A potential role for lamellar insulin-like growth factor-1 receptor in the pathogenesis of hyperinsulinaemic laminitis

The reason why a sustained high concentration of insulin induces laminitis in horses remains unclear. Cell proliferation occurs in the lamellae during insulin-induced laminitis and in other species high concentrations of insulin can activate receptors for the powerful cell mitogen, insulin-like growth factor (IGF)-1. The first aim of this study was to determine if IGF-1 receptors (IGF-1R) are activated in the hoof during insulin-induced laminitis. Gene expression for IGF-1R and the insulin receptor (InsR) was measured using qRT-PCR, in lamellar tissue from control horses and from horses undergoing a prolonged euglycaemic, hyperinsulinaemic clamp (p-EHC), during the mid-developmental (24 h) and acute (46 h) phases of insulin-induced laminitis. Gene expression for both receptors was decreased 13–32-fold (P < 0.05) at both time-points in the insulin-treated horses. A second aim was to determine if the down-regulation of the receptor genes could be accounted for by an increase in circulating IGF-1. Serum IGF-1 was measured at 0, 10, 25 and 46 h post-treatment in horses given a p-EHC for approximately 46 h, and in matched controls administered a balanced, electrolyte solution. There was no increase in serum IGF-1 concentrations during the p-EHC, consistent with down-regulation of both receptors by insulin. Stimulation of the IGF-1R by insulin may lead to inappropriate lamellar epidermal cell proliferation and lamellar weakening, a potential mechanism for hyperinsulinaemic laminitis. Targeting this receptor may provide insights into the pathogenesis or identify a novel therapy for hyperinsulinaemic laminitis.

A comprehensive investigation of the risky driving behaviour of young novice drivers

