Medicine (Northwest Academic Centre) - Research Publications
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ItemNo Preview AvailableDischarge Patterns of Human Tensor Palatini Motor Units during Sleep Onset(OXFORD UNIV PRESS INC, 2012-05-01)STUDY OBJECTIVES: Upper airway muscles such as genioglossus (GG) and tensor palatini (TP) reduce activity at sleep onset. In GG reduced muscle activity is primarily due to inspiratory modulated motor units becoming silent, suggesting reduced respiratory pattern generator (RPG) output. However, unlike GG, TP shows minimal respiratory modulation and presumably has few inspiratory modulated motor units and minimal input from the RPG. Thus, we investigated the mechanism by which TP reduces activity at sleep onset. DESIGN: The activity of TP motor units were studied during relaxed wakefulness and over the transition from wakefulness to sleep. SETTING: Sleep laboratory. PARTICIPANTS: Nine young (21.4 ± 3.4 years) males were studied on a total of 11 nights. INTERVENTION: Sleep onset. MEASUREMENTS AND RESULTS: Two TP EMGs (thin, hooked wire electrodes), and sleep and respiratory measures were recorded. One hundred twenty-one sleep onsets were identified (13.4 ± 7.2/subject), resulting in 128 motor units (14.3 ± 13.0/subject); 29% of units were tonic, 43% inspiratory modulated (inspiratory phasic 18%, inspiratory tonic 25%), and 28% expiratory modulated (expiratory phasic 21%, expiratory tonic 7%). There was a reduction in both expiratory and inspiratory modulated units, but not tonic units, at sleep onset. Reduced TP activity was almost entirely due to de-recruitment. CONCLUSIONS: TP showed a similar distribution of motor units as other airway muscles. However, a greater proportion of expiratory modulated motor units were active in TP and these expiratory units, along with inspiratory units, tended to become silent over sleep onset. The data suggest that both expiratory and inspiratory drive components from the RPG are reduced at sleep onset in TP.
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ItemPrevention of type 2 diabetes by lifestyle intervention in an Australian primary health care setting: Greater green triangle (GGT) diabetes prevention project(BMC, 2007-09-19)BACKGROUND: Randomised controlled trials demonstrate a 60% reduction in type 2 diabetes incidence through lifestyle modification programmes. The aim of this study is to determine whether such programmes are feasible in primary health care. METHODS: An intervention study including 237 individuals 40-75 years of age with moderate or high risk of developing type 2 diabetes. A structured group programme with six 90 minute sessions delivered during an eight month period by trained nurses in Australian primary health care in 2004-2006. Main outcome measures taken at baseline, three, and 12 months included weight, height, waist circumference, fasting plasma glucose and lipids, plasma glucose two hours after oral glucose challenge, blood pressure, measures of psychological distress and general health outcomes. To test differences between baseline and follow-up, paired t-tests and Wilcoxon rank sum tests were performed. RESULTS: At twelve months participants' mean weight reduced by 2.52 kg (95% confidence interval 1.85 to 3.19) and waist circumference by 4.17 cm (3.48 to 4.87). Mean fasting glucose reduced by 0.14 mmol/l (0.07 to 0.20), plasma glucose two hours after oral glucose challenge by 0.58 mmol/l (0.36 to 0.79), total cholesterol by 0.29 mmol/l (0.18 to 0.40), low density lipoprotein cholesterol by 0.25 mmol/l (0.16 to 0.34), triglycerides by 0.15 mmol/l (0.05 to 0.24) and diastolic blood pressure by 2.14 mmHg (0.94 to 3.33). Significant improvements were also found in most psychological measures. CONCLUSION: This study provides evidence that a type 2 diabetes prevention programme using lifestyle intervention is feasible in primary health care settings, with reductions in risk factors approaching those observed in clinical trials.
