Assessment of retinal structure and visual function in association with diabetic peripheral neuropathy

Diabetes is an increasingly prevalent disease worldwide. Providing early management of the complications can prevent morbidity and mortality in this population. Peripheral neuropathy, a significant complication of diabetes, is the major cause of foot ulceration and amputation in diabetes. Delay in attending to complication of the disease contributes to significant medical expenses for diabetic patients and the community. Early structural changes to the neural components of the retina have been demonstrated to occur prior to the clinically visible retinal vasculature complication of diabetic retinopathy. Additionally visual functionloss has been shown to exist before the ophthalmoscopic manifestations of vasculature damage. The purpose of this thesis was to evaluate the relationship between diabetic peripheral neuropathy and both retinal structure and visual function. The key question was whether diabetic peripheral neuropathy is the potential underlying factor responsible for retinal anatomical change and visual functional loss in people with diabetes. This study was conducted on a cohort with type 2 diabetes. Retinal nerve fibre layer thickness was assessed by means of Optical Coherence Tomography (OCT). Visual function was assessed using two different methods; Standard Automated Perimetry (SAP) and flicker perimetry were performed within the central 30 degrees of fixation. The level of diabetic peripheral neuropathy (DPN) was assessed using two techniques - Quantitative Sensory Testing and Neuropathy Disability Score (NDS). These techniques are known to be capable of detecting DPN at very early stages. NDS has also been shown as a gold standard for detecting 'risk of foot ulceration'. Findings reported in this thesis showed that RNFL thickness, particularly in the inferior quadrant, has a significant association with severity of DPN when the condition has been assessed using NDS. More specifically it was observed that inferior RNFL thickness has the ability to differentiate individuals who are at higher risk of foot ulceration from those who are at lower risk, indicating that RNFL thickness can predict late-staged DPN. Investigating the association between RNFL and QST did not show any meaningful interaction, which indicates that RNFL thickness for this cohort was not as predictive of neuropathy status as NDS. In both of these studies, control participants did not have different results from the type 2 cohort who did not DPN suggesting that RNFL thickness is not a marker for diagnosing DPN at early stages. The latter finding also indicated that diabetes per se, is unlikely to affect the RNFL thickness. Visual function as measured by SAP and flicker perimetry was found to be associated with severity of peripheral neuropathy as measured by NDS. These findings were also capable of differentiating individuals at higher risk of foot ulceration; however, visual function also proved not to be a maker for early diagnosis of DPN. It was found that neither SAP, nor flicker sensitivity have meaningful associations with DPN when neuropathy status was measured using QST. Importantly diabetic retinopathy did not explain any of the findings in these experiments. The work described here is valuable as no other research to date has investigated the association between diabetic peripheral neuropathy and either retinal structure or visual function.

Neuropsychological development in children with early and continuously treated phenylketonuria : association with biochemical markers

