Medicine (Northwest Academic Centre) - Research Publications

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    Socioeconomic status and quality of life in population-based Australian men: data from the Geelong Osteoporosis Study
    Brennan, SL ; Williams, LJ ; Berk, M ; Pasco, JA (WILEY, 2013-06-01)
    OBJECTIVE: To investigate the relationship between socioeconomic status (SES) and reported perceptions of quality of life (QOL) in a cross-sectional population-based analysis of a representative sample of Australian men. METHODS: In 917 randomly recruited men aged 24-92 years, we measured QoL in the domains of physical health, psychological health, environment and social relationships, using the Australian World Health Organization Quality of Life Instrument (WHOQOL-BREF). Residential addresses were cross-referenced with Australian Bureau of Statistics 2006 census data to ascertain SES. Participants were categorised into lower, mid, or upper SES based on the Index of Relative Socioeconomic Disadvantage and Advantage (IRSAD), the Index of Economic Resources (IER), and the Index of Education and Occupation (IEO). Lifestyle and health information was self-reported. RESULTS: Males of lower SES reported poorer satisfaction with physical health (OR=0.6, 95%CI 0.4-0.9, p=0.02), psychological health (OR=0.4, 95%CI 0.3-0.7, p<0.001) and environment (OR=0.5, 95%CI 0.3-0.7, p<0.001), although not social relationships (p=0.59). The poorest QOL for each domain was observed in the lower and upper SES groups, representing an inverse U-shaped pattern of association; however, statistical significance was only observed for psychological health (OR=0.5, 95%CI 0.4-0.7, p<0.001). These relationships were similar for IEO and IER. CONCLUSIONS: Men from lower and upper SES groups have lower QOL compared to their counterparts in the mid SES group.
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    The Role of Cancer-Testis Antigens as Predictive and Prognostic Markers in Non-Small Cell Lung Cancer
    John, T ; Starmans, MHW ; Chen, Y-T ; Russell, PA ; Barnett, SA ; White, SC ; Mitchell, PL ; Walkiewicz, M ; Azad, A ; Lambin, P ; Tsao, M-S ; Deb, S ; Altorki, N ; Wright, G ; Knight, S ; Boutros, PC ; Cebon, JS ; Cho, WCS (PUBLIC LIBRARY SCIENCE, 2013-07-23)
    BACKGROUND: Cancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival. METHODS: We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post-operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs. RESULTS: NY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28-5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07-0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression. CONCLUSIONS: NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.
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    Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin
    Moore, EM ; Mander, AG ; Ames, D ; Kotowicz, MA ; Carne, RP ; Brodaty, H ; Woodward, M ; Boundy, K ; Ellis, KA ; Bush, AI ; Faux, NG ; Martins, R ; Szoeke, C ; Rowe, C ; Watters, DA (AMER DIABETES ASSOC, 2013-10-01)
    OBJECTIVE: To investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes. RESEARCH DESIGN AND METHODS: Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n=480) or mild cognitive impairment (n=187) and those who were cognitively intact (n=687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n=104) or impaired glucose tolerance (n=22). RESULTS: Participants with diabetes (n=126) had worse cognitive performance than participants who did not have diabetes (n=1,228; adjusted odds ratio 1.51 [95% CI 1.03-2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05-4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19-0.92]). CONCLUSIONS: Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin.
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    Early prosthetic hip joint infection treated with debridement, prosthesis retention and biofilm-active antibiotics: functional outcomes, quality of life and complications
    Aboltins, C ; Dowsey, MM ; Peel, T ; Lim, WK ; Parikh, S ; Stanley, P ; Choong, PF (WILEY, 2013-07-01)
    BACKGROUND: Patients treated for early prosthetic joint infection (PJI) with surgical debridement, prosthesis retention and biofilm-active antibiotics, such as rifampicin or fluoroquinolones have a rate of successful infection eradication that is similar to patients treated with the traditional approach of prosthesis exchange. It is therefore important to consider other outcomes after PJI treatment that may influence management decisions, such as function, quality of life (QOL) and treatment-associated complications. AIMS: To describe rates of successful treatment for patients with PJI undergoing surgical debridement, prosthesis retention and biofilm-active antibiotics and compare their functional outcomes, QOL and complication rates to patients without PJI. METHODS: Nineteen patients treated for PJI after hip arthroplasty with debridement, prosthesis retention and biofilm-active antibiotics were matched to 76 controls who underwent hip arthroplasty with no infection. RESULTS: Cumulative survival free from treatment failure at 2 years was 88% (95% confidence interval, 59-97%). PJI cases had significant improvement from pre-arthroplasty to 12-months post-arthroplasty in function according to Harris Hip Score and QOL according to the 12-item Short Form Health Survey Physical Component Summary. There was no significant difference in the improvement between controls and cases. PJI was not a risk factor for poor function or QOL. Medical complications occurred more frequently in cases (6/19 (32%)) than controls (9/76 (12%); P = 0.04), with this difference being accounted for by drug reactions. Surgical complications were the same in the two groups. CONCLUSIONS: Treatment of PJI with debridement, prosthesis retention and biofilm-active antibiotics is successful, well tolerated and results in significant improvements in function and QOL, which are similar to patients without PJI.
