Changes in inflammatory mediators following eccentric exercise of the elbow flexors

The aims of this study were to examine the plasma concentrations of inflammatory mediators including cytokines induced by a single bout of eccentric exercise and again 4 weeks later by a second bout of eccentric exercise of the same muscle group. Ten untrained male subjects performed two bouts of the eccentric exercise involving the elbow flexors (6 sets of 5 repetitions) separated by four weeks. Changes in muscle soreness, swelling, and function following exercise were compared between the bouts. Blood was sampled before, immediately after, 1 h, 3 h, 6 h, 24 h (1 d), 48 h (2 d), 72 h (3 d), 96 h (4 d) following exercise bout to measure plasma creatine kinase (CK) activity, plasma concentrations of myoglobin (Mb), interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-4, IL-6, IL-8, IL-10, IL-12p40, tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), myeloperoxidase (MPO), prostaglandin E2 (PGE2), heat shock protein (HSP) 60 and 70. After the first bout, muscle soreness increased significantly, and there was also significant increase in upper arm circumference; muscle function decreased and plasma CK activity and Mb concentration increased significantly. These changes were significantly smaller after the second bout compared to the first bout, indicating muscle adaptation to the repeated bouts of the eccentric exercise. Despite the evidence of greater muscle damage after the first bout, the changes in cytokines and other inflammatory mediators were quite minor, and considerably smaller than that following endurance exercise. These results suggest that eccentric exercise-induced muscle damage is not associated with the significant release of cytokines into the systemic circulation. After the first bout, plasma G-CSF concentration showed a small but significant increase, whereas TNF-alpha and IL-8 showed significant decreases compared to the pre-exercise values. After the second bout, there was a significant increase in IL-10, and a significant decrease in IL-8. In conclusion, although there was evidence of severe muscle damage after the eccentric exercise, this muscle damage was not accompanied by any large changes in plasma cytokine concentrations. The minor changes in systemic cytokine concentration found in this study might reflect more rapid clearance from the circulation, or a lack of any significant metabolic or oxidative demands during this particular mode of exercise. In relation to the adaptation to the muscle damage, the anti-inflammatory cytokine IL-10 might work as one of the underlying mechanisms of action.

Integrated genomic characterization of endometrial carcinoma

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Mathematical modelling of controlled drug release from polymer micro-spheres : incorporating the effects of swelling, diffusion and dissolution via moving boundary problems

Controlled drug delivery is a key topic in modern pharmacotherapy, where controlled drug delivery devices are required to prolong the period of release, maintain a constant release rate, or release the drug with a predetermined release profile. In the pharmaceutical industry, the development process of a controlled drug delivery device may be facilitated enormously by the mathematical modelling of drug release mechanisms, directly decreasing the number of necessary experiments. Such mathematical modelling is difficult because several mechanisms are involved during the drug release process. The main drug release mechanisms of a controlled release device are based on the device’s physiochemical properties, and include diffusion, swelling and erosion. In this thesis, four controlled drug delivery models are investigated. These four models selectively involve the solvent penetration into the polymeric device, the swelling of the polymer, the polymer erosion and the drug diffusion out of the device but all share two common key features. The first is that the solvent penetration into the polymer causes the transition of the polymer from a glassy state into a rubbery state. The interface between the two states of the polymer is modelled as a moving boundary and the speed of this interface is governed by a kinetic law. The second feature is that drug diffusion only happens in the rubbery region of the polymer, with a nonlinear diffusion coefficient which is dependent on the concentration of solvent. These models are analysed by using both formal asymptotics and numerical computation, where front-fixing methods and the method of lines with finite difference approximations are used to solve these models numerically. This numerical scheme is conservative, accurate and easily implemented to the moving boundary problems and is thoroughly explained in Section 3.2. From the small time asymptotic analysis in Sections 5.3.1, 6.3.1 and 7.2.1, these models exhibit the non-Fickian behaviour referred to as Case II diffusion, and an initial constant rate of drug release which is appealing to the pharmaceutical industry because this indicates zeroorder release. The numerical results of the models qualitatively confirms the experimental behaviour identified in the literature. The knowledge obtained from investigating these models can help to develop more complex multi-layered drug delivery devices in order to achieve sophisticated drug release profiles. A multi-layer matrix tablet, which consists of a number of polymer layers designed to provide sustainable and constant drug release or bimodal drug release, is also discussed in this research. The moving boundary problem describing the solvent penetration into the polymer also arises in melting and freezing problems which have been modelled as the classical onephase Stefan problem. The classical one-phase Stefan problem has unrealistic singularities existed in the problem at the complete melting time. Hence we investigate the effect of including the kinetic undercooling to the melting problem and this problem is called the one-phase Stefan problem with kinetic undercooling. Interestingly we discover the unrealistic singularities existed in the classical one-phase Stefan problem at the complete melting time are regularised and also find out the small time behaviour of the one-phase Stefan problem with kinetic undercooling is different to the classical one-phase Stefan problem from the small time asymptotic analysis in Section 3.3. In the case of melting very small particles, it is known that surface tension effects are important. The effect of including the surface tension to the melting problem for nanoparticles (no kinetic undercooling) has been investigated in the past, however the one-phase Stefan problem with surface tension exhibits finite-time blow-up. Therefore we investigate the effect of including both the surface tension and kinetic undercooling to the melting problem for nanoparticles and find out the the solution continues to exist until complete melting. The investigation of including kinetic undercooling and surface tension to the melting problems reveals more insight into the regularisations of unphysical singularities in the classical one-phase Stefan problem. This investigation gives a better understanding of melting a particle, and contributes to the current body of knowledge related to melting and freezing due to heat conduction.

