oesophageal acidification indicative of a possible protective mechanism. 2) Prolonged studies in patients with proven oesophago-pharyngeal regurgitation demonstrated that the most common mechanism of oesophago-pharyngeal regurgitation is a transient, non-swallow related, relaxation of the DOS. 3) Experimental evaluation of the oesophago-DOS relaxation reflex revealed that it is upregulated in patients with reflux laryngitis, suggesting that the aberrant afferent signalling in the oesophagus may be a contributory factor mediating oesophago-pharyngeal regurgitation. 4) Measurement of oesophageal sensory thresholds in response to electrical stimulation and acid perfusion revealed that all patients, irrespective of the presence or absence of mucosal injury, exhibit acid-induced hypersensitisation. 5) The viscro-somatic referral pattern of acid- and electrically-induced chest pain is increased in patients with functional heartburn and non-erosive reflux disease. These findings support the hypothesis that central sensitisation of nociceptive pathways may contribute to symptom reporting in these heartburn populations.

  • (2014) Arora, Manit
    Abstract â Burnout among Australian orthopaedic trainees and the factors associated with it Aim: To study burnout prevalence and associated factors among Australian orthopaedic trainees. Method: We conducted a nationwide cross-sectional observational study using a 32-question survey consisting of a self-developed item set of 10 questions and a 22-question validated instrument (Maslach Burnout Inventory â Human Services Survey) to assess burnout. The survey was emailed to 236 orthopaedic registrar members of the Australian Orthopaedic Association. Results: 51 trainees completed the survey, yielding a response rate of 22%. Burnout prevalence among orthopaedic trainees was high (52%) despite high career satisfaction (89%). 55% of trainees were dissatisfied with their work-life balance. Burned out trainees were more likely to be dissatisfied with their choice of orthopaedics as a career (p=0.004) and with their work-balance (p=0.021) compared with their non-burned out counterparts. Females were more likely to be burned out than males and non-married trainees more than married trainees, although these associations were not significant. There was no observed trend for burnout with relation to seniority in the training program. Discussion: Burnout prevalence among Australian orthopaedic trainees is high despite high career satisfaction. There may be a role for active interventions aimed at combating burnout and improving work-life balance among orthopaedic trainees. Abstract â Job satisfaction among Australian orthopaedic surgeons and the factors associated with it Introduction: High job satisfaction has positive outcomes for patients, health institutions and surgeons. There has been no research into job satisfaction primarily among Australian orthopaedic surgeons and its associated factors. The aim of this study was to assess job satisfaction and associated factors among Australian orthopaedic surgeons. Method: We conducted a nationwide survey using a 24-item questionnaire consisting of a self-developed item set of 14 questions and a 10-question modified version of Warr-Cook-Wall Job Satisfaction instrument to assess job satisfaction. The survey was emailed to 1393 orthopaedic surgeon members of the Australian Orthopaedic Association. Results: 217 surgeons completed the survey, yielding a response rate of 16%. 88% of responders were either very satisfied or moderately satisfied with their jobs. 20% of responders were dissatisfied with their hours of work and a further 15% of responders were dissatisfied with the level of recognition they get for good work. Surgeons with higher job satisfaction were less likely to feel that workload severely compromised their personal/family life (p<0.001), had better perceived self-health (p=0.04), and were less likely to have considered leaving orthopaedic surgery in the last year (p<0.001). Discussion: Australian orthopaedic surgeons are highly satisfied with their jobs. There may be a role for active interventions aimed at improving hours of work and work-life balance.

  • (2011) You, Jingjing
    Prostate cancer (CaP) is a heterogeneous multifocal cancer with high prevalence worldwide, particularly in developed countries. The introduction of the prostate specific antigen (PSA) blood test for CaP diagnosis saw a dramatic increase in the reported incidence rate of CaP, but only a slight decrease in mortality, highlighting the importance of developing a more accurate CaP diagnostic test. Discovery of novel biomarkers has been the focus of cancer diagnostic research, with protein biomarkers of particular relevance due to their direct reflection of phenotype changes, resulting from pathophysiological conditions and their presence in the easy accessible body fluids. The aim of this PhD project was to detect, identify and verify potential novel CaP specific protein biomarkers that could distinguish CaP from benign prostatic hyperplasia (BPH) and healthy control groups; ideally identifying novel molecules that have the potential to improve the screening accuracy of the current CaP diagnostic test. Serum and tears were used as the sources of biomarkers in this study. As a circulatory body fluid, serum can reflect the molecular changes due to the presence of CaP. The tear film is of particular interest in CaP research, as both the prostate gland and the major tear producing gland, the lacrimal gland, are androgen regulated. Various proteomic approaches including gel based, mass spectrometry based and targeted antibody based techniques were used in this study to examine the serum and tear proteomes as well as for protein identification and quantitation. The key finding of the present study was the identification of five serum proteins (albumin, fetuin A, IGHM, hemopexin and C4BPA) and one peptide (VPSHAVVAR) derived from the tear protein, lactoferrin, as potential biomarkers for CaP. From these proteins, albumin and fetuin A were evaluated in a separate small sample group of subjects, with these results further indicating their potential for differentiating between CaP and control groups. Moreover, this was also the first study which has used MRM to validate presence of a novel tear protein dermcidin, to relatively quantify six tear proteins and to detect a potential CaP biomarker peptide in tears. The findings from this study suggest that, using larger sample size to verify the results presented, the development of more accurate and non-invasive clinical tests for the diagnosis of CaP may be possible.