PKU is a genetically inherited inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase. The failure of this enzyme causes incomplete metabolism of protein ingested in the diet, specifically the conversion of one amino acid, phenylalanine, to tyrosine, which is a precursor to the neurotransmitter dopamine. Rising levels of phenylalanine is toxic to the developing brain, disrupting the formation of white matter tracts. The impact of tyrosine deficiency is not as well understood, but is hypothesized to lead to a low dopamine environment for the developing brain. Detection in the newborn period and continuous treatment (a low protein phe-restricted diet supplemented with phenylalanine-free protein formulas) has resulted in children with early and continuously treated PKU now developing normal I.Q. However, deficits in executive function (EF) are common, leading to a rate of Attention Deficit Hyperactivity Disorder (ADHD) up to five times the norm. EF worsens with exposure to higher phenylalanine levels, however recent research has demonstrated that a high phenylalanine to tyrosine ratio (phenylalanine:tyrosine ratio), which is hypothesised to lead to poorer dopamine function, has a more negative impact on EF than phenylalanine levels alone. Research and treatment of PKU is currently phenylalanine-focused, with little investigation of the impact of tyrosine on neuropsychological development. There is no current consensus as to the veracity of tyrosine monitoring or treatment in this population. Further, the research agenda in this population has demonstrated a primary focus on EF impairment alone, even though there may be additional neuropsychological skills compromised (e.g., mood, visuospatial deficits). The aim of this PhD research was to identify residual neuropsychological deficits in a cohort of children with early and continuously treated phenylketonuria, at two time points in development (early childhood and early adolescence), separated by eight years. In addition, this research sought to determine which biochemical markers were associated with neuropsychological impairments. A clinical practice survey was also undertaken to ascertain the current level of monitoring/treatment of tyrosine in this population. Thirteen children with early and continuously treated PKU were tested at mean age 5.9 years and again at mean age 13.95 years on several neuropsychological measures. Four children with hyperphenylalaninemia (a milder version of PKU) were also tested at both time points and provide a comparison group in analyses. Associations between neuropsychological function and biochemical markers were analysed. A between groups analysis in adolescence was also conducted (children with PKU compared to their siblings) on parent report measures of EF and mood. Minor EF impairments were evident in the PKU group by age 6 years and these persisted into adolescence. Life-long exposure to high phenylalanine:tyrosine ratio and/or low tyrosine independent of phenylalanine were significantly associated with EF impairments at both time points. Over half the children with PKU showed severe impairment on a visuospatial task, and this was associated only with concurrent levels of tyrosine in adolescence. Children with PKU also showed a statistically significant decline in a language comprehension task from 6 years to adolescence (going from normal to subnormal), this deficit was associated with lifetime levels of phenylalanine. In comparison, the four children with hyperphenylalaninemia demonstrated normal function at both time points, across all measures. No statistically significant differences were detected between children with PKU and their siblings on the parent report of EF and mood. However, depressive symptoms were significantly correlated with: EF; long term high phe:tyr exposure; and low tyrosine levels independent of phenylalanine. The practice survey of metabolic clinics from 12 countries indicated a high level of variability in terms of monitoring/treatment of tyrosine in this population. Whilst over 80% of clinics surveyed routinely monitored tyrosine levels in their child patients, 25% reported treatment strategies to increase tyrosine (and thereby lower the phenylalanine:tyrosine ratio) under a variety of patient presentation conditions. Overall, these studies have shown that EF impairments associated with PKU provide support for the dopamine-deficiency model. A language comprehension task showed a different trajectory, serving a timely reminder that non-EF functions also remain vulnerable in this population; and that normal function in childhood does not guarantee normal function by adolescence. Mood impairments were associated with EF impairments as well as long term measures of phenylalanine:tyrosine and/or tyrosine. The implications of this research for enhanced clinical guidelines are discussed given varied current practice.

Comparative Studies Simplified in GPFlow

We present a novel, web-accessible scientific workflow system which makes large-scale comparative studies accessible without programming or excessive configuration requirements. GPFlow allows a workflow defined on single input values to be automatically lifted to operate over collections of input values and supports the formation and processing of collections of values without the need for explicit iteration constructs. We introduce a new model for collection processing based on key aggregation and slicing which guarantees processing integrity and facilitates automatic association of inputs, allowing scientific users to manage the combinatorial explosion of data values inherent in large scale comparative studies. The approach is demonstrated using a core task from comparative genomics, and builds upon our previous work in supporting combined interactive and batch operation, through a lightweight web-based user interface.

Interacting constraints of defensive pressure and ball displacement trajectories shape locomotor pointing behaviours in association football

Performance of locomotor pointing tasks (goal-directed locomotion) in sport is typically constrained by dynamic factors, such as positioning of opponents and objects for interception. In the team sport of association football, performers have to coordinate their gait with ball displacement when dribbling and when trying to prevent opponent interception when running to kick a ball. This thesis comprises two studies analysing the movement patterns during locomotor pointing of eight experienced youth football players under static and dynamic constraints by manipulating levels of ball displacement (ball stationary or moving) and defensive pressure (defenders absent, or positioned near or far during performance). ANOVA with repeated measures was used to analyse effects of these task constraints on gait parameters during the run-up and cross performance sub-phase. Experiment 1 revealed outcomes consistent with previous research on locomotor pointing. When under defensive pressure, participants performed the run-up more quickly, concurrently modifying footfall placements relative to the ball location over trials. In experiment 2 players coordinated their gait relative to a moving ball significantly differently when under defensive pressure. Despite no specific task instructions being provided beforehand, context dependent constraints interacted to influence footfall placements over trials and running velocity of participants in different conditions. Data suggest that coaches need to manipulate task constraints carefully to facilitate emergent movement behaviours during practice in team games like football.

