Higher Dietary Vitamin K Intake is Associated with Better Physical Function and Lower Long-Term Injurious Falls Risk in Community-Dwelling Older Women.

BACKGROUND: In recent years, a potential beneficial role of Vitamin K in neuromuscular function has been recognised. However, the optimal dietary intake of Vitamin K to support muscle function in the context of falls prevention remains unknown. OBJECTIVE: To examine the relationship of dietary Vitamin K1 and K2 with muscle function and long-term injurious fall-related hospitalisations in older women. DESIGN: Cohort study. PARTICIPANTS: 1347 community-dwelling older Australian women ≥70 years. MEASUREMENTS: A new Australian Vitamin K nutrient database, supplemented with published data, was used to calculate Vitamin K1 and K2 intake from a validated food frequency questionnaire at baseline (1998). Muscle function (grip strength and timed-up-and-go; TUG) as well plasma Vitamin D status (25OHD) were also assessed at baseline. Fall-related hospitalisations over 14.5 years were obtained from linked health records. Multivariable-adjusted logistic regression and Cox-proportional hazard models were used to analyse the data. RESULTS: Over 14.5 years of follow-up (14,774 person-years), 535 (39.7%) women experienced a fall-related hospitalisation. Compared to women with the lowest Vitamin K1 intake (Quartile 1, median 49 µg/d), those with the highest intake (Quartile 4, median 120 µg/d) had 29% lower odds (OR 0.71 95%CI 0.52-0.97) for slow TUG performance (>10.2 s), and 26% lower relative hazards of a fall-related hospitalisation (HR 0.74 95%CI 0.59-0.93) after multivariable adjustment. These associations were non-linear and plateaued at moderate intakes of ~70-100 µg/d. There was no relation to grip strength. Vitamin K2 intakes were not associated with muscle function or falls. CONCLUSION: A higher habitual Vitamin K1 intake was associated with better physical function and lower long-term injurious falls risk in community-dwelling older women. In the context of musculoskeletal health, Vitamin K1 found abundantly in green leafy vegetables should be promoted.

Calcaneal quantitative ultrasound is associated with all-cause and cardiovascular disease mortality independent of hip bone mineral density.

Osteoporosis has been linked with increased risk of cardiovascular disease previously. However, few studies have detailed bone and vascular information. In a prospective study of older women, we demonstrated heel quantitative ultrasound measures were associated with increased cardiovascular and all-cause mortality, independent of established cardiovascular risk factors. INTRODUCTION: Osteoporosis and low bone mineral density (BMD) have been previously linked to cardiovascular disease (CVD) and mortality. Calcaneal quantitative ultrasound (QUS) is used to evaluate bone material properties, especially in older women. However, it is uncertain whether it is related to risk of mortality. This study was aimed to investigate the association between calcaneal QUS measurements and 15-year all-cause and CVD mortality in 1404 older women (mean age 75.2 ± 2.7 years). METHODS: One thousand four hundred four older women, participants of Calcium Intake Fracture Outcome study (CAIFOS), had calcaneal bone measured at baseline (1998) and followed for 15 years. The primary outcomes, any deaths, and deaths attributable to cardiovascular causes ascertained by using linked data were obtained from Western Australia data linkage system. RESULTS: Over the 15 years of follow-up (17,955 person years), 584 of the women died, and 223 from CVD. For every standard deviation (SD), reduction in broadband ultrasound attenuation (BUA) in minimally and multivariable-adjusted model including cardiovascular risk factors increased relative hazards for all-cause (multivariable-adjusted HR 1.15; 95%CI: 1.06-1.26, p = 0.001) and CVD mortality (multivariable-adjusted HR 1.20; 95%CI: 1.04-1.38, p = 0.010). Such relationships also persisted when hip BMD was included in the model (all-cause mortality HR 1.19; 95%CI: 1.07-1.33, p = 0.002; CVD mortality HR 1.28; 95%CI: 1.07-1.53, p = 0.008). CONCLUSION: BUA is associated with all-cause and CVD mortality in older women independent of BMD and established CVD risk factors. Understanding why and how these are related may provide further insights about the bone-vascular nexus as well as therapeutic targets benefiting both systems.

