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1.  Ovine neuronal ceroid lipofuscinosis: a large animal model syntenic with the human neuronal ceroid lipofuscinosis variant CLN6. 
Journal of Medical Genetics  1998;35(9):717-721.
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited degenerative neurological diseases affecting children. A number of non-allelic variants have been identified within the human population and the genes for some of these have recently been identified. The underlying mechanism for the neuropathology remains an enigma; however, pioneering studies with the naturally occurring ovine model (OCL) have led to the proposal that these diseases represent lesions in specific hydrophobic protein degradation pathways. In this study, we show linkage between OCL and microsatellite markers on OAR 7q13-15. Using interspecies chromosome painting we establish that OAR 7q13-15 is syntenic with human chromosome 15q21-23, the region which was recently defined as the location of a newly identified late infantile variant (CLN6). We propose that our ovine model represents a mutation in the gene orthologous to that mutated in the human late infantile variant CLN6. The ovine linkage flock, consisting of 56 families, represents a powerful resource for positional cloning of this NCL gene. The availability of such a large animal model will have important implications for experimentation in downstream corrective therapies.
Images
PMCID: PMC1051422  PMID: 9733028
2.  Rainfall and sentinel chicken seroconversions predict human cases of Murray Valley encephalitis in the north of Western Australia 
BMC Infectious Diseases  2014;14(1):672.
Background
Murray Valley encephalitis virus (MVEV) is a flavivirus that occurs in Australia and New Guinea. While clinical cases are uncommon, MVEV can cause severe encephalitis with high mortality. Sentinel chicken surveillance is used at many sites around Australia to provide an early warning system for risk of human infection in areas that have low population density and geographical remoteness. MVEV in Western Australia occurs in areas of low population density and geographical remoteness, resulting in logistical challenges with surveillance systems and few human cases. While epidemiological data has suggested an association between rainfall and MVEV activity in outbreak years, it has not been quantified, and the association between rainfall and sporadic cases is less clear. In this study we analysed 22 years of sentinel chicken and human case data from Western Australia in order to evaluate the effectiveness of sentinel chicken surveillance for MVEV and assess the association between rainfall and MVEV activity.
Methods
Sentinel chicken seroconversion, human case and rainfall data from the Kimberley and Pilbara regions of Western Australia from 1990 to 2011 were analysed using negative binomial regression. Sentinel chicken seroconversion and human cases were used as dependent variables in the model. The model was then tested against sentinel chicken and rainfall data from 2012 and 2013.
Results
Sentinel chicken seroconversion preceded all human cases except two in March 1993. Rainfall in the prior three months was significantly associated with both sentinel chicken seroconversion and human cases across the regions of interest. Sentinel chicken seroconversion was also predictive of human cases in the models. The model predicted sentinel chicken seroconversion in the Kimberley but not in the Pilbara, where seroconversions early in 2012 were not predicted. The latter may be due to localised MVEV activity in isolated foci at dams, which do not reflect broader virus activity in the region.
Conclusions
We showed that rainfall and sentinel chickens provide a useful early warning of MVEV risk to humans across endemic and epidemic areas, and that a combination of the two indicators improves the ability to assess MVEV risk and inform risk management measures.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0672-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-014-0672-3
PMCID: PMC4273426  PMID: 25490948
Murray valley encephalitis; Sentinel chicken surveillance; Epidemiology; Human risk; Flavivirus; Environmental factors
3.  A pan-cancer proteomic perspective on The Cancer Genome Atlas 
Nature communications  2014;5:3887.
Protein levels and function are poorly predicted by genomic and transcriptomic analysis of patient tumors. Therefore, direct study of the functional proteome has the potential to provide a wealth of information that complements and extends genomic, epigenomic and transcriptomic analysis in The Cancer Genome Atlas (TCGA) projects. Here we use reverse-phase protein arrays to analyze 3,467 patient samples from 11 TCGA “Pan-Cancer” diseases, using 181 high-quality antibodies that target 128 total proteins and 53 post-translationally modified proteins. The resultant proteomic data is integrated with genomic and transcriptomic analyses of the same samples to identify commonalities, differences, emergent pathways and network biology within and across tumor lineages. In addition, tissue-specific signals are reduced computationally to enhance biomarker and target discovery spanning multiple tumor lineages. This integrative analysis, with an emphasis on pathways and potentially actionable proteins, provides a framework for determining the prognostic, predictive and therapeutic relevance of the functional proteome.
