Medicine (Western Health) - Research Publications
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ItemNo Preview AvailableTargeting transcription factors for therapeutic benefit in rheumatoid arthritis.(Frontiers Media SA, 2023)Rheumatoid arthritis (RA) is a destructive inflammatory autoimmune disease that causes pain and disability. Many of the currently available drugs for treating RA patients are aimed at halting the progression of the disease and alleviating inflammation. Further, some of these treatment options have drawbacks, including disease recurrence and adverse effects due to long-term use. These inefficiencies have created a need for a different approach to treating RA. Recently, the focus has shifted to direct targeting of transcription factors (TFs), as they play a vital role in the pathogenesis of RA, activating key cytokines, chemokines, adhesion molecules, and enzymes. In light of this, synthetic drugs and natural compounds are being explored to target key TFs or their signaling pathways in RA. This review discusses the role of four key TFs in inflammation, namely NF-κB, STATs, AP-1 and IRFs, and their potential for being targeted to treat RA.
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ItemNo Preview AvailablePostpartum uptake of diabetes screening tests in women with gestational diabetes: The PANDORA study(WILEY, 2023-03)AIMS: To determine rates and predictors of postpartum diabetes screening among Aboriginal and/or Torres Strait Islander and non-Indigenous women with gestational diabetes mellitus (GDM). METHODS: PANDORA is a prospective longitudinal cohort of women recruited in pregnancy. Postpartum diabetes screening rates at 12 weeks (75-g oral glucose tolerance test (OGTT)) and 6, 12 and 18 months (OGTT, glycated haemoglobin [HbA1C ] or fasting plasma glucose) were assessed for women with GDM (n = 712). Associations between antenatal factors and screening with any test (OGTT, HbA1C , fasting plasma glucose) by 6 months postpartum were examined using Cox proportional hazards regression. RESULTS: Postpartum screening rates with an OGTT by 12 weeks and 6 months postpartum were lower among Aboriginal and/or Torres Strait Islander women than non-Indigenous women (18% vs. 30% at 12 weeks, and 23% vs. 37% at 6 months, p < 0.001). Aboriginal and/or Torres Strait Islander women were more likely to have completed a 6-month HbA1C compared to non-Indigenous women (16% vs. 2%, p < 0.001). Screening by 6 months postpartum with any test was 41% for Aboriginal and/or Torres Strait Islander women and 45% for non-Indigenous women (p = 0.304). Characteristics associated with higher screening rates with any test by 6 months postpartum included, insulin use in pregnancy, first pregnancy, not smoking and lower BMI. CONCLUSIONS: Given very high rates of type 2 diabetes among Aboriginal and Torres Strait Islander women, early postpartum screening with the most feasible test should be prioritised to detect prediabetes and diabetes for intervention.
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ItemNo Preview AvailableMultiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer(NATURE PORTFOLIO, 2023-03)High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.
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ItemNo Preview AvailableDetecting the vitamin D receptor (VDR) protein in mouse and human skeletal muscle: Strain-specific, species-specific and inter-individual variation(ELSEVIER IRELAND LTD, 2023-12-01)Vitamin D, and its receptor (VDR), play roles in muscle development/function, however, VDR detection in muscle has been controversial. Using different sample preparation methods and antibodies, we examined differences in muscle VDR protein abundance between two mouse strains and between mice and humans. The mouse D-6 VDR antibody was not reliable for detecting VDR in mouse muscle, but was suitable for human muscle, while the rabbit D2K6W antibody was valid for mouse and human muscle. VDR protein was generally lower in muscles from C57 B l/6 than FVB/N mice and was higher in human than mouse muscle. Two putative VDR bands were detected in human muscle, possibly representing VDR isoforms/splice variants, with marked inter-individual differences. This study provides new information on detecting VDR in muscle and on inter-mouse strain and inter-human individual differences in VDR expression. These findings may have implications for future pre-clinical and clinical studies and prompt further investigation to confirm possible VDR isoforms in human muscle.