Effects of calcium supplementation on circulating osteocalcin and glycated haemoglobin in older women.

One year of calcium supplementation in older women led to modest reductions in total osteocalcin and undercarboxylated osteocalcin (ucOC), with no changes in muscle or fat mass, or glycated haemoglobin. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control. INTRODUCTION: Total osteocalcin (TOC) is a marker of bone turnover, while its undercarboxylated form has beneficial effects on glucose metabolism in mice. This post hoc analysis of a randomised double-blind, placebo-controlled trial examined whether 1 year of calcium supplementation affected circulating TOC, undercarboxylated osteocalcin (ucOC) or glycated haemoglobin (HbA1c) in 1368 older community-dwelling women (mean age 75.2 ± 2.7 years). METHODS: Women enrolled in the Calcium Intake Fracture Outcome Study trial (1998-2003) were supplemented with 1.2 g/d of elemental calcium (in the form of calcium carbonate) or placebo. Circulating TOC, ucOC and HbA1c was measured at 1 year (1999). RESULTS: After 1 year of calcium supplementation, TOC and ucOC levels were 17% and 22% lower compared with placebo (mean 22.7 ± 9.1 vs. 27.3 ± 10.9 µg/L and 11.1 ± 4.9 vs. 13.0 ± 5.7 µg/L, both P < 0.001). Carboxylated osteocalcin/ucOC was 6% lower after calcium supplementation (P < 0.05). Despite this, no differences in HbA1c were observed (calcium, 5.2 ± 0.6 vs. placebo, 5.3 ± 0.8%; P = 0.08). Calcium supplementation did not affect BMI, whole body lean or fat mass. In exploratory analyses, total calcium (dietary and supplemental) was inversely related to TOC and ucOC, indicating calcium intake is an important dietary determinant of osteocalcin levels. CONCLUSION: One year of calcium supplementation in older women led to modest reductions in TOC and ucOC, with no changes in muscle or fat mass, or HbA1c. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control.

Ageing Effects on 3-Dimensional Femoral Neck Cross-Sectional Asymmetry: Implications for Age-Related Bone Fragility in Falling.

This paper explores the effects of aging on femoral neck (FN) anatomy in a study of women aged 20-90years in relation to implications for FN fracture propensity in buckling. Five hundred and four participants were scanned by Quantitative Computed Tomography and analyzed using Quantitative Computed Tomography Pro BIT (Mindways). FN cross-section was split through geometric center into superior and inferior sectors. Bone mass, structural measurements, and bone mineral density were analyzed. Buckling ratio was calculated as ratio of buckling radius to cortical thickness. Between 2nd decade and 8th decade, age-related integral bone mass reduction in superior sector was substantially larger than in inferior sector (33% compared to 21%), especially in cortical bone superiorly compared to inferiorly (53% vs 21%; p < 0.001), principally due to reduction in cortical thickness, averaged cortical thickness (56%) with little difference in density. Superior and inferior sector trabecular bone mineral density reduction was similar at 41% and 43% respectively. Differential cortical bone loss in superior sector resulted in a 59% inferior displacement (δ) of center-of-mass from geometric center. Differences in δ and averaged cortical thickness with age accounted for a 151% increase in mean superior buckling ratio from 9 to 23. Analysis confirms significant progressive age-related superior cortical bone loss as the major age effect on FN structure with relative preservation of inferior cortex probably related to maintenance of inferior sector by regular loading as a result of standing and walking. Computation of buckling ratio may allow prediction of fracture propensity in a sideways fall.

Utility of four sarcopenia criteria for the prediction of falls-related hospitalization in older Australian women.

