30 results for Undergraduate, 2012

  • The Cost Effectiveness of Implantable Cardioverter Defibrillator Therapy in New Zealand

    De Silva, Praveen Handunnethi (2012)

    Undergraduate thesis
    University of Otago

    The Implanted Cardioverter Defibrillator (ICD) has emerged as one of the strongest therapeutic options for patients at high risk of SCD [65-67]. Despite this its high cost, in relation to other therapies, has made its use controversial in many patient groups. The repercussions are particularly visible in smaller countries like New Zealand where limited resources and doubts on cost effectiveness have resulted in lower implantation rates. The aims of this Thesis were to provide an estimation of ICD cost effectiveness in a New Zealand context and label the strongest and weakest influencers of cost effectiveness. ICD costs and efficacy data, for Secondary prevention patients and Primary prevention patient with LV dysfunction, were collected through a review of international literature and analysis of New Zealand data collected from 2000-2007. These were then entered into a computer model and run over a twenty year lifetime. Model inputs included the efficacy of an ICD in secondary and primary prevention, measured through Life Years Gained, implant mortality, the cost of an ICD, costs of adverse events, lead/battery replacement costs and cost of annual follow up. Results showed the average cost effectiveness of an ICD was NZ $107,191/ LYG, when used in secondary prevention and $178,291/ LYG in primary prevention. The overall range of cost effectiveness across all model inputs was $85,799/ LYG to $207,301/LYG. The strongest factors influencing cost effectiveness were efficacy of the device in both groups, the cost of battery replacements, longevity of ICD leads, mortality rate of primary prevention patients and the annual cost of follow up. The weakest influencers of cost effectiveness included the costs of initial ICD and implant procedure and the cost of adverse events occurring from ICDs. These findings correlated well with previous studies conducted overseas. New Zealand showed a similar range of cost effectiveness, when compared to international trials. Our estimate remained outside the range of cost effectiveness thresholds considered economically attractive however when assessed alongside other therapies was comparative to renal dialysis for end stage disease. The results of this thesis encourage an increase in implantation rates to match other Westernised countries and detail areas that need to be addressed to further improve cost effectiveness.

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  • Histamine mediated neuropeptide gene expression in bovine chromaffin cells

    Kaur, Joydeep (2012)

    Undergraduate thesis
    University of Otago

    The adrenal medulla regulates the acute stress response and is itself controlled through a variety of signals, including neuronal, endocrine and paracrine factors. Additionally, recent literature suggests that adrenal medullary function may also be influenced by signals from the immune system, such as interleukin-1, interleukin-6 and tumor necrosis factor-α. Secretions from the adrenal medulla may in return influence the immune response thereby suggesting a bi-directional relationship between the immune system and the stress response. Recent microarray data from our laboratory have indicated that isolated bovine adrenal medullary chromaffin cells are also responsive to histamine, another immune-derived signal. Exposure to histamine results in marked changes to their neuropeptide gene expression. The aims of this thesis were to investigate this histamine-mediated neuropeptide gene expression by using real time PCR to validate the microarray results, to examine the signalling mechanisms involved and to explore any interactions between histamine and other known regulators of adrenal medulla. Cultured bovine chromaffin cells were incubated in absence or presence of histamine for 6-48h. The mRNA was extracted and analysed using qRT-PCR for the neuropeptides which were vasoactive intestinal peptide (VIP) and galanin. Additional experiments were performed using protein kinase inhibitors to examine the signalling pathways involved. Immunocytochemistry was also carried out in an attempt to localise the histamine-induced changes VIP protein expression. The results confirm histamine induces an increase in both VIP and galanin mRNA, the latter being mediated by protein kinase C. The pathway responsible for stimulating VIP mRNA was not positively identified but does not involve protein kinase A or C. Synergistic interactions were seen between histamine and other adrenal medullary activators (PACAP and IL-6) for VIP but not galanin mRNA. Immunocytochemistry however did not show any localisation of VIP, which was probably due to the VIP antibody being very non-specific. Thus whether the changes in neuropeptide gene levels result in alterations in protein expression remains unresolved. Given that VIP and galanin are both implicated in anti-inflammatory roles these results are consistent with the concept of a bi-directional relationship between stress response and the immune system.

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  • 17α-hydroxylase and the androgen-treated sheep ovary – a model for Polycystic Ovary Syndrome (PCOS)

    Caldwell, Aimée Sarah Lee (2012)

    Undergraduate thesis
    University of Otago

    Polycystic Ovary Syndrome (PCOS) is the most common cause of infertility in women of reproductive age, with an estimated five to ten percent of women worldwide affected by the endocrine condition. The aetiology of PCOS remains, for the most part unclear, however, androgens have been implicated in the development of PCOS with hyperandrogenism being one of the most consistent PCOS traits. The products of a complex steroid pathway, androgens, in particular androstenedione and testosterone, are found to be significantly increased in many PCOS patients. The aim of this study was to investigate the activity of a key enzyme in the steroid pathway, 17α-hydroxylase, in the prenatally testosterone treated (T-treatment) sheep ovary and subsequently measure levels of androstenedione present in blood samples taken from the jugular and ovarian veins. In addition to this, a histological study of follicular mapping provided useful insights into the effect of T-treatment on aspects of ovine follicular development. Sheep ovaries and blood samples were collected from pre-pubertal (5 month old) and pubertal (10 month old) animals. Serial sections were examined to study follicle numbers and morphology. A radioactive in situ hybridisation (ISH) was undertaken to determine tissue location and levels of 17α-hydroxylase (17α-OH) mRNA. Androstenedione levels in blood were determined using ELISA. Results showed that while body weight was similar in both T-treated and control groups, T-treatment was associated with an increase in mean ovarian weight in both pre-pubertal and pubertal age groups. T-treated animals experienced some masculinisation of the external genitalia, which has also been reported by other researchers using this model. In pre-pubertal animals, T-treatment was associated with a significant increase in the total number of growing ovarian Type 3-5 follicles within the ovary. When analysed individually, all eight categories of follicles in this study were found to be increased with T-treatment however these proved to be not statistically significant, with the exception of degenerate follicles where a 14-fold increase was seen in T-treated ovaries. Pre-pubertal T-treated ovaries had a significant accumulation of antral follicles ≥4mm, while pubertal T-treated ovaries displayed an increase in follicles ≥1mm. During the isolation of these follicles, it was found that T-treated follicles were more likely to be unhealthy or haemorrhagic than those from control ovaries. Thecal tissue measurements showed that Type 4 and small Type 5 follicles from T-treated ovaries had a significantly larger thecal tissue layer – the site of androstenedione synthesis. In situ hybridisation results showed that expression of 17α-OH mRNA in the theca was significantly increased in Type 4 T-treated follicles and appeared stronger in Type 5 T-treated follicles. Despite 17α-OH being a key enzyme in the production of androstenedione, these results did not translate into a detectable difference in blood levels of androstenedione in both pre-pubertal and pubertal animals. The results of this study suggest that elements of a PCOS phenotype are evident in pre-pubertal, prenatally androgenised sheep. Further study of this model may provide more answers as to the development of PCOS and it’s symptoms and the role that androgens play in the development of the syndrome and the consequent infertility.

