'Sink or swim': An evaluation of the clinical characteristics of individuals with high bone mass

Summary High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. Introduction High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. Methods Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. Results Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m 2, p < 0.001). Conclusion Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.

Common variants in the region around Osterix are associated with bone mineral density and growth in childhood

Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 × 10-4; Australia: P = 3.7 × 10-4). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 × 10-11). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 × 10-5). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.

Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes

INTRODUCTION Although the high heritability of BMD variation has long been established, few genes have been conclusively shown to affect the variation of BMD in the general population. Extreme truncate selection has been proposed as a more powerful alternative to unselected cohort designs in quantitative trait association studies. We sought to test these theoretical predictions in studies of the bone densitometry measures BMD, BMC, and femoral neck area, by investigating their association with members of the Wnt pathway, some of which have previously been shown to be associated with BMD in much larger cohorts, in a moderate-sized extreme truncate selected cohort (absolute value BMD Z-scores = 1.5-4.0; n = 344). MATERIALS AND METHODS Ninety-six tag-single nucleotide polymorphism (SNPs) lying in 13 Wnt signaling pathway genes were selected to tag common genetic variation (minor allele frequency [MAF] > 5% with an r(2) > 0.8) within 5 kb of all exons of 13 Wnt signaling pathway genes. The genes studied included LRP1, LRP5, LRP6, Wnt3a, Wnt7b, Wnt10b, SFRP1, SFRP2, DKK1, DKK2, FZD7, WISP3, and SOST. Three hundred forty-four cases with either high or low BMD were genotyped by Illumina Goldengate microarray SNP genotyping methods. Association was tested either by Cochrane-Armitage test for dichotomous variables or by linear regression for quantitative traits. RESULTS Strong association was shown with LRP5, polymorphisms of which have previously been shown to influence total hip BMD (minimum p = 0.0006). In addition, polymorphisms of the Wnt antagonist, SFRP1, were significantly associated with BMD and BMC (minimum p = 0.00042). Previously reported associations of LRP1, LRP6, and SOST with BMD were confirmed. Two other Wnt pathway genes, Wnt3a and DKK2, also showed nominal association with BMD. CONCLUSIONS This study shows that polymorphisms of multiple members of the Wnt pathway are associated with BMD variation. Furthermore, this study shows in a practical trial that study designs involving extreme truncate selection and moderate sample sizes can robustly identify genes of relevant effect sizes involved in BMD variation in the general population. This has implications for the design of future genome-wide studies of quantitative bone phenotypes relevant to osteoporosis.

'Free' surfactant in gastric aspirates and bronchoalveolar lavage in children with and without reflux oesophagitis

Aim: Dipalmitoylphosphatidycholine (DPPC) is the characteristic and main constituent of surfactant. Adsorption of surfactant to epithelial surfaces may be important in the masking of receptors. The aims of the study were to (i) compare the quantity of free DPPC in the airways and gastric aspirates of children with gastroesophageal reflux disease (GORD) to those without and (ii) describe the association between free DPPC levels with airway cellular profile and capsaicin cough sensitivity. Methods: Children aged <14 years were defined as 'coughers' if a history of cough in association with their GORD symptoms was elicited before gastric aspirates and nonbronchoscopic bronchoalveolar lavage (BAL) were obtained during elective flexible upper gastrointestinal endoscopy. GORD was defined as histological presence of reflux oesophagitis. Spirometry and capsaicin cough-sensitivity test was carried out in children aged >6 years before the endoscopy. Results: Median age of the 68 children was 9 years (interquartile range (IQR) 7.2). Median DPPC level in BAL of children with cough (72.7 μg/mL) was similar to noncoughers (88.5). There was also no significant difference in DPPC levels in both BAL and gastric aspirates of children classified according to presence of GORD. There was no correlation between DPPC levels and cellular counts or capsaicin cough-sensitivity outcome measures. Conclusion: We conclude that free DPPC levels in the airways and gastric aspirate is not influenced by presence of cough or GORD defined by histological presence of reflux oesophagitis. Whether quantification of adsorbed surfactant differs in these groups remain unknown. Free DPPC is unlikely to have a role in masking of airway receptors. © 2006 Royal Australasian College of Physicians.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5–89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

Architectural changes of the biceps femoris after concentric or eccentric training