What explains the association between socioeconomic status and depression among Vietnamese adults?

Background Depression is a major public health problem worldwide and is currently ranked second to heart disease for years lost due to disability. For many decades, international research has found that depressive symptoms occur more frequently among low socioeconomic (SES) individuals than their more-advantaged peers. However, the reasons as to why those of low socioeconomic groups suffer more depressive symptoms are not well understood. Studies investigating the prevalence of depression and its association with SES emanate largely from developed countries, with little research among developing countries. In particular, there is a serious dearth of research on depression and no investigation of its association with SES in Vietnam. The aims of the research presented in this Thesis are to: estimate the prevalence of depressive symptoms among Vietnamese adults, examine the nature and extent of the association between SES and depression and to elucidate causal pathways linking SES to depressive symptoms Methods The research was conducted between September 2008 and November 2009 in Hue city in central Vietnam and used a combination of qualitative (in-depth interviews) and quantitative (survey) data collection methods. The qualitative study contributed to the development of the theoretical model and to the refinement of culturally-appropriate data collection instruments for the quantitative study. The main survey comprised a cross-sectional population–based survey with randomised cluster sampling. A sample of 1976 respondents aged between 25-55 years from ten randomly-selected residential zones (quarters) of Hue city completed the questionnaire (response rate 95.5%). Measures SES was classified using three indicators: education, occupation and income. The Center for Epidemiologic Studies-Depression (CES-D) scale was used to measure depressive symptoms (range0-51, mean=11.0, SD=8.5). Three cut-off points for the CES-D scores were applied: ‘at risk for clinical depression’ (16 or above), ‘depressive symptoms’ (above 21) and ‘depression’ (above 25). Six psychosocial indicators: life time trauma, chronic stress, recent life events, social support, self esteem, and mastery were hypothesized to mediate the association between SES and depressive symptoms. Analyses The prevalence of depressive symptoms were analysed using bivariate analyses. The multivariable analytic phase comprised of ordinary least squares regression, in accordance with Baron and Kenny’s three-step framework for mediation modeling. All analyses were adjusted for a range of confounders, including age, marital status, smoking, drinking and chronic diseases and the mediation models were stratified by gender. Results Among these Vietnamese adults, 24.3% were at or above the cut-off for being ‘at risk for clinical depression’, 11.9% were classified as having depressive symptoms and 6.8% were categorised as having depression. SES was inversely related to depressive symptoms: the least educated those with low occupational status or with the lowest incomes reported more depressive symptoms. Socioeconomicallydisadvantaged individuals were more likely to report experiencing stress (life time trauma, chronic stress or recent life events), perceived less social support and reported fewer personal resources (self esteem and mastery) than their moreadvantaged counterparts. These psychosocial resources were all significantly associated with depressive symptoms independent of SES. Each psychosocial factor showed a significant mediating effect on the association between SES and depressive symptoms. This was found for all measures of SES, and for males and females. In particular, personal resources (mastery, self esteem) and chronic stress accounted for a substantial proportion of the variation in depressive symptoms between socioeconomic groups. Social support and recent life events contributed modestly to socioeconomic differences in depressive symptoms, whereas lifetime trauma contributed the least to these inequalities. Conclusion This is the first known study in Vietnam or any developing country to systematically examine the extent to which psychosocial factors mediate the relationship between SES and depression. The study contributes new evidence regarding the burden of depression in Vietnam. The findings have practical relevance for advocacy, for mental health promotion and health-care services, and point to the need for programs that focus on building a sense of personal mastery and self esteem. More broadly, the work presented in this Thesis contributes to the international scientific literature on the social determinants of depression.

