Do anti-inflammatory agents promote linear ablation lesion discontinuities? : an electrophysiological examination

Background: Catheter ablation for atrial fibrillation (AF) is more efficacious than antiarrhythmic therapy. Post ablation recurrences reduce ablation effectiveness and are contributed by lesion discontinuity in the fibrotic linear ablation lesions. The anti-fibrotic role of statins in reducing AF is being assessed in current trials. By reducing the chronic pathological fibrosis that occurs in AF they may reduce AF. However if statins also have an effect on the acute therapeutic fibrosis of an ablation, this could exacerbate lesion discontinuity and AF recurrence. We tested the hypothesis that statins attenuate ablation lesion continuity in a recognised pig atrial linear ablation model. Aims: To assess whether Atorvastatin diminishes the bi-directional conduction block produced by a linear atrial ablation lesion. Methods: Sixteen pigs were randomised to statin (n=8) or placebo (n=8) with drug pre-treatment for 3 days and a further 4 weeks. At initial electrophysiological study (EPS1) 3D right atrium (RA) mapping and a vertical ablation linear lesion in the posterior RA with bidirectional conduction block were completed (Gepstein Circ 1999). Follow-up electrophysiological assessment (EPS2) at 28 days assessed bidirectional conduction block maintenance. Results: Data of 15/16 (statin=7) pigs were analysed. Mean lesion length was 3.7 ± 0.8cm with a mean of 17.9 ± 5.7 lesion applications. Bi-directional conduction block was confirmed in 15/15 pigs (100%) at EPS1 and EPS2. Conclusions: Atorvastatin did not affect ablation lesion continuity in this pig atrial linear ablation model. If patients are on long-term statins for AF reduction, periablation cessation is probably not necessary.

Proteasome inhibitors as anti-cancer agents

The ubiquitin (Ub)-proteasome pathway is the major nonlysosomal pathway of proteolysis in human cells and accounts for the degradation of most short-lived, misfolded or damaged proteins. This pathway is important in the regulation of a number of key biological regulatory mechanisms. Proteins are usually targeted for proteasome-mediated degradation by polyubiquitinylation, the covalent addition of multiple units of the 76 amino acid protein Ub, which are ligated to 1-amino groups of lysine residues in the substrate. Polyubiquitinylated proteins are degraded by the 26S proteasome, a large, ATP-dependent multicatalytic protease complex, which also regenerates monomeric Ub. The targets of this pathway include key regulators of cell proliferation and cell death. An alternative form of the proteasome, termed the immunoproteasome, also has important functions in the generation of peptides for presentation by MHC class I molecules. In recent years there has been a great deal of interest in the possibility that proteasome inhibitors, through elevation of the levels of proteasome targets, might prove useful as a novel class of anti-cancer drugs. Here we review the progress made to date in this area and highlight the potential advantages and weaknesses of this approach.

Adolescent involvement in anti-social and delinquent behaviours : predicting future injury risk

The purpose of this study was to challenge the broadly based focus of injury prevention strategies towards concern with the needs of young adolescents who engage in multiple anti-social and delinquent behaviours. Five hundred and forty 13-14 year olds reported on injuries and truancy, violence, illegal road behaviours, drug, and alcohol use. Engagement in these behaviours was found to contribute to the likelihood of an injury. Those engaging in the most anti-social and delinquent behaviours were around five times more likely to report medically-treated injuries in the past three months. Their likelihood of future injury was 1.8 times more likely when they were followed up three months later. The engagement in multiple delinquent and illegal behaviours thus significantly increased the likelihood of injury and identifies a particularly vulnerable group. The findings also suggest that reaching these young people represents a key target for change strategies in injury prevention programs.