doi:10.1038/ncomms4887
PMCID: PMC4109726  PMID: 24871328
Proteomics; TCGA; Pan-Cancer; protein expression; protein networks
4.  Signal verification can promote reliable signalling 
The central question in communication theory is whether communication is reliable, and if so, which mechanisms select for reliability. The primary approach in the past has been to attribute reliability to strategic costs associated with signalling as predicted by the handicap principle. Yet, reliability can arise through other mechanisms, such as signal verification; but the theoretical understanding of such mechanisms has received relatively little attention. Here, we model whether verification can lead to reliability in repeated interactions that typically characterize mutualisms. Specifically, we model whether fruit consumers that discriminate among poor- and good-quality fruits within a population can select for reliable fruit signals. In our model, plants either signal or they do not; costs associated with signalling are fixed and independent of plant quality. We find parameter combinations where discriminating fruit consumers can select for signal reliability by abandoning unprofitable plants more quickly. This self-serving behaviour imposes costs upon plants as a by-product, rendering it unprofitable for unrewarding plants to signal. Thus, strategic costs to signalling are not a prerequisite for reliable communication. We expect verification to more generally explain signal reliability in repeated consumer–resource interactions that typify mutualisms but also in antagonistic interactions such as mimicry and aposematism.
doi:10.1098/rspb.2013.1560
PMCID: PMC3790478  PMID: 24068354
aposematism; handicap principle; honest signalling; mimicry; plant–animal communication; sanction
5.  Posture, Flexibility and Grip Strength in Horse Riders 
Journal of Human Kinetics  2014;42:113-125.
Since the ability to train the horse to be ambidextrous is considered highly desirable, rider asymmetry is recognized as a negative trait. Acquired postural and functional asymmetry can originate from numerous anatomical regions, so it is difficult to suggest if any is developed due to riding. The aim of this study was therefore to assess symmetry of posture, strength and flexibility in a large population of riders and to determine whether typical traits exist due to riding. 127 right handed riders from the UK and USA were categorized according to years riding (in 20 year increments) and their competition level (using affiliated test levels). Leg length, grip strength and spinal posture were measured and recorded by a physiotherapist. Standing and sitting posture and trunk flexibility were measured with 3-D motion capture technology. Right-left differences were explored in relation to years riding and rider competitive experience. Significant anatomical asymmetry was found for the difference in standing acromion process height for a competition level (−0.07±1.50 cm Intro/Prelim; 0.02±1.31 cm Novice; 0.43±1.27 cm Elementary+; p=0.048) and for sitting iliac crest height for years riding (−0.23±1.36 cm Intro/Prelim; 0.01±1.50 cm Novice; 0.86±0.41 cm Elementary+; p=0.021). For functional asymmetry, a significant interaction was found for lateral bending ROM for years riding x competition level (p=0.047). The demands on dressage riders competing at higher levels may predispose these riders to a higher risk of developing asymmetry and potentially chronic back pain rather than improving their symmetry.
doi:10.2478/hukin-2014-0066
PMCID: PMC4234750  PMID: 25414745
asymmetry; leg length; equine; back pain; laterality; equestrian
6.  The role and significance of nurses in managing transitions to palliative care: a qualitative study 
BMJ Open  2014;4(9):e006026.
Objectives
Nurses are generally present, and often influential, in supporting patient and family acceptance of medical futility and in assisting doctors in negotiating referral to palliative care. Yet the specificities of the nursing role and how nurses may contribute to timely and effective referrals is not well understood. This study aimed to systematically explore hospital-based nurses’ accounts of the transition to palliative care, and the potential role of nurses in facilitating more effective palliative care transitions.
Design
Qualitative study using semistructured interviews.
Setting
Two health services with public as well as private clinical environments in a major metropolitan area of Australia.
Participants
Hospital-based nurses (n=20) who regularly work with patients at the point of referral and in managing transitions to palliative care.