Young novice drivers - that is, drivers aged 16-25 years who are relatively inexperienced in driving on the road and have a novice (Learner, Provisional) driver's licence - have been overrepresented in car crash, injury and fatality statistics around the world for decades. There are numerous persistent characteristics evident in young novice driver crashes, fatalities and offences, including variables relating to the young driver themselves, broader social influences which include their passengers, the car they drive, and when and how they drive, and their risky driving behaviour in particular. Moreover, there are a range of psychosocial factors influencing the behaviour of young novice drivers, including the social influences of parents and peers, and person-related factors such as age-related factors, attitudes, and sensation seeking. Historically, a range of approaches have been developed to manage the risky driving behaviour of young novice drivers. Traditional measures predominantly relying upon education have had limited success in regulating the risky driving behaviour of the young novice driver. In contrast, interventions such as graduated driver licensing (GDL) which acknowledges young novice drivers' limitations - principally pertaining to their chronological and developmental age, and their driving inexperience - have shown to be effective in ameliorating this pervasive public health problem. In practice, GDL is a risk management tool that is designed to reduce driving at risky times (e.g., at night) or in risky driving conditions (e.g., with passengers), while still enabling novice drivers to obtain experience. In this regard, the GDL program in Queensland, Australia, was considerably enhanced in July 2007, and major additions to the program include mandated Learner practice of 100 hours recorded in a logbook, and passenger limits during night driving in the Provisional phase. Road safety researchers have also continued to consider the influential role played by the young driver's psychosocial characteristics, including psychological traits and states. In addition, whilst the majority of road safety user research is epidemiological in nature, contemporary road safety research is increasingly applying psychological and criminological theories. Importantly, such theories not only can guide young novice driver research, they can also inform the development and evaluation of countermeasures targeting their risky driving behaviour. The research is thus designed to explore the self-reported behaviours - and the personal, psychosocial, and structural influences upon the behaviours - of young novice drivers This thesis incorporates three stages of predominantly quantitative research to undertake a comprehensive investigation of the risky driving behaviour of young novices. Risky driving behaviour increases the likelihood of the young novice driver being involved in a crash which may harm themselves or other road users, and deliberate risky driving such as driving in excess of the posted speed limits is the focus of the program of research. The extant literature examining the nature of the risky behaviour of the young novice driver - and the contributing factors for this behaviour - while comprehensive, has not led to the development of a reliable instrument designed specifically to measure the risky behaviour of the young novice driver. Therefore the development and application of such a tool (the Behaviour of Young Novice Drivers Scale, or BYNDS) was foremost in the program of research. In addition to describing the driving behaviours of the young novice, a central theme of this program of research was identifying, describing, and quantifying personal, behavioural, and environmental influences upon young novice driver risky behaviour. Accordingly the 11 papers developed from the three stages of research which comprise this thesis are framed within Bandura's reciprocal determinism model which explicitly considers the reciprocal relationship between the environment, the person, and their behaviour. Stage One comprised the foundation research and operationalised quantitative and qualitative methodologies to finalise the instrument used in Stages Two and Three. The first part of Stage One involved an online survey which was completed by 761 young novice drivers who attended tertiary education institutions across Queensland. A reliable instrument for measuring the risky driving behaviour of young novices was developed (the BYNDS) and is currently being operationalised in young novice driver research in progress at the Centre for Injury Research and Prevention in Philadelphia, USA. In addition, regression analyses revealed that psychological distress influenced risky driving behaviour, and the differential influence of depression, anxiety, sensitivity to punishments and rewards, and sensation seeking propensity were explored. Path model analyses revealed that punishment sensitivity was mediated by anxiety and depression; and the influence of depression, anxiety, reward sensitivity and sensation seeking propensity were moderated by the gender of the driver. Specifically, for males, sensation seeking propensity, depression, and reward sensitivity were predictive of self-reported risky driving, whilst for females anxiety was also influential. In the second part of Stage One, 21 young novice drivers participated in individual and small group interviews. The normative influences of parents, peers, and the Police were explicated. Content analysis supported four themes of influence through punishments, rewards, and the behaviours and attitudes of parents and friends. The Police were also influential upon the risky driving behaviour of young novices. The findings of both parts of Stage One informed the research of Stage Two. Stage Two was a comprehensive investigation of the pre-Licence and Learner experiences, attitudes, and behaviours, of young novice drivers. In this stage, 1170 young novice drivers from across Queensland completed an online or paper survey exploring their experiences, behaviours and attitudes as a pre- and Learner driver. The majority of novices did not drive before they were licensed (pre-Licence driving) or as an unsupervised Learner, submitted accurate logbooks, intended to follow the road rules as a Provisional driver, and reported practicing predominantly at the end of the Learner period. The experience of Learners in the enhanced-GDL program were also examined and compared to those of Learner drivers who progressed through the former-GDL program (data collected previously by Bates, Watson, & King, 2009a). Importantly, current-GDL Learners reported significantly more driving practice and a longer Learner period, less difficulty obtaining practice, and less offence detection and crash involvement than Learners in the former-GDL program. The findings of Stage Two informed the research of Stage Three. Stage Three was a comprehensive exploration of the driving experiences, attitudes and behaviours of young novice drivers during their first six months of Provisional 1 licensure. In this stage, 390 of the 1170 young novice drivers from Stage Two completed another survey, and data collected during Stages Two and Three allowed a longitudinal investigation of self-reported risky driving behaviours, such as GDL-specific and general road rule compliance; risky behaviour such as pre-Licence driving, crash involvement and offence detection; and vehicle ownership, paying attention to Police presence, and punishment avoidance. Whilst the majority of Learner and Provisional drivers reported compliance with GDL-specific and general road rules, 33% of Learners and 50% of Provisional drivers reported speeding by 10-20 km/hr at least occasionally. Twelve percent of Learner drivers reported pre-Licence driving, and these drivers were significantly more risky as Learner and Provisional drivers. Ten percent of males and females reported being involved in a crash, and 10% of females and 18% of males had been detected for an offence, within the first six months of independent driving. Additionally, 75% of young novice drivers reported owning their own car within six months of gaining their Provisional driver's licence. Vehicle owners reported significantly shorter Learner periods and more risky driving exposure as a Provisional driver. Paying attention to Police presence on the roads appeared normative for young novice drivers: 91% of Learners and 72% of Provisional drivers reported paying attention. Provisional drivers also reported they actively avoided the Police: 25% of males and 13% of females; 23% of rural drivers and 15% of urban drivers. Stage Three also allowed the refinement of the risky behaviour measurement tool (BYNDS) created in Stage One; the original reliable 44-item instrument was refined to a similarly reliable 36-item instrument. A longitudinal exploration of the influence of anxiety, depression, sensation seeking propensity and reward sensitivity upon the risky behaviour of the Provisional driver was also undertaken using data collected in Stages Two and Three. Consistent with the research of Stage One, structural equation modeling revealed anxiety, reward sensitivity and sensation seeking propensity predicted self-reported risky driving behaviour. Again, gender was a moderator, with only reward sensitivity predicting risky driving for males. A measurement model of Akers' social learning theory (SLT) was developed containing six subscales operationalising the four constructs of differential association, imitation, personal attitudes, and differential reinforcement, and the influence of parents and peers was captured within the items in a number of these constructs. Analyses exploring the nature and extent of the psychosocial influences of personal characteristics (step 1), Akers' SLT (step 2), and elements of the prototype/willingness model (PWM) (step 3) upon self-reported speeding by the Provisional driver in a hierarchical multiple regression model found the following significant predictors: gender (male), car ownership (own car), reward sensitivity (greater sensitivity), depression (greater depression), personal attitudes (more risky attitudes), and speeding (more speeding) as a Learner. The research findings have considerable implications for road safety researchers, policy-makers, mental health professionals and medical practitioners alike. A broad range of issues need to be considered when developing, implementing and evaluating interventions for both the intentional and unintentional risky driving behaviours of interest. While a variety of interventions have been historically utilised, including education, enforcement, rehabilitation and incentives, caution is warranted. A multi-faceted approach to improving novice road safety is more likely to be effective, and new and existing countermeasures should capitalise on the potential of parents, peers and Police to be a positive influence upon the risky behaviour of young novice drivers. However, the efficacy of some interventions remains undetermined at this time. Notwithstanding this caveat, countermeasures such as augmenting and strengthening Queensland's GDL program and targeting parents and adolescents particularly warrant further attention. The findings of the research program suggest that Queensland's current-GDL can be strengthened by increasing compliance of young novice drivers with existing conditions and restrictions. The rates of speeding reported by the young Learner driver are particularly alarming for a number of reasons. The Learner is inexperienced in driving, and travelling in excess of speed limits places them at greater risk as they are also inexperienced in detecting and responding appropriately to driving hazards. In addition, the Learner period should provide the foundation for a safe lifetime driving career, enabling the development and reinforcement of non-risky driving habits. Learners who sped reported speeding by greater margins, and at greater frequencies, when they were able to drive independently. Other strategies could also be considered to enhance Queensland's GDL program, addressing both the pre-Licence adolescent and their parents. Options that warrant further investigation to determine their likely effectiveness include screening and treatment of novice drivers by mental health professionals and/or medical practitioners; and general social skills training. Considering the self-reported pre-licence driving of the young novice driver, targeted education of parents may need to occur before their child obtains a Learner licence. It is noteworthy that those participants who reported risky driving during the Learner phase also were more likely to report risky driving behaviour during the Provisional phase; therefore it appears vital that the development of safe driving habits is encouraged from the beginning of the novice period. General education of parents and young novice drivers should inform them of the considerably-increased likelihood of risky driving behaviour, crashes and offences associated with having unlimited access to a vehicle in the early stages of intermediate licensure. Importantly, parents frequently purchase the car that is used by the Provisional driver, who typically lives at home with their parents, and therefore parents are ideally positioned to monitor the journeys of their young novice driver during this early stage of independent driving. Parents are pivotal in the development of their driving child: they are models who are imitated and are sources of attitudes, expectancies, rewards and punishments; and they provide the most driving instruction for the Learner. High rates of self-reported speeding by Learners suggests that GDL programs specifically consider the nature of supervision during the Learner period, encouraging supervisors to be vigilant to compliance with general and GDL-specific road rules, and especially driving in excess of speed limit. Attitudes towards driving are formed before the adolescent reaches the age when they can be legally licensed. Young novice drivers with risky personal attitudes towards driving reported more risky driving behaviour, suggesting that countermeasures should target such attitudes and that such interventions might be implemented before the adolescent is licensed. The risky behaviours and attitudes of friends were also found to be influential, and given that young novice drivers tend to carry their friends as their passengers, a group intervention such as provided in a school class context may prove more effective. Social skills interventions that encourage the novice to resist the negative influences of their friends and their peer passengers, and to not imitate the risky driving behaviour of their friends, may also be effective. The punishments and rewards anticipated from and administered by friends were also found to influence the self-reported risky behaviour of the young novice driver; therefore young persons could be encouraged to sanction the risky, and to reward the non-risky, driving of their novice friends. Adolescent health programs and related initiatives need to more specifically consider the risks associated with driving. Young novice drivers are also adolescents, a developmental period associated with depression and anxiety. Depression, anxiety, and sensation seeking propensity were found to be predictive of risky driving; therefore interventions targeting psychological distress, whilst discouraging the expression of sensation seeking propensity whilst driving, warrant development and trialing. In addition, given that reward sensitivity was also predictive, a scheme which rewards novice drivers for safe driving behaviour - rather than rewarding the novice through emotional and instrumental rewards for risky driving behaviour - requires further investigation. The Police were also influential in the risky driving behaviour of young novices. Young novice drivers who had been detected for an offence, and then avoided punishment, reacted differentially, with some drivers appearing to become less risky after the encounter, whilst for others their risky behaviour appeared to be reinforced and therefore was more likely to be performed again. Such drivers saw t