Numerous sarcopenia definitions are not associated with increased falls-related hospitalization risk over 5 years to 9.5 years in older community-dwelling Australian women. Measures of muscle strength and physical function, but not appendicular lean mass (measured by dual-energy X-ray absorptiometry) may help discriminate the risk of falls-related hospitalization. INTRODUCTION: The aim of this prospective, population-based cohort study of 903 Caucasian-Australian women (mean age 79.9 ± 2.6 years) was to compare the clinical utility of four sarcopenia definitions for the prediction of falls-related hospitalization over 9.5 years. METHODS: The four definitions were the United States Foundation for the National Institutes of Health (FNIH), the European Working Group on Sarcopenia in Older People (EWGSOP), and modified FNIH (AUS-POPF) and EWGSOP (AUS-POPE) definitions using Australian population-specific cut points (< 2 SD below the mean of young healthy Australian women). Components of sarcopenia including muscle strength, physical function, and appendicular lean mass (ALM) were quantified using hand grip strength, timed-up-and-go (TUG), and dual-energy X-ray absorptiometry (DXA), respectively. Incident 9.5-year falls-related hospitalization were captured by linked data. RESULTS: Baseline prevalence of sarcopenia according to FNIH (9.4%), EWGSOP (24.1%), AUS-POPF (12.0%), and AUS-POPE (10.7%) differed substantially. Sarcopenia did not increase the relative hazard ratio (HR) for falls-related hospitalization before or after adjustment for age (aHR): FNIH aHR 1.00 95%CI (0.69-1.47), EWGSOP aHR 1.20 95%CI (0.93-1.54), AUS-POPF aHR 0.96 95%CI (0.68-1.35), and AUS-POPE aHR 1.33 95%CI (0.94-1.88). When examining individual components of sarcopenia, only muscle strength and physical function but not ALM (adjusted for height2 or BMI) were associated with falls-related hospitalization. CONCLUSION: Current definitions of sarcopenia were not associated with falls-related hospitalization risk in this cohort of community-dwelling older Australian women. Finally, measures of muscle strength and physical function, but not ALM (measured by DXA) may help discriminate the risk of falls-related hospitalization.

Establishing an Operational Definition of Sarcopenia in Australia and New Zealand: Delphi Method Based Consensus Statement.

BACKGROUND: Globally there are several operational definitions for sarcopenia, complicating clinical and research applications. OBJECTIVE: The objective of the Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR) Task Force on Diagnostic Criteria for Sarcopenia was to reach consensus on the operational definition of sarcopenia for regional use by clinicians and researchers. METHOD: A four-Phase modified Delphi process was undertaken in which 24 individuals with expertise or a recognised interest in sarcopenia from different fields across Australia and New Zealand were invited to be Task Force members. An initial face-to-face meeting was held in Adelaide, South Australia, in November 2017, followed by two subsequent online Phases conducted by electronic surveys. A final Phase was used to approve the final statements. Responses were analysed using a pre-specified strategy. The level of agreement required for consensus was 80%. RESULTS: In Phase 2, 94.1% of Task Force respondents voted in favour of adopting an existing operational definition of sarcopenia. In Phase 3, 94.4% of respondents voted in favour of adopting the European Working Group on Sarcopenia in Older People (EWGSOP) definition as the operational definition for sarcopenia in Australia and New Zealand. CONCLUSION: With consensus achieved, the ANZSSFR will adopt, promote and validate the EWGSOP operational definition of sarcopenia for use by clinicians and researchers in Australia and New Zealand.

Differences in femoral neck structure between elderly Caucasian and Chinese populations: a cross-sectional study of Perth-Beijing cohorts.

