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(2009)Journal ArticleMaternal obesity due to long-term high-fat diet (HFD) consumption leads to faster growth in offspring during suckling, and increased adiposity at 20 days of age. Decreased expression of the orexigenic neuropeptide Y (NPY) and increased anorexigenic proopiomelanocortin (POMC) mRNA expression were observed in the fed state. However, hunger is the major drive to eat and hypothalamic appetite regulators change in response to meals. Therefore it is important to compare both satiated and fasting states. Female Sprague Dawley rats (8 weeks old) were fed a cafeteria-style HFD (15.33kJ/g) or chow for 5 weeks before mating, with the same diet continuing throughout gestation and lactation. At postnatal day 20, male pups were killed either after overnight fasting or in the fed state. Pups from obese dams were hyperphagic during both pre- and post-weaning periods. Pups from obese dams had higher hypothalamic mRNA expression of POMC and NPY Y1 receptor, but lower hypothalamic melanocortin-4 receptor (MC4R) and its downstream target single-minded gene 1 (Sim1), in the fed state. Overnight fasting reduced circulating glucose, insulin, and leptin and increased hypothalamic NPY Y1 receptor mRNA in pups from both lean and obese dams. Hypothalamic NPY and agouti-related protein were only increased by fasting in pups from obese dams; reductions in MC4R and Sim1 were only seen in pups from lean dams. At weaning, the suppressed orexigenic signals in offspring from obese dams were normalized after overnight fasting, while anorexigenic signaling appeared impaired in these animals. This may contribute to their hyperphagia and faster growth.
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(2009)Journal ArticleCortical asymmetries are well established in humans for language and motor regions and correlate with handedness. Here the authors investigate structural differences in the hemispheres of left- and right-handed common marmosets using surface photography and histology. The hand preferences of 11 marmosets were assessed over their adult life span using a simple reaching task. A significant correlation was found between the length of the right lateral sulcus/brain weight and the % right-hand preference (r = .86, p = .001). Cortical thickness on the superior bank of the right lateral sulcus posteriorly was also positively correlated with % right-hand preference (r = .69, p = .025). Comparison of this site with previously published functional maps of the marmoset cortex show this area corresponds to SII, a region involved in tactile processing and somatosensory discriminations. It is suggested that the correlation between SII thickness and right-hand preference would be consistent with the fact that right-handed marmosets are more proactive than left-handers in exploring novel objects by touch. Enlargement of a cortical area involved tactile discriminations could be a precursor to the evolution of right-handedness as a population bias.
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(2009)Journal ArticleStudy Design : Prospective experimental Objectives : To investigate inter-rater and intra-rater reliability of electrical perceptual threshold (EPT) testing in assessing somatosensory function in healthy volunteers. Setting: Spinal Injuries Unit, Royal North Shore Hospital, Sydney, NSW, Australia Methods: Cutaneous electrical stimulation of 4 dermatomes at American Spinal Injuries Association (ASIA) sensory key points (C3, T1, L3, S2) was performed on 40 control subjects. The lowest ascending stimulus intensity at which sensation was perceived was recorded as the EPT. Mean EPT values for each dermatome, as determined by 2 testers at two time points, were examined and plotted against a normative template. Differences and associations between intra- and inter-rater measurements, and left-right measurements were investigated. EPT results for 2 people with spinal cord injuries were also examined. Results : EPT measurements from left and right sides, obtained from the two time points and two testers, were found to be strongly associated, with the exception of left and right side measurements at the S2 dermatome. No significant differences in the mean EPT for tester or time period were found. The intra- and inter-rater reliability was good for all dermatomes tested. Mean EPT measurements fell within the range of a normative template at each of the 4 dermatomes tested. Conclusion : EPT is an objective, reproducible and quantifiable method of assessing sensation in a control group. However, caution should be applied in certain dermatomes such as S2 where there was large variation between left and right side measurements. Sponsorship : New South Wales Office of Science and Medical Research
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(2009)ReportThe 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.