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    Sex-differences in reasons for non-participation at recruitment: Geelong Osteoporosis Study.
    Markanday, S ; Brennan, SL ; Gould, H ; Pasco, JA (Springer Science and Business Media LLC, 2013-03-18)
    BACKGROUND: Understanding reasons for non-participation in health studies can help guide recruitment strategies and inform researchers about potential sources of bias in their study sample. Whilst there is a paucity of literature regarding this issue, it remains highly plausible that men and women may have varied reasons for declining an invitation to participate in research. We aimed to investigate sex-differences in the reasons for non-participation at baseline of the Geelong Osteoporosis Study (GOS). METHODS: The GOS, a prospective cohort study, randomly recruited men and women aged 20 years and over from a region in south-eastern Australia using Commonwealth electoral rolls (2001-06 and 1993-97, respectively). Reasons for non-participation (n=1,200) were documented during the two recruitment periods. We used the Pearson's chi squared test to explore differences in the reasons for non-participation between men and women. RESULTS: Non-participation in the male cohort was greater than in the female cohort (32.9% vs. 22.9%; p<0.001). Overall, there were sex-differences in the reasons provided for non-participation (p<0.001); apparent differences related to time constraints (men 26.3% vs. women 10.4%), frailty/inability to cope with or understand the study (men 18.7% vs. women 30.6%), and reluctance over medical testing (men 1.1% vs women 9.9%). No sex-differences were observed for non-participation related to personal reason/disinterest, and language- or travel-related reasons. CONCLUSIONS: Improving participation rates in epidemiological studies may require different recruitment strategies for men and women in order to address sex-specific concerns about participating in research.
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    Identification of Molecular Subtypes of Gastric Cancer With Different Responses to PI3-Kinase Inhibitors and 5-Fluorouracil
    Lei, Z ; Tan, IB ; Das, K ; Deng, N ; Zouridis, H ; Pattison, S ; Chua, C ; Feng, Z ; Guan, YK ; Ooi, CH ; Ivanova, T ; Zhang, S ; Lee, M ; Wu, J ; Ngo, A ; Manesh, S ; Tan, E ; Teh, BT ; So, JBY ; Goh, LK ; Boussioutas, A ; Lim, TKH ; Flotow, H ; Tan, P ; Rozen, SG (W B SAUNDERS CO-ELSEVIER INC, 2013-09-01)
    BACKGROUND & AIMS: Almost all gastric cancers are adenocarcinomas, which have considerable heterogeneity among patients. We sought to identify subtypes of gastric adenocarcinomas with particular biological properties and responses to chemotherapy and targeted agents. METHODS: We compared gene expression patterns among 248 gastric tumors; using a robust method of unsupervised clustering, consensus hierarchical clustering with iterative feature selection, we identified 3 major subtypes. We developed a classifier for these subtypes and validated it in 70 tumors from a different population. We identified distinct genomic and epigenomic properties of the subtypes. We determined drug sensitivities of the subtypes in primary tumors using clinical survival data, and in cell lines through high-throughput drug screening. RESULTS: We identified 3 subtypes of gastric adenocarcinoma: proliferative, metabolic, and mesenchymal. Tumors of the proliferative subtype had high levels of genomic instability, TP53 mutations, and DNA hypomethylation. Cancer cells of the metabolic subtype were more sensitive to 5-fluorouracil than the other subtypes. Furthermore, in 2 independent groups of patients, those with tumors of the metabolic subtype appeared to have greater benefits with 5-fluorouracil treatment. Tumors of the mesenchymal subtype contain cells with features of cancer stem cells, and cell lines of this subtype are particularly sensitive to phosphatidylinositol 3-kinase-AKT-mTOR inhibitors in vitro. CONCLUSIONS: Based on gene expression patterns, we classified gastric cancers into 3 subtypes, and validated these in an independent set of tumors. The subgroups have differences in molecular and genetic features and response to therapy; this information might be used to select specific treatment approaches for patients with gastric cancer.