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  • Phenotyping Asthma using an Electronic Nose

    Liley, Albert James (2012)

    Undergraduate thesis
    University of Otago

    Rationale: Asthma is a chronic respiratory condition affecting many millions of people worldwide. The recommended long-term preventative treatment for asthma is corticosteroid medication. Improvement in asthma symptoms in response to corticosteroids is not universal, and prescription to non-responsive patients is costly and potentially dangerous. The assessment of whether patients will respond to corticosteroid treatment is an important clinical problem. This study investigated the utility of a gas sensor array, the ‘Electronic nose’, in predicting response to steroid among asthmatics and in differentiating asthmatics from healthy controls using exhaled breath. The anti-inflammatory actions of steroids and the biochemical basis of steroid response are complex and may be better quantified by the electronic nose than by single biomarkers. In parallel with the assessment of steroid response a study was conducted on the ability of the electronic nose to predict sputum eosinophil counts among asthmatics. Eosinophil count is a predictor of steroid response and can be used as a guide to asthma treatment. Statement of problems: Can steroid-responsive and non-steroid responsive asthmatics be distinguished using electronic nose analysis of exhaled breath? Is sputum eosinophil count able to be predicted by electronic nose analysis of exhaled breath? Methods: 47 patients (27 asthmatics, 20 healthy controls) participated in the study. Asthmatic patients completed a two-week trial of oral prednisone. Asthmatics were classified as steroid responsive if FEV1 improved by 15%, PC20AMP improved by >300%, or ACQ (asthma control questionnaire) improved by >0.5 points over the steroid course. 16 asthmatics were steroid responsive and 11 asthmatics were steroid unresponsive. Breath samples were taken before and after the steroid course. A sputum sample was taken prior to the steroid course. Asthmatics were defined as eosinophilic if their sputum cell count contained more than 3% eosinophils. Healthy controls provided a single breath sample and sputum sample. Main results: Steroid responsive and non-steroid responsive asthmatics were unable to be distinguished either before or after the steroid course (no significant principal component differences, Mdistances0.2). Healthy controls were significantly differentiated from pre-steroid asthmatics (PC2, PC4, PC6, p=0.0090, 0.000060, 0.0090 respectively, M-distance=4.66,p=0.031) and less differentiated from post-steroid asthmatics (PC6, p=0.0016, Mdistance=3.80,p=0.16). A multilayer perceptron based predictive model for the comparison was associated with a cross-validation value (CVV) of 83% between controls and pre-steroid samples and 70% between controls and post-steroid samples. Improvement in ACQ (PC6, p=0.0041) and improvement in FEV1 (PC6, p=0.045) could be detected based on differences in samples before and after the steroid course. A principal component from pre-steroid asthmatics was strongly correlated with sputum eosinophil counts (coefficient=0.615, p=0.0082). Breathprints from eosinophilic and noneosinophilic asthmatics were significantly differentiated (PC4, p=0.0033, M-distance=2.00, p=0.0020). A predictive model for the comparison was associated with a CVV of 77%. Conclusions: Steroid responsive and non-steroid responsive asthmatics cannot be differentiated on the basis of exhaled breath analysis by electronic nose. Healthy controls and asthmatics can be significantly differentiated on this basis. Electronic nose readings are correlated with sputum eosinophil counts and eosinophilic and non-eosinophilic asthma can be significantly differentiated.

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  • Cardiac function and β-adrenergic receptor responsiveness in the isolated human diabetic myocardium

    Wang, Heng-Yu Simon (2012)

    Undergraduate thesis
    University of Otago

    The prevalence of type 2 diabetic mellitus is closely associated with cardiovascular complications. Diabetic patients with preserved ejection fraction (EF) are at high risk of developing heart failure. Until now, little is known about the etiology of the impaired cardiac performance in diabetic patients with preserved EF. Hence this study aimed to address this by investigating the cardiac function of these diabetic patients. We hypothesised that isolated cardiac muscles from diabetic patients will have reduced cardiac performance both at basal conditions, and after β-adrenoceptor (β-AR) stimulation mimicking a physiological stress response. Using isolated cardiac muscles obtained from right atrial appendages of patients undergoing coronary artery bypass grafting, functional characteristics of non-diabetic (n = 8) and diabetic myocardium (n = 6) were compared. (Samples from patients who had acute coronary artery disease and reduced EF (< 40%) were excluded.) Contractile and relaxation parameters of both cohorts were first determined under basal conditions, then in response to a β-AR agonist (dobutamine, 1x10-7 to 1x10-5 M). In addition, Langendorff-perfused isolated hearts from non-diabetic and diabetic ZDF rats were also implemented to compare cardiac function. Compared to non-diabetics patients, the developed force (Fdev) of diabetic human cardiac muscles was not different. However, a slower rate of maximum contraction (+dF/dtmax) and relaxation (-dF/dtmax), as well as prolonged relaxation times during the force-length relationship were observed in diabetic muscles (p < 0.05). A significantly longer relaxation time was also observed during force-frequency relationship in the diabetic muscles (p < 0.05). Moreover, diabetic cardiac muscles were less responsive to β-AR stress response, as shown by the reduced increase in Fdev, +dF/dtmax and -dF/dtmax, as well as smaller reduction in relaxation times. These observations were consistent with the results obtained from the isolated rat hearts. Ultimately, this study showed that diabetic patients with adequate systolic function, as indicated by preserved ejection fraction, suffer from diastolic dysfunctional characteristics and exhibit a reduction in the β-AR.