Structural skeletal differences of the femoral neck of older Beijing-Chinese and Perth-Caucasian women were compared; adjusting for frame size-related differences, Beijing-Chinese have lower periosteal width; however, indices of internal bone distribution suggest that Beijing-Chinese may exhibit increased resistance to fracture that may relate to the reduced hip fracture incidence. INTRODUCTION: Ethnic differences in skeletal structure may relate to differences in hip fracture risk in Chinese and Caucasian populations. 2D mass, size, and structural biomechanics were compared in the two populations. METHODS: Quantitative computed tomography-derived geometric variables were compared in age-matched community-derived female populations, 196 Beijing-Chinese 76.5 ± 4.8 (mean ± SD) years and 237 Perth-Caucasians 77.1 ± 5.0 years. These included scanned area (A), periosteal width (W), bone mineral content (BMC), aBMD, bone cross-sectional area (bCSA), section modulus (Z) and buckling ratio (BR). Assumption-free measures included sigma (σ), related to the distribution of bone in the scanned image previously identified as a predictor of hip fracture, and delta (δ), the center-of-mass displacement from the geometric center. RESULTS: Compared to Beijing-Chinese, Perth-Caucasians were heavier (Beijing-Chinese 58.7 ± 11.8; Perth-Caucasians 66.1 ± 11.0 kg), taller (154.9 ± 16.7 vs 158.9 ± 6.0 cm), and had higher BMC, A, and W. After adjustment for frame size, BMC was not significantly different but W remained higher in Perth-Caucasians. Differences in variables aBMD, Z, BR, and σ favored higher resistance to failure with Beijing-Chinese before and after adjustment for frame size. δ was similar in both populations; bCSA was higher in Beijing-Chinese before adjustment for frame size but not after. CONCLUSIONS: Bone mass differences in two populations were related to frame size differences. However, femoral neck width remained smaller in Beijing-Chinese suggesting effects of local genetic and environmental factors. In Beijing-Chinese participants compared to Perth-Caucasians, internal bone distribution suggests increased resistance to deformation if exposed to same force that may, in-part, relate to reduced incidence of hip fracture in Beijing-Chinese.

Multifaceted interaction of bone, muscle, lifestyle interventions and metabolic and cardiovascular disease: role of osteocalcin.

Undercarboxylated osteocalcin (ucOC) may play a role in glucose homeostasis and cardiometabolic health. This review examines the epidemiological and interventional evidence associating osteocalcin (OC) and ucOC with metabolic risk and cardiovascular disease. The complexity in assessing such correlations, due to the observational nature of human studies, is discussed. Several studies have reported that higher levels of ucOC and OC are correlated with lower fat mass and HbA1c. In addition, improved measures of glycaemic control via pharmacological and non-pharmacological (e.g. exercise or diet) interventions are often associated with increased circulating levels of OC and/or ucOC. There is also a relationship between lower circulating OC and ucOC and increased measures of vascular calcification and cardiovascular disease. However, not all studies have reported such relationship, some with contradictory findings. Equivocal findings may arise because of the observational nature of the studies and the inability to directly assess the relationship between OC and ucOC on glycaemic control and cardiovascular health in humans. Studying OC and ucOC in humans is further complicated due to numerous confounding factors such as sex differences, menopausal status, vitamin K status, physical activity level, body mass index, insulin sensitivity (normal/insulin resistance/T2DM), tissue-specific effects and renal function among others. Current observational and indirect interventional evidence appears to support a relationship between ucOC with metabolic and cardiovascular disease. There is also emerging evidence to suggest a direct role of ucOC in human metabolism. Further mechanistic studies are required to (a) clarify causality, (b) explore mechanisms involved and

Obesity and hypertension in Australian young people: results from the Australian Health Survey 2011-2012.

BACKGROUND: Few studies have focused on the prevalence of obesity and hypertension among young people (ages 15-24). AIM: To characterise the prevalence of obesity and systolic hypertension in young people aged 15-24 years across Australia. METHODS: Using data from the 2011-2012 Australian Health Survey, a national cross-sectional population-based survey, we included 2163 young people aged 15-24 years. Risk factors were estimated using multinomial logistic regression. RESULTS: The prevalence of obesity increased from 8% to 15% through the ages of 15-24 among males, but the prevalence of overweight and obesity were both 14% for females across all age groups. Low levels of physical activity were a strong risk factor for obesity for both males (odds ratio (OR) 5.95, 95% confidence intervals (CI)1.83-19.36) and females (OR 3.20 95% CI 0.69-14.87). Low socioeconomic status was associated with obesity among females only (first quintile OR 4.65, 95% CI 1.97-10.99). Although the prevalence of hypertension was low (4% males, 3% females), the prevalence of high normal blood pressure was substantial, especially among males (28% males, 14% females). CONCLUSIONS: Overweight, obesity and high normal blood pressure were highly prevalent among Australian young people. Low levels of physical activity were identified as a risk factor for obesity for both male and females. Programmes targeting physical activity participation may need to be tailored differently for males and females, with a focus on females during early adolescence but early adult life for males.

