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.

Introduction. Locating men in the work-life nexus

In the last two decades there has been a plethora of research on a range of subjects collectively and rhetorically known as ‘work-life balance’. The bulk of this research, which spans disciplines including feminist sociology, industrial relations and management, has focused on the significant concerns of employed women and/or dual career couples. Less attention has been devoted to scholarship which explicitly examines men and masculinities in this context. Meanwhile, public and organizational discourse is largely espoused in gender neutral terms, often neglecting salient gendered issues which differentially impact the ability of women and men to successfully integrate their work and non-work lives. This edited book brings together empirical studies of the work-life nexus with a specific focus on men’s working time arrangements, how men navigate and traverse paid work and family commitments, and the impact of public and organizational policies on men’s participation in work, leisure, and other life domains. The book is innovative in that it presents both macro (institutional, how policy affects practice) and micro (individual, from men’s own perspectives) level studies, allowing for a rich and contrasting exploration of how men’s participation in paid work and other domains is divided, conflicted, or integrated. The essays in this volume address issues of fundamental social, labor market, and economic change which have occurred over the last 20 years and which have profoundly affected the way work, care, leisure and community have evolved in different contexts. Taking an international focus, Men, Wage Work and Family contrasts various public and organizational policies and how these policies impact men’s opportunities and participation in paid work and non-work domains in industrialised countries in Europe, North America, and Australia.

Contributors to life satisfaction in parents of an adult child with Down syndrome

Aim: This study investigated: (1) concurrent relationships between measures of family life and parental satisfaction with life in parents of an adult with Down syndrome and (2) influence of early family functioning on current parental satisfaction. Method: Sixty-two families were interviewed using a semi-structured interview, and responded to a series of questionnaires related to family functioning when their child with Down syndrome was between 7 and 15 years. Fifteen years later parents were asked to provide data on their current situation, including mental health, and satisfaction and difficulties with respect to care-giving in relation to their adult child. Results: Over half the families provided data to the second phase of the study. Life circumstances were appreciably worse for a small group of families than had been the case 15 years previously; however, these changes were generally unrelated to their parenting role. Overall, parents reported experiencing satisfaction from their care-giving role and did not report high levels of difficulties emanating from this role. Conclusions: Most parents demonstrated good levels of personal functioning, although there was a small group for whom this was not the case. Earlier functioning did not make a strong contribution to current levels of life satisfaction.

The effectiveness of a four layer compression bandage system in comparison to Class 3 compression hosiery on healing and quality of life for patients with venous leg ulcers : a randomised controlled trial

There are an increasing number of compression systems available for treatment of venous leg ulcers and limited evidence on the relative effectiveness of these systems. The purpose of this study was to conduct a randomised controlled trial to compare the effectiveness of a 4-layer compression bandage system with Class 3 compression hosiery on healing and quality of life in patients with venous leg ulcers. Data were collected from 103 participants on demographics, health, ulcer status, treatments, pain, depression and quality of life for 24 weeks. After 24 weeks, 86% of the 4-layer bandage group and 77% of the hosiery group were healed (p=0.24). Median time to healing for the bandage group was 10 weeks, in comparison to 14 weeks for the hosiery group (p=0.018). Cox proportional hazards regression found participants in the 4-layer system were 2.1 times (95% CI 1.2–3.5) more likely to heal than those in hosiery, while longer ulcer duration, larger ulcer area and higher depression scores significantly delayed healing. No differences between groups were found in quality of life or pain measures. Findings indicate these systems were equally effective in healing patients by 24 weeks, however a 4-layer system may produce a more rapid response.

The impact of temperature on years of life lost in Brisbane, Australia

Temperature is an important determinant of health. A better knowledge of how temperature affects population health is important not only to the scientific community, but also to the decision-makers who develop and implement early warning systems and intervention strategies to mitigate the health effects of extreme temperatures. The temperature–health relationship is also of growing interest as climate change is projected to shift the overall temperature distribution higher. Previous studies have examined the relative risks of temperature-related mortality, but the absolute measure of years of life lost is also useful as it combines the number of deaths with life expectancy. Here we use years of life lost to provide a novel measure of the impact of temperature on mortality in Brisbane, Australia. We also project the future temperature-related years of life lost attributable to climate change. We show that the association between temperature and years of life lost is U-shaped, with increased years of life lost for cold and hot temperatures. The temperature-related years of life lost will worsen greatly if future climate change goes beyond a 2 �C increase and without any adaptation to higher temperatures. This study highlights that public health adaptation to climate change is necessary.