New players for advanced prostate cancer and the rationalisation of insulin-sensitising medication

Obesity and type 2 diabetes are recognised risk factors for the development of some cancers and, increasingly, predict more aggressive disease, treatment failure, and cancer-specific mortality. Many factors may contribute to this clinical observation. Hyperinsulinaemia, dyslipidaemia, hypoxia, ER stress, and inflammation associated with expanded adipose tissue are thought to be among the main culprits driving malignant growth and cancer advancement. This observation has led to the proposal of the potential utility of “old players” for the treatment of type 2 diabetes and metabolic syndrome as new cancer adjuvant therapeutics. Androgen-regulated pathways drive proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen deprivation therapy (ADT) exploits this dependence to systemically treat advanced prostate cancer resulting in anticancer response and improvement of cancer symptoms. However, the initial therapeutic response from ADT eventually progresses to castrate resistant prostate cancer (CRPC) which is currently incurable. ADT rapidly induces hyperinsulinaemia which is associated with more rapid treatment failure. We discuss current observations of cancer in the context of obesity, diabetes, and insulin-lowering medication. We provide an update on current treatments for advanced prostate cancer and discuss whether metabolic dysfunction, developed during ADT, provides a unique therapeutic window for rapid translation of insulin-sensitising medication as combination therapy with antiandrogen targeting agents for the management of advanced prostate cancer.