A Kallikrein 15 (KLK15) single nucleotide polymorphism located close to a novel exon shows evidence of association with poor ovarian cancer survival

KLK15 over-expression is reported to be a significant predictor of reduced progression-free survival and overall survival in ovarian cancer. Our aim was to analyse the KLK15 gene for putative functional single nucleotide polymorphisms (SNPs) and assess the association of these and KLK15 HapMap tag SNPs with ovarian cancer survival. Results In silico analysis was performed to identify KLK15 regulatory elements and to classify potentially functional SNPs in these regions. After SNP validation and identification by DNA sequencing of ovarian cancer cell lines and aggressive ovarian cancer patients, 9 SNPs were shortlisted and genotyped using the Sequenom iPLEX Mass Array platform in a cohort of Australian ovarian cancer patients (N = 319). In the Australian dataset we observed significantly worse survival for the KLK15 rs266851 SNP in a dominant model (Hazard Ratio (HR) 1.42, 95% CI 1.02-1.96). This association was observed in the same direction in two independent datasets, with a combined HR for the three studies of 1.16 (1.00-1.34). This SNP lies 15bp downstream of a novel exon and is predicted to be involved in mRNA splicing. The mutant allele is also predicted to abrogate an HSF-2 binding site. Conclusions We provide evidence of association for the SNP rs266851 with ovarian cancer survival. Our results provide the impetus for downstream functional assays and additional independent validation studies to assess the role of KLK15 regulatory SNPs and KLK15 isoforms with alternative intracellular functional roles in ovarian cancer survival.

Leg Clubs - Beyond the ulcers : case studies based on participatory action research

Based on Participatory Action Research (PAR), the case studies in this paper examine the psychosocial benefits and outcomes for clients of community based Leg Clubs. The Leg Club model was developed in the United Kingdom (UK) to address the issue of social isolation and non-compliance to leg ulcer treatment. Principles underpinning the Leg Club are based on the Participatory Action Framework (PAR) where the input and involvement of participants is central. This study identifies the strengths of the Leg Club in enabling and empowering people to improve the social context in which they function. In addition it highlights the potential of expanding operations that are normally clinically based (particularly in relation to chronic conditions) but transferable to community settings in order that that they become “agents of change” for addressing such issues as social isolation and the accompanying challenges that these present, including no-compliance to treatment.

Australian journalism studies after ‘Journalism’: breaking down the disciplinary boundaries (for good)

This paper argues that if journalism is to remain a relevant and dynamic academic discipline, it must urgently reconsider the constrained, heavily-policed boundaries traditionally placed around it (particularly in Australia). A simple way of achieving this is to redefine its primary object of study: away from specific, rigid, professional inputs, towards an ever-growing range of media outputs. Such a shift may allow the discipline to freely re-assess its pedagogical and epistemological relationships to contemporary newsmaking practices (or, the ‘new’ news).

Association between ambient ultraviolet radiation and risk of esophageal cancer

OBJECTIVES: Ecological studies have suggested an inverse relationship between latitude and risks of some cancers. However, associations between solar ultraviolet radiation (UVR) exposure and esophageal cancer risk have not been fully explored. We therefore investigated the association between nevi, freckles, and measures of ambient UVR over the life-course with risks of esophageal cancers. METHODS: We compared estimated lifetime residential ambient UVR among Australian patients with esophageal cancer (330 esophageal adenocarcinoma (EAC), 386 esophago-gastric junction adenocarcinoma (EGJAC), and 279 esophageal squamous cell carcinoma (ESCC)), and 1471 population controls. We asked people where they had lived at different periods of their life, and assigned ambient UVR to each location based on measurements from NASA's Total Ozone Mapping Spectrometer database. Freckling and nevus burden were self-reported. We used multivariable logistic regression models to estimate the magnitude of associations between phenotype, ambient UVR, and esophageal cancer risk. RESULTS: Compared with population controls, patients with EAC and EGJAC were less likely to have high levels of estimated cumulative lifetime ambient UVR (EAC odds ratio (OR) 0.59, 95% confidence interval (CI) 0.35-0.99, EGJAC OR 0.55, 0.34-0.90). We found no association between UVR and risk of ESCC (OR 0.91, 0.51-1.64). The associations were independent of age, sex, body mass index, education, state of recruitment, frequency of reflux, smoking status, alcohol consumption, and H. pylori serostatus. Cases with EAC were also significantly less likely to report high levels of nevi than controls. CONCLUSIONS: These data show an inverse association between ambient solar UVR at residential locations and risk of EAC and EGJAC, but not ESCC.

