Mechanical stimulation of the pro-angiogenic capacity of human fracture haematoma: Involvement of VEGF mechano-regulation

Compromised angiogenesis appears to be a major limitation in various suboptimal bone healing situations. Appropriate mechanical stimuli support blood vessel formation in vivo and improve healing outcomes. However, the mechanisms responsible for this association are unclear. To address this question, the paracrine angiogenic potential of early human fracture haematoma and its responsiveness to mechanical loading, as well as angiogenic growth factors involved, were investigated in vitro. Human haematomas were collected from healthy patients undergoing surgery within 72. h after bone fracture. The haematomas were embedded in a fibrin matrix, and cultured in a bioreactor resembling the in vivo conditions of the early phase of bone healing (20 compression, 1. Hz) over 3. days. Conditioned medium (CM) from the bioreactor was then analyzed. The matrices were also incubated in fresh medium for a further 24. h to evaluate the persistence of the effects. Growth factor (GF) concentrations were measured in the CM by ELISAs. In vitro tube formation assays were conducted on Matrigel with the HMEC-1 cell line, with or without inhibition of vascular endothelial growth factor receptor 2 (VEGFR2). Cell numbers were quantified using an MTS test. In vitro endothelial tube formation was enhanced by CM from haematomas, compared to fibrin controls. The angiogenesis regulators, vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGF-β1), were released into the haematoma CM, but not angiopoietins 1 or 2 (Ang1, 2), basic fibroblast growth factor (bFGF) or platelet-derived growth factor (PDGF). Mechanical stimulation of haematomas, but not fibrin controls, further increased the induction of tube formation by their CM. The mechanically stimulated haematoma matrices retained their elevated pro-angiogenic capacity for 24. h. The pro-angiogenic effect was cancelled by inhibition of VEGFR2 signalling. VEGF concentrations in CM tended to be elevated by mechanical stimulation; this was significant in haematomas from younger, but not from older patients. Other GFs were not mechanically regulated. In conclusion, the paracrine pro-angiogenic capacity of early human haematomas is enhanced by mechanical stimulation. This effect lasts even after removing the mechanical stimulus and appears to be VEGFR2-dependent.

Birth control : to what extent do women report being informed and involved in decisions about pregnancy and birth procedures?

Background: Health policy, guidelines, and standards advocate giving patients comprehensive information and facilitating their involvement in health-related decision-making. Routine assessment of patient reports of these processes is needed. Our objective was to examine decision-making processes, specifically information provision and consumer involvement in decision-making, for nine pregnancy, labour, and birth procedures, as reported by maternity care consumers in Queensland, Australia. Methods: Participants were women who had a live birth in Queensland in a specified time period and were not found to have had a baby that died since birth, who completed the extended Having a Baby in Queensland Survey, 2010 about their maternity care experiences, and who reported at least one of the nine procedures of interest. For each procedure, women answered two questions that measured perceived (i) receipt of information about the benefits and risks of the procedure and (ii) role in decision-making about the procedure. Results: In all, 3,542 eligible women (34.2%) completed the survey. Between 4% (for pre-labour caesarean section) and 60% (for vaginal examination) of women reported not being informed of the benefits and risks of the procedure they experienced. Between 2% (epidural) and 34% (episiotomy) of women reported being unconsulted in decision-making. Over one quarter (26%) of the women who experienced episiotomy reported being neither informed nor consulted. Conclusions: There is an urgent need for interventions that facilitate information provision and consumer involvement in decision-making about several perinatal procedures, especially those performed within the time-limited intrapartum care episode.

Friendships in the early years

Having a best friend or close friend is closely connected to children’s health and well being in the early years. Having friends safeguards children from social isolation and is associated with academic attainment and social success. In early childhood, children often make friends through play or other shared activities. This chapter investigates friendships and children’s well being in the early years of schooling. Drawing on direct accounts and representations from interviews with young children about friendships, the chapter outlines characteristics of friendship and strategies children use to make friends and manage disputes as they negotiate roles in play and shared spaces. Three key dimensions of friendship are evident in the children’s accounts: friendship is enduring, friendship is mutual and friendship involves an emotional investment. This chapter provides educators with an understanding of the important role that friendships have for happiness and wellbeing in the early years.