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ItemNo Preview AvailableSocioeconomic status and quality of life in population-based Australian men: data from the Geelong Osteoporosis Study(WILEY, 2013-06)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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ItemWeight loss on stimulant medication: how does it affect body composition and bone metabolism? - A prospective longitudinal study(BMC, 2012)OBJECTIVE: Children treated with stimulant medication for attention deficit hyperactivity disorder (ADHD) often lose weight. It is important to understand the implications of this during growth. This prospective study was designed to quantify the changes in body composition and markers of bone metabolism on starting treatment. METHODS: 34 children (29 boys) aged 4.7 to 9.1 years newly diagnosed with ADHD were treated with dexamphetamine or methylphenidate, titrating the dose to optimise the therapeutic response. Medication was continued for as long as clinically indicated. Body composition and bone density (dual-energy X-ray absorptiometry) were measured at baseline, 6 months and 3 years; changes were analysed in Z-scores based on data from 241 healthy, local children. Markers of bone turnover were measured at baseline, 3 months and 3 years. RESULTS: Fat loss of 1.4±0.96kg (total fat 5.7±3.6 to 4.3±3.1kg, p<0.001) occurred in the first 6 months. There were significant reductions over 3 years in the sex and height corrected Z-scores for lean tissue, bone mineral content, bone mineral density and ratio of central to total fat (-0.84±0.86, p=0.003; -0.55±0.31, p<0.0001; -0.41±0.28, p<0.0001 and -0.55±0.62, p=0.006 respectively). Propeptide of type I collagen indicated a significant reduction in bone turnover after 3 months (564±202 to 458±96ng/ml, p=0.019), which was fully recovered after 3 years (619±276ng/ml). CONCLUSIONS: Stimulant medication was associated with early fat loss and reduced bone turnover. Lean tissue including bone increased more slowly over 3 years of continuous treatment than would be expected for growth in height. There was long-term improvement in the proportion of central fat for height. This study shows that relatively minor reductions in weight on stimulant medication can be associated with long-term changes in body composition. Further study is required to determine the effects of these changes on adult health.
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ItemThe Role of Cancer-Testis Antigens as Predictive and Prognostic Markers in Non-Small Cell Lung Cancer(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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ItemInhibition of Protein Farnesylation Arrests Adipogenesis and Affects PPARγ Expression and Activation in Differentiating Mesenchymal Stem Cells(HINDAWI LTD, 2007)Protein farnesylation is required for the activation of multiple proteins involved in cell differentiation and function. In white adipose tissue protein, farnesylation has shown to be essential for the successful differentiation of preadipocytes into adipocytes. We hypothesize that protein farnesylation is required for PPARgamma2 expression and activation, and therefore for the differentiation of human mesenchymal stem cells (MSCs) into adipocytes. MSCs were plated and induced to differentiate into adipocytes for three weeks. Differentiating cells were treated with either an inhibitor of farnesylation (FTI-277) or vehicle alone. The effect of inhibition of farnesylation in differentiating adipocytes was determined by oil red O staining. Cell survival was quantified using MTS Formazan. Additionally, nuclear extracts were obtained and prelamin A, chaperon protein HDJ-2, PPARgamma, and SREBP-1 were determined by western blot. Finally, DNA binding PPARgamma activity was determined using an ELISA-based PPARgamma activation quantification method. Treatment with an inhibitor of farnesylation (FTI-277) arrests adipogenesis without affecting cell survival. This effect was concomitant with lower levels of PPARgamma expression and activity. Finally, accumulation of prelamin A induced an increased proportion of mature SREBP-1 which is known to affect PPARgamma activity. In summary, inhibition of protein farnesylation arrests the adipogenic differentiation of MSCs and affects PPARgamma expression and activity.