The contribution of psychosocial factors to socioeconomic differences in food purchasing

In developed countries the relationship between socioeconomic position (SEP) and health is unequivocal. Those who are socioeconomically disadvantaged are known to experience higher morbidity and mortality from a range of chronic diet-related conditions compared to those of higher SEP. Socioeconomic inequalities in diet are well established. Compared to their more advantaged counterparts, those of low SEP are consistently found to consume diets less consistent with dietary guidelines (i.e. higher in fat, salt and sugar and lower in fibre, fruit and vegetables). Although the reasons for dietary inequalities remain unclear, understanding how such differences arise is important for the development of strategies to reduce health inequalities. Both environmental (e.g. proximity of supermarkets, price, and availability of foods) and psychosocial (e.g. taste preference, nutrition knowledge) influences are proposed to account for inequalities in food choices. Although in the United States (US), United Kingdom (UK), and parts of Australia, environmental factors are associated with socioeconomic differences in food choices, these factors do not completely account for the observed inequalities. Internationally, this context has prompted calls for further exploration of the role of psychological and social factors in relation to inequalities in food choices. It is this task that forms the primary goal of this PhD research. In the small body of research examining the contribution of psychosocial factors to inequalities in food choices, studies have focussed on food cost concerns, nutrition knowledge or health concerns. These factors are generally found to be influential. However, since a range of psychosocial factors are known determinants of food choices in the general population, it is likely that a range of factors also contribute to inequalities in food choices. Identification of additional psychosocial factors of relevance to inequalities in food choices would provide new opportunities for health promotion, including the adaption of existing strategies. The methodological features of previous research have also hindered the advancement of knowledge in this area and a lack of qualitative studies has resulted in a dearth of descriptive information on this topic. This PhD investigation extends previous research by assessing a range of psychosocial factors in relation to inequalities in food choices using both quantitative and qualitative techniques. Secondary data analyses were undertaken using data obtained from two Brisbane-based studies, the Brisbane Food Study (N=1003, conducted in 2000), and the Sixty Families Study (N=60, conducted in 1998). Both studies involved main household food purchasers completing an interviewer-administered survey within their own home. Data pertaining to food-purchasing, and psychosocial, socioeconomic and demographic characteristics were collected in each study. The mutual goals of both the qualitative and quantitative phases of this investigation were to assess socioeconomic differences in food purchasing and to identify psychosocial factors relevant to any observed differences. The quantitative methods then additionally considered whether the associations examined differed according to the socioeconomic indicator used (i.e. income or education). The qualitative analyses made a unique contribution to this project by generating detailed descriptions of socioeconomic differences in psychosocial factors. Those with lower levels of income and education were found to make food purchasing choices less consistent with dietary guidelines compared to those of high SEP. The psychosocial factors identified as relevant to food-purchasing inequalities were: taste preferences, health concerns, health beliefs, nutrition knowledge, nutrition concerns, weight concerns, nutrition label use, and several other values and beliefs unique to particular socioeconomic groups. Factors more tenuously or inconsistently related to socioeconomic differences in food purchasing were cost concerns, and perceived adequacy of the family diet. Evidence was displayed in both the quantitative and qualitative analyses to suggest that psychosocial factors contribute to inequalities in food purchasing in a collective manner. The quantitative analyses revealed that considerable overlap in the socioeconomic variation in food purchasing was accounted for by key psychosocial factors of importance, including taste preference, nutrition concerns, nutrition knowledge, and health concerns. Consistent with these findings, the qualitative transcripts demonstrated the interplay between such influential psychosocial factors in determining food-purchasing choices. The qualitative analyses found socioeconomic differences in the prioritisation of psychosocial factors in relation to food choices. This is suggestive of complex cultural factors that distinguish advantaged and disadvantaged groups and result in socioeconomically distinct schemas related to health and food choices. Compared to those of high SEP, those of lower SEP were less likely to indicate that health concerns, nutrition concerns, or food labels influenced food choices, and exhibited lower levels of nutrition knowledge. In the absence of health or nutrition-related concerns, taste preferences tended to dominate the food purchasing choices of those of low SEP. Overall, while cost concerns did not appear to be a main determinant of socioeconomic differences in food purchasing, this factor had a dominant influence on the food choices of some of the most disadvantaged respondents included in this research. The findings of this study have several implications for health promotion. The integrated operation of psychosocial factors on food purchasing inequalities indicates that multiple psychosocial factors may be appropriate to target in health promotion. It also seems possible that the inter-relatedness of psychosocial factors would allow health promotion targeting a single psychosocial factor to have a flow-on affect in terms of altering other influential psychosocial factors. This research also suggests that current mass marketing approaches to health promotion may not be effective across all socioeconomic groups due to differences in the priorities and main factors of influence in food purchasing decisions across groups. In addition to the practical recommendations for health promotion, this investigation, through the critique of previous research, and through the substantive study findings, has highlighted important methodological considerations for future research. Of particular note are the recommendations pertaining to the selection of socioeconomic indicators, measurement of relevant constructs, consideration of confounders, and development of an analytical approach. Addressing inequalities in health has been noted as a main objective by many health authorities and governments internationally. It is envisaged that the substantive and methodological findings of this thesis will make a useful contribution towards this important goal.