Purpose To determine i) the architectural adaptations of the biceps femoris long head (BFlf) following concentric or eccentric strength training interventions; ii) the time course of adaptation during training and detraining. Methods Participants in this randomized controlled trial (control [n=28], concentric training group [n=14], eccentric training group [n=14], males) completed a 4-week control period, followed by 6 weeks of either concentric- or eccentric-only knee flexor training on an isokinetic dynamometer and finished with 28 days of detraining. Architectural characteristics of BFlf were assessed at rest and during graded isometric contractions utilizing two-dimensional ultrasonography at 28 days pre-baseline, baseline, days 14, 21 and 42 of the intervention and then again following 28 days of detraining. Results BFlf fascicle length was significantly longer in the eccentric training group (p<0.05, d range: 2.65 to 2.98) and shorter in the concentric training group (p<0.05, d range: -1.62 to -0.96) after 42 days of training compared to baseline at all isometric contraction intensities. Following the 28-day detraining period, BFlf fascicle length was significantly reduced in the eccentric training group at all contraction intensities compared to the end of the intervention (p<0.05, d range: -1.73 to -1.55). There was no significant change in fascicle length of the concentric training group following the detraining period. Conclusions These results provide evidence that short term resistance training can lead to architectural alterations in the BFlf. In addition, the eccentric training-induced lengthening of BFlf fascicle length was reversed and returned to baseline values following 28 days of detraining. The contraction mode specific adaptations in this study may have implications for injury prevention and rehabilitation.

The trend toward pre-graduation professional work experience for Australian young planners: Essential experience or essentially exploitation

This paper explores the changing employment expectations that frame the early professional work experiences of young planners in Australia. In particular, it considers the rising popularity of pre-graduation professional work experience as a precursor to formal entry into the workforce as a practising planner. This shift is being driven in part by employer expectations that graduates will already have ‘real world’ and relevant work experience. However, an equally significant driver appears to be a growing desire for early career and graduate planners to find ways to distinguish themselves from their peers in an increasingly tight labour market. Using data from an ongoing research project into the formative work experiences of young people this paper describes the three main types of pre-graduation professional work experience undertaken by young planners. It highlights the potential challenges and benefits of pre-graduation work experience from a legal, social and ethical perspective as well as from the perspective of young planners themselves. The paper concludes by reflecting on the role of the planning profession – employers, peak bodies and planning educators – in managing the tensions between producing ‘work ready’ graduates and safeguarding the employment conditions of early career planning professionals.

Director independence or decision bias? An investigation of alternative sources of agency costs in board decision making

Research into boards traditionally focuses on independent monitoring of management, with studies focused on the effect of board independence on firm performance. This thesis aims to broaden the research tradition by consolidating prior research and investigating how agents may circumvent independent monitoring. Meta-analysis of previous board independence-firm performance studies indicated no systematic relationship between board independence and firm performance. Next, a series of experiments demonstrated that the presentation of recommendations to directors may bias decision making irrespective of other information presented and the independence of the decision maker. Together, results suggest that independence may be less important than the agent's motivation to misdirect the monitoring process.

Reconceptualising inclusion as participation: Neoliberal buck-passing or strategic by-passing?

This paper investigates increases in the identification of special educational needs in the New South Wales (NSW) government school system over the last two decades, which are then discussed with senior public servants working within the NSW Department of Education and Communities (DEC). Participant narratives indicate deep structural barriers to inclusion that are perpetuated by the discourses and practices of regular and special education. Despite policies that speak of ‘working together’ for ‘every student’ and ‘every school’, students who experience difficulty in schools and with learning often remain peripheral to the main game, even though their number is said to be increasing. There is, however, some positive progress being made. Findings suggest that key policy figures within the NSW DEC are keenly aware of the barriers and have adopted alternative strategies to drive inclusion via a new discourse of ‘participation’ which is underpinned by the linking of student assessment and the resourcing of schools.

The functional liminality of the not-dead-yet students, or, how public schooling became compulsory: A glancing history

This paper redefines the focus for narrating histories of education in the USA through a ‘glancing history’. It highlights the important role played by ‘not-dead-yet students’ who occupied a liminal place on the scale of life in late nineteenth- and early twentieth-century. Traditional histories of education have been more singularly focused on the advent and dynamics of public schooling, ignoring the functionality of such child subjects to public schooling’s existence. This paper argues that public schools as historical objects cannot be understood outside of a broader trinary system of prior institutions that were established for ‘delinquent’ and ‘special’ children. These prior institutions facilitated the formation of ‘the public’ in public schooling less in opposition to ‘the private’ and more in consonance with ‘the human’. The existence of prior institutions enabled the enforcement of compulsory attendance legislation. Compulsory attendance legislation, in place across all existing states by 1918, was concerned more with the conditions for exclusion and exemption than with compelling attendance. Thus, at the most immediate level, this paper historicizes some of the discursive and hence institutional events that linked an array of tutelary complexes by the early 1900s, and which enabled such legislation. This part of the argument extends the notion of institution to consider broader places of confinement and systematicity. It examines the prior practice of reservation and slavery systems, and the efficacy they lent to further institutionalized segregation in the USA. At a second level, the narrative reflects on how such a narration has become possible. It considers how histories of education can currently be rethought and rewritten around the notion of dis/ability, historicizing the formation of dis/ability as identity categories made noticeable in part (and circularly) through the crystallization of a segregated but linked common schooling system. The paper thus provides a counter-memory against dominant economic foundationalist and psychomedical accounts of schooling’s past. It documents both ‘external’ conditions of possibility for public schooling’s emergence and ‘internal’ effects that emerged through the experiences of confinement