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    Immunogenicity and Immunomodulatory Properties of Hepatocyte-like Cells Derived from Human Amniotic Epithelial Cells
    Tee, JY ; Vaghjiani, V ; Liu, YH ; Murthi, P ; Chan, J ; Manuelpillai, U (BENTHAM SCIENCE PUBL LTD, 2013-01-01)
    Hepatocyte transplantation is being trialled as an alternative to whole organ transplant for patients with acute liver failure and liver specific metabolic diseases. Due to the scarcity of human hepatocytes, hepatocyte-like cells (HLC) generated from stem cells may become a viable alternative to hepatocyte transplantation. Human amniotic epithelial cells (hAEC) from the placenta have stem cell-like properties and can be differentiated into HLC. Naïve hAEC have low immunogenicity and exert immunomodulatory effects that may facilitate allogeneic transplantation. However, whether the immunogenicity and immunomodulatory properties alter with differentiation into HLC are unknown. We further characterized HLC generated from hAEC, examined changes in human leucocyte antigens (HLA) and co-stimulatory molecules and effects exerted by the HLC on human peripheral blood mononuclear cells (PBMC). HLC derived from hAEC expressed proteins found in hepatocytes, had CYP3A4 drug metabolizing enzyme activity and secreted urea. IFN-γ treatment increased HLA Class IA, Class II and co-stimulatory molecule CD40 expression in the HLC. IFN-γ treated HLC stimulated proliferation of PBMC in one-way mixed lymphocyte reactions and were more immunogenic than undifferentiated hAEC. However, the HLC showed immunomodulatory properties and inhibited mitogen induced PBMC proliferation in vitro. PBMC proliferation may have been inhibited by IL-6, TGF-β1, PGE2 and HLA-G secreted by the HLC. The retention of immunomodulatory properties may enable HLC grafts to survive for longer periods despite the immunogenicity of the HLC.
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    Homeobox genes and down-stream transcription factor PPAR gamma in normal and pathological human placental development
    Murthi, P ; Kalionis, B ; Cocquebert, M ; Rajaraman, G ; Chui, A ; Keogh, RJ ; Evain-Brion, D ; Fournier, T (W B SAUNDERS CO LTD, 2013-04-01)
    The placenta provides critical transport functions between the maternal and fetal circulations during intrauterine development. Formation of this interface is controlled by nuclear transcription factors including homeobox genes. Here we summarize current knowledge regarding the expression and function of homeobox genes in the placenta. We also describe the identification of target transcription factors including PPARγ, biological pathways regulated by homeobox genes and their role in placental development. The role of the nuclear receptor PPARγ, ligands and target genes in human placental development is also discussed. A better understanding of these pathways will improve our knowledge of placental cell biology and has the potential to reveal new molecular targets for the early detection and diagnosis of pregnancy complications including human fetal growth restriction.
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    Physical comorbidities in men with mood and anxiety disorders: a population-based study
    Sanna, L ; Stuart, AL ; Pasco, JA ; Kotowicz, MA ; Berk, M ; Girardi, P ; Brennan, SL ; Williams, LJ (BMC, 2013-04-24)
    BACKGROUND: The mind-body nexus has been a topic of growing interest. Further data are however required to understand the specific relationship between mood and anxiety disorders and individual physical health conditions, and to verify whether these psychiatric disorders are linked to overall medical burden. METHODS: This study examined data collected from 942 men, 20 to 97 years old, participating in the Geelong Osteoporosis Study. A lifetime history of mood and anxiety disorders was identified using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP). The presence of medical conditions (lifetime) was self-reported and confirmed by medical records, medication use or clinical data. Anthropometric measurements and socioeconomic status (SES) were determined and information on medication use and lifestyle was obtained via questionnaire. Logistic regression models were used to test the associations. RESULTS: After adjustment for age, socioeconomic status, and health risk factors (body mass index, physical activity and smoking), mood disorders were associated with gastro oesophageal reflux disease (GORD), recurrent headaches, blackouts and/or epilepsy, liver disorders and pulmonary disease in older people, whilst anxiety disorders were significantly associated with thyroid, GORD and other gastrointestinal disorders, and psoriasis. Increased odds of high medical burden were associated with both mood and anxiety disorders. CONCLUSIONS: Our study provides further population-based evidence supporting the link between mental and physical illness in men. Understanding these associations is not only necessary for individual management, but also to inform the delivery of health promotion messages and health care.
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    The association between fruit and vegetable consumption and mental health disorders: Evidence from five waves of a national survey of Canadians
    McMartin, SE ; Jacka, FN ; Colman, I (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2013-03-01)
    OBJECTIVE: The objective of this study was to examine the association between fruit and vegetable intake (FVI) and mental health disorders. METHOD: This study used data from the Canadian Community Health Survey (CCHS), a repeated cross-sectional study of Canadians with five waves between 2000 until 2009 (n=296,121 aged 12 years or older). FVI was assessed based on frequency of consumption. The primary outcome was a major depressive episode over the previous 12 months. Logistic regression models adjusted for age, gender, household income, education, physical activity, chronic illness and smoking. RESULTS: In the first wave, greater FVI was significantly associated with lower odds of depression (OR: 0.85 95% CI:0.78-0.92). A combined estimate of all 5 waves demonstrated similar results (OR: 0.72; 95% CI: 0.71-0.75). Relative to those with the lowest FVI, those with the greatest FVI also had significantly lower odds of suffering from distress (OR: 0.87 95% CI: 0.78-0.98). These results were consistent across other waves. Perceived poor mental health status and previous diagnosis of a mood disorder and anxiety disorder also demonstrated statistically significant inverse associations with FVI (all p<0.05). CONCLUSION: These findings suggest a potentially important role of a healthy diet in the prevention of depression and anxiety.