“Nobody’s holding a gun to your head…” examining current discourses surrounding victims of online fraud

The current discourse surrounding victims of online fraud is heavily premised on an individual notion of greed. The strength of this discourse permeates the thinking of those who have not experienced this type of crime, as well as victims themselves. The current discourse also manifests itself in theories of victim precipitation, which again assigns the locus of blame to individuals for their actions in an offence. While these typologies and categorisations of victims have been critiqued as “victim blaming” in other fields, this has not occurred with regard to online fraud victims, where victim focused ideas of responsibility for the offence continue to dominate. This paper illustrates the nature and extent of the greed discourse and argues that it forms part of a wider construction of online fraud that sees responsibility for victimisation lie with the victims themselves and their actions. It argues that the current discourse does not take into account the level of deception and the targeting of vulnerability that is employed by the offender in perpetrating this type of crime. It concludes by advocating the need to further examine and challenge this discourse, especially with regard to its potential impact for victim’s access to support services and the wider criminal justice system.

Targeted control of feral pigs in far north Queensland : defining management units using molecular techniques

The feral pig, Sus scrofa, is a widespread and abundant invasive species in Australia. Feral pigs pose a significant threat to the environment, agricultural industry, and human health, and in far north Queensland they endanger World Heritage values of the Wet Tropics. Historical records document the first introduction of domestic pigs into Australia via European settlers in 1788 and subsequent introductions from Asia from 1827 onwards. Since this time, domestic pigs have been accidentally and deliberately released into the wild and significant feral pig populations have become established, resulting in the declaration of this species as a class 2 pest in Queensland. The overall objective of this study was to assess the population genetic structure of feral pigs in far north Queensland, in particular to enable delineation of demographically independent management units. The identification of ecologically meaningful management units using molecular techniques can assist in targeting feral pig control to bring about effective long-term management. Molecular genetic analysis was undertaken on 434 feral pigs from 35 localities between Tully and Innisfail. Seven polymorphic and unlinked microsatellite loci were screened and fixation indices (FST and analogues) and Bayesian clustering methods were used to identify population structure and management units in the study area. Sequencing of the hyper-variable mitochondrial control region (D-loop) of 35 feral pigs was also examined to identify pig ancestry. Three management units were identified in the study at a scale of 25 to 35 km. Even with the strong pattern of genetic structure identified in the study area, some evidence of long distance dispersal and/or translocation was found as a small number of individuals exhibited ancestry from a management unit outside of which they were sampled. Overall, gene flow in the study area was found to be influenced by environmental features such as topography and land use, but no distinct or obvious natural or anthropogenic geographic barriers were identified. Furthermore, strong evidence was found for non-random mating between pigs of European and Asian breeds indicating that feral pig ancestry influences their population genetic structure. Phylogenetic analysis revealed two distinct mitochondrial DNA clades, representing Asian domestic pig breeds and European breeds. A significant finding was that pigs of Asian origin living in Innisfail and south Tully were not mating randomly with European breed pigs populating the nearby Mission Beach area. Feral pig control should be implemented in each of the management units identified in this study. The control should be coordinated across properties within each management unit to prevent re-colonisation from adjacent localities. The adjacent rainforest and National Park Estates, as well as the rainforest-crop boundary should be included in a simultaneous control operation for greater success.

The beliefs which influence young males to speed and strategies to slow them down : informing the content of anti-speeding messages

Young male drivers are over-represented in road-related fatalities. Speeding represents a pervasive and significant contributor to road trauma. Anti-speeding messages represent a long-standing strategy aimed at discouraging drivers from speeding. These messages, however, have not always achieved their persuasive objectives which may be due, in part, to them not always targeting the most salient beliefs underpinning the speeding behavior of particular driver groups. The current study elicited key beliefs underpinning speeding behavior as well as strategies used to avoid speeding, using a well-validated belief-based model, the Theory of Planned Behavior and in-depth qualitative methods. To obtain the most comprehensive understanding about the salient beliefs and strategies of young male drivers, how such beliefs and strategies compared with those of drivers of varying ages and gender, was also explored. Overall, 75 males and females (aged 17-25 or 30-55 years) participated in group discussions. The findings revealed beliefs that were particularly relevant to young males and that would likely represent key foci for developing message content. For instance, the need to feel in control and the desire to experience positive affect when driving were salient advantages; while infringements were a salient disadvantage and, in particular, the loss of points and the implications associated with potential licence loss as opposed to the monetary (fine) loss (behavioral beliefs). For normative influences, young males appeared to hold notable misperceptions (compared with other drivers, such as young females); for instance, young males believed that females/girlfriends were impressed by their speeding. In the case of control beliefs, the findings revealed low perceptions of control with respect to being able to not speed and a belief that something “extraordinary” would need to happen for a young male driver to lose control of their vehicle while speeding. The practical implications of the findings, in terms of providing suggestions for devising the content of anti-speeding messages, are discussed.