Inter-sector senior leader transitions : experience and outcomes

Purpose The purpose of this article is to explore the experience of senior leaders who move into the public sector from other sectors of the economy, a process we refer to as inter-sector senior leader transitions. This is a little researched area of public sector leadership yet has significant implications for fundamental public sector reform. Design/methodology/approach We employed an interview design to elicit senior leaders' stories of their transition into the public sector. Findings The data suggest that successful senior leader transitions are more likely when a set of conditions is met; (1) the leader transitions into CEO role, rather than levels below CEO, (2) Ministers provide inter-sector transition support, (3) senior leaders develop responses to stress, (4) senior leaders reject high formalization, (5) their change processes focus on building capacity, and (6) senior leaders confront dysfunctional organizational relationships directly. Research limitations/implications The research relies on a relatively small sample. However, access to senior managers at this level can be difficult. Nevertheless, those senior managers who participated were very willing to share their stories. Practical implications If public sector organizations are to realize the value of successful leaders from other sectors, they need to invest in structured processes that facilitate the transition. A laissez-faire approach is not viable given the cost of such transitions. Originality/value The paper focuses on a little researched area of leadership experience which has significant implications for the development and change of the public sector.

Australian pharmacists' understanding of their continuing professional development obligations

Background The adoption of continuing professional development (CPD) in Australia is still relatively new [expand]. There is limited information on how Australian pharmacists have engaged with the CPD requirements for registration. Aim To explore Australian registered pharmacists’ understanding and engagement with the requirement for CPD credits for registration. Method The Pharmacy Board of Australia’s CPD requirements for registration was used as a guide to design an online survey to ascertain Australian pharmacists understanding and engagement in the acquisition of CPD credits for registration. Results A total of 278 pharmacists responded to the survey – 66% were female and 30% were male (4% did not disclose their gender). 63% of respondents felt that it would not be difficult to acquire 40 CPD credits annually; with pharmacists identifying that Group 1 activities were a preferred way of acquiring CPD credits. The majority of pharmacists (91%) believed that they knew what the current CPD requirements for general registration are and 77% felt that there has been enough guidance provided to assist them. Despite this, 26% of participants had never used self directed learning plans and 38% did not know how to undertake self-directed learning. 76% of participants were under the common misconception that CPD is synonymous with continuing education. Conclusion The majority of registered pharmacists believe they understand and can engage in the acquisition of CPD credits for registration. However, some aspects of the process was not understood. The key link of how this process aims to develop individual practice needs to be further developed within the profession.

Pharmacists' understanding of their CPD obligations

The article offers information on the requirement of the continuing professional development (CPD) training and lifelong learning for the legal registration of the Australian practitioners and pharmacists. Topics discussed include reviewing the competitiveness and pharmacy practice benefits, strategic planning for getting the requirement of CPD, and improving and broadening of the knowledge and developing the personal and professional qualities of pharmacists.

The disenfranchisement of prisoners : Roach v Electoral Commissioner & Anor - modernity v feudalism

David Brown takes a road trip to Canberra for the Roach fixture at the High Court where modernity is attempting a fight-back against the resurrection of civil death. With echoes of Hunter S Thompson as rugby league follower, the author recounts a trip to Canberra to observe a case in which Vickie Lee Roach, an Indigenous woman prisoner, challenged (successfully as it later turns out) the Howard government's 2006 legislation disenfranchising all serving prisoners.

Polymorphisms in inflammation pathway genes and endometrial cancer risk

BACKGROUND Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. METHODS To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls. RESULTS Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples. CONCLUSIONS These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.

Benthic shift in a Solomon Islands' lagoon : corals to cyanobacteria

In June 2011 a large phytoplankton bloom resulted in a catastrophic mortality event that affected a large coastal embayment in the Solomon Islands. This consisted of an area in excess of 20 km2 of reef and soft sandy habitats in Marovo Lagoon, the largest double barrier lagoon in the world. This embayment is home to over 1200 people leading largely subsistence lifestyles depending on the impacted reefs for majority of their protein needs. A toxic diatom (Psuedo-nitzchia spp.) and toxic dinoflagellate (Pyrodinium bahamense var. compressum) reached concentrations of millions of cells per litre. The senescent phytoplankton bloom led to complete de-oxygenation of the water column that reportedly caused substantial mortality of marine animal life in the immediate area within a rapid timeframe (24 h). Groups affected included holothurians, crabs and reef and pelagic fish species. Dolphins, reptiles and birds were also found dead within the area, indicating algal toxin accumulation in the food chain. Deep reefs and sediments, whilst initially unaffected, have now been blanketed in large cyanobacterial mats which have negatively impacted live coral cover especially within the deep reef zone (> 6 m depth). Reef recovery within the deep zone has been extremely slow and may indicate an alternative state for the system.