Evaluation of a simplified hip structure analysis method for the prediction of incident hip fracture events.

UNLABELLED: Many attempts have been made to improve the predictive ability of areal bone mineral density (aBMD) which integrates bone mass and area. The addition of an extra variable derived from the hip dual-energy X-ray (DXA) image TR_σ, which describes distribution of mass within the scanned area of the trochanter, improved prediction of 15-year hip fracture probability in elderly women. INTRODUCTION: Two-dimensional DXA imaging of the proximal femur to produce an aBMD is a clinically useful predictor of future fracture risk. Further analysis of the DXA image to produce an eight-variable hip structure analysis (Beck HSA) has been developed to improve understanding of structural factors determining hip bone strength at each of three proximal femur sites, the narrow femoral neck (NN), intertrochanter (TR) and shaft (S). Recently, data on four measurements derived from the currently used eight Beck HSA variables were used to capture population variation in bone structure at each site. These include two previously used variables, the localised aBMD and the sub-periosteal width (W) applying to 5-mm sections (at each sites), and two new variables, standard deviation of normalised mineral-mass projection profile distribution (σ), and displacement between centre-of-mineral mass and geometric centre-of-mineral mass of projection profile (δ). METHODS: Using a cohort of 1159 women, mean baseline age 75, who sustained 139 hip fractures over 15 years, we determined whether these measures significantly improved 15-year hip fracture prediction compared to current approach utilising age and total hip aBMD. To describe the most parsimonious model for hip fracture risk prediction, the 12 base measures (4 from each site), total hip aBMD and age were evaluated in stepwise logistic regression models. RESULTS: The final model included TR_σ, total hip aBMD and age and provided improved utility for hip fracture prediction compared to total hip aBMD and age alone (C-statistic 0.73 vs. 0.69, P = 0.009 and net reclassification improvement 0.164, P < 0.001, respectively). CONCLUSIONS: Addition of TR_σ to total hip aBMD and age substantially improved prediction of 15-year hip fracture risk in this cohort of elderly women.

Benign and Malignant Proliferative Fibro-osseous and Osseous Lesions of the Oral Cavity of Dogs.

Ossifying fibroma (OF) and fibrous dysplasia (FD) are benign, intraosseous, proliferative fibro-osseous lesions (PFOLs) characterized by replacement of normal bone by a fibrous matrix with various degrees of mineralization and ossification. Osteomas are benign tumors composed of mature, well-differentiated bone. Clinical, imaging, and histologic features of 15 initially diagnosed benign PFOLs and osteomas of the canine oral cavity were evaluated. Final diagnoses after reevaluation were as follows: OF (3 cases), FD (4 cases), low-grade osteosarcoma (LG-OSA) (3 cases), and osteoma (5 cases). Histology alone often did not result in a definitive diagnosis for PFOL. OF appeared as a well-circumscribed, radiopaque mass with some degree of bone lysis on imaging. Most lesions of FD showed soft tissue opacity with bone lysis and ill-defined margins. Low-grade OSA appeared as a lytic lesion with a mixed opacity and ill-defined margins. Osteomas were characterized by a mineralized, expansile, well-circumscribed lesion. Although histologic features of PFOLs were typically bland, the lesions diagnosed as LG-OSA had some features of malignancy (eg, bone invasion or a higher mitotic index). Treatment varied widely. Of the 10 dogs with benign PFOL or osteoma with known outcome (10/12), 9 showed either complete response (6/10) or stable disease (3/10) after treatment. Of the 2 dogs with LG-OSA with known outcome, 1 showed complete response after curative intent surgery, but 1 patient had recurrence after partial maxillectomy. Definitive diagnosis of mandibular/maxillary PFOL is challenging via histopathologic examination alone, and accurate diagnosis is best achieved through assimilation of clinical, imaging, and histopathologic features.