The development of an effective vaccine against Chlamydia : utilisation of a non-toxic mucosal adjuvant to generate a protective mucosal response

Chlamydia is responsible for a wide range of diseases with enormous global economic and health burden. As the majority of chlamydial infections are asymptomatic, a vaccine has greatest potential to reduce infection and disease prevalence. Protective immunity against Chlamydia requires the induction of a mucosal immune response, ideally, at the multiple sites in the body where an infection can be established. Mucosal immunity is most effectively stimulated by targeting vaccination to the epithelium, which is best accomplished by direct vaccine application to mucosal surfaces rather than by injection. The efficacy of needle-free vaccines however is reliant on a powerful adjuvant to overcome mucosal tolerance. As very few adjuvants have proven able to elicit mucosal immunity without harmful side effects, there is a need to develop non-toxic adjuvants or safer ways to administered pre-existing toxic adjuvants. In the present study we investigated the novel non-toxic mucosal adjuvant CTA1-DD. The immunogenicity of CTA1-DD was compared to our "gold-standard" mucosal adjuvant combination of cholera toxin (CT) and cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN). We also utilised different needle-free immunisation routes, intranasal (IN), sublingual (SL) and transcutaneous (TC), to stimulate the induction of immunity at multiple mucosal surfaces in the body where Chlamydia are known to infect. Moreover, administering each adjuvant by different routes may also limit the toxicity of the CT/CpG adjuvant, currently restricted from use in humans. Mice were immunised with either adjuvant together with the chlamydial major outer membrane protein (MOMP) to evaluate vaccine safety and quantify the induction of antigen-specific mucosal immune responses. The level of protection against infection and disease was also assessed in vaccinated animals following a live genital or respiratory tract infectious challenge. The non-toxic CTA1-DD was found to be safe and immunogenic when delivered via the IN route in mice, inducing a comparable mucosal response and level of protective immunity against chlamydial challenge to its toxic CT/CpG counterpart administered by the same route. The utilisation of different routes of immunisation strongly influenced the distribution of antigen-specific responses to distant mucosal surfaces and also abrogated the toxicity of CT/CpG. The CT/CpG-adjuvanted vaccine was safe when administered by the SL and TC routes and conferred partial immunity against infection and pathology in both challenge models. This protection was attributed to the induction of antigen-specific pro-inflammatory cellular responses in the lymph nodes regional to the site of infection and rather than in the spleen. Development of non-toxic adjuvants and effective ways to reduce the side effects of toxic adjuvants has profound implications for vaccine development, particularly against mucosal pathogens like Chlamydia. Interestingly, we also identified two contrasting vaccines in both infection models capable of preventing infection or pathology exclusively. This indicated that the development of pathology following an infection of vaccinated animals was independent of bacterial load and was instead the result of immunopathology, potentially driven by the adaptive immune response generated following immunisation. While both vaccines expressed high levels of interleukin (IL)-17 cytokines, the pathology protected group displayed significantly reduced expression of corresponding IL-17 receptors and hence an inhibition of signalling. This indicated that the balance of IL-17-mediated responses defines the degree of protection against infection and tissue damage generated following vaccination. This study has enabled us to better understand the immune basis of pathology and protection, necessary to design more effective vaccines.

Female students’ interactions in a middle school engineering project : a case study

Targeting females at high school or earlier may be a key towards engaging them in science, technology, engineering and mathematics (STEM) education. This ethnographic study, part of a three-year longitudinal research project, investigated Year 8 female students’ learning about engineering concepts associated with designing, constructing, testing, and evaluating a catapult. There was a series of lead-up lessons and four lessons for the catapult challenge (total of 18 x 45-minute lessons) over a nine-week period. Data from two girls within a focus group showed that they needed to: (1) receive clarification on engineering terms to facilitate more fluent discourse, (2) question and debate conceptual understandings without peers being judgemental, and (3) have multiple opportunities for engaging with materials towards designing, constructing and explaining key concepts learnt. There are implications for teachers facilitating STEM education, such as: clarifying STEM terms, articulating how students can interact in non-judgmental ways, and providing multiple opportunities for interacting within engineering education.

