Medicine (RMH) - Research Publications
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ItemNo Preview AvailableGata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14(AMER SOC MICROBIOLOGY, 2011-11)The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.
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ItemMinimum technical standards and recommendations for traumatic brain injury specialist rehabilitation teams in sudden-onset disasters (for Disaster Rehabilitation Committee special session) (Abstract)(Elsevier BV, 2018-07)Introduction/Background: Sudden-onset disasters (SODs) result in increased number of survivors with complex and long-term disabling injuries, including traumatic brain injury (TBI) that warrants comprehensive specialist rehabilitation. This presentation highlights the minimum technical standards required for specialised TBI rehabilitation teams and their integration into WHO Emergency Medical Teams (EMTs) to facilitate comprehensive management of TBI survivors in disaster settings. Material and method: A team of medical rehabilitation physicians from the Royal Melbourne Hospital conducted a comprehensive review of literature for TBI management, based on the WHO core-guidelines for ‘Minimum technical standards and recommendations for rehabilitation for EMTs’. These were endorsed by a specialist TBI expert panel in the Asia-Pacific region. Results: Comprehensive rehabilitation programs improve functional outcomes and quality of life of TBI survivors. It is recommended that specialised TBI care teams need to be embedded into EMTs for disaster response and management for early diagnosis, management and social reintegration. This guidance documents the minimum standards for deployment of TBI specialist rehabilitation teams in the context of SODs, including: skill requirements, team configuration and profile, professional competencies for management of TBI and complications, list of required equipment and consumables, information management/dissemination. Conclusion: TBI rehabilitation should commence from the early response phase in SODs by accredited rehabilitation professionals to minimise complications and disability. Integration of specialised TBI rehabilitation professionals into EMTs for disaster response will improve functional outcomes of survivors.
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ItemNo Preview AvailableRefugee health update(Medicine Today, 2012-03-01)
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ItemNo Preview AvailablePrevalence and risk factors for symptoms of common mental disorders in early and late pregnancy in Vietnamese women: A prospective population-based study(Elsevier, 2013-04-05)BACKGROUND: Little is known about the prevalence of and risk factors for common mental disorders (CMD) in pregnant women in low-income countries. The aim of this study was to establish the prevalence of and psychosocial risk factors for clinically significant symptoms of CMD in early and late pregnancy in women in rural Viet Nam. METHODS: A population-based sample of women was surveyed in early and late pregnancy. CMD were assessed by the Edinburgh Postnatal Depression Scale-Viet Nam Validation and psychosocial risks by study-specific structured interviews. RESULTS: In total 497/523 (97%) eligible women were recruited and 419 (84%) provided complete data. Prevalence of CMD only in early pregnancy was 22.4% (95% CI 18.4-26.4); only in late pregnancy was 10.7% (95% CI 7.8-13.7) and at both assessment waves was 17.4% (95% CI 13.8-21.1). Non-economic and economic coincidental life adversity, intimate partner violence, past pregnancy loss, and childhood abuse were positively associated with persistent antenatal CMD. Older age, having a preference for the baby's sex, and nulli- or primiparity were risk factors for CMD in early pregnancy. CONCLUSIONS: Persistent antenatal CMD are prevalent in rural areas of Viet Nam. Psychosocial risk factors play a major role in this significant public health problem.
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ItemNo Preview AvailableImprovements in patient care: videoconferencing to improve access to interpreters during clinical consultations for refugee and immigrant patients(CSIRO Publishing, 2015)OBJECTIVE: To demonstrate the suitability of accessing interpreters via videoconference for medical consultations and to assess doctor and patient perceptions of this compared with either on-site or telephone interpreting. METHODS: We assessed the suitability and acceptability of accessing interpreters via videoconference during out-patient clinical consultations in two situations: (i) when the doctor and patient were in a consulting room at a central hospital and the interpreter sat remotely; and (ii) when the doctor, patient and interpreter were each at separate sites (during a telehealth consultation). The main outcome measures were patient and doctor satisfaction, number of problems recorded and acceptability compared with other methods for accessing an interpreter. RESULTS: Ninety-eight per cent of patients were satisfied overall with the use of an interpreter by video. When comparing videoconference interpreting with telephone interpreting, 82% of patients thought having an interpreter via video was better or much better, 15% thought it was the same and 3% considered it worse. Compared with on-site interpreting, 16% found videoconferencing better or much better, 58% considered it the same and 24% considered it worse or much worse. CONCLUSIONS: The present study has demonstrated that accessing an interpreter via videoconference is well accepted and preferred to telephone interpreting by both doctors and patients.