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ItemNo Preview AvailableAssociations Between Aldosterone-Renin-Ratio and Bone Parameters Derived from Peripheral Quantitative Computed Tomography and Impact Microindentation in Men.(Springer Science and Business Media LLC, 2023-11)Components of the renin-angiotensin-aldosterone system (RAAS) are present on bone cells. One measure of RAAS activity, the aldosterone-renin-ratio (ARR), is used to screen for primary aldosteronism. Associations between ARR and bone mineral density are conflicting. This study investigated associations between ARR and peripheral quantitative computed tomography (pQCT) and impact microindentation (IMI). Male participants (n = 431) were from the Geelong Osteoporosis Study. "Likely" primary aldosteronism was defined as ARR ≥ 70 pmol/mIU. Another group, "possible" primary aldosteronism, was defined as either ARR ≥ 70 pmol/mIU or taking a medication that affects the RAAS, but not a beta blocker, and renin < 15 mU/L. Using pQCT, images at 4% and 66% of radial (n = 365) and tibial (n = 356) length were obtained. Using IMI measurements, bone material strength index (BMSi; n = 332) was determined. Associations between ARR or likely/possible primary aldosteronism and IMI or pQCT-derived bone parameters were tested using median regression. ARR and aldosterone values were not associated with any of the pQCT-derived bone variables in either unadjusted or adjusted analyses. Men with likely primary aldosteronism (n = 16), had lower adjusted total bone area (radial 66% site, - 12.5%). No associations were observed for men with possible primary aldosteronism (unadjusted or adjusted). No associations with BMSi were observed (p > 0.05). There were no associations between ARR or aldosterone and pQCT-derived bone parameters. Men with likely primary aldosteronism had lower bone area, suggesting clinically high levels of ARR may have a negative impact on bone health.
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ItemNo Preview AvailableFood provision in Australian aged care homes does not meet protein needs of residents: A call for reform(WILEY, 2023-10-30)AIM: Malnutrition is common in older adults in aged care homes, partly due to inadequate protein intake. Menu planning guidelines are available however, adherence to guidelines is unknown. This study aimed to determine; (i) what are the average serving sizes of menu items provided and do they meet recommended portion sizes? (ii) does consumption from a 'typical' menu provide sufficient protein? and (iii) can substituting a 'typical' menu with high-protein options enable residents to achieve protein adequacy? METHODS: This study involved 572 residents (73% female; aged 86.4 ± 7.3 years) from 60 aged-care homes in Australia involved in a 2-year cluster-randomised trial. During the trial, food intake was recorded quarterly using visual estimation of plate-waste and 42 061 foods analysed. As part of a secondary analysis of these data, portion sizes of foods were compared to guidelines by calculating the mean (95% confidence interval). Items were deemed inadequate if the upper 95% confidence interval remained below recommended portion sizes. RESULTS: On average 47% of breakfast and 80% of lunch/dinner items were below recommended portion sizes. Relative protein intakes, from a typical menu (most consumed foods), was 0.9 g and 0.8 g/kg body weight/day for females and males; both below recommendations. Substituting regular items with higher protein equivalents increased protein intake to 1.3 g and 1.2 g/kg body weight/day, for females and males, respectively. CONCLUSION: Aged care homes in Australia are not meeting menu planning guidelines resulting in insufficient protein being provided. Reform to menu guidelines including provision of high-protein foods, will ensure protein adequacy in older adults in aged-care homes.
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ItemNo Preview AvailableExploring new balance and gait factors that are associated with osteosarcopenia in patients with a previous fall and/or fracture history.(Elsevier BV, 2023-10-06)Osteosarcopenic individuals have poor muscle function and increased bone fragility, which results in a severe detriment to health outcomes. Hence, there is a necessity to discover easily accessible factors associated with osteosarcopenia to develop timely interventions. This study aimed to determine new sensitive balance and/or gait variables that are associated with osteosarcopenia in a population of older people with a history of falls and/or fractures. In a cross-sectional cohort study, 306 men and women aged ≥65 years completed a series of questionnaires, clinical assessments and muscle strength and function tests. Subsequently, participants were separated into osteopenia, osteoporosis and osteosarcopenia, groups for comparison and further analysis. Osteosarcopenia performed worse than osteopenia and osteoporosis in grip strength, gait speed, physical function scores and in multiple gait and balance indices (p<0.001). During posturography testing, there were larger elliptical areas with eyes open (p = 0.003), and eyes closed (p = 0.043) and increased sway velocity on a firm platform (p = 0.007) in the osteosarcopenia group, compared to osteoporosis. Limits of stability and eyes open ellipse area significantly contributed to the multivariable model (p = 0.029 and p = 0.038, respectively), suggesting that these balance parameters, along with grip strength, may be useful in identifying older adults with osteosarcopenia from those with only osteopenia/osteoporosis. Older adults with osteosarcopenia and a history of falls and/or fractures demonstrated inferior strength, function, and gait characteristics. This study identified indices of balance that were sensitive discriminators for osteosarcopenia and could be easily implemented into routine assessment.