A potential HIV epidemic among male street laborers in urban Vietnam

Background: Mass migration to Asian cities is a defining phenomenon of the present age, as hundreds of millions of people move from rural areas or between cities in search of economic prosperity. Although many do prosper, large numbers of people experience significant social disadvantage. This is especially the case among poorly educated, migrant unskilled unregistered male laborers who do much of the manual work throughout the cities. These men are at significant risk for many health problems, including HIV infection. However, to date there has been little research in developing countries to explain the determinants of this risk, and thereby to suggest feasible preventive strategies. Objectives and Methodology: Using combined qualitative and quantitative methods, the aim of this study was to explore the social contexts that affect health vulnerabilities and to develop conceptual models to predict risk behaviors for HIV [illicit drug use, unsafe sex, and non-testing for HIV] among male street laborers in Hanoi, Vietnam. Qualitative Research: Sixteen qualitative interviews revealed a complex variety of life experiences, beliefs and knowledge deficits that render these mostly poor and minimally educated men vulnerable to health problems including HIV infection. This study formed a conceptual model of numerous stressors related to migrants’ life experiences in urban space, including physical, financial and social factors. A wide range of coping strategies were adopted to deal with stressors – including problem-focused coping (PFC) and emotion-focused coping (EFC), pro-social and anti-social, active and passive. These men reported difficulty in coping with stressors because they had weak social networks and lacked support from formal systems. A second conceptual model emerged that highlighted equivalent influences of individual psychological factors, social integration, social barriers, and accessibility regarding drug use and sexual risk behavior. Psychological dimensions such as tedium, distress, fatalism and revenge, were important. There were strong effects of collective decision-making and fear of social isolation on shaping risk behaviors. These exploratory qualitative interviews helped to develop a culturally appropriate instrument for the quantitative survey and informed theoretical models of the factors that affect risk behaviors for HIV infection. Quantitative Research: The Information-Motivation-Behavioral Skills (IMB) model was adopted as the theoretical framework for a large-scale survey. It was modified to suit the contexts of these Vietnamese men. By doing a social mapping technique, 450 male street laborers were interviewed in Hanoi, Vietnam. The survey revealed that the risk of acquiring and transmitting HIV was high among these men. One in every 12 men reported homosexual or bisexual behavior. These men on average had 3 partners within the preceding year, and condom use was inconsistent. One third had had sex with commercial sex workers (CSW) and only 30% of them reported condom use; 17% used illicit drugs sometimes, with 66.7% of them frequently sharing injecting equipment with peers. Despite the risks, only 19.8% of men had been tested for HIV during the previous 12 months. These men have limited HIV knowledge and only moderate motivation and perceived behavioral skills for protective behavior. Although rural-to-urban migration was not associated with sexual risk behavior, three elements of the IMB model and depression associated with the process of mobility were significant determinants of sexual behavior. A modified model that incorporated IMB elements and psychosocial stress was found to be a better fit than the original IMB model alone in predicting protected sex behavior among the men. Men who were less psychologically and socially stressed, better informed and motivated for HIV prevention were more likely to demonstrate behavioral skills, and in turn were more likely to engage in safer sexual behavior. With regard to drug use, although the conventional model accounted for slightly less variance than the modified IMB model, data were of better fit for the conventional model. Multivariate analyses revealed that men who originated from urban areas, those who were homo- or bi-sexually identified and had better knowledge and skills for HIV prevention were more likely to access HIV testing, while men who had more sexual partners and those who did not use a condom for sex with CSW were least likely to take a test. The modified IMB model provided a better fit than the conventional model, as it explained a greater variance in HIV testing. Conclusions and Implications: This research helps to highlight a potential hidden HIV epidemic among street male, unskilled, unregistered laborers. This group has multiple vulnerabilities to HIV infection through both their partners and peers. However, most do not know their HIV status and have limited knowledge about preventing infection. This is the first application of a modified IMB model of risk behaviors for HIV such as drug use, condom use, and uptake of HIV testing to research with male street laborers in urban settings. The study demonstrated that while the extended IMB model had better fit than the conventional version in explaining the behaviors of safe sex and HIV testing, it was not so for drug use. The results provide interesting directions for future research and suggest ways to effectively design intervention strategies. The findings should shed light on culturally appropriate HIV preventive education and support programs for these men. As Vietnam has much in common with other developing countries in Southeast Asia, this research provides evidence for policy and practice that may be useful for public health systems in similar countries.