Results
Four significant themes emerged from thematic analysis. These include: (1) professional dynamics and the roles played by nurses in initiating the transition to palliative care; (2) the value of nurses’ informal interactions in timely and effective transitions; (3) the emerging challenge of managing task-oriented nursing versus intense emotional nursing work at the point of medical futility and (4) the emotional burden experienced by nurses within this clinical context. Nurses self-reported occupying critical albeit complex roles in the management of medical futility and the transition to palliative care. They reported experiencing significant emotional burden in balancing interpersonal and interprofessional relationships during this time.
Conclusions
The results suggest that nurses may be utilised in a more formalised and systematic fashion in the context of managing medical futility and the need to topicalise the transition, with the focus shifted away from medical referrals towards more team-based and patient-centred timely transitions. Further research focused on the experiences of doctors, allied health professionals, patients and families is required to provide a broader interdisciplinary understanding of futility and contributions to the negotiation of palliative care.
doi:10.1136/bmjopen-2014-006026
PMCID: PMC4179576  PMID: 25270859
QUALITATIVE RESEARCH; PALLIATIVE CARE
7.  Factors influencing women’s decisions to drink alcohol during pregnancy: findings of a qualitative study with implications for health communication 
Background
Despite Australian guidelines advising abstinence from alcohol during pregnancy, a relatively high number of Australian women continue to drink alcohol while pregnant. While some call for greater advocacy of the need for abstinence, others have expressed concern that abstinence messages may be harmful to pregnant women and their unborn babies due to the anxiety they could provoke. We present findings on women's deliberations over drinking alcohol during pregnancy, particularly their emotional dimensions, to inform debates about public health messages and practitioner-patient discussions regarding alcohol use during pregnancy.
Methods
Semi-structured face-to-face interviews were conducted with 40 women in their homes. Our sample comprised women aged 34–39, drawn from the Australian Longitudinal Study on Women’s Health, living in the Greater Brisbane Area who were pregnant, or had recently given birth, in 2009. An inductive qualitative framework analysis approach was used to identify and interpret themes explaining why pregnant women choose to drink or not.
Results
Women generally described drinking small amounts of alcohol during pregnancy as being a low risk activity and talked about the importance of alcohol to their social lives as a reason for continuing to drink or finding abstinence a burden; sensitisation to the judgements of others was not widespread. Women predominantly assessed the risk of their drinking in terms of the kinds of alcoholic beverages consumed rather than alcohol content. In reflecting on the advice they recalled receiving, women described their healthcare practitioners as being relaxed about the risks of alcohol consumption.
Conclusions
The significance of alcohol to women’s identity appeared to be an important reason for continued alcohol use during pregnancy among otherwise risk averse women. Anxiety about alcohol consumption during pregnancy was not widespread. However, obstetricians were an important mediator of this. Health messages that dispel the notion that wine is a “healthy” choice of alcoholic beverage, that provide women with strategies to help them avoid drinking, that advise the broader public not to pressure women to drink if they do not want to, and educate women about the effects of ethanol on maternal and fetal bodies, should be considered.
doi:10.1186/1471-2393-14-246
PMCID: PMC4122767  PMID: 25060554
Pregnancy; Alcohol; Qualitative research; Risk; Consumption; Patient-practitioner communication; Public health promotion
9.  Leptin inhibits proliferation of breast cancer cells at supraphysiological concentrations by inhibiting mitogen-activated protein kinase signaling 
Oncology Letters  2014;8(1):374-378.
Leptin is a hormone secreted by white fat tissue and signals the amount of overall body fat to the hypothalamus. The circulating concentration of leptin correlates with the level of obesity. Breast cancer risk is higher in obese postmenopausal women compared with postmenopausal women of a normal weight, and high leptin concentrations may contribute to this risk. In the present study, SK-BR-3 and MDA-MB-231 breast cancer cell lines were treated with various concentrations (6.25–1,600 ng/ml) of recombinant leptin and changes in cell proliferation were assessed. The SK-BR-3 breast cancer cells exhibited a concentration-dependent increase in proliferation with physiological leptin concentrations (<100 ng/ml), but no further increase in proliferation at high leptin concentrations (>100 ng/ml) was observed. Cell proliferation was not affected at supraphysiological leptin concentrations (>800 ng/ml) in SK-BR-3 cells, whereas it decreased in MDA-MB-231 cells. Therefore, cell signaling and cell cycle changes were assessed at supraphysiological concentrations (1,600 ng/ml). In the two cell lines, leptin treatment decreased the mitogen-activated protein kinase (MAPK) cell signaling pathway activation. Leptin treatment did not increase Akt phosphorylation or significantly alter the cell population distribution across cell cycle stages. To the best of our knowledge, leptin-induced growth inhibition of breast cancer cells at supraphysiological concentrations has not been reported in the literature to date, and the findings of this study suggest that reduced MAPK activity may be the underlying cause. Thus, the effect of leptin on breast cancer growth warrants further investigation since leptin is considered to be one of the main mediators in the obesity-breast cancer connection.