Consumption of a whey protein-enriched diet may prevent hepatic steatosis associated with weight gain in elderly women.

BACKGROUND AND AIMS: Protein consumption has been associated with cardio-metabolic benefits, including weight loss and improved insulin sensitivity, and may have potential benefits for individuals with fatty liver disease (FLD). We investigated the effect of increasing dietary protein intake from whey relative to carbohydrate on hepatic steatosis. METHODS AND RESULTS: A two-year randomized, double-blind, placebo-controlled trial of 30 g/day whey protein-supplemented beverage (protein) or an energy-matched low-protein high-carbohydrate beverage (control) for cardio-metabolic and bone health in 219 healthy elderly women, recruited from the Western Australian general population. Hepatic steatosis was quantified using computed tomographic liver-to-spleen (L/S) ratio. FLD was defined as liver-to-spleen difference <10 Hounsfield units. At baseline, FLD prevalence was 11.4%. Control and protein groups were similar in body mass index (BMI), insulin resistance, L/S ratio and FLD prevalence at baseline. At two-years, dietary protein increased by 20 g in the protein, but not the control, group. Total energy intake and physical activity remained similar between groups. At two-years, BMI and FLD prevalence increased in both groups, with no between group differences. L/S ratio increased in control, but not protein, group at two-years, with no between group differences. In a within group comparison, change in BMI correlated with changes in L/S ratio in control (r = 0.37, P = 0.0007), but not with protein group (r = 0.04, P = 0.73). CONCLUSION: Increasing dietary protein intake from whey relative to carbohydrate does not reduce weight, hepatic steatosis or the prevalence of FLD in elderly women. However, it may prevent worsening of hepatic steatosis associated with weight gain. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry (Registration no. ACTRN012607000163404).

Dilemmas in the compassionate supply of investigational cancer drugs.

In Australia, patients who want to access medicines that are not yet approved have only two options: to enroll in a clinical trial if they are eligible, or obtain their medicine through 'compassionate supply', which is provided at the discretion of the manufacturer. In this article, we explore ethical issues associated with the provision of oncology medicines that are still in development, either prior to regulatory approval or government reimbursement.

The effects of probiotic bacteria on glycaemic control in overweight men and women: a randomised controlled trial.

BACKGROUND/OBJECTIVES: Evidence from animal and in vitro models suggest a role of probiotic bacteria in improving glycaemic control and delaying the onset of type 2 diabetes. However, the evidence from controlled trials in humans is limited. The objective was to determine if the probiotic bacteria L. acidophilus La5 and B. animalis subsp lactis Bb12, supplemented in a whole food (yoghurt) or isolated (capsules) form, can improve biomarkers of glycaemic control. SUBJECTS/METHODS: Following a 3-week washout period, 156 overweight men and women over 55 years (mean age: 67 ± 8 years; mean body mass index (31 ± 4 kg/m(2)) were randomized to a 6-week double-blinded parallel study. The four intervention groups were: (A) probiotic yoghurt plus probiotic capsules; (B) probiotic yoghurt plus placebo capsules; (C) control milk plus probiotic capsules; and (D) control milk plus placebo capsules. Outcome measurements, including fasting glucose, insulin, glycated haemoglobin and Homoeostasis Model Assessment of Insulin Resistance (HOMA-IR), were performed at baseline and week 6. RESULTS: Relative to the milk-control group, probiotic yoghurt resulted in a significantly higher HOMA-IR (0.32 ± 0.15, P=0.038), but did not have a significant effect on the other three measures of glycaemic control (P>0.05). Relative to placebo capsules, probiotic capsules resulted in a significantly higher fasting glucose (0.15 ± 0.07 mmol/l, P=0.037), with no significant effect on the other three measures of glycaemic control (P>0.05). Further analyses did not identify other variables as contributing to these adverse findings. CONCLUSIONS: Data from this study does not support the hypothesis that L. acidophilus La5 and B. animalis subsp lactis Bb12, either in isolated form or as part of a whole food, benefit short-term glycaemic control. Indeed, there is weak data for an adverse effect of these strains on glucose homoeostasis.