No hiding place

As public and private space becomes a focus for development values, contests occur between the unequal parties having a stake in the use of public space, such as central and local government, young people, communities and site developers. It is within the monitoring, recording and control procedures that young people’s use of public space is constructed as a threat to social order in need of surveillance and exclusion. This forms a major and contemporary feature in shaping thinking about urban and rural working class young people in the UK.

Sun, sea, sex, sand and soap

A recent issue of Young People Now (November 1995) mentioned the new (UK) Channel 4 television soap opera Hollyoaks by Phil Redmond, which raises the issue of the role of ‘soaps’ in the daily lives of young people. Australian soaps are especially popular in Britain and of interest to those who work with young people, because they have a high proportion of youthful looking actors and actresses and frequently depict scenes involving young people and apparent ‘real’ teenage dilemmas.

Young people, public space and new urbanism

The first of three articles in this issue addressing the public space topic considers public space and young people in the light of a range of papers delivered at the 27th International Conference on 'Making Cities Livable', held in Vienna, Austria, in July 2000. Under the overarching concept of the "liveable city" the conference themes of 'Rediscovery of public space' and 'Cities for the wellbeing of children' attracted a broad mix of those interested in the planning, design and management of urban space. A number of themes percolated through the conference which stimulated the writers to examine the nexus between urban development, young people and public space. There is an ongoing need to examine the meaning of public space in the face of powerful urban development trends. A model of public space practice is required which incorporates a vision of inclusive public spaces, fosters the interactivity of design, planning, social policy and management, and resources for greater communication and strategic action between stake holders from the most local of levels to those at state and international levels. The speed and magnitude of contemporary urban development makes community input and influence difficult, particularly for those impacted on by the exclusionary tendencies of much urban development. It is critical that a range of meaningful and sustainable mechanisms are developed which allow young people’s conceptions of what constitutes youth-friendly space to be directly made and taken account of.

Caught on camera

The emergence of shopping malls in Europe, the UK and Australia over the last thirty years or so, raises questions about the disruptive effects of such capital intensive developments on local area shopping facilities, transport and other infrastructures and the maintenance of artificially high prices for goods, whereby the promised greater choice of shops and prices is rarely a genuine free market of competition leading to lower prices. A central question to be addressed is whom these centres represent and belong to. While many claim to exist to ‘serve the community’ almost all malls and centres are private property and the community of shoppers has few, if any rights compared with the conventional high street, which is a public thoroughfare. This permits the management of the centres through their own private security staff, to observe, follow, eject and refuse further admission to anyone considered to be ‘undesirable’. What is different about the newest shopping centres is the routine use of increasingly sophisticated CCTV surveillance equipment to observe and record, for later evidential and entry restriction use, the movements of centre visitors.

Children and young people using public space : models of rights, optimism and wellbeing

This presentation discusses topics and issues that connect closely with the Conference Themes and themes in the ARACY Report Card. For example, developing models of public space that are safe, welcoming and relevant to children and young people will impact on their overall wellbeing and may help to prevent many of the tensions occurring in Australia and elsewhere around the world. This area is the subject of ongoing international debate, research and policy formation, relevant to concerns in the ARACY Report Card about children and young people’s health and safety, participation, behaviours and risks and peer and family relationships.

Young people and the social exclusion of their public and private space

This paper explores the concept of social exclusion as it impacts on young people within their local communities and the wider British, European and Australian context in terms of surveillance and other control measures.

Young people, children and their social and spatial citizenship rights

The use of public space by young people and children is a major issue in a number of countries and a range of measures are deployed to to control public space which restrict their social and spatial citizenship rights.

Let the children (and young people) play-where, how, why?

This paper reports on current research work with children and young people on the importance of public and private space for good health, wellbeing, social, educational and developmental outcomes. In many urban locations in Australia and elsewhere, public space is under attack from developers and attempts by authorities to control public space (Watson 2006). Private space in the home and garden-backyard is also under attack from development densification and trends towards bigger houses on smaller plots of land where gardens disappear altogether or a postage stamp remains (Gleeson and Sipe 2006). At the same time public policy advocates the benefits of outdoor exercise, set alongside fears about using public space exacerbated by notions of ‘stranger danger’ and control measures such as child and youth ‘curfews’. In this increasingly complex context, it is important to discover what children and young people value and need most in using private (home) and public space. In conjunction with the University of Otago, New Zealand, children and young people are consulted to discover how they use public space in parks and shopping centres and home space and the issues encountered and their proposals for improvement, to better inform policy debate, planning and formulation (ARACY 2009).