Are lifecycle funds appropriate as default options in participant-directed retirement plans?

The appropriateness of default investment options in participant-directed retirement plans like 401(k) has been in sharp focus given that most participants fail to nominate an investment option to direct their contributions. In United States (US), prior to the Pension Protection Act (PPA) of 2006, plan fiduciaries often selected a money market fund as the default option. Whilst this ‘low risk and low return’ investment option was considered to be a ‘safe’ choice by many fiduciaries who were fearful of litigation risk, it was heavily criticized for resulting in inadequate wealth at retirement, particularly when retirees were living much longer and facing inflation risk (see, for example, Viceira, 2008; Skinner, 2009)...

Understanding the abnormal brain activity in epilepsy as a potential predictor of the onset of an epileptic seizure

The Brain Research Institute (BRI) uses various types of indirect measurements, including EEG and fMRI, to understand and assess brain activity and function. As well as the recovery of generic information about brain function, research also focuses on the utilisation of such data and understanding to study the initiation, dynamics, spread and suppression of epileptic seizures. To assist with the future focussing of this aspect of their research, the BRI asked the MISG 2010 participants to examine how the available EEG and fMRI data and current knowledge about epilepsy should be analysed and interpreted to yield an enhanced understanding about brain activity occurring before, at commencement of, during, and after a seizure. Though the deliberations of the study group were wide ranging in terms of the related matters considered and discussed, considerable progress was made with the following three aspects. (1) The science behind brain activity investigations depends crucially on the quality of the analysis and interpretation of, as well as the recovery of information from, EEG and fMRI measurements. A number of specific methodologies were discussed and formalised, including independent component analysis, principal component analysis, profile monitoring and change point analysis (hidden Markov modelling, time series analysis, discontinuity identification). (2) Even though EEG measurements accurately and very sensitively record the onset of an epileptic event or seizure, they are, from the perspective of understanding the internal initiation and localisation, of limited utility. They only record neuronal activity in the cortical (surface layer) neurons of the brain, which is a direct reflection of the type of electrical activity they have been designed to record. Because fMRI records, through the monitoring of blood flow activity, the location of localised brain activity within the brain, the possibility of combining fMRI measurements with EEG, as a joint inversion activity, was discussed and examined in detail. (3) A major goal for the BRI is to improve understanding about ``when'' (at what time) an epileptic seizure actually commenced before it is identified on an eeg recording, ``where'' the source of this initiation is located in the brain, and ``what'' is the initiator. Because of the general agreement in the literature that, in one way or another, epileptic events and seizures represent abnormal synchronisations of localised and/or global brain activity the modelling of synchronisations was examined in some detail. References C. M. Michel, G. Thut, S. Morand, A. Khateb, A. J. Pegna, R. Grave de Peralta, S. Gonzalez, M. Seeck and T. Landis, Electric source imaging of human brain functions, Brain Res. 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Schmitz, Axonal gap junc ions between principal neurons: A novel source of network oscillations, and perhaps epileptogenesis., Rev. Neuroscience , 13 (1), 2002, 1. doi:10.1146/annurev.neuro.27.070203.144303 M. Scheffer, J. Bascompte, W. A. Brock, V. Brovkin, S. R. Carpenter, V. Dakos, H. Held, E. H. van Nes, M. Rietkerk and G. Sugihara, Early-warning signals for critical transitions, Nature , 461 (7260), 2009, 53--59. doi:10.1038/nature08227 K. Murphy, A Brief Introduction to Graphical Models and Bayesian Networks , 2008, http://www.cs.ubc.ca/murphyk/Bayes/bnintro.html . R. C. Bradley, An elementary

Use of simple pharmacokinetic modeling to characterize exposure of Australians to perfluorooctanoic acid and perfluorooctane sulfonic acid

Perflurooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) have been used for a variety of applications including fluoropolymer processing, fire-fighting foams and surface treatments since the 1950s. Both PFOS and PFOA are polyfluoroalkyl chemicals (PFCs), man-made compounds that are persistent in the environment and humans; some PFCs have shown adverse effects in laboratory animals. Here we describe the application of a simple one compartment pharmacokinetic model to estimate total intakes of PFOA and PFOS for the general population of urban areas on the east coast of Australia. Key parameters for this model include the elimination rate constants and the volume of distribution within the body. A volume of distribution was calibrated for PFOA to a value of 170ml/kgbw using data from two communities in the United States where the residents' serum concentrations could be assumed to result primarily from a known and characterized source, drinking water contaminated with PFOA by a single fluoropolymer manufacturing facility. For PFOS, a value of 230ml/kgbw was used, based on adjustment of the PFOA value. Applying measured Australian serum data to the model gave mean+/-standard deviation intake estimates of PFOA of 1.6+/-0.3ng/kgbw/day for males and females >12years of age combined based on samples collected in 2002-2003 and 1.3+/-0.2ng/kg bw/day based on samples collected in 2006-2007. Mean intakes of PFOS were 2.7+/-0.5ng/kgbw/day for males and females >12years of age combined based on samples collected in 2002-2003, and 2.4+/-0.5ng/kgbw/day for the 2006-2007 samples. ANOVA analysis was run for PFOA intake and demonstrated significant differences by age group (p=0.03), sex (p=0.001) and date of collection (p<0.001). Estimated intake rates were highest in those aged >60years, higher in males compared to females, and higher in 2002-2003 compared to 2006-2007. The same results were seen for PFOS intake with significant differences by age group (p<0.001), sex (p=0.001) and date of collection (p=0.016).

Incorporating adverse event relatedness into dose-finding clinical trial designs

Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have ‘doubtful’ or ‘possible’ relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events ‘probably’ or ‘definitely’ related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.

Why 'down under' is a cut above: a comparison of rates of and reasons for caesarean section in England and Australia

Background Most studies examining determinants of rising rates of caesarean section have examined patterns in documented reasons for caesarean over time in a single location. Further insights could be gleaned from cross-cultural research that examines practice patterns in locations with disparate rates of caesarean section at a single time point. Methods We compared both rates of and main reason for pre-labour and intrapartum caesarean between England and Queensland, Australia, using data from retrospective cross-sectional surveys of women who had recently given birth in England (n = 5,250) and Queensland (n = 3,467). Results Women in Queensland were more likely to have had a caesarean birth (36.2%) than women in England (25.1% of births; OR = 1.44, 95% CI = 1.28-1.61), after adjustment for obstetric characteristics. Between-country differences were found for rates of pre-labour caesarean (21.2% vs. 12.2%) but not for intrapartum caesarean or assisted vaginal birth. Compared to women in England, women in Queensland with a history of caesarean were more likely to have had a pre-labour caesarean and more likely to have had an intrapartum caesarean, due only to a previous caesarean. Among women with no previous caesarean, Queensland women were more likely than women in England to have had a caesarean due to suspected disproportion and failure to progress in labour. Conclusions The higher rates of caesarean birth in Queensland are largely attributable to higher rates of caesarean for women with a previous caesarean, and for the main reason of having had a previous caesarean. Variation between countries may be accounted for by the absence of a single, comprehensive clinical guideline for caesarean section in Queensland. Keywords: Caesarean section; Childbirth; Pregnancy; Cross-cultural comparison; Vaginal birth after caesarean; Previous caesarean section; Patient-reported data; Quality improvement

Mammographic density-a review on the current understanding of its association with breast cancer

There has been considerable recent interest in the genetic, biological and epidemiological basis of mammographic density (MD), and the search for causative links between MD and breast cancer (BC) risk. This report will critically review the current literature on MD and summarize the current evidence for its association with BC. Keywords 'mammographic dens*', 'dense mammary tissue' or 'percent dens*' were used to search the existing literature in English on PubMed and Medline. All reports were critically analyzed. The data were assigned to one of the following aspects of MD: general association with BC, its relationship with the breast hormonal milieu, the cellular basis of MD, the generic variations of MD, and its significance in the clinical setting. MD adjusted for age, and BMI is associated with increased risk of BC diagnosis, advanced tumour stage at diagnosis and increased risk of both local recurrence and second primary cancers. The MD measures that predict BC risk have high heritability, and to date several genetic markers associated with BC risk have been found to also be associated with these MD risk predictors. Change in MD could be a predictor of the extent of chemoprevention with tamoxifen. Although the biological and genetic pathways that determine and perhaps modulate MD remain largely unresolved, significant inroads are being made into the understanding of MD, which may lead to benefits in clinical screening, assessment and treatment strategies. This review provides a timely update on the current understanding of MD's association with BC risk.