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ItemAnionic Phospholipid Interactions of the Prion Protein N Terminus Are Minimally Perturbing and Not Driven Solely by the Octapeptide Repeat Domain(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2010-10-15)Although the N terminus of the prion protein (PrP(C)) has been shown to directly associate with lipid membranes, the precise determinants, biophysical basis, and functional implications of such binding, particularly in relation to endogenously occurring fragments, are unresolved. To better understand these issues, we studied a range of synthetic peptides: specifically those equating to the N1 (residues 23-110) and N2 (23-89) fragments derived from constitutive processing of PrP(C) and including those representing arbitrarily defined component domains of the N terminus of mouse prion protein. Utilizing more physiologically relevant large unilamellar vesicles, fluorescence studies at synaptosomal pH (7.4) showed absent binding of all peptides to lipids containing the zwitterionic headgroup phosphatidylcholine and mixtures containing the anionic headgroups phosphatidylglycerol or phosphatidylserine. At pH 5, typical of early endosomes, quartz crystal microbalance with dissipation showed the highest affinity binding occurred with N1 and N2, selective for anionic lipid species. Of particular note, the absence of binding by individual peptides representing component domains underscored the importance of the combination of the octapeptide repeat and the N-terminal polybasic regions for effective membrane interaction. In addition, using quartz crystal microbalance with dissipation and solid-state NMR, we characterized for the first time that both N1 and N2 deeply insert into the lipid bilayer with minimal disruption. Potential functional implications related to cellular stress responses are discussed.
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ItemGlutamate weighted imaging contrast in gliomas with 7 Tesla magnetic resonance imaging(ELSEVIER SCI LTD, 2019)INTRODUCTION: Diffuse gliomas are incurable malignancies, which undergo inevitable progression and are associated with seizure in 50-90% of cases. Glutamate has the potential to be an important glioma biomarker of survival and local epileptogenicity if it can be accurately quantified noninvasively. METHODS: We applied the glutamate-weighted imaging method GluCEST (glutamate chemical exchange saturation transfer) and single voxel MRS (magnetic resonance spectroscopy) at 7 Telsa (7 T) to patients with gliomas. GluCEST contrast and MRS metabolite concentrations were quantified within the tumour region and peritumoural rim. Clinical variables of tumour aggressiveness (prior adjuvant therapy and previous radiological progression) and epilepsy (any prior seizures, seizure in last month and drug refractory epilepsy) were correlated with respective glutamate concentrations. Images were separated into post-hoc determined patterns and clinical variables were compared across patterns. RESULTS: Ten adult patients with a histo-molecular (n = 9) or radiological (n = 1) diagnosis of grade II-III diffuse glioma were recruited, 40.3 +/- 12.3 years. Increased tumour GluCEST contrast was associated with prior adjuvant therapy (p = .001), and increased peritumoural GluCEST contrast was associated with both recent seizures (p = .038) and drug refractory epilepsy (p = .029). We distinguished two unique GluCEST contrast patterns with distinct clinical and radiological features. MRS glutamate correlated with GluCEST contrast within the peritumoural voxel (R = 0.89, p = .003) and a positive trend existed in the tumour voxel (R = 0.65, p = .113). CONCLUSION: This study supports the role of glutamate in diffuse glioma biology. It further implicates elevated peritumoural glutamate in epileptogenesis and altered tumour glutamate homeostasis in glioma aggressiveness. Given the ability to non-invasively visualise and quantify glutamate, our findings raise the prospect of 7 T GluCEST selecting patients for individualised therapies directed at the glutamate pathway. Larger studies with prospective follow-up are required.
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ItemA genome-wide association study of corneal astigmatism: The CREAM Consortium(MOLECULAR VISION, 2018-02-05)PURPOSE: To identify genes and genetic markers associated with corneal astigmatism. METHODS: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. RESULTS: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). CONCLUSIONS: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.
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ItemBody Mass Index and Vascular Disease in Men Aged 65 Years and Over: HIMS (Health In Men Study)(WILEY, 2017-12)BACKGROUND: Understanding the relationship between body mass index (BMI) and vascular disease at older age has become increasingly important in the many countries where both average age and BMI are rising. METHODS AND RESULTS: In this prospective cohort study, 12 203 men (aged ≥65) were recruited in 1996-1999 from the general population in Perth, Australia. To limit reverse causality, analyses excluded those with past vascular disease and the first 4 years of follow-up. During a further 8 (SD3) years of follow-up, there were 1136 first-ever major vascular events (nonfatal myocardial infarction, nonfatal stroke, or death from any vascular cause). Cox regression (adjusted for age, education, and smoking) related BMI at recruitment to incidence of major vascular events. At ages 65 to 94, the lowest risk of major vascular events was at ≈ 22.5 to 25 kg/m2. In the higher BMI range (≥25 kg/m2), 5 kg/m2 higher BMI was associated with 33% higher risk of major vascular events (hazard ratio, 1.33 [95% confidence interval, 1.18-1.49]): 24% higher risk of ischemic heart disease (1.24 [1.06-1.46]); 34% higher risk of stroke (1.34 [1.11-1.63]); and 78% higher risk of other vascular death (1.78 [1.32-2.41]). In the lower BMI range, there were fewer events and no strong evidence of an association (hazard ratio per 5 kg/m2 higher BMI, 0.82 [95% confidence interval, 0.61-1.12]). CONCLUSIONS: In this population of older men, risk of major vascular events was lowest at ≈ 22.5 to 25 kg/m2. Above this range, BMI was strongly related to incidence of major vascular events, with each 5 kg/m2 higher BMI associated with ≈30% higher risk.