doi:10.3892/ol.2014.2085
PMCID: PMC4063604  PMID: 24959279
leptin; breast cancer; obesity; cell proliferation; mitogen-activated protein kinase cell signaling pathway
10.  A qualitative study of influences on older women’s practitioner choices for back pain care 
Background
Back pain is an increasingly prevalent health concern amongst Australian women for which a wide range of treatment options are available, offered by biomedical, allied health and complementary and alternative medicine (CAM) providers. Although there is an emerging literature on patterns of provider utilisation, less is known about the reasons why women with back pain select their chosen practitioner. In this paper we explore the influences on back pain sufferers’ decision-making about treatment seeking with practitioners for their most recent episode of back pain.
Methods
Drawing on 50 semi-structured interviews with women aged 60–65 years from the Australian Longitudinal Study on Women’s Health (ALSWH) who have chronic back pain, we focus on the factors which influence their choice of practitioner. Analysis followed a framework approach to qualitative content analysis, augmented by NVivo 9 qualitative data analysis software. Key themes were identified and tested for rigour through inter-rater reliability and constant comparison.
Results
The women identified four predominant influences on their choice of practitioner for back pain: familiarity with treatment or experiences with individual practitioners; recommendations from social networks; geographical proximity of practitioners; and, qualifications and credentials of practitioners. The therapeutic approach or evidence-base of the practices being utilised was not reported by the women as central to their back pain treatment decision making.
Conclusions
Choice of practitioner appears to be unrelated to the therapeutic approaches, treatment practices or the scientific basis of therapeutic practices. Moreover, anecdotal lay reports of effectiveness and the ‘treatment experience’ may be more influential than formal qualifications in guiding women’s choice of practitioner for their back pain. Further work is needed on the interpersonal, collective and subjective underpinnings of practitioner choice, particularly over time, in order to better understand why women utilise certain practitioners for back pain.
doi:10.1186/1472-6963-14-131
PMCID: PMC3998023  PMID: 24655816
Back pain; Women; Qualitative; Interviews; Australia
11.  Key considerations for the experimental training and evaluation of cancer odour detection dogs: lessons learnt from a double-blind, controlled trial of prostate cancer detection 
BMC Urology  2014;14:22.
Background
Cancer detection using sniffer dogs is a potential technology for clinical use and research. Our study sought to determine whether dogs could be trained to discriminate the odour of urine from men with prostate cancer from controls, using rigorous testing procedures and well-defined samples from a major research hospital.
Methods
We attempted to train ten dogs by initially rewarding them for finding and indicating individual prostate cancer urine samples (Stage 1). If dogs were successful in Stage 1, we then attempted to train them to discriminate prostate cancer samples from controls (Stage 2). The number of samples used to train each dog varied depending on their individual progress. Overall, 50 unique prostate cancer and 67 controls were collected and used during training. Dogs that passed Stage 2 were tested for their ability to discriminate 15 (Test 1) or 16 (Tests 2 and 3) unfamiliar prostate cancer samples from 45 (Test 1) or 48 (Tests 2 and 3) unfamiliar controls under double-blind conditions.
Results
Three dogs reached training Stage 2 and two of these learnt to discriminate potentially familiar prostate cancer samples from controls. However, during double-blind tests using new samples the two dogs did not indicate prostate cancer samples more frequently than expected by chance (Dog A sensitivity 0.13, specificity 0.71, Dog B sensitivity 0.25, specificity 0.75). The other dogs did not progress past Stage 1 as they did not have optimal temperaments for the sensitive odour discrimination training.