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  • The role of prolactin in pregnancy-induced changes in food intake

    Stenhouse, Natasha Danielle (2012)

    Undergraduate thesis
    University of Otago

    Pregnancy is associated with a significant increase in food intake. This occurs in order to supply the mother with sufficient energy to support both herself and the developing fetus throughout pregnancy and lactation when metabolic demand is high. This increase in food intake occurs despite an elevation in circulating levels of the appetite-suppressing hormone leptin. Hence, pregnancy is considered a state of leptin resistance. The hormone prolactin, the levels of which are significantly increased during pregnancy, is thought to be involved in increasing food intake during pregnancy. Exogenous administration of prolactin in rodents is associated with increased food intake and reduced response to leptin. As such, it is possible that the pregnancy-induced increases in prolactin may have the same effect. We hypothesised that prolactin acts centrally to mediate the changes in food intake that occur during pregnancy. Thus, the aim of this experiment was to measure food intake during pregnancy in mice that specifically lack prolactin receptors in the brain. To characterise food intake in these mice, food intake and bodyweight were measured daily in non-pregnant, pregnant and lactating neuron-specific prolactin receptor knockout mice and controls. This neuron-specific prolactin receptor knockout model has lost prolactin receptors throughout the brain and thus exhibits impaired central prolactin response. Immunohistochemistry for phosphorylated signal transducer and activator of transcription 5 (pSTAT5), a marker of prolactin receptor activation, was performed in order to assess the success of the knockout animal. Finally, because there appeared to be a difference in bodyweight in the non-pregnant knockout animals, non-pregnant mice were subjected to a fast and refeed protocol and then placed on a high fat diet in order to further characterise their food intake regulatory systems. Food intake increased significantly over pregnancy and was higher still during lactation in both animal groups. Bodyweight also increased over pregnancy, then remained stable during the lactation period. Food intake was significantly higher throughout pregnancy in the knockout animals compared with the controls. Unexpectedly, food intake and bodyweight were significantly higher in the non-pregnant knockout animals compared with the controls suggesting a basal difference in bodyweight regulation. Immunohistochemistry for pSTAT5 demonstrated significant, but not complete loss, of the prolactin receptor throughout the brain, specifically in the arcuate nucleus and medial preoptic area. There was no significant difference between the animal groups in the fast and refeed protocol. The high fat diet data demonstrated that the knockout animals on a high fat diet gained significantly more weight than the control animals on a control diet. The results obtained did not support our hypothesis that prolactin action in the brain critically mediates changes in food intake during pregnancy. However, interpretation of these results was complicated by the non-pregnant animal results and the incomplete nature of the knockout. It remains possible the remaining prolactin-responsive neurons in the brain may mediate prolactin action to stimulate food intake. This latter interpretation is supported by the changes in bodyweight in the non-pregnant knockout animals. Despite the failure to support or disprove our hypothesis, a significant step towards characterisation of this knockout model was made.

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  • The structure of the mucosal folds within the pancreaticobiliary junction

    PURVIS, NIMA SCOTT (2012)

    Undergraduate thesis
    University of Otago

    BACKGROUND: This investigation concerns a structure within the pancreaticoduodenal region of the body, known as the pancreaticobiliary junction (PBJ), which is formed from the convergence of the terminal common bile and main pancreatic ducts. Certain components of this junction such as the sphincter of Oddi have been well documented within the literature, but surprisingly little is known about the folds that line the mucosa in this region. These structures are understood to prevent reflux of duodenal content, but whether this is achieved through an active rather than purely passive mechanism has yet to be determined. AIMS: The principal aim of this study was to investigate the distribution and length of the mucosal folds within the terminal bile and pancreatic ducts. A secondary aim was to identify features within the folds that are consistent with an active function, including smooth muscle, innervation and hormonal receptors. METHODS: PBJ specimens from 10 human cadavers (five male, 66-90 years old) were embedded in paraffin and sectioned transversely (3-4 μm thickness) at 200 μm intervals, beginning at the major duodenal papilla. These sections were stained with hematoxylin and eosin, and immunohistochemically with anti-actin, anti-S100, and anti-cholecystokinin A for detection of smooth muscle actin, innervation, and cholecystokinin A receptors, respectively. Three surgical specimens (2 male, 63-72 years old) were also evaluated. ImageJ software was used to measure mean fold length and distribution, as well as the relative distribution of S100 and the density of smooth muscle actin staining within the folds of the terminal bile and pancreatic ducts. The morphology of the folds was also examined in one additional specimen under scanning electron microscopy.

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  • The Interface of Metastatic Tumours and the Immune System

    Muhsin, Morad-Remy (2012)

    Undergraduate thesis
    University of Otago

    Primary tumours are rarely lethal; instead most cancer deaths are due to the spreading of the tumour to other sites in the body (metastasis). One major pathway of metastatic disease is the migration of tumour cells from the primary tumour to the draining lymph node. In this study, we examined the interaction of tumour cells and their apoptotic vesicles (ApoV) with CD169+ macrophages within the subcapsular sinus of the lymph node using CD169-/- mice. As previously shown by our laboratory, lymphoma-derived microvesicles bind to the CD169 receptor expressed by macrophages. In this study, we have successfully confirmed the binding of melanoma-derived ApoV by CD169. We then established lymph node metastatic models of B16 melanoma using forelimb, ear, and skin tumour implantation. In addition, we have attempted a novel flank abrasion method developed by Dr. Jason Waithman (Telethon Institute for Child Health Research, Australia). We next addressed the importance of CD169-macrophage lymph node barriers on tumour spread and the impact of metastatic disease in the lymph node on the immune response against tumours. Strikingly, tumour progression within the draining lymph node was significantly lower in CD169-/- mice compared to wild-type mice. However, this finding was confined only to our murine subcutaneous melanoma model, and not the intravenous lung metastases model. Furthermore, we investigated the effects of melanoma-derived ApoV on the lung tumour progression. Interestingly, pretreatment of mice with tumour ApoV significantly increased the number of metastatic foci on lungs. This suggests that chemotherapy of tumours may cause the release of ApoV as pro-metastatic agents. To our knowledge, this is the first report of apoptotic cell products enhancing tumour metastasis. Therefore our results provide an important starting point to understand the role of CD169 and tumour vesicles in the anti-tumour response and in preventing metastatic disease.

