Genetic control of bone density and turnover: Role of the collagen 1α1, estrogen receptor, and vitamin D receptor genes

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1α1 (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.

Cost effectiveness of bone density measurements

Objective. To assess the cost-effectiveness of bone density screening programmes for osteoporosis. Study design. Using published and locally available data regarding fracture rates and treatment costs, the overall costs per fracture prevented, cost per quality of life year (QALY) saved and cost per year of life gained were estimated for different bone density screening and osteoporosis treatment programmes. Main outcome measures. Cost per fracture prevented, cost per QALY saved, and cost per year of life gained. Results. In women over the age of 50 years, the costs per fracture prevented of treating all women with hormone replacement therapy, or treating only if osteoporosis is demonstrated on bone density screening were £32,594 or £23,867 respectively. For alendronate therapy for the same groups, the costs were £171,067 and £14,067 respectively. Once the background rate of treatment with alendronate reaches 18%, bone density screening becomes cost-saving. Costs estimates per QALY saved ranged from £1,514 to £39,076 for osteoporosis treatment with alendronate following bone density screening. Conclusions. For relatively expensive medications such as alendronate, treatment programmes with prior bone density screening are far more cost effective than those without, and in some circumstances become cost-saving. Costs per QALY of life saved and per year of life gained for osteoporosis treatment with prior bone density screening compare favourably with treatment of hypertension and hypercholesterolemia.

Spatio-temporal modelling of cancer data in Queensland using Bayesian methods

Cancer is the leading contributor to the disease burden in Australia. This thesis develops and applies Bayesian hierarchical models to facilitate an investigation of the spatial and temporal associations for cancer diagnosis and survival among Queenslanders. The key objectives are to document and quantify the importance of spatial inequalities, explore factors influencing these inequalities, and investigate how spatial inequalities change over time. Existing Bayesian hierarchical models are refined, new models and methods developed, and tangible benefits obtained for cancer patients in Queensland. The versatility of using Bayesian models in cancer control are clearly demonstrated through these detailed and comprehensive analyses.

Submission to the Senate Economics References Committee Inquiry into affordable housing 20 August 2014: De-risking development of medium density housing to improve housing affordability and boost supply

This submission addresses the problem of housing price inflation, the chronic under-supply of new housing stock, and the resultant decline in housing affordability for low and middle income households. It specifically focusses on the supply of medium density housing (multi-unit development) in Melbourne, although we believe that the observations made about housing in supply in Melbourne are relevant in other urban centres and to other types of housing supply. In terms of medium density housing (MDH) our concern also extends to the poor quality and design. Why the market tends to deliver generic apartments of poor quality and design which are uncompetitive with lower density housing and amenity despite planning objectives, and how this apparently intractable problem can be overcome is the topic of this submission...

Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

Introduction: Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T1-weighted (T1w), T2*- weighted (T2*w) and quantitative T2*(qT 2*) imaging. Methods: Six patients with an asymptomatic carotid stenosis underwent high resolution T1w, T2*w and qT2*MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem™, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. Results: The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T1w, T 2*w and qT2*sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T1w, T 2*w and qT2*, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. Conclusion: This study showed that a suitable imaging window for T 1w, T2*w and qT2*signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients.

Effects of fish density distribution and effort distribution on catchability

The effects of fish density distribution and effort distribution on the overall catchability coefficient are examined. Emphasis is also on how aggregation and effort distribution interact to affect overall catch rate [catch per unit effort (cpue)]. In particular, it is proposed to evaluate three indices, the catchability index, the knowledge parameter, and the aggregation index, to describe the effectiveness of targeting and the effects on overall catchability in the stock area. Analytical expressions are provided so that these indices can easily be calculated. The average of the cpue calculated from small units where fishing is random is a better index for measuring the stock abundance. The overall cpue, the ratio of lumped catch and effort, together with the average cpue, can be used to assess the effectiveness of targeting. The proposed methods are applied to the commercial catch and effort data from the Australian northern prawn fishery. The indices are obtained assuming a power law for the effort distribution as an approximation of targeting during the fishing operation. Targeting increased catchability in some areas by 10%, which may have important implications on management advice.

Modelling growth rate of Penaeus monodon Fabricius in intensively managed ponds: effects of temperature, pond age and stocking density

Records of shrimp growth and water quality made during 12 crops from each of 48 ponds, over a period of 6.5 years, were provided by a Queensland, Australia, commercial shrimp farm, These data were analysed with a new growth model derived from the Gompertz model. The results indicate that water temperature, mortality and pond age significantly affect growth rates. After 180 days, shrimp reach 34 g at constant 30 degrees C, but only 15 g after the same amount of time at 20 degrees C. Mortality, through thinning the density of shrimp in the ponds, increased the growth rate, but the effect is small. With continual production, growth rates at first remained steady, then appeared to decrease for the sixth and seventh crop, after which they have increased steadily with each crop. It appears that conservative pond management, together with a gradual improvement in husbandry techniques, particularly feed management, brought about this change. This has encouraging implications for the long-term sustainability of the farming methods used. The growth model can be used to predict productivity, and hence, profitability, of new aquaculture locations or new production strategies.