Conclusions
Although two dogs appeared to have learnt to select prostate cancer samples during training, they did not generalise on a prostate cancer odour during robust double-blind tests involving new samples. Our study illustrates that these rigorous tests are vital to avoid drawing misleading conclusions about the abilities of dogs to indicate certain odours. Dogs may memorise the individual odours of large numbers of training samples rather than generalise on a common odour. The results do not exclude the possibility that dogs could be trained to detect prostate cancer. We recommend that canine olfactory memory is carefully considered in all future studies and rigorous double-blind methods used to avoid confounding effects.
doi:10.1186/1471-2490-14-22
PMCID: PMC3945616  PMID: 24575737
Prostate cancer; Cancer detection dogs; Cancer odour; Olfactory memory; Multiple sample learning
12.  Bagged gene shaving for the robust clustering of high-throughput data 
The analysis of high-throughput data sets, such as microarray data, often requires that individual variables (genes, for example) be grouped into clusters of variables with highly correlated values across all samples. Gene shaving is an established method for generating such clusters, but is overly sensitive to the input data: changing just one sample can determine whether or not an entire cluster is found. This paper describes a clustering method based on the bootstrap aggregation of gene shaving clusters, which overcomes this and other problems, and applies the new method to a large gene expression microarray dataset from brain tumour samples.
PMCID: PMC3879957  PMID: 20940121
bootstrap aggregation; clustering; gene shaving; glioblastoma
13.  Health Care Utilisation and Out-of-Pocket Expenditure Associated with Back Pain: A Nationally Representative Survey of Australian Women 
PLoS ONE  2013;8(12):e83559.
Background
Back pain impacts on a significant proportion of the Australian population over the life course and has high prevalence rates among women, particularly in older age. Back pain care is characterised by multiple practitioner and self-prescribed treatment options, and the out-of-pocket costs associated with consultations and self-prescribed treatments have not been examined to date.
Objective
To analyse the extent of health care practitioner consultations and self-prescribed treatment for back pain care among Australian women, and to assess the self-reported costs associated with such usage.
Methods
Survey of 1,310 women (response rate 80.9%) who reported seeking help for back pain from the ‘1946-51 cohort’ of the Australian Longitudinal Study on Women’s Health. Women were asked about their use of health care practitioners and self-prescribed treatments for back pain and the costs associated with such usage.
Results
In the past year 76.4% consulted a complementary and alternative practitioner, 56% an allied health practitioner and 59.2% a GP/medical specialist. Overall, women consulted with, on average, 3.0 (SD = 2.0) different health care practitioners, and had, on average, 12.2 (SD = 9.7) discrete health care practitioner consultations for back pain. Average self-reported out-of-pocket expenditure on practitioners and self-prescribed treatments for back pain care per annum was AU$873.10.
Conclusions
Multiple provider usage for various but distinct purposes (i.e. pain/mobility versus anxiety/stress) points to the need for further research into patient motivations and experiences of back pain care in order to improve and enhance access to and continuity of care. Our results suggest that the cost of back pain care represents a significant burden, and may ultimately limit women’s access to multiple providers. We extrapolate that for Australian working-age women, total out-of-pocket expenditure on back pain care per annum is in excess of AU$1.4billion, thus indicating the prominence of back pain as a major economic, social and health burden.
doi:10.1371/journal.pone.0083559
PMCID: PMC3869794  PMID: 24376716
14.  Sustainable, efficient livestock production with high biodiversity and good welfare for animals 
What is the future for livestock agriculture in the world? Consumers have concerns about sustainability but many widely used livestock production methods do not satisfy consumers' requirements for a sustainable system. However, production can be sustainable, occurring in environments that: supply the needs of the animals resulting in good welfare, allow coexistence with a wide diversity of organisms native to the area, minimize carbon footprint and provide a fair lifestyle for the people working there. Conservation need not just involve tiny islands of natural vegetation in a barren world of agriculture, as there can be great increases in biodiversity in farmed areas. Herbivores, especially ruminants that consume materials inedible by humans, are important for human food in the future. However, their diet should not be just ground-level plants. Silvopastoral systems, pastures with shrubs and trees as well as herbage, are described which are normally more productive than pasture alone. When compared with widely used livestock production systems, silvopastoral systems can provide efficient feed conversion, higher biodiversity, enhanced connectivity between habitat patches and better animal welfare, so they can replace existing systems in many parts of the world and should be further developed.