Words and Silences : The journal of the International Oral History Association

Words and Silences is the official on-line journal of the International Oral History Association. It is an internationally peer reviewed, high quality forum for oral historians from a wide range of disciplines and a means for the professional community to share projects and current trends of oral history from around the world. We are extremely pleased to release the first online issue of Word &Silences. This e-journal is the result of long standing discussion and debate about the best way to publish a quality bilingual oral history journal (including a blind peer reviewed section) as a viable solution to mounting difficulties associated with publishing in print. We have discovered that an online version is also not without its challenges and requires tremendous labor intensive dedication. We strongly encourage members to assist us with small review process tasks in the future, so that we can ensure the sustainability of an annual W&S publication for our members and beyond.

Genetic association of the KLK4 locus with risk of prostate cancer

The Kallikrein-related peptidase, KLK4, has been shown to be significantly overexpressed in prostate tumours in numerous studies and is suggested to be a potential biomarker for prostate cancer. KLK4 may also play a role in prostate cancer progression through its involvement in epithelial-mesenchymal transition, a more aggressive phenotype, and metastases to bone. It is well known that genetic variation has the potential to affect gene expression and/or various protein characteristics and hence we sought to investigate the possible role of single nucleotide polymorphisms (SNPs) in the KLK4 gene in prostate cancer. Assessment of 61 SNPs in the KLK4 locus (±10 kb) in approximately 1300 prostate cancer cases and 1300 male controls for associations with prostate cancer risk and/or prostate tumour aggressiveness (Gleason score <7 versus ≥7) revealed 7 SNPs to be associated with a decreased risk of prostate cancer at the Ptrend<0.05 significance level. Three of these SNPs, rs268923, rs56112930 and the HapMap tagSNP rs7248321, are located several kb upstream of KLK4; rs1654551 encodes a non-synonymous serine to alanine substitution at position 22 of the long isoform of the KLK4 protein, and the remaining 3 risk-associated SNPs, rs1701927, rs1090649 and rs806019, are located downstream of KLK4 and are in high linkage disequilibrium with each other (r2≥0.98). Our findings provide suggestive evidence of a role for genetic variation in the KLK4 locus in prostate cancer predisposition.

Multilevel determinants of breast cancer survival : association with geographic remoteness and area-level socioeconomic disadvantage

A major priority for cancer control agencies is to reduce geographical inequalities in cancer outcomes. While the poorer breast cancer survival among socioeconomically disadvantaged women is well established, few studies have looked at the independent contribution that area- and individual-level factors make to breast cancer survival. Here we examine relationships between geographic remoteness, area-level socioeconomic disadvantage and breast cancer survival after adjustment for patients’ socio- demographic characteristics and stage at diagnosis. Multilevel logistic regression and Markov chain Monte Carlo simulation were used to analyze 18 568 breast cancer cases extracted from the Queensland Cancer Registry for women aged 30 to 70 years diagnosed between 1997 and 2006 from 478 Statistical Local Areas in Queensland, Australia. Independent of individual-level factors, area-level disadvantage was associated with breast-cancer survival (p=0.032). Compared to women in the least disadvantaged quintile (Quintile 5), women diagnosed while resident in one of the remaining four quintiles had significantly worse survival (OR 1.23, 1.27, 1.30, 1.37 for Quintiles 4, 3, 2 and 1 respectively).) Geographic remoteness was not related to lower survival after multivariable adjustment. There was no evidence that the impact of area-level disadvantage varied by geographic remoteness. At the individual level, Indigenous status, blue collar occupations and advanced disease were important predictors of poorer survival. A woman’s survival after a diagnosis of breast cancer depends on the socio-economic characteristics of the area where she lives, independently of her individual-level characteristics. It is crucial that the underlying reasons for these inequalities be identified to appropriately target policies, resources and effective intervention strategies.