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(2009)ThesisColorectal cancer (CRC) remains a significant burden in contemporary society due to an aging population, unhealthy dietary choices and an increasingly sedentary lifestyle. While the underlying defects for many hereditary forms of CRC have been determined, many genetic and epigenetic changes promoting common sporadic CRCs have yet to be identified. The Mutated in Colorectal Cancer (MCC) gene, identified in 1991, was initially thought to be responsible for the hereditary form of CRC, familial adenomatous polyposis, before the discovery of the susceptibility gene Adenomatous Polyposis Coli (APC), which then became the focus of intense research. Recent data, however, suggests that MCC may also be important in the development of CRC. I have investigated the mechanism of MCC gene silencing, the putative structure, and multiple functions of MCC. MCC was frequently silenced by promoter hypermethylation in CRC cell lines and primary tumours. MCC methylation showed strong molecular and clinicopathological associations with hallmarks of the serrated neoplasia pathway. Furthermore, MCC methylation was more frequent in serrated precursor lesions compared with adenomas, thus occurring early during carcinogenesis. MCC is highly conserved in complex multicellular organisms. Re-introduction of MCC in CRC cell lines resulted in partial G1 to S phase, and G2/M phase cell cycle blocks, potentially by upregulating cell cycle inhibitor gene transcription and interfering with the process of mitotic checkpoints and division, respectively. Changes in MCC levels also modulated NF?B pathway signalling, the pathway required for maintaining cell viability and proliferation in colonic epithelial cells. In particular, MCC overexpression suppressed both TNF? and LPS-induced NF?B activation, decreasing both the magnitude and rate of cellular responses. Overexpression also resulted in downregulation of proteins involved in canonical NF?B pathway signalling, while increasing the transcription of non-canonical NF?B genes. Therefore, MCC may direct activation of this pathway to a specific subset of NF?B-regulated genes. These data provide a molecular basis for the role of MCC as a tumour suppressor gene in CRC. MCC may have multiple functions, regulating cell cycle progression and modulating NF?B pathway signalling, either through direct involvement in pathway signalling cascades, or by providing a scaffold on which signalling events can occur.
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(2009)ThesisDiscovery of the ability of mesenchymal stem cells (MSCs) to differentiate into cells of non-mesodermal tissues, particularly neuronal cells, have raised the possibility of utilising MSCs in regenerative/reparative therapies for neurological disorders. However, a number of hurdles remain to be resolved. This thesis aims to address some of these issues by investigating the characteristics of bone marrow-derived human MSCs (hMSCs) during long-term culture, the potential of hMSCs to differentiate in vitro toward the neuronal lineage under the influence of cytokines, and the effects of intracerebral transplantation in the hemiparkinsonian rat model. During expansion culture hMSCs were found to display the expected characteristics of MSC populations, and also constitutively expressed neural and pluripotency markers simultaneously with mesodermal markers. Analysis of hMSC long-term subcultivation revealed an optimal period for commencing neuronal differentiation (first 6-8 passages), and also showed the absence of spontaneous neural differentiation. Application of neural-inducing cytokines and culture conditions resulted in the generation of an immature neuronal-like phenotype by hMSCs. Through live cell microscopy it was demonstrated for the first time that cytokine-based hMSC neuronal differentiation occurs through active and dynamic cellular processes involving outgrowth and motility of cellular extensions. In addition, single- and multiple-stage cytokine-based strategies for inducing dopaminergic neuronal-like cells from hMSCs were investigated. These studies revealed that FGF-2 and EGF exerted the greatest benefits for hMSC neuronal differentiation. Undifferentiated and neuronal-primed hMSCs were transplanted intracerebrally into the striatum and substantia nigra of cyclosporine-treated hemiparkinsonian rats. Grafted hMSCs could be clearly identified at 1-day and 7-days post-transplantation; however, grafts were gradually lost over time, with complete absence by 21-days. Co-transplantation with olfactory ensheathing cells, neuronal-priming prior to grafting, and nigral as well as striatal grafting could not provide engraftment and differentiation advantages. Immunohistological analysis demonstrated the presence of innate inflammatory responses (microglia and astrocyte activation) at graft sites, fibronectin deposition by hMSCs, and lack of endogenous host neurogenesis. The results of my PhD work indicate that cytokine-based culture methods are capable of differentiating hMSCs to an immature neuronal-like phenotype, and host-mediated innate inflammatory responses may be a key contributing factor for the failure of in vivo hMSC engraftment.
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(2009)ThesisAmyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unclear aetiology, although the general consensus is of a multifactorial disease. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous metal chelator. The first and inducible enzyme is indoleamine 2,3-dioxygenase (IDO). As the extent of the involvement of the KP in ALS is unknown, the main aim of this thesis was to attempt to answer that question. The techniques used in this work include HPLC, GC/MS, RT-PCR, immunohistochemistry and immunocyctochemsitry. The main findings of this project are: (1) the complete KP is present in the mouse motor neuron cell line, NSC-34; (2) QUIN toxicity on NSC-34 cells may be ameliorated through the administration of NMDA antagonists, neuroprotective kynurenines, kynurenine inhibitor and QUIN monoclonal antibody; (3) in ALS patients, QUIN CSF and serum levels are significantly elevated, while PIC serum levels are significantly reduced; (4) ALS brain and spinal cord tissue show extensive microglia activation and positive immunoreactivity IDO and QUIN in spinal motor neurons and Betz cells in the motor cortex; and (5) kynurenine pathway inhibitor and analogue, R061-8048 and tranilast, are able to prolong the survival in the G93A SOD1 ALS transgenic mouse model. In conclusion, this study provide the first strong evidence for the involvement of the KP in ALS, and these data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which is amenable to KP analogue and inhibitor in ALS transgenic mice.