doi:10.1098/rspb.2013.2025
PMCID: PMC3790492  PMID: 24068362
sustainability; silvopastoral; livestock; biodiversity; animal welfare; conservation
15.  The effect of very low-calorie diets on renal and hepatic outcomes: a systematic review 
Very low-calorie diets (VLCDs) are an effective means by which to induce clinically significant weight loss. However, their acceptance by health care practitioners and the public is generally lower than that for other nonsurgical weight loss methods. Whilst there is currently little evidence to suggest they have any detrimental effect on hepatic and renal health, data assessing these factors remain limited. We carried out a systematic review of the literature on randomized controlled trials that had a VLCD component and that reported outcomes for hepatic and renal health, published between January 1980 and December 2012. Cochrane criteria were followed, and eight out of 196 potential articles met the inclusion criteria. A total of 548 participants were recruited across the eight studies. All eight studies reported significant weight loss following the VLCD. Changes in hepatic and renal outcomes were variable but generally led to either no change or improvements in either of these. Due to the heterogeneity in the quality and methodology of the studies included, the effect of VLCDs on hepatic and renal outcomes remains unclear at this stage. Further standardized research is therefore required to fully assess the impact of VLCDs on these outcome measures, to better guide clinical practice.
doi:10.2147/DMSO.S51151
PMCID: PMC3798146  PMID: 24143118
obesity; liver; kidney; weight loss; health
17.  Modulating microtubule stability enhances the cytotoxic response of cancer cells to paclitaxel 
Cancer research  2011;71(17):5806-5817.
The extracellular matrix protein TGFBI enhances the cytotoxic response of cancer cells to paclitaxel by affecting integrin signals that stabilize microtubules. Extending the implications of this knowledge, we tested the more general hypothesis that cancer cell signals which increase microtubule stability before exposure to paclitaxel may increase its ability to stablize microtubules and thereby enhance its cytotoxicity. Toward this end, we performed an siRNA screen to evaluate how genetic depletion affected microtubule stabilization, cell viability and apoptosis. High content microscopical analysis was performed in the absence or presence of paclitaxel. Kinase knockdowns that stabilized microtubules strongly enhanced the effects of paclitaxel treatment. Conversely, kinase knockdowns that enhanced paclitaxel-mediated cytotoxicity sensitized cells to microtubule stabilization by paclitaxel. The siRNA screen identified several genes that have not been linked previously to in microtubule regulation or paclitaxel response. Gene shaving and Bayesian resampling used to classify these genes suggested three pathways of paclitaxel-induced cell death related to apoptosis and microtubule stability, apoptosis alone, or neither process. Our results offer a functional classification of the genetic basis for paclitaxel sensitivity and they support the hypothesis that stablizing microtubules prior to therapy could enhance antitumor responses to paclitaxel treatment.
doi:10.1158/0008-5472.CAN-11-0025
PMCID: PMC3679477  PMID: 21775522
Microtubule stability; paclitaxel; ovarian cancer; targeted therapy; antimitotic therapy
18.  Gene Expression Profiling of Ampullary Carcinomas Classifies Ampullary Carcinomas into Biliary-Like and Intestinal-Like Subtypes That Are Prognostic of Outcome 
PLoS ONE  2013;8(6):e65144.
Background
Adenocarcinomas of the ampulla of Vater are classified as biliary cancers, though the exact epithelium of origin for these cancers is not known. We sought to molecularly classify ampullary adenocarcinomas in comparison to known adenocarcinomas of the pancreas, bile duct, and duodenum by gene expression analysis.
Methods
We analyzed 32 fresh-frozen resected, untreated periampullary adenocarcinomas (8 pancreatic, 2 extrahepatic biliary, 8 duodenal, and 14 ampullary) using the Affymetrix U133 Plus 2.0 genome array. Unsupervised and supervised hierarchical clustering identified two subtypes of ampullary carcinomas that were molecularly and histologically characterized.