Using digital storytelling as a change agent for women’s participation in the Turkish public sphere

This thesis builds on the scholarship and practical know-how that have emerged from digital storytelling projects around the world with diverse groups of participants in a range of institutions. I have used the results of these projects to explore the opportunities Digital Storytelling workshop practice may hold for women’s participation in the public sphere in Turkey. Through theoretical discussion and practical experimentation, I examine the potential of Digital Storytelling workshop practice as a means to promote agency and self-expression in a feminist activist organisation, focusing in particular on whether Digital Storytelling can be used as a change agent – as a tool for challenging the idea of public sphere in ways that make it more inclusive of women’s participation. The thesis engages with feminist scholarship’s critiques of the public/private dichotomy, as well as the concept of gender, to seek connections with narrative identity in the light of the analysis of the Digital Storytelling workshops and the digital stories that were created in a feminist context. The study on which this thesis is based saw the introduction of Digital Storytelling to Turkey for the first time through workshops in Istanbul and Antakya, conducted in partnership with the feminist activist organisation Amargi Women’s Academy. Applying the principles of feminist post-structuralist discourse analysis as used by Judith Baxter (2003), I examine two sets of data collected in this project. First, I analyse the interactions during the Digital Storytelling workshops, where women from Amargi created their digital stories in a collaborative setting. This is done through participatory observation notes and in-depth interviews with the workshop participants and facilitators. Second, I seek to uncover the strategies that these women used to ‘speak back to power’ in their digital stories, reading these as texts. I conclude that women from the Amargi network used the workshops to create digital content in order to communicate their concerns about issues that can be classified as gender-specific matters. During this process, they also cooperated, established new connections, and at the end of the process even defined new ways of using, circulating and repurposing their digital stories for feminist activism in Turkey. My research thereby contributes equally to feminist discourse analysis, the study of new-media usage and uptake among non-professionals, and the study of media–public sphere interactions in a particular national setting: Turkey. My conclusion indicates that the process of production is as important as the product itself, and from that I am able to draw out some strategies for developing digitally equipped women’s activism in Turkey.

Disobedient Citizens : Press Depictions of Striking School Teachers in NSW and Anti-Vietnam War Demonstrators in NSW and Victoria in 1968

Across Australia in 1968, students demonstrating against the Vietnam War engaged in confrontational behaviour. The metropolitan daily newspapers,the most important source of news for most people, enthusiastically reported the scenes. The demonstrations were exciting. Sensational headlines and photographs captured the interest of readers and influenced their opinions. But radical opposition to government policies at the time was not limited to university students opposing the Vietnam War. Teachers had become increasingly critical of conditions in schools, with Victorian secondary school teachers having stopped work on a number of occasions since 1965. In October 1968, both primary and secondary school teachers in New South Wales participated in eastern Australia’s first state-wide teachers’ strike. As Sydney’s Sun commented on 1 October 1968, “The teachers’ strike threw the ... education system into chaos ... A huge proportion of the State’s 2764 schools were silent and empty.” Similarities with the anti-war demonstrations were obvious. Although not as confrontational, the New South Wales teachers’ strike was a publicity-seeking action. This examination of the teachers’ more restrained, but more effective, approach to challenging government policies provides a new voice and vision to our understandings of the diverse nature of radicalism in Australia in the 1960s.

Tolerance, Freedom, Justice and Peace?: Britain, Australia and anti-Muslim Racism in the UK and Australia before 11 September 2001

Since 11 September 2001, Muslim minorities have experienced intensive "othering" in “Western” countries, above all in those US-led anglophone nations which invaded Afghanistan and Iraq to prosecute their "war on terror". This paper examines the cases of Britain and Australia, where whole communities of Muslims have been criminalised as "evil" and a "fifth column" enemy within by media, politicians, the security services and the criminal justice system. Although constituted by disparate ethnic groups, the targeted communities in each of these nations have experienced similar treatment in the State's anti-terrorist measures, as well as ideological responses and everyday racism, making comparable the two cases.

Purine Nucleoside Phosphorylase mediated molecular chemotherapy and conventional chemotherapy: A tangible union against chemoresistant cancer

