Medicine & Health

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  • (2011) Mittal, Rajat
    Introduction: Chronic wounds are costly to treat and are an increasing health problem. The aetiology of chronic wounds is multi-factorial, but recent evidence suggests that bacteria play an important role and be responsible for a majority of chronic infections. S. epidermidis and P. aeruginosa are commonly associated with chronic wounds. A major part of the virulence is their ability to form biofilms. Biofilms are a complex community of bacteria adhering to surfaces and imbedded in a biopolymer matrix that aids the bacteria in surface attachment, has water, nutrient and oxygen channels and protects the bacteria from host and antimicrobial agents. This high resistance of biofilms presents challenges to the medical community for fighting infections. Recently, topical negative pressure (TNP) dressings have been used in chronic wounds to aid healing. Although there is some research evaluating the effect of TNP dressings on biofilms, there is no research on the efficacy of a combination of TNP dressings and antiseptic instillation. Aims: Our aims were to identify the minimum eradication concentration (MEC) and the minimum biofilm eradication concentration (MBEC) of S. epidermidis and P. aeruginosa against a range of antiseptics and use sub-inhibitory concentrations of antiseptics in an in vitro wound model to assess the efficacy of TNP dressings in combination with antiseptic instillation. Method: Biofilms were generated in a biofilm generator (24 coupons at a time) with a 24 hour batch phase and a 24 hour flow-through phase. Coupons were then transferred to an in vitro wound chamber. Each wound chamber had 6 coupons. Wound chambers were subjected to various frequency of antiseptic instillation with and without TNP. 5 coupons were prepared for quantitative measurements using standard microbiological methods, while 1 coupon was prepared for scanning electron microscopy. Results: S epidermidis: MBEC of PI against S. epidermidis lay between 0.078 mg/ml and 0.156 mg/ml while the MEC was 4.883 μg/ml. The MBEC of HA against S. epidermidis was between 0.025 mg/ml and 0.05 mg/ml while the MEC was 3.125 μg/ml. Increasing frequency of antiseptic instillations without TNP resulted in a reduction in bacterial load ranging from 0.5 to 1.5 log10 reduction. Combining antiseptic instillations with TNP resulted in a greater decrease in bacterial numbers, ranging from 0.5 to almost 2.5 log10 reduction. PI instillation 12 times per day in combination with TNP was the most effective and resulted in an almost 2.5 log10 reduction in bacterial numbers. The SEM images complemented the results observed with colony counts. P aeruginosa: MBEC of PB against P. aeruginosa lay between 0.05 mg/ml and 0.20 mg/ml while the MEC was 0.2mg/ml. The MBEC of HA against P. aeruginosa was > 0.05 mg/ml while the MEC was < 3.125 μg/ml. Similar to the results observed with S. epidermidis, increasing frequency of antiseptic instillation resulted in an increased reduction in bacterial numbers. Combining TNP with PI instillation resulted in a greater decrease in bacterial numbers (7 log10 reduction) compared with PI instillation alone (5 log10 reduction). 3 times per day PB instillation resulted in approximately 0.5 log10 reduction in bacterial numbers. Addition of TNP to 3 times per day PB instillation resulted in a greater decrease in bacterial numbers (1.5 log10 reduction). Although higher frequency of PB instillation resulted in a greater decrease in bacterial load, the additive effect of TNP to PB instillation was not present. The SEM complemented these findings. Conclusion: MBEC of PI against S. epidermidis lay between 0.078 mg/ml and 0.156 mg/ml while the MEC was 4.883 μg/ml. The MBEC of HA against S. epidermidis was between 0.025 mg/ml and 0.05 mg/ml while the MEC was 3.125 μg/ml. MBEC of PB against P. aeruginosa lay between 0.05 mg/ml and 0.20 mg/ml while the MEC was 0.2mg/ml. The MBEC of HA against P. aeruginosa was > 0.05 mg/ml while the MEC was < 3.125 μg/ml. The use of TNP in combination with antiseptic instillation resulted in a greater reduction of bacterial numbers when compared with instillation alone.