Results
Hierarchical clustering of periampullary carcinomas segregated ampullary carcinomas into two subgroups, which were distinctly different from pancreatic carcinomas. Non-pancreatic periampullary adenocarcinomas were segregated into two subgroups with differing prognoses: 5 year RFS (77% vs. 0%, p = 0.007) and 5 year OS (100% vs. 35%, p = 0.005). Unsupervised clustering analysis of the 14 ampullary samples also identified two subgroups: a good prognosis intestinal-like subgroup and a poor prognosis biliary-like subgroup with 5 year OS of 70% vs. 28%, P = 0.09. Expression of CK7+/CK20- but not CDX-2 correlated with these two subgroups. Activation of the AKT and MAPK pathways were both increased in the poor prognostic biliary-like subgroup. In an independent 80 patient ampullary validation dataset only histological subtype (intestinal vs. pancreaticobiliary) was significantly associated with OS in both univariate (p = 0.006) and multivariate analysis (P = 0.04).
Conclusions
Gene expression analysis discriminated pancreatic adenocarcinomas from other periampullary carcinomas and identified two prognostically relevant subgroups of ampullary adenocarcinomas. Histological subtype was an independent prognostic factor in ampullary adenocarcinomas.
doi:10.1371/journal.pone.0065144
PMCID: PMC3679143  PMID: 23776447
19.  Further Insight into the Depth-Dependent Microstructural Response of Cartilage to Compression Using a Channel Indentation Technique 
Stress relaxation and structural analysis were used to investigate the zonally differentiated microstructural response to compression of the integrated cartilage-on-bone tissue system. Fifteen cartilage-on-bone samples were divided into three equal groups and their stress relaxation responses obtained at three different levels of axial compressive strain defined as low (~20%), medium (~40%) and high (~60%). All tests were performed using a channel indenter which included a central relief space designed to capture the response of the matrix adjacent to the directly loaded regions. On completion of each stress relaxation test and while maintaining the imposed axial strain, the samples were formalin fixed, decalcified, and then sectioned for microstructural analysis. Chondron aspect ratios were used to determine the extent of relative strain at different zonal depths. The stress relaxation response of cartilage to all three defined levels of axial strain displayed an initial highly viscous response followed by a significant elastic response. Chondron aspect ratio measurements showed that at the lowest level of compression, axial deformation was confined to the superficial cartilage layer, while in the medium and high axial strain samples the deformation extended into the midzone. The cells in the deep zone remained undeformed for all compression levels.
doi:10.1155/2013/358192
PMCID: PMC3638672  PMID: 24023589
20.  Silencing of microRNA families by seed-targeting tiny LNAs 
Nature genetics  2011;43(4):371-378.
The challenge of understanding the widespread biological roles of animal microRNAs (miRNAs) has prompted the development of genetic and functional genomics technologies for miRNA loss-of-function studies. However, tools for exploring the functions of entire miRNA families are still limited. We developed a method that enables antagonism of miRNA function using seed-targeting 8-mer locked nucleic acid (LNA) oligonucleotides, termed tiny LNAs. Transfection of tiny LNAs into cells resulted in simultaneous inhibition of miRNAs within families sharing the same seed with concomitant upregulation of direct targets. In addition, systemically delivered, unconjugated tiny LNAs showed uptake in many normal tissues and in breast tumors in mice, coinciding with long-term miRNA silencing. Transcriptional and proteomic profiling suggested that tiny LNAs have negligible off-target effects, not significantly altering the output from mRNAs with perfect tiny LNA complementary sites. Considered together, these data support the utility of tiny LNAs in elucidating the functions of miRNA families in vivo.
doi:10.1038/ng.786
PMCID: PMC3541685  PMID: 21423181
21.  Utilisation of complementary and alternative medicine (CAM) practitioners within maternity care provision: results from a nationally representative cohort study of 1,835 pregnant women 
Background
There is little known about women’s concurrent use of conventional and complementary health care during pregnancy, particularly consultation patterns with complementary and alternative medicine (CAM). This study examines health service utilisation among pregnant women including consultations with obstetricians, midwives, general practitioners (GPs) and CAM practitioners.
Methods
A sub-study of pregnant women (n=2445) was undertaken from the nationally-representative Australian Longitudinal Study on Women’s Health (ALSWH). Women’s consultations with conventional practitioners (obstetricians, GPs and midwives) and CAM practitioners for pregnancy-related health conditions were analysed. The analysis included Pearson chi-square tests to compare categorical variables.