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  • Recombinant Virus-Like Particles Presenting Epitopes for Antibody Generation

    McCulloch, Tim (2012)

    Undergraduate thesis
    University of Otago

    Virus-like particles (VLP) have been shown to be effective vessels for drug or gene delivery, and vaccination. Much research has focused on the generation of VLP carrying heterologous tumour antigens to initiate cell-mediated immunity against tumours, where the VLP enhances the immunogenicity of the attached antigen. However, VLP can also be modified to incorporate an antigen on the surface to facilitate antibody generation. Purification tags or specific coupling sites could also be incorporated onto the surface of the particles, improving their functionality. This study aimed to utilise the immune stimulatory properties of VLP to generate antibodies against a heterologous model antigen, producing a scaffold for delivery and enhancement of antibody mediated subunit vaccines. More specifically, Human Norovirus (HuNV) and Rabbit hemorrhagic disease virus (RHDV) capsid proteins were engineered to express the YG1 epitope from human tumour necrosis factor-alpha (hTNF-α) at positions predicted to be displayed on the surface of the VLP. Amino acids positions 368 of HuNV and 306 of RHDV capsid proteins were identified in the literature as confirmed sites of peptide insertion, with each locating to the exposed loops of the capsid protein P domain. Recombinant gene constructs expressing the YG1 peptide at these sites were produced by PCR. VLP were expressed in a baculovirus expression system and purified using differential centrifugation and cesium chloride gradient separation. Following expression, recombinant VLP assembly was confirmed by electron microscopy, and while the RHDV VLP was less stable than HuNV, they were both able to form particles. Rats immunised with these recombinant VLP generated IgA and IgG antibodies specific for both the native VLP carrier and the YG1 epitope. Thus initial data indicates that HuNV and RHDV VLP can be genetically engineered to act as vaccine delivery systems, leading to enhanced peptide based subunit vaccines. The confirmed insertion sites could also be used to incorporate purification tags, specific coupling sites, or allow multi-epitope capability, where peptides can be included at both the N-terminus and on the surface of the same VLP.

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  • The arterial supply of the ulnar nerve and cubital tunnel ischaemia

    Harris, Chelsea (2012)

    Undergraduate thesis
    University of Otago

    Background: The ulnar nerve is a major nerve in the upper limb and is susceptible to injury, particularly in the region of the cubital tunnel. A suspected mechanism of injury at this site is ischaemia. Whilst this can be caused by mechanical stress (stretching, compression) on the nerve in the tunnel, there may also be fundamental differences between and within individuals in the arterial supply of the nerve in this region. The nature of the arterial supply to the ulnar nerve has received relatively little attention, and a more detailed understanding could aid in the diagnosis, treatment and prevention of ischaemic injury to the nerve. Aims: The first aim of this study was to investigate the extrinsic arterial supply to the ulnar nerve by dissection. The second aim was to analyse the intrinsic arterial anatomy of the ulnar nerve in the cubital tunnel by semi-quantitative histology. Methods: Twelve cadaver upper limbs (paired upper limbs from six body donors; four female, two male; age range 66 – 90 years) were dissected to record the presence of visible arterial branches contacting the ulnar nerve and their arteries of origin. The distances between bony landmarks and the origins of the major arterial branches supplying the ulnar nerve were measured, together with their diameters. For the study of intrinsic arterial supply, 5µm thick histological sections of the nerve were taken from standardised sites within the cubital tunnel and 5cm proximally and distally. The sections were stained with haematoxylin and eosin, and the combined total cross-sectional area (CSA) of all arteries with a minimum CSA of 80µm² was measured. This was then expressed as a percentage of the total nerve CSA. Results: The extrinsic arterial anatomy of the ulnar nerve was found to be very variable. The superior ulnar collateral artery (SUCA), inferior ulnar collateral artery (IUCA), posterior ulnar recurrent artery (PURA), brachial and ulnar arteries all contributed, although SUCA was the most consistent of these (9 of 12 specimens). There were no detectable branches from the anterior ulnar recurrent artery (AURA). Variations were found in the extrinsic arteries of some specimens: four limbs had high proximal brachial bifurcations; two had unusual SUCA origins; and in nine the PURA and AURA originated from a common stalk. The mean CSA of arteries within the ulnar nerve in the cubital tunnel was not significantly different from standardised sites proximal and distal to the tunnel (cubital tunnel vs. proximal, p=0.76; cubital tunnel vs. distal, p=0.24). However, in two specimens with aberrant SUCA origins there was a significantly greater proportion of CSA occupied by arteries in the cubital tunnel. Extrinsic and intrinsic supply were found to have a direct positive relationship in nine of the 12 specimens: the greater the number of arterial branches supplying the ulnar nerve and the larger their diameter, the greater the proportional CSA of the intraneural arteries. Conclusions: The extrinsic arterial supply of the ulnar nerve is very variable. The SUCA, IUCA, PURA, brachial and ulnar arteries all contribute but the SUCA is most consistent between individuals. The intrinsic arterial supply (as determined by the proportion of CSA occupied by intraneural arteries) does not appear to be significantly different in the cubital tunnel compared to adjacent proximal and distal sites. Accepting the relatively small sample size in this study, these results suggest that the nature of the intrinsic arterial supply to the nerve is unlikely to be a major factor in the predisposition to ulnar nerve ischaemia, but the variability of the extrinsic arterial supply of the nerve could be important.  