  • (2016) Mirzaei, Hadis
    Coeliac disease (CD), also known as gluten-sensitive enteropathy, is a chronic disorder with characteristic small intestinal mucosal changes associated with nutrient malabsorption. To date, CD is still diagnosed using histology. The treatment of CD is to follow a gluten-free diet (GFD). The detection of mucosal healing in treated CD patients is important because it can determine the possibility of developing long-term manifestations of CD, such as intestinal lymphoma. According to current guidelines, duodenal biopsy is the most accurate method available for detection of mucosal healing. However, there are difficulties in early detection of healing because it may take up to three years for the biopsy to show healing. Confocal laser endomicroscopy (CLE) is a novel endoscopic method that permits on-site microscopy of the gastrointestinal mucosa. It improves the accuracy of targeted biopsies and enhances the diagnostic outcome in CD, allowing high-resolution in vivo histological analysis. Although computer-aided diagnosis (CAD) has been studied in different medical imaging techniques including computed tomography (CT), magnetic resonance imaging (MRI) and histology slides, its role has not yet been established for CLE images. Aims and methods The main goal of our first study was to design computer-based image-processing (computer-assisted-design [CAD]) techniques for use in the diagnosis of different stages of CD during endoscopy. The aim of this work was to design algorithms that could be implemented by computer software developers who need meticulous step-by-step procedures. My main contribution was to qualitatively define the characteristics of CAD images: this approach differed to previous studies which had mostly used quantitative descriptions in the diagnosis of CD in its different stages. This work is important as quantitative descriptions are non-subjective and can be used by non-experts such as computer software developers, whereas qualitative descriptions are subjective and can only be used by expert medical doctors with significant knowledge in the field. The main goal of our second study was to develop more complex criteria that can detect the severity of CD as well as detecting early signs of healing which cannot be detected using current methods of assessment. We assessed the possibility of enterocyte regeneration as the first sign of mucosal healing using confocal endomicroscopy and histology. These new features can significantly improve CD diagnostic capacity. Results Using the leave-one-out cross-validation scheme, in the first study, 80 images were used for derivative and validation cohorts. Results for our first cohort were 96% sensitivity (probability of detecting images with either villous atrophy [VA] or crypt hypertrophy [CH]) and 89% specificity (probability of detecting normal images). In the validation cohort, a new set of images was used. Due to their overall lower quality, this set of images was more challenging. Results for this cohort were 91% accuracy, 97% sensitivity, 79% specificity, 93% sensitivity and 87% specificity. In the second study, 800 CLE images were produced from 17 subjects. These images were paired with 80 forceps biopsies for analysis. The receiver operating characteristic (ROC) area, using a cut-off of ‘1’, showed the area under the curve (AUC) of 0.94 (95% confidence interval [CI]: 0.83–1.00) for CLE and 0.94 (95% CI: 0.82–1.00) for histopathology. Conclusion In conclusion, we have shown that our algorithm for the automated diagnosis of CD is highly accurate and can be incorporated into the CLE processor for real-time CD diagnosis. In our first study, we proved that CLE accurately detects the enterocyte and goblet cellular regeneration that is representative of CD treatment response. Through CLE, detailed mucosal information is provided, thus enabling endoscopists to make accurate CD diagnoses as well as instantaneously assessing the healing process in treated patients. Future directions The results of our second study can be incorporated into the already developed algorithm and increase the diagnostic capacity of CAD systems. There is also the possibility of detecting fluorescein leakage in the intestinal mucosa of CD patients. Although this leakage has been studied broadly in inflammatory bowel disease, its diagnostic role in CD has never been studied. This could be the major extension to the work reported in this thesis.

  • (2017) Veera, Jacqueline Margaret
    Background Accurate delineation of treatment volumes for radiotherapy is a crucial step in radiation treatment, but can be associated with considerable uncertainty and variability. Magnetic resonance imaging (MRI) has a proven benefit in the staging of cervical cancer and for image guided adaptive brachytherapy; however there is a paucity of data for the role of MRI in delineating external beam radiotherapy treatment volumes. Aims 1) Quantify the proportion of women with cervical cancer in whom there is evidence to support the use of MRI for radiotherapy planning (RTP), 2) Evaluate the effect of an educational intervention on MRI consistency of volume delineation for external beam target volumes, and 3) Assess volume delineation for external beam radiotherapy on MRI compared to the current standard of care, computer tomography (CT) imaging. Methods Data from an Australian model for estimating the optimal radiotherapy utilization rate for cervical cancer were used and a literature review was performed for each patient group to assess the evidence for the use of MRI for RTP. To evaluate the second aim contours from eleven clinicians were analysed before and after an educational intervention. For the third aim, twenty patients with locally advanced cervical cancer underwent a dedicated MR simulation with a 3T Skyra MRI following CT simulation, four clinicians independently contoured each CT and MRI dataset. The Dice Similarity Co-efficient (DSC) and Mean Average Surface Distance (MASD) was calculated for each structure. Results The use of an MRI for radiotherapy planning is supported in 49% of women overall with cervical cancer. The educational intervention resulted in an improvement in contouring the gross tumour, however a variable response for the other target volumes was observed. MRI contouring was associated with less variability between clinicians compared to CT contouring for most structures including the gross tumour, uterus and parametria. The overall target volume demonstrated a high level of contouring consistency on both CT and MRI, with a small improvement in the MASD seen for MRI contouring. Conclusion MRI simulation for external beam radiotherapy in cervical cancer reduces target volume variability compared to CT.