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ItemIncreased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin(AMER DIABETES ASSOC, 2013-10)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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ItemWestern Ontario and McMaster Universities Osteoarthritis Index (WOMAC)(AUSTRALIAN PHYSIOTHERAPY ASSOC, 2009)
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ItemGait disorders are associated with non-cardiovascular falls in elderly people: a preliminary study.(Springer Science and Business Media LLC, 2005-12-01)BACKGROUND: The association between unexplained falls and cardiovascular causes is increasingly recognized. Neurally mediated cardiovascular disorders and hypotensive syndromes are found in almost 20 percent of the patients with unexplained falls. However, the approach to these patients remains unclear. Gait assessment might be an interesting approach to these patients as clinical observations suggests that those with cardiovascular or hypotensive causes may not manifest obvious gait alterations. Our primary objective is to analyze the association between gait disorders and a non-cardiovascular cause of falls in patients with unexplained falls. A second objective is to test the sensitivity and specificity of a gait assessment approach for detecting non-cardiovascular causes when compared with intrinsic-extrinsic classification. METHODS: Cross-sectional study performed in a falls clinic at a university hospital in 41 ambulatory elderly participants with unexplained falls. Neurally mediated cardiovascular conditions, neurological diseases, gait and balance problems were assessed. Gait disorder was defined as a gait velocity < 0.8 m/s or Tinetti Gait Score < 9. An attributable etiology of the fall was determined in each participant. Comparisons between the gait assessment approach and the attributable etiology regarding a neurally mediated cardiovascular cause were performed. Fisher exact test was used to test the association hypothesis. Sensitivity and specificity of gait assessment approach and intrinsic-extrinsic classification to detect a non-cardiovascular mediated fall was calculated with 95% confidence intervals (CI95%). RESULTS: A cardiovascular etiology (orthostatic and postprandial hypotension, vasovagal syndrome and carotid sinus hypersensitivity) was identified in 14% of participants (6/41). Of 35 patients with a gait disorder, 34 had a non-cardiovascular etiology of fall; whereas in 5 out of 6 patients without a gait disorder, a cardiovascular diagnosis was identified (p < 0.001). Sensitivity and specificity of the presence of gait disorder for identifying a non-cardiovascular mediated cause was 97.1% (CI95% = 85-99) and 83% (CI95% = 36-99), respectively. CONCLUSION: In community dwelling older persons with unexplained falls, gait disorders were associated with non-cardiovascular diagnosis of falls. Gait assessment was a useful approach for the detection of a non-cardiovascular mediated cause of falls, providing additional value to this assessment.
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ItemCalcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes(ELSEVIER SCIENCE INC, 2010-06)The therapeutic goal of increasing bone mass by co-treatment of parathyroid hormone (PTH) and an osteoclast inhibitor has been complicated by the undefined contribution of osteoclasts to the anabolic activity of PTH. To determine whether active osteoclasts are required at the time of PTH administration, we administered a low dose of the transient osteoclast inhibitor salmon calcitonin (sCT) to young rats receiving an anabolic PTH regimen. Co-administration of sCT significantly blunted the anabolic effect of PTH as measured by peripheral quantitative computer tomography (pQCT) and histomorphometry in the femur and tibia, respectively. To determine gene targets of sCT, we carried out quantitative real time PCR and microarray analysis of metaphyseal samples 1.5, 4 and 6.5h after administration of a single injection of PTH, sCT or PTH+sCT. Known targets of PTH action, IL-6, ephrinB2 and RANKL, were not modified by co-administration with sCT. Surprisingly, at all time points, we noted a significant upregulation of sclerostin mRNA by sCT treatment, as well as down-regulation of two other osteocyte gene products, MEPE and DMP1. Immunohistochemistry confirmed that sCT administration increased the percentage of osteocytes expressing sclerostin, suggesting a mechanism by which sCT reduced the anabolic effect of PTH. Neither mRNA for CT receptor (Calcr) nor labeled CT binding could be detected in sclerostin-enriched cells differentiated from primary calvarial osteoblasts. In contrast, osteocytes freshly isolated from calvariae expressed a high level of Calcr mRNA. Furthermore immunohistochemistry revealed co-localization of CT receptor (CTR) and sclerostin in some osteocytes in calvarial sections. Taken together these data indicate that co-treatment with sCT can blunt the anabolic effect of PTH and this may involve direct stimulation of sclerostin production by osteocytes. These data directly implicate calcitonin as a negative regulator of bone formation through a previously unsuspected mechanism.