Background Late stage Ovarian Cancer is essentially incurable primarily due to late diagnosis and its inherent heterogeneity. Single agent treatments are inadequate and generally lead to severe side effects at therapeutic doses. It is crucial to develop clinically relevant novel combination regimens involving synergistic modalities that target a wider repertoire of cells and lead to lowered individual doses. Stemming from this premise, this is the first report of two- and three-way synergies between Adenovirus-mediated Purine Nucleoside Phosphorylase based gene directed enzyme prodrug therapy (PNP-GDEPT), docetaxel and/or carboplatin in multidrug-resistant ovarian cancer cells. Methods The effects of PNP-GDEPT on different cellular processes were determined using Shotgun Proteomics analyses. The in vitro cell growth inhibition in differentially treated drug resistant human ovarian cancer cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The involvement of apoptosis and implicated proteins in effects of different treatments was established using flow cytometry based detection of M30 (an early marker of apoptosis), cell cycle analyses and finally western blot based analyses. Results Efficacy of the trimodal treatment was significantly greater than that achieved with bimodal- or individual treatments with potential for 10-50 fold dose reduction compared to that required for individual treatments. Of note was the marked enhancement in apoptosis that specifically accompanied the combinations that included PNP-GDEPT and accordingly correlated with a shift in the expression of anti- and pro-apoptotic proteins. PNP-GDEPT mediated enhancement of apoptosis was reinforced by cell cycle analyses. Proteomic analyses of PNP-GDEPT treated cells indicated a dowregulation of proteins involved in oncogenesis or cancer drug resistance in treated cells with accompanying upregulation of apoptotic- and tumour- suppressor proteins. Conclusion Inclusion of PNP-GDEPT in regular chemotherapy regimens can lead to significant enhancement of the cancer cell susceptibility to the combined treatment. Overall, these data will underpin the development of regimens that can benefit patients with late stage ovarian cancer leading to significantly improved efficacy and increased quality of life.

Modelling passenger flow at airport terminals : individual agent decision model for stochastic passenger behaviour

Airport system is complex. Passenger dynamics within it appear to be complicate as well. Passenger behaviours outside standard processes are regarded more significant in terms of public hazard and service rate issues. In this paper, we devised an individual agent decision model to simulate stochastic passenger behaviour in airport departure terminal. Bayesian networks are implemented into the decision making model to infer the probabilities that passengers choose to use any in-airport facilities. We aim to understand dynamics of the discretionary activities of passengers.

Roll the dice, rational agent : should extra-curial punishment mitigate an offender's sentence?

It was rugby league State of Origin night 2008 and a group of adults had descended upon a house in Eagleby, Brisbane to have some drinks and to celebrate the game. At 11pm that evening, Shane Thomas Davidson entered the bedroom of the homeowner’s 10-year-old son, TC. Davidson approached the bed and began to massage the boy’s penis under his clothing, which caused TC to wake. Davidson stated, ‘Show me how big your willy is and I’ll show you how big mine is’. TC refused the request and after a small period of time, left the bedroom and told his father what had happened...

Combination of MEK-ERK inhibitor and hyaluronic acid has a synergistic effect on anti-hypertrophic and pro-chondrogenic activities in osteoarthritis treatment

We hypothesised that a potentially disease-modifying osteoarthritis (OA) drug such as hyaluronic acid (HA) given in combination with anti-inflammatory signalling agents such as mitogen-activated protein kinase kinase–extracellular signal-regulated kinase (MEK-ERK) signalling inhibitor (U0126) could result in additive or synergistic effects on preventing the degeneration of articular cartilage. Chondrocyte differentiation and hypertrophy were evaluated using human OA primary cells treated with either HA or U0126, or the combination of HA + U0126. Cartilage degeneration in menisectomy (MSX) induced rat OA model was investigated by intra-articular delivery of either HA or U0126, or the combination of HA + U0126. Histology, immunostaining, RT-qPCR, Western blotting and zymography were performed to assess the expression of cartilage matrix proteins and hypertrophic markers. Phosphorylated ERK (pERK)1/2-positive chondrocytes were significantly higher in OA samples compared with those in healthy control suggesting the pathological role of that pathway in OA. It was noted that HA + U0126 significantly reduced the levels of pERK, chondrocyte hypertrophic markers (COL10 and RUNX2) and degenerative markers (ADAMTs5 and MMP-13), however, increased the levels of chondrogenic markers (COL2) compared to untreated or the application of HA or U0126 alone. In agreement with the results in vitro, intra-articular delivery of HA + U0126 showed significant therapeutic improvement of cartilage in rat MSX OA model compared with untreated or the application of HA or U0126 alone. Our study suggests that the combination of HA and MEK-ERK inhibition has a synergistic effect on preventing cartilage degeneration.