Plasma metabolomics reveals biomarkers of the atherosclerosis

Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality in industrialized societies. The lack of metabolite biomarkers has impeded the clinical diagnosis of atherosclerosis so far. In this study, stable atherosclerosis patients (n=16) and age- and sex-matched non-atherosclerosis healthy subjects (n=28) were recruited from the local community (Harbin, P. R. China). The plasma was collected from each study subject and was subjected to metabolomics analysis by GC/MS. Pattern recognition analyses (principal components analysis, orthogonal partial least-squares discriminate analysis, and hierarchical clustering analysis) commonly demonstrated plasma metabolome, which was significantly different from atherosclerotic and non-atherosclerotic subjects. The development of atherosclerosis-induced metabolic perturbations of fatty acids, such as palmitate, stearate, and 1-monolinoleoylglycerol, was confirmed consistent with previous publication, showing that palmitate significantly contributes to atherosclerosis development via targeting apoptosis and inflammation pathways. Altogether, this study demonstrated that the development of atherosclerosis directly perturbed fatty acid metabolism, especially that of palmitate, which was confirmed as a phenotypic biomarker for clinical diagnosis of atherosclerosis.

In vitro functional characterisation of IGF-I : VN-induced breast cancer progression

Members of the insulin-like growth factor (IGF) family have been shown to play critical roles in normal growth and development, as well as in tumour biology. The IGF system is complex and the biological effects of the IGFs are determined by their diverse interactions between many molecules, including their interactions with extracellular matrix (ECM) proteins. Recent studies have demonstrated that IGFs associate with the ECM protein vitronectin (VN) through IGF-binding proteins (IGFBP) and that this interaction modulates IGF-stimulated biological functions, namely cell migration and cell survival through the cooperative involvement of the type-I IGF receptor (IGF-1R) and VN-binding integrins. Since IGFs play important roles in the transformation and progression of breast cancer and VN has been found to be over-expressed at the leading edge of breast tumours, this project aimed to describe the effects of IGF-I:VN interactions on breast cell function. This was undertaken to dissect the molecular mechanisms underlying IGF-I:VN-induced responses and to design inhibitors to block the effects of such interactions. The studies described herein demonstrate that the increase in migration of MCF-7 breast cancer cells in response to the IGF-I:IGFBP-5:VN complex is accompanied by differential expression of genes known to be involved in migration, invasion and/or survival, including Tissue-factor (TF), Stratifin (SFN), Ephrin-B2, Sharp-2 and PAI-1. This „migration gene signature‟ was confirmed using real-time PCR analysis. Substitution of the native IGF-I within the IGF-I:IGFBP:VN complex with the IGF-I analogue, \[L24]\[A31]-IGF-I, which has a reduced affinity for the IGF-1R, failed to stimulate cell migration and interestingly, also failed to induce the differential gene expression. This supports the involvement of the IGF-1R in mediating these changes in gene expression. Furthermore, lentiviral shRNA-mediated stable knockdown of TF and SFN completely abrogated the increased cell migration induced by IGF-I:IGFBP:VN complexes in MCF-7 cells. Indeed, when these cells were grown in 3D Matrigel™ cultures a decrease in the overall size of the 3D spheroids in response to the IGF-I:IGFBP:VN complexes was observed compared to the parental MCF-7 cells. This suggests that TF and SFN have a role in complex-stimulated cell survival. Moreover, signalling studies performed on cells with the reduced expression of either TF or SFN had a decreased IGF-1R activation, suggesting the involvement of signalling pathways downstream of IGF-1R in TF- and/or SFN-mediated cell migration and cell survival. Taken together, these studies provide evidence for a common mechanism activated downstream of the IGF-1R that induces the expression of the „migration gene signature‟ in response to the IGF-I:IGFBP:VN complex that confers breast cancer cells the propensity to migrate and survive. Given the functional significance of the interdependence of ECM and growth factor (GF) interactions in stimulating processes key to breast cancer progression, this project aimed at developing strategies to prevent such growth factor:ECM interactions in an effort to inhibit the downstream functional effects. This may result in the reduction in the levels of ECM-bound IGF-I present in close proximity to the cells, thereby leading to a reduction in the stimulation of IGF-1R present on the cell surface. Indeed, the inhibition of IGF-I-mediated effects through the disruption of its association with ECM would not alter the physiological levels of IGF-I and potentially only exert effects in situations where abnormal over expression of ECM proteins are found; namely carcinomas and hyperproliferative diseases. In summary, this PhD project has identified novel, innovative and realistic strategies that can be used in vitro to inhibit the functions exerted by the IGF-I:IGFBP:VN multiprotein complexes critical for cancer progression, with a potential to be translated into in vivo investigations. Furthermore, TF and SFN were found to mediate IGF-I:IGFBP:VN-induced effects, thereby revealing their potential to be used as therapeutic targets or as predictive biomarkers for the efficacy of IGF-1R targeting therapies in breast cancer patients. In addition to its therapeutic and clinical scope, this PhD project has significantly contributed to the understanding of the role of the IGF system in breast tumour biology by providing valuable new information on the mechanistic events underpinning IGF-I:VN-mediated effects on breast cell functions. Furthermore, this is the first instance where favourable binding sites for IGF-II, IGFBP-3 and IGFBP-5 on VN have been identified. Taken together, this study has functionally characterised the interactions between IGF-I and VN and through innovative strategies has provided a platform for the development of novel therapies targeting these interactions and their downstream effects.