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  • An investigation of the correlations between subjective and objective measures of bowel inflammation in Spondyloarthritis

    Bloomer, Chris (2012)

    Undergraduate thesis
    University of Otago

    Introduction: Spondyloarthritis (SpA) and Inflammatory Bowel Disease (IBD) are related conditions of unknown aetiology demonstrating both common clinical features and common genetic and immunological pathomechanisms. Patients with SpA frequently exhibit intestinal inflammation and many develop significant gastrointestinal symptoms. Conversely, many patients with IBD develop an inflammatory arthritis. It has been proposed that an increase in intestinal permeability is an important mechanism in the aetiology of both conditions. However, to date the association between symptoms, intestinal pathology and altered gut permeability has been poorly elucidated. Methods: Patients who fulfilled the Assessments in Spondyloarthritis Internation Society (ASAS) criteria for axial spondyloarthritis were recruited to the study. Gastrointestinal symptoms were assessed using the Dudley Inflammatory bowel symptom Disease Questionnaire (DISQ). Intestinal permeability was measured using the three sugars test, which measures the differential urine recovery of ingested sucralose, L-rhamnose, and lactulose. Small-intestinal lesions were assessed with wireless capsule endoscopy (WCE). An indirect measure of intestinal inflammation (faecal calprotectin) was also used. Drug therapy – including the use and dose of NSAIDs was recorded. Patients with SpA were assessed clinically including a measure of disease activity - the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and CRP. Results: In total, 35 patients and 15 healthy controls completed the DISQ and underwent a sucralose, lactulose and L-rhamnose absorption test to assess intestinal permeability. Ten patients underwent WCE. The majority of patients were taking NSAIDs (25/35). DISQ scores were significantly increased in patients compared to controls (p<0.001). Intestinal permeability was not significantly different between patients and controls, and was not associated with DISQ or BASDAI scores. Faecal calprotectin results were high in some patients, but the correlation with DISQ scores was not significant (p=0.169) although a trend was apparent. WCE showed mild to severe ulcerations/erosions to be remarkably common (8 out of 9 complete studies). Macroscopic lesions of the duodenum appeared to be associated with bowel symptoms, while some severe lesions in the jejunum and ileum 3 were often asymptomatic. Conclusions: We conclude that both gastrointestinal symptoms and intestinal lesions are common in SpA patients. The use of non-steroidal anti-inflammatory drugs appears to be a associated with intestinal symptoms in SpA patients, but ileocolonic ulceration is commonly asymptomatic. The DISQ appears to be a good screening tool for identifying patients with bowel symptoms which are more common with upper GI involvement and especially with lesions in the duodenum. Faecal calprotectin and WCE identified a high proportion of SpA patients as having asymptomatic lesions of the jejunum and ileum, common sites of inflammation in IBD.

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  • Optimal Management of ST-Segment Elevation Myocardial Infarction

    McKay, Emma (2012)

    Undergraduate thesis
    University of Otago

    Background: ST-segment elevation myocardial infarction (STEMI) is a high-risk clinical scenario within the acute coronary syndrome spectrum. It is associated with poor clinical outcomes, particularly if acute reperfusion and appropriate care protocols are not initiated in a timely fashion. Consequently, optimal STEMI management represents a significant challenge to modern health-care provision. Aims: This thesis intends to provide insight into contemporary, optimal STEMI management, with a specific focus on documented quality indicators. Methods: Chapter 1 is a discussion of the modern approach to STEMI management. We explored particularly how primary percutaneous coronary intervention (PCI) and thrombolysis are integrated as acute reperfusion options into systems of care. Chapter 2 comprises a systematic review concerning the evolving use of pre-hospital electrocardiograph (ECG) technology in improving reperfusion times and clinical outcomes, with specific consideration as to how this may be used in pathways of care. In Chapter 3, a four-year study of reperfusion-eligible patients presenting to Dunedin Hospital between 2004 and 2008 was performed. Morbidity and mortality outcomes were assessed with one-year follow-up. Cases were analysed by age, gender, and hour of presentation to observe any effect these factors had on quality of care and clinical outcomes. Results: Eighteen studies describing the use of pre-hospital ECG in improving door to balloon times or mortality outcomes were identified after a systematic literature search. While these studies were generally small and methodologically represented lower level evidence, they appeared to support the utility of this evolving technology in newer models of care to significantly reduce reperfusion times; however, there were limited reported data on mortality or changes in other outcomes. Variable approaches to pre-hospital ECG use, reporting of outcomes, and study quality precluded formal quantitative meta-analysis. A four-year review of Dunedin Hospital STEMI care identified a cohort ranging between 60 to 79 cases each year. There was a significant increase in the use of primary PCI across the years 2004–2008 (12.9% to 81.0%, p<0.001), with an accompanying reduction in the use of thrombolytic (lytic) drugs and non-use of acute reperfusion. Apart from an increase in the use of evidence-based therapies, no other significant changes were identified over the study period. In-hospital mortality ranged from 3.3% to 9.7% (p=0.511); at one year this ranged from 5.0% to 19.6% (p=0.125), and unadjusted for differing baseline characteristics did not differ between lytic or primary PCI therapy. Rates of bleeding were notably high, particularly in patients receiving thrombolysis. Older patients fared worse in many clinical outcomes assessed, as did women. Out-of-hours presentation was not observed to be associated with differences in institutional performance or clinical outcomes. Conclusions: The systematic review of pre-hospital ECGs supports use in improving reperfusion times, and potentially as a means to facilitate regional cardiac networks. There remain some uncertainties about the specifics of technology, implementation, and cost effectiveness. It is technology that is potentially rapidly evolving and advancing, but already appears to be practicable with well-described examples of implementation reducing reperfusion times. Larger studies will be required to demonstrate ability to improve hard clinical outcomes. Review of real-world outcomes at this institution indicates results latterly consistent with benchmarks of international trial and registry data. That there were no differences in mortality between thrombolysis and primary PCI supports the mixed-strategy approach, assuming continued allowance for the individual patient context. Identification of potential unequal provision of care due to age or gender provides potential targets for future quality improvement initiatives.