Wife beating: A measure to deal with marital disharmony or a license for misconduct

Wife beating is not a new phenomena rather it has been practiced from pre historic time till date. This was due to the fact that in all the civilizations and under all religions, woman was considered subjugated to men. Her natural physical weakness had also made her vulnerable for violence. Islam reinforced womanhood by protecting her rights and providing her respect in the family and society at large. However, it is not interpreted accurately in male dominant society due to the existence of a patriarchal social setup. Adding to the ignorance regarding the position of women in Islam, the presence of injustice and mal practices in contemporary Muslim societies has been taken up as a weak point of Islam by non Muslims as well by less informed Muslims. The reasons for denying women’s rights in Pakistani society could be summed up as lack of education, ignorance about Islamic teachings, feudal and tribal cultural traditions, male dominated patriarchal attitudes, poverty, unemployment and misinterpretations regarding precise teachings of Quran and Sunnah. There are many misconceptions regarding the stance of Islam on wife beating as well. It is commonly understood that Islam gives permission for wife beating in the Quranic verse 4:34. This article will describe the relationship between husband and wife in the light of Quranic verse4:34 and will explore the sanctions of wife beating and its dimensions. Furthermore, it will aim to remove misunderstandings and prejudged opinions related to the concerned issue, in the light of Quran and Sunnah.

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Developing novel drugs against the unicellular parasite Plasmodium is complicated by the paucity of simple screening systems. Heat-shock proteins are an essential class of proteins for the parasite's cyclical life style between different cellular milieus and temperatures. The molecular chaperone Hsp90 assists a large variety of proteins, but its supporting functions for many proteins that are important for cancer have made it into a well-studied drug target. With a better understanding of the differences between Hsp90 of the malarial parasite and Hsp90 of its human host, new therapeutic options might become available. We have generated a set of isogenic strains of the budding yeast Saccharomyces cerevisiae where the essential yeast Hsp90 proteins have been replaced with either of the two human cytosolic isoforms Hsp90 alpha or Hsp90 beta, or with Hsp90 from Plasmodium falciparum (Pf). All strains express large amounts of the Flag-tagged Hsp90 proteins and are viable. Even though the strain with Pf Hsp90 grows more poorly, it provides a tool to reconstitute additional aspects of the parasite Hsp90 complex and its interactions with substrates in yeast as a living test tube. Upon exposure of the set of Hsp90 test strains to the two Hsp90 inhibitors radicicol (Rd) and geldanamycin (GA), we found that the strain with Pf Hsp90 is relatively more sensitive to GA than to Rd compared to the strains with human Hsp90's. This indicates that this set of yeast strains could be used to screen for new Pf Hsp90 inhibitors with a wider therapeutic window.

Sri Lankan entrepreneurs in Australia: Chance or choice?

Purpose Ethnic entrepreneurship is, and always has been, a means of survival. However, there is limited literature on ethnic entrepreneurship in Australia and therefore, an understanding of ethnic entrepreneurs’ motivations to become self-employed. The purpose of this paper is to report the influential factors in the decision to engage in self-employment through case studies of members of Melbourne’s Sri Lankan community informed by the mixed embeddedness approach. Design/methodology/approach The mixed embeddedness approach frames the study where the authors examine the motivations for business of five Sri Lankan entrepreneurs. Narratives are used to construct individual case studies, which are then analyzed in terms of the motivations for, resources used and challenges faced on the entrepreneurial journey. Findings For these ethnic entrepreneurs, their entrepreneurial activity results from a dynamic match between local market opportunities and the specific ethnic resources available to them at the time of founding. The self-employment decision was not prompted by a lack of human capital but an inability to use that human capital in alternative means of employment at specific points in time. Moreover the authors highlight the importance of social and cultural capital as resources used to overcome challenges on the entrepreneurial journey. Originality/value In this community, entrepreneurship was not a result of a lack of human capital but how it was utilized in combination with social and cultural capitals in the given opportunity structure. The mixed embeddedness approach enables the uncovering of how ethnic network ties were used in light of the opportunities available to build entrepreneurial activity.

Characterisation of k-Variegated Graphs, k greater-than-or-equal-to 3

A graph is said to be k-variegated if its vertex set can be partitioned into k equal parts such that each vertex is adjacent to exactly one vertex from every other part not containing it. Bednarek and Sanders [1] posed the problem of characterizing k-variegated graphs. V.N. Bhat-Nayak, S.A. Choudum and R.N. Naik [2] gave the characterization of 2-variegated graphs. In this paper we characterize k-variegated graphs for k greater-or-equal, slanted 3.

Inhibition of 3-hydroxy-3-methylglutaryl coenzyme a reductase by cytosolic proteins - real or artifact

The inhibitory effect of FeSO4-dependent cytosolic protein on microsomal HMGCoA reductase is on the enzyme activity and not an artifact of loss of the product, mevalonate, through phosphorylation, unlike that of ATP.Mg effect.