Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Addressing alcohol related harms within maxillofacial trauma practice

Background A brief intervention, conducted in the acute setting care setting after an alcohol-related injury, has been reported to be highly beneficial in reducing the risk of re-injury and in reducing subsequent level of alcohol consumption. This project aimed to understand Australasian Oral and Maxillofacial Surgeons' attitudes, knowledge and skills in terms of alcohol screening and brief intervention within acute settings for patients admitted with facial trauma. Materials and Methods A web-based survey was made available to all members (n=200-250) of the Australian and New Zealand Association of Oral and Maxillofacial Surgeons (ANZAOMS), promoted through a number of email bulletins sent by the Association to all members. Implied consent is assumed for participants who complete the online survey. The survey explored their current level of involvement in treating patients with alcohol-relatd facial trauma, as well as their knowledge of and attitudes towards alcohol screening and brief intervention. The survey also explored their willingness for further training and involvement in implementing a SBI program. Parts of the survey were based on a hypothetical case with facial injury and drinking history which was presented to the participants and the participants were asked to give their response to this scenario. Results A total of 58 surgeons completed the on-line survey. 91% of surgeons surveyed were males and 88% were consultant surgeons. 71% would take alcohol history; 29% would deliver a brief alcohol intervention and 14% would refer the patients to an alcohol treatment service or clinician. 40% agreed to have adequate training in managing patients with alcohol-related injuries, while 17% and 19% felt they had adequate time and resources. 76% of surgeons reported the need for more information on where to refer patients for appropriate alcohol treatment. Conclusion The study findings confirm the challenges and barriers to implementing brief alcohol intervention in current practice. There are service gaps that exist, as well as opportunities for training.

Ecionines A and B, two new cytotoxic pyridoacridine alkaloids from the Australian marine sponge, Ecionemia geodides

Chemical investigations of the Australian marine sponge Ecionemia geodides resulted in the isolation of two new pyridoacridine alkaloids, ecionines A (1) and B (2), along with the previously isolated marine natural products, biemnadin (3) and meridine (4). Compounds 1 and 2 both contain an imine moiety, which is rare for the pyridoacridine structure class. The chemical structures of 1 and 2 were determined by extensive 1D and 2D NMR and MS data analyses. All compounds were tested against a panel of human bladder cancer cell lines, the increasingly metastatic TSU-Pr1 series (TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1- B2) and the superficial bladder cancer cell line 5637. Ecionine A (1) displayed cytotoxicity against all cell lines, with IC50 values ranging from 3 to 7 mM. This is the first report of chemistry from the sponge genus Ecionemia.

Effectiveness of a puppet show on iodine knowledge, attitudes and behaviour of elementary students and the indirect effects on their parents and households in Ho Chi Minh City : a pilot study

Deficiencies in iodine levels have been shown to seriously affect a child’s intellectual development and learning capacity.1 In South-East Asia, iodine deficiency remains a major public health concern. Approximately 30% of the region’s population of 503.6 million have insufficient iodine intake, and only 61% of households have access to iodized salt.1 For this reason, it is necessary to initiate effective, community-based health promotion activities that are targeted toward populations of various ages. A puppet show is one imaginative and entertaining method of health education that has been advocated for use in communicating positive health behaviours to children.2e5 The authors undertook a literature review and found no studies assessing the effectiveness of a puppet show to teach an iodine education programme...

Implementation of sustainable evidence-based practice for the assessment and management of pain in residential aged care facilities

Pain is common in residential aged care facilities (RACFs). In 2005, the Australian Pain Society developed 27 recommendations for good practice in the identification, assessment, and management of pain in these settings. This study aimed to address implementation of the standards and evaluate outcomes. Five facilities in Australia participated in a comprehensive evaluation of RACF pain practice and outcomes. Pre-existing pain management practices were compared with the 27 recommendations, before an evidence-based pain management program was introduced that included training and education for staff and revised in-house pain-management procedures. Post-implementation audits evaluated the program's success. Aged care staff teams also were assessed on their reports of self-efficacy in pain management. The results show that before the implementation program, the RACFs demonstrated full compliance on 6 to 12 standards. By the project's completion, RACFs demonstrated full compliance with 10 to 23 standards and major improvements toward compliance in the remaining standards. After implementation, the staff also reported better understanding of the standards (p < .001) or of facility pain management guidelines (p < .001), increased confidence in therapies for pain management (p < .001), and increased confidence in their training to assess pain (p < .001) and recognize pain in residents with dementia who are nonverbal (p = .003). The results show that improved evidence-based practice in RACFs can be achieved with appropriate training and education. Investing resources in the aged care workforce via this implementation program has shown improvements in staff self-efficacy and practice.