Spatial and temporal distribution of tropical phytoplankton species and biomass in the Gulf of Carpenteria, Australia

The biomass and species composition of tropical phytoplankton in Albatross Bay, Gulf of Carpentaria, northern Australia, were examined monthly for 6 yr (1986 to 1992). Chlorophyll a (chl a) concentrations were highest (2 to 5.7 mu g l(-1)) in the wet season at inshore sites, usually coinciding with low salinities (30 to 33 ppt) and high temperatures (29 to 32 degrees C). At the offshore sites chi a concentrations were lower (0.2 to 2 mu g l(-1)) and did not vary seasonally. Nitrate and phosphate concentrations were generally low (0 to 3.68 mu M and 0.09 to 3 mu M for nitrate and phosphate respectively), whereas silicate was present in concentrations in the range 0.19 to 13 mu M. The phytoplankton community was dominated by diatoms, particularly at the inshore sites, as determined by a combination of microscopic and high-performance liquid chromatography (HPLC) pigment analyses. At the offshore sites the proportion of green flagellates increased. The cyanobacterium genus Trichodesmium and the diatom genera Chaetoceros, Rhizosolenia, Bacteriastrum and Thalassionema dominated the phytoplankton caught in 37 mu m mesh nets; however, in contrast to many other coastal areas studied worldwide there was no distinct species succession of the diatoms and only Trichodesmium showed seasonal changes in abundance. This reflects a stable phytoplankton community in waters without pulses of physical and chemical disturbances. These results are discussed in the context of the commercial prawn fishery in the Gulf of Carpentaria and the possible effect of phytoplankton on prawn larval growth and survival.

Learning Temporal Alignment Uncertainty for Efficient Event Detection

In this paper we tackle the problem of efficient video event detection. We argue that linear detection functions should be preferred in this regard due to their scalability and efficiency during estimation and evaluation. A popular approach in this regard is to represent a sequence using a bag of words (BOW) representation due to its: (i) fixed dimensionality irrespective of the sequence length, and (ii) its ability to compactly model the statistics in the sequence. A drawback to the BOW representation, however, is the intrinsic destruction of the temporal ordering information. In this paper we propose a new representation that leverages the uncertainty in relative temporal alignments between pairs of sequences while not destroying temporal ordering. Our representation, like BOW, is of a fixed dimensionality making it easily integrated with a linear detection function. Extensive experiments on CK+, 6DMG, and UvA-NEMO databases show significant performance improvements across both isolated and continuous event detection tasks.

On the order of the fractional Laplacian in determining the spatio-temporal evolution of a space-fractional model of cardiac electrophysiology

Space-fractional operators have been used with success in a variety of practical applications to describe transport processes in media characterised by spatial connectivity properties and high structural heterogeneity altering the classical laws of diffusion. This study provides a systematic investigation of the spatio-temporal effects of a space-fractional model in cardiac electrophysiology. We consider a simplified model of electrical pulse propagation through cardiac tissue, namely the monodomain formulation of the Beeler-Reuter cell model on insulated tissue fibres, and obtain a space-fractional modification of the model by using the spectral definition of the one-dimensional continuous fractional Laplacian. The spectral decomposition of the fractional operator allows us to develop an efficient numerical method for the space-fractional problem. Particular attention is paid to the role played by the fractional operator in determining the solution behaviour and to the identification of crucial differences between the non-fractional and the fractional cases. We find a positive linear dependence of the depolarization peak height and a power law decay of notch and dome peak amplitudes for decreasing orders of the fractional operator. Furthermore, we establish a quadratic relationship in conduction velocity, and quantify the increasingly wider action potential foot and more pronounced dispersion of action potential duration, as the fractional order is decreased. A discussion of the physiological interpretation of the presented findings is made.

The effects of +Gz force on the bone mineral density of fighter pilots

HYPOTHESIS Bone is a metabolically active tissue which responds to high strain loading. The purpose of this study was to examine the bone response to high +Gz force loading generated during high performance flying. METHODS The bone response to +Gz force loading was monitored in 10 high performance RAAF pilots and 10 gender-, age-, height-, weight-matched control subjects. The pilots were stationed at the RAAF base at Pearce, Western Australia, all completing the 1-yr flight training course. The pilots flew the Pilatus PC-9 aircraft, routinely sustaining between 2.0 and 6.0 +Gz. Bone mineral density (BMD) and bone mineral content (BMC) were measured at baseline and 12 mo, using the Hologic QDR 2000+ bone densitometer. RESULTS After controlling for change in total body weight and fat mass, the pilots experienced a significant increase in BMD and BMC for thoracic spine, pelvis, and total body, in the magnitude of 11.0%, 4.9%, and 3.7%, respectively. However, no significant changes in bone mineral were observed in the pilots lumbar spine, arms or legs. The control group experienced a significant decrease in pelvic BMC, with no other bone mineral changes observed at any site. CONCLUSIONS These findings suggest that site specific BMD is increased in response to high +Gz forces generated during high performance flying in a PC-9.