Beliefs underlying blood donors’ intentions to donate during two phases of an avian influenza outbreak

Using a Theory of Planned Behavior (TPB) framework the current study explored the beliefs of current blood donors (N=172) about donating during a low and high-risk phase of a potential avian influenza outbreak. While the majority of behavioral, normative, and control beliefs identified in preliminary research differed as a function of donors’ intentions to donate during both phases of an avian influenza outbreak, regression analyses suggested that the targeting of different specific beliefs during each phase of an outbreak would yield most benefit in bolstering donors’ intentions to remain donating. The findings provide insight in how to best motivate donors in different phases of an avian influenza outbreak.

Determinants of drink-driving and association between drink-driving and road traffic fatalities in Ghana

Aim The objective is to establish determinants of drink-driving and its association with traffic crashes in Ghana. Methods A multivariable logistic regression was used to establish significant determinants of drink-driving and a bivariate logistic regression to establish the association between drink–driving and road traffic crashes in Ghana. Results In total, 2,736 motorists were randomly stopped for breath testing of whom 8.7% tested positive for alcohol. Among the total participants, 5.5% exceeded the legal BAC limit of 0.08%. Formal education is associated with a reduced likelihood of drink-driving compared with drivers without formal education. The propensity to drink-drive is 1.8 times higher among illiterate drivers compared with drivers with basic education. Young adult drivers also recorded elevated likelihoods for driving under alcohol impairment compared with adult drivers. The odds of drink-driving among truck drivers is OR=1.81, (95% CI=1.16 to 2.82) and two wheeler riders is OR=1.41, (95% CI=0.47 to 4.28) compared with car drivers. Contrary to general perception, commercial car drivers have a significant reduced likelihood of 41%, OR=0.59, (95% CI=0.38 to 0.92) compared with the private car driver. Bivariate analysis conducted showed a significant association between the proportion of drivers exceeding the legal BAC limit and road traffic fatalities, p<0.001. The model predicts a 1% increase in the proportion of drivers exceeding the legal BAC to be associated with a 4% increase in road traffic fatalities, 95% CI= 3% to 5% and vice versa. Conclusion A positive and significant association between roadside alcohol prevalence and road traffic fatality has been established. Scaling up roadside breath test, determining standard drink and disseminating to the populace and formulating policies targeting the youth such as increasing minimum legal drinking age and reduced legal BAC limit for the youth and novice drivers might improve drink-driving related crashes in Ghana.

Fraud risk and the visibility of carbon

In recent years, carbon has been increasingly rendered ‘visible’ both discursively and through political processes that have imbued it with economic value. Greenhouse gas (GHG) emissions have been constructed as social and environmental costs and their reduction or avoidance as social and economic gain. The ‘marketisation’ of carbon, which has been facilitated through various compliance schemes such as the European Union Emissions Trading Scheme (EU ETS), the Kyoto Protocol, the proposed Australian Emissions Reduction Scheme and through the voluntary carbon credit market, have attempted to bring carbon into the ‘foreground’ as an economic liability and/or opportunity. Accompanying the increasing economic visibility of carbon are reports of frauds and scams – the ‘gaming of carbon markets’(Chan 2010). As Lohmann (2010: 21) points out, ‘what are conventionally classed as scams or frauds are an inevitable feature of carbon offset markets, not something that could be eliminated by regulation targeting the specific businesses or state agencies involved’. This paper critiques the disparate discourses of fraud risk in carbon markets and examines cases of fraud within emerging landscapes of green criminology.

Examining the stability of transport behaviours for high-risk early adolescents

Transport related injury is a leading cause of death and disability for adolescents and represents a substantial burden on public health and the community as a whole. Adolescents appear to have a growing risk of harm due to the co-existence of increasing alcohol use and engagement in risky transport behaviours. Understanding more about the development and stability of these behaviours by young adolescents over time could be beneficial in targeting transport injury prevention interventions for high-risk adolescents. In Australia alcohol use begins to increase significantly through the early and middle adolescent years even though the majority of these young people are still in school. Aim This paper reports on changes over a six month period in alcohol use, anger management experiences and transport risk taking behaviours including riding a bicycle without a helmet and under-age driving for high-risk adolescents and non high-risk early adolescents. Year 9 students (N=1,005) from 20 schools in Queensland, Australia completed a baseline survey in the first half of 2012 and at a six month follow up. Respondents at both times were asked about their engagement in risk taking behaviours measured by Mak’s adolescent delinquency scale, which included five transport related items. They were also asked to rate their alcohol use for the preceding three month period. The stability of these risk taking indicators was measured by comparing baseline results with the six month follow up. Results High-risk adolescents were more likely to report change in their alcohol use and transport behaviours when compared with non high-risk adolescents over a six month period. There were no significant changes in control of anger for either group. Demographic characteristics were not shown to have any significant effect on the stability of risk indicators for high-risk adolescents and non high-risk adolescents. Differences were found in the stability of risk taking indicators for high-risk adolescents and non high-risk adolescents. The findings of this paper have implications in targeting transport risk behaviour change interventions to meet the needs of high-risk adolescents.