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ItemNo Preview AvailableCirculating lipocalin-2 and features of metabolic syndrome in community-dwelling older women: A cross-sectional study.(Elsevier BV, 2023-11)Lipocalin-2 (LCN2) is released by several cell types including osteoblasts and adipocytes and has been suggested as a marker of renal dysfunction, metabolic syndrome (MetS) and type 2 diabetes (T2D). Whether LCN2 is linked to these diseases in older women remains unknown. This study investigated whether LCN2 is related to features of MetS and T2D in older women. This cross-sectional study included 705 non-diabetic women (mean age 75.1 ± 2.6 years) for MetS analysis and 76 women (mean age 75.4 ± 2.8 years) with T2D. Total circulating LCN2 levels were analysed using a two-step chemiluminescent microparticle monoclonal immunoassay. MetS was determined by a modified National Cholesterol Education Program Adult Treatment Panel III classification. Multivariable-adjusted logistic regression analysis was used to assess odds ratios between LCN2 quartiles and MetS. Women in the highest LCN2 quartile had approximately 3 times greater risk for MetS compared to women in the lowest quartile (OR 3.05; 95%CI 1.86-5.02). Women with T2D or MetS scores of ≥ 3 had higher LCN2 levels compared to women with a MetS score of 0 (p < 0.05). Higher LCN2 correlated with higher body mass index, fat mass, triglycerides and glycated haemoglobin and lower high-density lipoprotein cholesterol and estimated glomerular filtration rate (p < 0.05). Higher circulating levels of LCN2 are associated with worsened cardio-metabolic risk factors and increased odds of MetS and T2D in older women. Whether it can be used as a biomarker for identifying those at risk for MetS and T2D should be explored further.
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ItemUndercarboxylated osteocalcin and ibandronate combination ameliorates hindlimb immobilization-induced muscle wasting(WILEY, 2023-04-11)Immobilization leads to muscle wasting and insulin resistance, particularly during ageing. It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism. Bisphosphonates, an anti-osteoporosis treatment, might protect muscle wasting independent of ucOC. We hypothesize that the combination of ucOC and ibandronate (IBN) treatments has superior protective effects against immobilization-induced muscle wasting and insulin resistance than either treatment alone. C57BL/6J mice were hindlimb-immobilized for two weeks, with injections of vehicle, ucOC (90 ng/g daily) and/or IBN (2 μg/g weekly). Insulin/oral glucose tolerance tests (ITT/OGTT) were performed. Immediately after immobilization, muscles (extensor digitorum longus (EDL), soleus, tibialis anterior, gastrocnemius and quadriceps) were isolated and measured for muscle mass. Insulin-stimulated glucose uptake (EDL and soleus) was examined. Phosphorylation/expression of proteins in anabolic/catabolic pathways were examined in quadriceps. Primary human myotubes derived from older adult muscle biopsies were treated with ucOC and/or IBN, then signalling proteins were analysed. Combined treatment, but not individual treatments, significantly increased the muscle weight/body weight ratio in immobilized soleus (31.7%; P = 0.013) and quadriceps (20.0%; P = 0.0008) muscles, concomitant with elevated p-Akt (S473)/Akt ratio (P = 0.0047). Combined treatment also enhanced whole-body glucose tolerance (16.6%; P = 0.0011). In human myotubes, combined treatment stimulated greater activation of ERK1/2 (P = 0.0067 and 0.0072) and mTOR (P = 0.036), and led to a lesser expression of Fbx32 (P = 0.049) and MuRF1 (P = 0.048) than individual treatments. These findings suggest a potential therapeutic role for the ucOC and bisphosphonates combination in protecting against muscle wasting induced by immobilization and ageing. KEY POINTS: It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism. Bisphosphonates, an anti-osteoporosis treatment, might protect against muscle wasting independent of ucOC. The combination treatment of ucOC and ibandronate was shown to exert a greater therapeutic effect against immobilization-induced muscle wasting, and led to greater activation of anabolic pathway and less expression of catabolic signalling proteins in myotubes derived from older adults, compared with individual treatments. The combination treatment was found to improve whole-body glucose tolerance. Our findings suggest a potential therapeutic role for the ucOC and bisphosphonates combination in protecting against muscle wasting induced by immobilization and ageing.
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ItemImpact of subclinical hypothyroidism on health-related quality of life: a narrative review(WILEY, 2021-09-01)A biochemical diagnosis of subclinical hypothyroidism (SCH) is defined by an elevated serum thyroid-stimulating hormone (TSH) with a normal serum free thyroxine (FT4). This paper discusses SCH in the Australian population, the impact of SCH on health-related quality of life (HRQoL), and the evidence for thyroid hormone therapy as well as exercise therapy to improve HRQoL in SCH. The prevalence of SCH in Australia is approximately 4-5% and is higher in females and the elderly. Current evidence suggests thyroid hormone therapy is not associated with an improvement in HRQoL. However, there does appear to be a subgroup of those with SCH that experience an impairment in HRQoL who may potentially benefit from treatment. Because the majority of research to date has been done in elderly, largely asymptomatic individuals, this may not be representative of the entire SCH population. In addition, alternative treatments, such as exercise therapy, have not been well explored in the literature, despite exercise therapy's effects on HRQoL in other populations. Further research is required to define clearly which individuals with SCH are likely to experience an impaired HRQoL, as well as explore the effects of thyroid hormone therapy and exercise therapy in these individuals.