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  • Prevalence and characteristics of acute headaches and dizziness in mild head injury

    Cowley, Tessa Katarina (2012)

    Undergraduate thesis
    University of Otago

    Little research has been undertaken into the prevalence and characteristics of the acute symptoms following mild head injury, especially within the first month. This study recruited 75 mild head injury patients identified by the Christchurch Hospital Emergency Department and followed them up at 1 week, 1 month and 3 months via questionnaire over the phone. Participants described their symptoms in their own words before being asked more specific questions by the researcher, who then determined which type of headache and dizziness were present, along with the prevalence of other symptoms. The major causes of these mild head injuries were physical altercation (22, 29%) and sports injury (22, 29%), with the remainder due to household accidents (7, 9%), traffic accidents (6, 8%) and “other” (18, 24%). Forty-seven participants were male and 28 were female, and the response rate was 56.4%. The number of participants with headaches decreased with each follow up, 55 (73%) on presentation, 37 (49%) at one week, 22 (32%) at one month, and 11 (27%) at three months. The most common type of headache was consistently tension-type (one week, 35%, one month, 26%, three months, 36%), with the amount of other types varying at each follow up. The number of participants with dizziness was 14 (19%) on presentation, 18 (24%) at one week, 9 (13%) at one month and 3 (6%) at three months. The number of participants whose dizziness occurred with position change at one week was 12 (16%), at one month was 7 (10%), and at three months was 3 (6%). The data provided in this study contributed to the literature surrounding mild head injury and the acute symptoms, especially headaches and dizziness, following it. The fact that tension-type headaches are the most common type of acute post-traumatic headache is of great interest, as is the information that the majority of all headaches have resolved by the three month follow up. Novel information was also reported for dizziness. The prevalence of dizziness increased from presentation to the one week follow up and the resolution differed between dizziness occurring with position change and dizziness occurring without position change, with dizziness occurring with position change being the only type to persist past the 3 month follow up. An extension of this study with greater numbers is indicated.

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  • Investigating steroid hormone feedback in a mouse model of polycystic ovarian syndrome

    Moore, Aleisha (2012)

    Undergraduate thesis
    University of Otago

    Polycystic ovarian syndrome (PCOS) is the most common cause of infertility among women of reproductive age worldwide. Although the aetiology is unclear, there are a number of neuroendocrine disruptions which identify PCOS as a state of impaired steroid hormone feedback. Steroid hormones act through a neuronal network to regulate the activity of gonadotropin-releasing hormone (GnRH) neurons, the key cells responsible for controlling fertility. We employed a murine model of PCOS by prenatal androgen (PNA) exposure to investigate steroid hormone feedback to the GnRH neuronal network in adult female offspring. Initial investigation of ovarian morphology was conducted to characterise the model. PNA treatment significantly reduced the area of the adult ovary containing corpora lutea (p<0.001). This indicates an increase in excitatory input did not occur. However, plasma LH levels showed no difference between vehicle- and PNA-treated mice, thus, further work is still required to show whether PNA treatment impairs the LH surge required for ovulation. Ultimately, this study supports that PNA treatment in the mouse results in a PCOS- like phenotype and that PCOS, a state of impaired steroid hormone feedback by gonadal steroid hormones, involves alterations to central brain circuits important to fertility.

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  • The clinical anatomy of the chorda tympani: a micro-CT study

    McManus, Lauren Jane (2012)

    Undergraduate thesis
    University of Otago

    Background: Few studies have attempted to define the intraosseous course of the chorda tympani (CT) a bilateral nerve that conveys taste from the anterior two-thirds of the tongue and provides parasympathetic innervation to the submandibular and sublingual salivary glands. This is surprising given that iatrogenic injury of the CT is a well-known complication of middle ear surgery and results in taste disturbance, dry mouth, and unpleasant sensory symptoms. Aims: The principle aim of the study was to accurately define the posterior canaliculus (PC) of the CT in the temporal bone to provide guidance for middle ear surgery. A secondary aim was to evaluate the proximity of the PC to a groove which is drilled in the temporal bone during the insertion of a subannular ventilation tube (an otosurgical procedure). Methods: 40 cadaver temporal bones from 27 cadavers (15 male, mean age 75 years, 13 bilateral) were scanned using a SkyScan micro-CT scanner. 3-D multiplanar reconstructions were generated using the software platform Amira 4.1. Images were oriented to Reid’s axial, sagittal and coronal planes using data from the orientation of the semicircular canals and a mathematical algorithm. The PC of the CT was measured in relation to reproducible bony landmarks, the stylomastoid foramen, tympanic sulcus, external auditory meatus and facial nerve canal, using image processing programmes ImageJ and Fiji, and Amira. In the applied follow-up study, 10 of the 40 temporal bones were drilled by an ear surgeon as for subannular ventilation tube placement. The temporal bones were then reimaged and oriented to Reid’s planes as above and the proximity of the drilled groove to the PC analysed. The angulation of the tympanic membrane was also measured in all 40 cadaver temporal bones. Results: Quantitative data showed that the CT originated from the facial nerve outside the skull in 6 specimens and from within the facial canal in 34. In the latter, the PC originated a mean of 3.2 ± 1.8mm above the stylomastoid foramen at an angle of 18 ± 9° to the sagittal plane and 13 ± 6° to the coronal plane. The posterior canaliculus was 12.3 ± 3.8mm long with maximum and minimum diameters of 1.2 ± 0.2mm and 0.4 ± 0.1mm, respectively. As the PC travelled cranially it became closer to the tympanic sulcus and external auditory meatus and more distant from the facial nerve canal. It entered the middle ear at a height 62 ± 10% of the height of the tympanic membrane. In the applied study, drilling the temporal bone for subannular ventilation tube placement had the potential to cause iatrogenic injury in two cases (20%). The tympanic membrane was found to be angled at a mean value of 34° (range 16 to 45°) to the parasagittal plane and 42° (range 22 to 58°) to the axial plane. Conclusions: This novel micro-CT study defines the precise anatomy of the PC which houses the CT. These data and those from the applied study relating to subannular tube placement may help the surgeon protect the CT from iatrogenic injury. This thesis has also documented, more precisely than ever before, the angle of the human tympanic membrane which lies at a greater angle to the axial and parasagittal planes than previously reported.