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(2009)ThesisNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and in its advanced stage, has a poor clinical outcome. Resistance to chemotherapeutic agents, either intrinsic or acquired, is the primary cause of treatment failure in NSCLC. Tubulin binding agents (TBAs), such as paclitaxel and vinorelbine are important components in the treatment of NSCLC. Upregulation of the neuronal specific class III β-tubulin (β-III-tubulin) is frequently found in drug resistant cancer cell lines and human tumours, lending support that βIII-tubulin might play a role in the development of drug resistance in cancer cells. However, to date, compelling evidence supporting its direct role in drug resistance and response has been lacking. To address its role in NSCLC, RNA interference (RNAi) was employed to knock down βIII-tubulin expression in two drug naive NSCLC cell lines, Calu-6 and H460. Specific knockdown of βIII-tubulin resulted in increased sensitivity to TBAs and DNA damaging agents, two classes of agents that are commonly used in the treatment of NSCLC. Increased sensitivity to TBAs and DNA damaging agents in the βIII-tubulin knockdown cells was due to an increased propensity of the cells to undergo apoptosis, suggesting that this tubulin isotype may be a cellular survival factor. Interestingly, specific knockdown of βII- or βIVb-tubulin hypersensitised the cells to Vinca alkaloids but not taxanes, demonstrating that each isotype is unique in terms of drug-target interactions. Moreover, the β-tubulin isotype composition of a cell can influence response, and therefore resistance to TBAs. To determine whether βIII-tubulin differentially regulates microtubule behaviour and influences cell proliferation via an effect on microtubule dynamics, siRNAs were used to knockdown βIII-tubulin expression in H460 cells stably expressing GFP-βI-tubulin and the dynamic instability behaviour of individual microtubules was measured by time-lapse microscopy. In the absence of drug, silencing of βIII tubulin alone did not significantly affect the dynamic instability of interphase microtubules. However, at the IC50 for proliferation of either paclitaxel or vincristine, the overall dynamicity was suppressed significantly in the βIII-tubulin silenced cells as compared to the control, indicating that βIII-tubulin knockdown induces paclitaxel or vincristine sensitivity by enhancing the ability of these agents to suppress microtubule dynamics. At a concentration of drug that represented the IC50 for mitotic arrest, for either paclitaxel or vincristine, increased apoptosis induction was found to play a dominant role in βIII-tubulin knockdown, further supporting a role for βIII-tubulin as a cellular survival factor. Collectively, when βIII-tubulin is overexpressed in tumours cells, it is highly likely to be promoting cellular survival and resistance to TBAs. In addition to its proposed role in drug resistance, high expression of βIII-tubulin in tumours of non-neuronal origin such as NSCLC, has been positively correlated with the degree of tumour aggressiveness. H460 cells are known to display substrate- independent growth in soft agar and tumourigenicity in nude mice and provided an ideal model to investigate the role of βIII-tubulin in tumourigenesis. To address the role of βIII-tubulin, H460 cells stably expressing βIII-tubulin shRNA were generated, validated and examined using both in vitro and in vivo methods of tumourigenesis. Colony formation of H460 cells stably expressing βIII-tubulin shRNA was dramatically reduced in soft agar and significantly delayed tumour growth and reduced tumour incidence of subcutaneous xenografted tumours in nude mice when compared to respective controls. These results provide new insights into the function of βIII-tubulin and suggest that βIII-tubulin may play an important role in tumour development and progression in lung cancer. In conclusion, β-tubulin isotype status can serve as a valuable molecular marker capable of distinguishing patients with differential sensitivity to TBAs. These results not only shed new light on the role of specific β-tubulin isotypes in the response to TBAs, but also the role of βIII-tubulin in the biology of cancer that will lead to new treatment strategies for NSCLC.
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(2009)ReportThis report describes key findings from the e-male survey, a national, online survey of men who have sex with men (MSM) in Australia. The survey was conducted in 2008 by the National Centre in HIV Social Research and attracted over 4,000 men to the survey site. The project aimed to assess whether internet use builds social capital amongst gay and other homosexually active men and the implications of online social networks for HIV prevention. The project also assessed the advantages and disadvantages of internet-based recruitment and data collection among Australian MSM.
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(2009)Journal ArticleA key aim of educational course design is to encourage students to adopt deeper approaches to learning. This article reports the findings of three studies that explored how medical students responded to three carefully designed educational course units. The findings suggest that while a subgroup of the students responded by adopting deeper approaches (as intended by the designers of the course units), another subgroup responded by adopting more surface approaches. Two further subgroups displayed minimal changes in their approaches despite significant changes in their learning contexts. The finding (in all three studies) of a notable proportion of students adopting more surface approaches is of particular concern, as this could adversely affect the impact of even the most carefully designed educational program. These findings suggest that the context-dependent nature of approaches to learning merits further investigation as it may be more complex than previously described in the literature.