Estimating cell diffusivity and cell proliferation rate by interpreting IncuCyte ZOOM™ assay data using the Fisher-Kolmogorov model

Background: Standard methods for quantifying IncuCyte ZOOM™ assays involve measurements that quantify how rapidly the initially-vacant area becomes re-colonised with cells as a function of time. Unfortunately, these measurements give no insight into the details of the cellular-level mechanisms acting to close the initially-vacant area. We provide an alternative method enabling us to quantify the role of cell motility and cell proliferation separately. To achieve this we calibrate standard data available from IncuCyte ZOOM™ images to the solution of the Fisher-Kolmogorov model. Results: The Fisher-Kolmogorov model is a reaction-diffusion equation that has been used to describe collective cell spreading driven by cell migration, characterised by a cell diffusivity, D, and carrying capacity limited proliferation with proliferation rate, λ, and carrying capacity density, K. By analysing temporal changes in cell density in several subregions located well-behind the initial position of the leading edge we estimate λ and K. Given these estimates, we then apply automatic leading edge detection algorithms to the images produced by the IncuCyte ZOOM™ assay and match this data with a numerical solution of the Fisher-Kolmogorov equation to provide an estimate of D. We demonstrate this method by applying it to interpret a suite of IncuCyte ZOOM™ assays using PC-3 prostate cancer cells and obtain estimates of D, λ and K. Comparing estimates of D, λ and K for a control assay with estimates of D, λ and K for assays where epidermal growth factor (EGF) is applied in varying concentrations confirms that EGF enhances the rate of scratch closure and that this stimulation is driven by an increase in D and λ, whereas K is relatively unaffected by EGF. Conclusions: Our approach for estimating D, λ and K from an IncuCyte ZOOM™ assay provides more detail about cellular-level behaviour than standard methods for analysing these assays. In particular, our approach can be used to quantify the balance of cell migration and cell proliferation and, as we demonstrate, allow us to quantify how the addition of growth factors affects these processes individually.

Unpacking the perceived opportunity to misbehave: The influence of spatio-temporal and social dimensions on consumer misbehavior

Purpose This study aims to use opportunity as a theoretical lens to investigate how the spatio-temporal and social dimensions of the consumption environment create perceived opportunities for consumers to misbehave. Design/methodology/approach Drawing on routine activity theory and social impact theory, the authors use two experiments to demonstrate that spatio-temporal and social dimensions can explain consumer theft in retail settings. Findings Study 1 reveals mixed empirical support for the basic dimensions of routine activity theory, which posits that the opportunity to thieve is optimised when a motivated offender, suitable target and the absence of a capable formal guardian transpire in time and space. Extending the notion of guardianship, Study 2 tests social impact theory and shows that informal guardianship impacts the likelihood of theft under optimal routine activity conditions. Originality/value The study findings highlight important implications for academicians and retail managers: rather than focusing on the uncontrollable characteristics of thieving offenders, more controllable spatio-temporal and social factors of the retail environment can be actively monitored and manipulated to reduce perceived opportunities for consumer misbehaviour.

High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19

OBJECTIVE To refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidate genes for endometriosis. DESIGN Case-control study. SETTING Academic research. PATIENT(S) Cases=3,223 women with surgically confirmed endometriosis; controls=1,190 women without endometriosis and 7,060 population samples. INTERVENTION(S) Analysis of 11,984 single nucleotide polymorphisms on chromosome 10. MAIN OUTCOME MEASURE(S) Allele frequency differences between cases and controls. RESULT(S) Linkage analyses on families grouped by endometriosis symptoms (primarily subfertility) provided increased evidence for linkage (logarithm of odds score=3.62) near a previously reported linkage peak. Three independent association signals were found at 96.59 Mb (rs11592737), 105.63 Mb (rs1253130), and 124.25 Mb (rs2250804). Analyses including only samples from linkage families supported the association at all three regions. However, only rs11592737 in the cytochrome P450 subfamily C (CYP2C19) gene was replicated in an independent sample of 2,079 cases and 7,060 population controls. CONCLUSION(S) The role of the CYP2C19 gene in conferring risk for endometriosis warrants further investigation.

A high-density association screen of 155 ion transport genes for involvement with common migraine

The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.