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  • Maternal obesity predisposes offspring to obesity; understanding the role for elevated Interleukin-6

    Campbell, Samantha Rosalind Shanti (2012)

    Undergraduate thesis
    University of Otago

    Obesity has quickly become an epidemic, and there has been a concomitant increase in the prevalence of obesity during pregnancy. Together human and animal studies have revealed that over-nutrition is a high risk factor for the development of obesity in offspring. The arcuate nucleus of the hypothalmus is located near a leaky brain-blood barrier, allowing neurons to receive blood-borne signals from the body, such as insulin, leptin and glucose, about energy expenditure. There are two populations of neurons within the arcuate nucleus that are specific for modulating weight regulation; neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons. The early development of the NPY and POMC-containing neurons places these peptidergic systems as likely targets for maternal obesity influenced disruption during embryonic and fetal development. Inflammation can be caused by the secretion of pro-inflammatory cytokines from adipose tissue macrophages, and there is evidence of elevated low-level chronic inflammation in obese individuals. A high fat diet (HFD) has also been shown to stimulate a local pro-inflammatory condition in the hypothalamus, resulting in changes in the hypothalamic regulation of energy homeostasis. Previous studies have shown that one of these cytokines, specifically Interleukin 6 (IL-6) is elevated in the maternal and placental circulation of obese mothers, in comparison to mothers of a normal weight. As elevated pro-inflammatory cytokines are a hallmark of maternal obesity, it is proposed that IL-6 may be involved in the mechanism influencing the development of weight regulation centres within the fetal brain, predisposing offspring to obesity throughout life. Therefore we hypothesised that cells within the arcuate nucleus of the fetal brain are responsive to IL-6. In vitro organotypic slice culture experiments were carried out to test this hypothesis. Fetal brains were sectioned on a Vibratome and the response of IL-6 was tested at different concentrations on the arcuate nucleus. The phosphorylation and translocation of Signal Transducer and Activator of Transcription 3 (STAT3) to the nucleus is a marker for IL-6 receptor signalling. Thus single-label immunocytochemistry detected immuno-positive phosphorylated STAT3 cells and bilateral cell counts of the fetal arcuate nucleus were performed. These studies revealed that there was no increase in the number of immuno-positive pSTAT3 cells under stimulation of IL-6 in the arcuate nucleus. Results did show a reduction in the number of immuno-positive pSTAT3 cells seen in higher concentrations of IL-6 (10 ng/ml and 100 ng/ml) in the fetal arcuate nucleus. Therefore, we conclude that cells within the fetal arcuate nucleus are responsive to IL-6 at concentrations of 10 ng/ml and 100 ng/ml IL-6.

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  • VEGF Levels in Women with Gynaecological Cancers

    Lee, Jeffrey (2012)

    Undergraduate thesis
    University of Otago

    Background: High blood levels of Vascular Endothelial Growth Factor (VEGF) have been reported in patients with gynaecological cancer and have been correlated with advanced disease and poor outcome. However, results are few and varied and most studies used single measurements. There is also debate as to whether serum or plasma measurement reflects circulating VEGF. Aims: To describe and compare the properties of serum and plasma VEGF in women with ovarian and endometrial cancer. To clarify their relationships with platelets and investigate their correlation with disease activity. In addition we wished to investigate the effect of green tea (which has known angiogenic activities) consumption on blood VEGF. Methods: VEGF was measured by ELISA method in serum and plasma in women with gynaecological cancers. Serial measurements were taken in women with endometrial or ovarian cancer, and in women without cancer. Blood samples were also obtained in women before and after surgery for endometrial or ovarian cancer. The association of platelets and CRP to blood VEGF was determined using combined data. In addition, the effect of green tea on serum and plasma VEGF was evaluated in women with persistent cancer who were treated with 6 days oral green tea extracts equivalent of 900mg EGCG daily. Results: The median week to week coefficient of variance (CV) was approximately 10% for serum and 30% for plasma VEGF. There was significant overlap in VEGF concentrations between women with disease and control. Serum VEGF but not plasma correlated with platelets and CRP and there appeared to be a multiplicative relationship between plasma and serum VEGF. There was no significant difference between blood VEGF before and after surgery. Short term green tea extracts were safe but did not lead to significant changes in blood VEGF. Conclusion: Blood VEGF measurements are elevated in some women with advanced gynaecological cancers, single measurements appear a reliable indication of the levels in different patients but levels did not appear to be a good indicator of change in tumour load within individual patients. Serum VEGF varied with platelet count and CRP and may be reflection of the systemic response to advanced malignancy. It is not clear to what extent plasma VEGF reflects circulating VEGF. We did not see a reduction in blood VEGF after consumption of green tea. Future studies are needed to assess to what extent plasma VEGF reflect circulating VEGF, and the effect of green tea extracts.

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  • Induced Pluripotent Stem Cells: An Alternative to Embryonic Stem Cells?

    Bridge, Sophie Elizabeth (2012)

    Undergraduate thesis
    University of Otago

    Human stem cell research is a new field with many promises, but progress towards a clinical setting has been complicated by scientific and ethical challenges. The most heated discourse over stem cell research to date has focused on the source of human embryonic stem cells (ESCs). Different views on the moral status of the human embryo have plagued all aspects of the debate (and decision-making) on stem cells. Opponents of ESC research consider that embryos symbolize the start of life and therefore should not be sacrificed as a source of stem cells. In 2006, a way of de-differentiating somatic cells to a pluripotent state was realized. The advent of these induced pluripotent stem cells (iPSCs) appeared to circumvent concerns over embryo destruction, and hence iPSCs have been touted as an ideal (and ethical) way forward for stem cell research. However, at least for the foreseeable future, scientific investigations involving iPSCs are likely to drive further embryo destruction. As a result, iPSC research (on its present trajectory) is inevitably (and perhaps surprisingly) complicit in embryo destruction and is inextricably locked in to the moral status debate. Furthermore, iPSCs not only have scientific challenges of their own, but they have the potential to lead to the development of controversial assisted reproductive techniques (ARTs). In other words, the emergence of iPSCs has not only failed to circumvent the central moral concern with ESCs, but they have also raised a host of other novel ethical complexities. Consequently, there are a number of flaws in the commonly heard argument that ESCs are ethically problematic and that iPSCs are a morally superior option. The current state of knowledge is hugely problematic due to moral complicity and scientific challenges, and the stem cell field is plagued by uncertainty and risk. The moral frameworks that have been conventionally used as a basis of stem cell ethics have so far proved inadequate, failing to provide clear guidance on how best to come to terms with the notion of respect for embryos that are being destroyed, and on the potential of iPSCs to create embryo-like entities.