B-lactamase-mediated resistance to antimicrobials : the relationship between genotype and phenotype

This thesis examined the ability to predict the emergence of bacteria resistant to antibiotics using genetic markers in the bacteria. Bacteria containing the genetic markers were able to become resistant to antibiotics, whereas bacteria that did not have the genetic markers remained susceptible. Existing techniques can identify the presence of resistance by looking at the characteristics of the bacteria during growth. However, having the ability to predict antibiotic resistance before it emerges could improve the preservation of currently available antibiotics and minimise treatment failure.

Identification of eusynstyelamide B as a potent cell cycle inhibitor following the generation and screening of an ascidian-derived extract library using a real time cell analyzer

Ascidians are marine invertebrates that have been a source of numerous cytotoxic compounds. Of the first six marine-derived drugs that made anticancer clinical trials, three originated from ascidian specimens. In order to identify new anti-neoplastic compounds, an ascidian extract library (143 samples) was generated and screened in MDA-MB-231 breast cancer cells using a real-time cell analyzer (RTCA). This resulted in 143 time-dependent cell response profiles (TCRP), which are read-outs of changes to the growth rate, morphology, and adhesive characteristics of the cell culture. Twenty-one extracts affected the TCRP of MDA-MB-231 cells and were further investigated regarding toxicity and specificity, as well as their effects on cell morphology and cell cycle. The results of these studies were used to prioritize extracts for bioassay-guided fractionation, which led to the isolation of the previously identified marine natural product, eusynstyelamide B (1). This bis-indole alkaloid was shown to display an IC50 of 5 μM in MDA-MB-231 cells. Moreover, 1 caused a strong cell cycle arrest in G2/M and induced apoptosis after 72 h treatment, making this molecule an attractive candidate for further mechanism of action studies.

Circulating fragments of N-Terminal Pro-B-Type Natriuretic Peptides in plasma of heart failure patients

BACKGROUND: The use of nonstandardized N-terminal pro-B-type natriuretic peptide (NT-proBNP) assays can contribute to the misdiagnosis of heart failure (HF). Moreover, there is yet to be established a common consensus regarding the circulating forms of NT-proBNP being used in current assays. We aimed to characterize and quantify the various forms of NT-proBNP in the circulation of HF patients. METHODS: Plasma samples were collected from HF patients (n = 20) at rest and stored at -80 degrees C. NT-proBNP was enriched from HF patient plasma by use of immunoprecipitation followed by mass spectrometric analysis. Customized homogeneous sandwich AlphaLISA (R) immunoassays were developed and validated to quantify 6 fragments of NT-proBNP. RESULTS: Mass spectrometry identified the presence of several N- and C-terminally processed forms of circulating NT-proBNP, with physiological proteolysis between Pro2-Leu3, Leu3-Gly4, Pro6-Gly7, and Pro75-Arg76. Consistent with this result, AlphaLISA immunoassays demonstrated that antibodies targeting the extreme N or C termini measured a low apparent concentration of circulating NT-proBNP. The apparent circulating NT-proBNP concentration was increased with antibodies targeting nonglycosylated and nonterminal epitopes (P < 0.05). CONCLUSIONS: In plasma collected from HF patients, immunoreactive NT-proBNP was present as multiple N- and C-terminally truncated fragments of the full length NT-proBNP molecule. Immunodetection of NT-proBNP was significantly improved with the use of antibodies that did not target these terminal regions. These findings support the development of a next generation NT-proBNP assay targeting nonterminal epitopes as well as avoiding the central glycosylated region of this molecule. (c) 2013 American Association for Clinical Chemistry

In vitro investigations on the effect of dermal fibroblasts on keratinocyte responses to ultraviolet B radiation