  • (2007) Wittmann, Johannes
    Pancreatic cancer kills over 1700 people each year in Australia. In 2000, there were 1908 new cases diagnosed and it remains one of the least treatable malignancies. In the USA, it was the fourth leading cause of cancer death in 2004, with 31,860 new cases and 31,270 recorded deaths. Photodynamic therapy (PDT) is a novel, potentially useful treatment for locally advanced pancreatic cancer with only limited research and clinical work addressing this until now. PDT induces non-thermal, cytotoxic and ischaemic injury to a targeted volume of tissue. During PDT, a photosensitizer is activated by non-thermal light in the presence of oxygen, generating cytotoxic oxygen species and inducing cellular injury and microvascular occlusion. The aim of this thesis was to conduct an animal safety study using two second generation photosensitizers, talaporfin sodium and verteporfin, to assess the risks of pancreatic PDT by looking at injury to organs adjacent to the pancreas and assessing recovery from PDT treatment of the pancreas. The Syrian Golden hamster animal model was used to compare the results of this research to previous work by other authors. The study design incorporated a number of additional experiments, including quantitative tissue fluorescence techniques, plasma level analysis and histopathology techniques. The methods for the animal safety study were similar to the approach used in the clinical setting and provided vital data on the likely risks and side effects of phototherapy in humans. The first study, looking at talaporfin sodium, found likely risks of duodenal injury, gastric injury and death with a limited effect on normal pancreas at photosensitizer doses likely to be employed for pancreatic cancer PDT. The second study, using verteporfin, found similar results with a more potent effect on the normal pancreas at studied drug doses. Both agents had short drug-light intervals, ranging from 15 minutes to 2 hours, reducing the need for pre-treatment hospitalization and short photosensitivity periods of about one to two weeks. Some animals suffered minor cutaneous photosensitivity injuries. A human pancreatic cancer PDT pilot study is feasible and the risks and complications should be acceptable.

  • (2011) Yang, Lu
    It is now generally accepted that activated pancreatic stellate cells (PSCs) are the principal effector cells in pancreatic fibrosis, a characteristic histological feature of chronic pancreatitis. PSC activation is associated with loss of cytoplasmic vitamin A containing lipid droplets, expression of cytoskeletal protein alpha-smooth muscle actin (αSMA), increased proliferation, and synthesis and secretion of extracellular matrix (ECM) proteins (the latter, in turn, influence gene expression patterns of PSCs during the activation process). One of the leading causes of chronic pancreatitis is alcohol abuse and in vitro studies have established that alcohol and cytokines (known to be released during pancreatic necroinflammation) can individually activate PSCs. However, during alcohol-induced pancreatic injury, PSCs are likely to be exposed to a combination of ethanol and cytokines (rather than individual factors). Therefore, aims of this study were 1) to investigate the combined effects of ethanol and cytokines on PSCs; 2) to assess and compare gene expression profiles of PSCs cultured on matrices that mimick normal and diseased pancreas - MatrigelTM and collagen I, respectively; 3) to validate and study the influence of selected genes (e.g. transgelin) on PSC activation. Results of this study demonstrated that i) at low doses, ethanol (5mM), IL-1 (0.5pg/mL) or TNFα (10U/mL) alone have negligible effects on PSC activation. However, PSCs treated with a combination of ethanol and cytokines exhibit significantly increased activation; ii) in PSCs cultured on different matrices (MatrigelTM, collagen I and plastic) several genes are dysregulated (fold change>2, p<0.001 and q<0.25) as follows: a) PSCs on collagen I vs MatrigelTM 146 dysregulated genes (76↓, 70↑); b) PSCs on matrigel vs plastic 619 dysregulated genes (297↓, 322↑); and c) PSCs on collagen I vs plastic 432 dysregulated genes (178↓, 254↑); iii) selected genes (transgelin and lumican) are increased in PSCs cultured on fibrous ECM and are associated with PSC activation; iv) inhibition of transgelin expression in PSCs decreases cell proliferation. Thus, studies in this thesis have i) provided evidence in support of the hypothesis that PSCs can be activated synergistically by alcohol and cytokines, ii) shown that the gene expression profile of PSCs is altered by ECM components during PSC activation and; iii) identified a possible molecular target specific for PSCs in the diseased pancreas.