Five-year decline in estimated glomerular filtration rate associated with a higher risk of renal disease and atherosclerotic vascular disease clinical events in elderly women.

BACKGROUND: Estimated glomerular filtration rate (eGFR) has been demonstrated to predict atherosclerotic vascular disease (ASVD)-associated clinical events independent of traditional vascular risk factors. Recent studies have demonstrated that eGFR decline over time may improve prediction of ASVD-associated mortality risk in chronic kidney disease (CKD) patients. AIM: The aim of this study is to evaluate the association between 5-year change in eGFR with renal disease and ASVD-associated clinical events. DESIGN: Prospective observational study. METHODS: A total of 1012 women over the age of 70 years from the Calcium Intake Fracture Outcome Study were included. Baseline characteristics including baseline and 5-year creatinine, participants' comorbidities and complete verified 10-year records for ASVD and renal disease-associated hospitalization and/or mortality were obtained using the Western Australian Data Linkage System. RESULTS: Participants were stratified according to annual rate of eGFR change in quartiles [≤-1.2 (first quartile), >-1.2 to 0.1 (second quartile), >0.1-1.7 (third quartile) and >1.7 ml/min/1.73 m(2)/year (fourth quartile)]. In the adjusted model, compared with participants in the fourth quartile, those in the first and/or second quartiles of annual eGFR change had significantly higher risk of renal disease and/or ASVD-associated clinical events. However, the association with renal clinical events was more pparent in participants with baseline eGFR of <60 ml/min/1.73 m(2). CONCLUSION: The results of this study suggest that the inclusion of long-term eGFR change over time might augment prognostication for renal disease and ASVD-associated clinical events in elderly women.

Significant association between common polymorphisms in the aromatase gene CYP19A1 and bone mineral density in postmenopausal women.

17ß-Estradiol is important in maintaining bone structure, and regulation of its synthesis plays an important role in the development of postmenopausal osteoporosis. We and others have demonstrated associations between variation in the CYP19A1 gene (encoding aromatase) and areal bone mineral density (aBMD) phenotypes in women. In the present study 33 tag polymorphisms were genotyped across the CYP19A1 gene in a population of 1,185 Caucasian postmenopausal women to test the association between sequence variations, total DXA hip aBMD, and circulating 17ß-estradiol levels. An in silico bioinformatics analysis was performed for single nucleotide polymorphisms (SNPs) associated with aBMD to identify putative functional effects, while linkage disequilibrium analysis of these SNPs was undertaken with previously published sequence variants. Five SNPs located in the central third of the gene were strongly associated with total-hip aBMD after adjustment for age (P = 0.006-0.013). A haplotype analysis of these five SNPs revealed an association between the haplotype C-G-G-G-C and increased aBMD (P = 0.008) and the haplotype A-A-A-A-A and a decreased aBMD (P = 0.021). The haplotype frequency was 9.0% for C-G-G-G-C and 15.4% for A-A-A-A-A, with the variation in mean total-hip aBMD explained by the haplotype analyses being 5% and 7%, respectively. None of these polymorphisms was significantly associated with circulating 17ß-estradiol levels. In conclusion, common genetic variations within the CYP19A1 gene are significantly associated with aBMD in postmenopausal Caucasian women.

The calcium scare--what would Austin Bradford Hill have thought?