  • (2013) Ataie Kachoie, Parvin
    Minocycline is a well-tolerated and safe tetracycline which has a range of non-antibiotic pharmacological properties including anti-inflammatory and cell-modulatory effects. This project investigated the potential of minocycline for the treatment of ovarian cancer with respect to its effects on the inflammatory factors and signaling pathways involved in this malignancy. Several novel findings were made. Minocycline was found to effectively suppress both constitutive and IL-1B or 4-hydroxyestradiol-stimulated IL-6 expression in human ovarian cancer cells. Additionally, minocycline down-regulated the IL-6 receptor system and blocked the activation of STAT3 and ERK1/2. In nude mice, acute administration of minocycline led to significant suppression of plasma and tumor IL-6 levels along with inhibition of p-STAT3, p-ERK1/2 and MCL-1. Minocycline also inhibited cellular migration, invasion and adhesion associated with suppression of MMP-2 and 9. Minocycline blocked hypoxia-induced surge in IL-6, sIL6R and VEGF. In vivo, oral minocycline dramatically reduced tumor weight and malignant ascites volume. IL-6, sIL6R and VEGF levels were highly suppressed in plasma, ascites fluid and tumors by minocycline. Explaining its inhibitory effect on malignant ascites, minocycline treatment led to attenuation of tumoral p-ERK1/2, p-Akt and TGF-B1 whereas VE-cadherin was enhanced. The molecular mechanism behind minocycline effects could be attributed to modulation of NF-kB. Minocycline suppressed constitutive NF-kB activation in ovarian cancer cells which highly correlated with attenuation of IKK activation; IkB phosphorylation and degradation; and p65 phosphorylation and nuclear translocation. The inhibition of IKK was associated with suppression of TAK1 activity and its dissociation from TAB1. Further studies demonstrated that minocycline reduced TGF-B1 expression. Enforced TGF-B1 expression induced NF-kB activity and minocycline rescued this effect. Consistent with this, shRNA-mediated TGF-B1 knock-down abrogated the inhibitory effect of minocycline on NF-kB. These results suggest that the minocycline-induced suppression of NF-kB is mediated -at least in part- through inhibition of TGF-B1. In line with this minocycline administration in mice led to suppression of p65 phosphorylation and nuclear translocation accompanied by down-regulation of NF-kB activity. Our results may prove to be an important attribute to the upcoming clinical trials of minocycline in ovarian cancer.

  • (2017) Choi, Philip
    This thesis investigates immune-mediated thrombocytopenia: the natural history of immune thrombocytopenia (ITP), a novel treatment strategy for ITP, and the diagnosis of heparin-induced thrombocytopenia (HIT). Retrospective study New international consensus guidelines on the diagnosis of ITP have recently been proposed (Rodeghiero et al, Blood 2009 113:2386-2393). Previous estimates of prevalence and the natural history of ITP may no longer remain relevant. We reviewed 129 patients who met revised criteria for the diagnosis of ITP. 49% of newly diagnosed primary ITP patients did not need treatment at presentation and remained free from grade III/IV bleeding or the need for future treatment. In contrast, patients who required treatment at presentation but were still thrombocytopenic at 1 month, were significantly more likely to remain refractory to medical therapies and experience grade III/IV bleeding. Prospective study We investigated the use of a novel combination of conventional therapies in ITP given over 4 weeks: 20 patients were enrolled onto phase IIb study of oral dexamethasone 40mg day 1-4, oral cyclosporine 2.5-3mg/kg/daily day 1-28 and intravenous low-dose rituximab 100mg day 7, 14, 21 and 28. There were no therapy-related serious adverse side effects and 6 month response rate was 60%. This study highlights the possibility of achieving an enduring remission for some patients from as little as 4 weeks of therapy. Diagnosis of HIT study Antibodies against Platelet factor (PF)4/heparin complexes are found in patients who have heparin-induced thrombocytopenia (HIT) and in asymptomatic patients undergoing cardiac surgery. The clinical significance of these antibodies in the latter group remains uncertain. We examined the incidence and time course of anti-PF4/heparin antibodies in patients undergoing cardiac surgery using a commercially available IgG specific ELISA kit in common clinical use. After identifying serum containing anti-PF4/heparin antibodies, we assessed their reactivity against a panel of 16 mutant(m)PF4 proteins and native PF4 (nPF4) purified in-house to determine if any differences exist with clinically pathogenic HIT samples. 24% of cardiac surgery patients are positive on commercial HIT screening versus only 8% by nPF4. We postulate that some patients identified by commercial HIT screening may be cross-reacting to PF4/nucleic acid complexes.