The neglected dimension of community liveability : impact on social connectedness and active ageing in higher density accommodation

Purpose This thesis is about liveability, place and ageing in the high density urban landscape of Brisbane, Australia. As with other major developed cities around the globe, Brisbane has adopted policies to increase urban residential densities to meet the main liveability and sustainability aim of decreasing car dependence and therefore pollution, as well as to minimise the loss of greenfield areas and habitats to developers. This objective hinges on urban neighbourhoods/communities being liveable places, which residents do not have to leave for everyday living. Community/neighbourhood liveability is an essential ingredient in healthy ageing in place and has a substantial impact upon the safety, independence and well-being of older adults. It is generally accepted that ageing in place is optimal for both older people and the state. The optimality of ageing in place generally assumes that there is a particular quality to environments or standard of liveability in which people successfully age in place. The aim of this thesis was to examine if there are particular environmental qualities or aspects of liveability that test optimality and to better understand the key liveability factors that contribute to successful ageing in place. Method A strength of this thesis is that it draws on two separate studies to address the research question of what makes high density liveable for older people. In Chapter 3, the two methods are identified and differentiated as Method 1 (used in Paper 1) and Method 2 (used in Papers 2, 3, 4 and 5). Method 1 involved qualitative interviews with 24 inner city high density Brisbane residents. The major strength of this thesis is the innovative methodology outlined in the thesis as Method 2. Method 2 involved a case study approach employing qualitative and quantitative methods. Qualitative data was collected using semi-structured, in-depth interviews and time-use diaries completed by participants during the week of tracking. The quantitative data was gathered using Global Positioning Systems for tracking and Geographical Information Systems for mapping and analysis of participants’ activities. The combination of quantitative and qualitative analysis captured both participants’ subjective perceptions of their neighbourhoods and their patterns of movement. This enhanced understanding of how neighbourhoods and communities function and of the various liveability dimensions that contribute to active ageing and ageing in place for older people living in high density environments. Both studies’ participants were inner-city high density residents of Brisbane. The study based on Method 1 drew on a wider age demographic than the study based on Method 2. Findings The five papers presented in this thesis by publication indicate a complex inter-relationship of the factors that make a place liveable. The first three papers identify what is comparable and different between the physical and social factors of high density communities/neighbourhoods. The last two papers explore relationships between social engagement and broader community variables such as infrastructure and the physical built environments that are risk or protective factors relevant to community liveability, active ageing and ageing in place in high density. The research highlights the importance of creating and/or maintaining a barrier-free environment and liveable community for ageing adults. Together, the papers promote liveability, social engagement and active ageing in high density neighbourhoods by identifying factors that constitute liveability and strategies that foster active ageing and ageing in place, social connections and well-being. Recommendations There is a strong need to offer more support for active ageing and ageing in place. While the data analyses of this research provide insight into the lived experience of high density residents, further research is warranted. Further qualitative and quantitative research is needed to explore in more depth, the urban experience and opinions of older people living in urban environments. In particular, more empirical research and theory-building is needed in order to expand understanding of the particular environmental qualities that enable successful ageing in place in our cities and to guide efforts aimed at meeting this objective. The results suggest that encouraging the presence of more inner city retail outlets, particularly services that are utilised frequently in people’s daily lives such as supermarkets, medical services and pharmacies, would potentially help ensure residents fully engage in their local community. The connectivity of streets, footpaths and their role in facilitating the reaching of destinations are well understood as an important dimension of liveability. To encourage uptake of sustainable transport, the built environment must provide easy, accessible connections between buildings, walkways, cycle paths and public transport nodes. Wider streets, given that they take more time to cross than narrow streets, tend to .compromise safety - especially for older people. Similarly, the width of footpaths, the level of buffering, the presence of trees, lighting, seating and design of and distance between pedestrian crossings significantly affects the pedestrian experience for older people and impacts upon their choice of transportation. High density neighbourhoods also require greater levels of street fixtures and furniture for everyday life to make places more useable and comfortable for regular use. The importance of making the public realm useful and habitable for older people cannot be over-emphasised. Originality/value While older people are attracted to high density settings, there has been little empirical evidence linking liveability satisfaction with older people’s use of urban neighbourhoods. The current study examined the relationships between community/neighbourhood liveability, place and ageing to better understand the implications for those adults who age in place. The five papers presented in this thesis add to the understanding of what high density liveable age-friendly communities/ neighbourhoods are and what makes them so for older Australians. Neighbourhood liveability for older people is about being able to age in place and remain active. Issues of ageing in Australia and other areas of the developed world will become more critical in the coming decades. Creating livable communities for all ages calls for partnerships across all levels of government agencies and among different sectors within communities. The increasing percentage of older people in the community will have increasing political influence and it will be a foolish government who ignores the needs of an older society.