UNLABELLED: Detailed consideration of the suggested association between calcium supplementation and heart attacks has revealed weakness in the evidence which make the hypothesis highly implausible. INTRODUCTION: The aim of this study was to evaluate the strength of the evidence that calcium supplementation increases the risk of myocardial infarction. METHODS: This study used critical examination of a meta-analysis of the effects of calcium supplements on heart attacks in five prospective trials on 8,016 men and women, and consideration of related publications by the same author. RESULTS: The meta-analysis was found to be subject to several limitations including non-adherence to the clinical protocol, multiple endpoint testing and failure to correctly adjust for endpoint ascertainment. The main risk factors for myocardial infarction were not available for 65% of the participants, and none of the trials had cardiovascular disease as its primary endpoint. There were more overweight participants, more subjects on thyroxine and more men on calcium than on placebo. In particular, over 65% of all the heart attacks were self-reported. When the evidence was considered in the light of Austin Bradford Hill's six main criteria for disease causation, it was found not to be biologically plausible or strong or to reflect a dose-response relationship or to be consistent or to reflect the relationship between the trends in calcium supplementation and heart attacks in the community or to have been confirmed by experiment. The addition of a more recent trial on 1,460 women over 5 years reduced the relative risk to 1.23 (P = 0.0695). CONCLUSION: Present evidence that calcium supplementation increases heart attacks is too weak to justify a change in prescribing habits.

Homozygous deletion of the UGT2B17 gene is not associated with osteoporosis risk in elderly Caucasian women.

UNLABELLED: Previously, homozygous deletion of the UGT2B17 gene has shown association with hip fracture. Using a high-throughput qRT-PCR assay, we genotyped UGT2B17 copy number variation (CNV) in 1,347 elderly Caucasian women and examined for effects on bone phenotypes. We found no evidence of association between UGT2B17 CNV and osteoporosis risk in this population. INTRODUCTION: Genetic studies of osteoporosis commonly examine SNPs in candidate genes or whole genome analyses, but insertions and deletions of DNA, collectively called CNV, also comprise a large amount of the genetic variability between individuals. Previously, homozygous deletion of the UGT2B17 gene in CNV 4q13.2, which encodes an enzyme that mediates the glucuronidation of steroid hormones, has shown association with the risk of hip fracture. METHODS: We used a quantitative real-time PCR assay for genotyping the UGT2B17 CNV in a well-characterized population study of 1,347 Caucasian women aged 75.2 ± 2.7 years (mean ± SD), to assess the effect of the CNV on bone mass density (BMD) at the total hip site and osteoporosis risk. RESULTS: The UGT2B17 CNV distribution was consistent with the expected Hardy-Weinberg distribution and not different from frequencies previously reported in a Caucasian population. Data from ANCOVA of age- and weight-adjusted BMD for UGT2B17 CNV genotype showed no significant difference between genotype groups. Individuals with homozygous or heterozygous deletion of the UGT2B17 gene showed no increased risk of incident fragility fracture. CONCLUSIONS: These data suggest that quantitative real-time PCR is a rapid and efficient technique for determination of candidate CNVs, including the UGT2B17 CNV; however, we found no evidence of an effect of UGT2B17 CNV on osteoporosis risk in elderly Caucasian women.

PathGrid: a service-orientated architecture for microscopy image analysis.

This paper describes 'PathGrid'--an analysis and data integration system, developed initially to meet the demands in the analysis of medical microscopy imaging data. An overview of the current system is given, describing the techniques used in developing the data handling infrastructure and the analysis algorithm development. The use of software created in the context of systems designed for the astronomy domain is noted, specifically infrastructure from the astronomy virtual observatory movement for data discovery, access and workflow management, and astronomical image analysis software adapted for the analysis of high-throughput astronomy imaging surveys. This paper notes the applicability of the techniques from the astronomy domain. The testbed infrastructure deployment is described, emphasizing its speed and ease of use and support. The validity of the analysis techniques is confirmed through the pilot study described here--with the application to a large sample of immunohistochemistry microscopy data obtained in part for assessing the oestrogen receptor status of breast cancers. The analysis showed that the specificity and sensitivity values for the automatic scoring using PathGrid were within the errors of those obtained via a 'gold standard' manual pathologist scoring.