Exposure to ultraviolet radiation is closely linked to the development of skin cancers in humans. The ultraviolet B (UVB) radiation wavelength (280-320 nm), in particular, causes DNA damage in epidermal keratinocytes, which are linked to the generation of signature premalignant mutations. Interactions between dermal fibroblasts and keratinocytes play a role in epidermal repair and regeneration after UVB-induced damage. To investigate these processes, established two and three-dimensional culture models were utilized to study the impact of fibroblast-keratinocyte crosstalk during the acute UVB response. Using a coculture system it was observed that fibroblasts enhanced keratinocyte survival and the repair of cyclobutane pyrimidine dimers (CPDs) after UVB radiation exposure. These findings were also mirrored in irradiated human skin coculture models employed in this study. Fibroblast coculture was shown to play a role in the expression and activation of members of the apoptotic cascade, including caspase-3 and Bad. Interestingly, the expression and phosphorylation of p53, a key player in the regulation of keratinocyte cell fate postirradiation, was also shown to be influenced by fibroblast-produced factors. This study highlights the importance of synergistic interactions between fibroblasts and keratinocytes in maintaining a functional epidermis while promoting repair and regeneration following UVB radiation-induced damage.

What is plan B? Using Foucault's archaeology to enhance policy analysis

Many governments in western democracies conduct the work of leading their societies forward through policy generation and implementation. Despite government attempts at extensive negotiation, collaboration and debate, the general populace in these same countries frequently express feelings of disempowerment and undue pressure to be compliant, often leading to disengagement. Here we outline Plan B: a process for examining how policies that emerge from good intentions are frequently interpreted as burdensome or irrelevant by those on whom they have an impact. Using a case study of professional standards for teachers in Australia, we describe how we distilled Foucault’s notions of archaeology into a research approach centring on the creation of ‘polyhedrons of intelligibility’ as an alternative approach by which both policy makers and those affected by their policies may understand how their respective causes are supported and adversely affected.

Magnetic resonance imaging: An accurate, radiation-free, alternative to computed tomography for the primary imaging and three-dimensional reconstruction of the bony orbit

Purpose: To determine the extent to which the accuracy of magnetic resonance imaging (MRI) based virtual 3-dimensional (3D) models of the intact orbit can approach that of the gold standard, computed tomography (CT) based models. The goal was to determine whether MRI is a viable alternative to CT scans in patients with isolated orbital fractures and penetrating eye injuries, pediatric patients, and patients requiring multiple scans in whom radiation exposure is ideally limited. Materials and Methods: Patients who presented with unilateral orbital fractures to the Royal Brisbane and Women’s Hospital from March 2011 to March 2012 were recruited to participate in this cross-sectional study. The primary predictor variable was the imaging technique (MRI vs CT). The outcome measurements were orbital volume (primary outcome) and geometric intraorbital surface deviations (secondary outcome)between the MRI- and CT-based 3D models. Results: Eleven subjects (9 male) were enrolled. The patients’ mean age was 30 years. On average, the MRI models underestimated the orbital volume of the CT models by 0.50 0.19 cm3 . The average intraorbital surface deviation between the MRI and CT models was 0.34 0.32 mm, with 78 2.7% of the surface within a tolerance of 0.5 mm. Conclusions: The volumetric differences of the MRI models are comparable to reported results from CT models. The intraorbital MRI surface deviations are smaller than the accepted tolerance for orbital surgical reconstructions. Therefore, the authors believe that MRI is an accurate radiation-free alternative to CT for the primary imaging and 3D reconstruction of the bony orbit. �

Autologous human kidney proximal tubule epithelial cells (PTEC) modulate dendritic cell (DC), T cell and B cell responses

This is a comprehensive study of human kidney proximal tubular epithelial cells (PTEC) which are known to respond to and mediate the pathological process of a range of kidney diseases. It identifies various molecules expressed by PTEC and how these molecules participate in down-regulating the inflammatory process, thereby highlighting the clinical potential of these molecules to treat various kidney diseases. In the disease state, PTEC gain the ability to regulate the immune cell responses present within the interstitium. This down-regulation is a complex interaction of contact dependent/independent mechanisms involving various immuno-regulatory molecules including PD-L1, sHLA-G and IDO. The overall outcome of this down-regulation is suppressed DC maturation, decreased number of antibody producing B cells and low T cell responses. These manifestations within a clinical setting are expected to dampen the ongoing inflammation, preventing the damage caused to the kidney tissue.