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  • Preimplantation Genetic Diagnosis: From Clinic to Eugenic Fears and Disability Concerns

    Anderson, Hamish (2012)

    Undergraduate thesis
    University of Otago

    Preimplantation genetic diagnosis (PGD) is an assisted reproductive technology introduced to detect embryos with genes associated with certain genetically-based diseases. The rationale for this procedure that has been carried out for over 20 years is to bring about the birth of children not affected by the genetic condition in question. The inevitable selection of one embryo over another has constituted the crux of the main opposition to PGD over the years, especially among those for whom all embryos have a moral value equivalent to that of fully developed humans. However, with time this core ethical dilemma has been joined by others, characterised in particular by fears about the eugenic nature of PGD, and concerns that its use devalues people with disabilities. The practical issues that are most relevant emerge in connection with Huntington’s disease testing, HLA-typing and preimplantation genetic screening (PGS). In order to look in some detail at the major issues in these areas, considerable attention is paid to the current state of the scientific base of PGD, and the dominant issues that arise in the clinic. In considering general ethical issues, there is discussion around principles such as autonomy, non-maleficence and truthfulness. In terms of eugenic fears, the controversy surrounds the concern that PGD is a reincarnation of the eugenics of the early 20th century, which culminated in the horrors of the Holocaust. This worry is evaluated for its legitimacy, and then reanalysed in the context of Agar’s definition of liberal eugenics. Overall, the fears about eugenics are shown to be unfounded, due to the current lack of class bias, lack of coercion and the well-grounded science upon which the procedure is based. The final issue analysed is what is termed the ‘expressivist objection’. This describes arguments that claim that the way PGD is practised causes harm to the disability community. This view emerges from the social model of disability, which stands in opposition to the prevalent medical model. In drawing together these various strands, I conclude that the potential harms expressed are not sufficiently serious to outweigh the advantages that PGD brings. It is concluded that PGD is currently practised in a responsible and measured way that effectively balances potential dangers with the immense benefits that can be achieved. On the other hand, major changes in the reasons for undertaking PGD in the future may substantially alter the ethical horizon.

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  • The Hamstring Muscles: Proximal Musculotendinous Junctions

    Storey, Richard Norman (2012)

    Undergraduate thesis
    University of Otago

    Background: Acute hamstring strains are common injuries in sports, responsible for excluding athletes for a considerable amount of time from participation and competition. This places a substantial burden on professional sporting organisations and healthcare systems. Aims: To describe patterns in the site and mechanism of hamstring strains and examine the morphology of the proximal tendon and musculotendinous junctions (MTJs) of these muscles using dissection and magnetic resonance imaging (MRI). Methods: Two systematic literature reviews were undertaken, firstly to ascertain the site and mechanism of hamstring strains in the medical imaging literature and secondly to review the anatomy of the hamstring muscles relevant to acute strains. The morphology of the proximal MTJs of biceps femoris long head (BFlh), semitendinosus (ST), and semimembranosus (SM) was investigated using two methods: (i) individual muscles in ten thighs from five male cadavers (aged 64-85 years) were dissected and measured in situ and then resected, embedded in jelly and serially sectioned for scaled photography; (ii) the hamstring muscles of 11 physically active men (aged 18-30 years) were imaged bilaterally using MRI. In each study group, the length, volume and cross-sectional area of the proximal tendon and muscle belly were measured. In addition, novel measurements of the muscle-tendon interface area at the proximal MTJs were taken in cadavers and the MTJs in both groups were reconstructed three-dimensionally (3-D) using Amira 4 software. The relative force of muscle contraction at the proximal MTJ was estimated by calculating a muscle belly volume to muscle-tendon interface area ratio. Comparisons were made between the three hamstring muscles and between study groups. Results: The literature review of hamstring strains indicated that the most frequently injured hamstring muscle is BFlh (65.8% of all acute strains). The MTJ was the site of injury in 73% of strains, usually the proximal MTJ. The site and mechanism of hamstring strains appear to be related: powerful eccentric contraction as occurs in sprinting is commonly associated with BFlh strains with or without additional pathology in ST, and, slow-speed stretching injuries predominantly affect SM but can also involve adjacent muscles such as quadratus femoris. Review of the anatomical literature showed that the morphology of these proximal structures is not well understood. Three-dimensional reconstruction showed a similar proximal tendon and MTJ morphology in elderly cadavers and young active men. In both groups SM consistently had the longest proximal tendon in all specimens and, on average, MTJ, the latter extending over 20 cm2 in both groups. In cadavers the MTJ of SM also had the greatest muscle-tendon interface area (84.6 ±31.5 cm2). Muscle belly volume was more than three times greater in young active men than in elderly male cadavers. Muscle belly volume/MTJ interface area ratios suggested that BFlh experiences the greatest forces at its proximal MTJ, with a ratio of 1.68, compared to 1.65 for the proximal region of ST, and 1.24 for SM. ST muscle fibres inserted proximally into both the common proximal tendon of BFlh and directly into the ischial tuberosity. The hierarchy of hamstring muscle peak cross-sectional area varied among the young active men but was constant in elderly cadavers. Conclusions: These results suggest that the morphology of the proximal MTJ is relatively consistent. However, key differences were evident between hamstring muscles. Estimation of force transfer at the proximal MTJ suggests that the architecture of the proximal MTJ in BFlh and ST may render them vulnerable to acute strains during powerful muscle contraction. In contrast, the larger muscle-tendon interface found in SM suggests less concentration of force at the MTJ and its longer proximal free tendon may explain its vulnerability to slow speed stretching injuries.

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