Results
The survey was completed by 1835 women (response rate = 79.2%). A substantial number (49.4%) of respondents consulted with a CAM practitioner for pregnancy-related health conditions. Many participants consulted only with a CAM practitioner for assistance with certain conditions such as neck pain (74.6%) and sciatica (40.4%). Meanwhile, women consulted both CAM practitioners and conventional maternity health professionals (obstetricians, midwives and GPs) for back pain (61.8%) and gestational diabetes (22.2%). Women visiting a general practitioner (GP) 3–4 times for pregnancy care were more likely to consult with acupuncturists compared with those consulting a GP less often (p=<0.001, x2=20.5). Women who had more frequent visits to a midwife were more likely to have consulted with an acupuncturist (p=<0.001, x2=18.9) or a doula (p=<0.001, x2=23.2) than those visiting midwives less frequently for their pregnancy care.
Conclusions
The results emphasise the necessity for a considered and collaborative approach to interactions between pregnant women, conventional maternity health providers and CAM practitioners to accommodate appropriate information transferral and co-ordinated maternity care. The absence of sufficient clinical evidence regarding many commonly used CAM practices during pregnancy also requires urgent attention.
doi:10.1186/1471-2393-12-146
PMCID: PMC3534226  PMID: 23231765
Pregnancy; Complementary medicine; Health services; Interprofessional; Integrative medicine
22.  iBAG: integrative Bayesian analysis of high-dimensional multiplatform genomics data 
Bioinformatics  2012;29(2):149-159.
Motivation: Analyzing data from multi-platform genomics experiments combined with patients’ clinical outcomes helps us understand the complex biological processes that characterize a disease, as well as how these processes relate to the development of the disease. Current data integration approaches are limited in that they do not consider the fundamental biological relationships that exist among the data obtained from different platforms.
Statistical Model: We propose an integrative Bayesian analysis of genomics data (iBAG) framework for identifying important genes/biomarkers that are associated with clinical outcome. This framework uses hierarchical modeling to combine the data obtained from multiple platforms into one model.
Results: We assess the performance of our methods using several synthetic and real examples. Simulations show our integrative methods to have higher power to detect disease-related genes than non-integrative methods. Using the Cancer Genome Atlas glioblastoma dataset, we apply the iBAG model to integrate gene expression and methylation data to study their associations with patient survival. Our proposed method discovers multiple methylation-regulated genes that are related to patient survival, most of which have important biological functions in other diseases but have not been previously studied in glioblastoma.
Availability: http://odin.mdacc.tmc.edu/∼vbaladan/.
Contact: veera@mdanderson.org
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts655
PMCID: PMC3546799  PMID: 23142963
23.  Long-Term Survival in HIV Positive Patients with up to 15 Years of Antiretroviral Therapy 
PLoS ONE  2012;7(11):e48839.
Background
Life expectancy has increased for newly diagnosed HIV patients since the inception of combination antiretroviral treatment (cART), but there remains a need to better understand the characteristics of long-term survival in HIV-positive patients. We examined long-term survival in HIV-positive patients receiving cART in the Australian HIV Observational Database (AHOD), to describe changes in mortality compared to the general population and to develop longer-term survival models.
Methods
Data were examined from 2,675 HIV-positive participants in AHOD who started cART. Standardised mortality ratios (SMR) were calculated by age, sex and calendar year across prognostic characteristics using Australian Bureau of Statistics national data as reference. SMRs were examined by years of duration of cART by CD4 and similarly by viral load. Survival was analysed using Cox-proportional hazards and parametric survival models.
Results
The overall SMR for all-cause mortality was 3.5 (95% CI: 3.0–4.0). SMRs by CD4 count were 8.6 (95% CI: 7.2–10.2) for CD4<350 cells/µl; 2.1 (95% CI: 1.5–2.9) for CD4 = 350–499 cells/µl; and 1.5 (95% CI: 1.1–2.0) for CD4≥500 cells/µl. SMRs for patients with CD4 counts <350 cells/µL were much higher than for patients with higher CD4 counts across all durations of cART. SMRs for patients with viral loads greater than 400 copies/ml were much higher across all durations of cART. Multivariate models demonstrated improved survival associated with increased recent CD4, reduced recent viral load, younger patients, absence of HBVsAg-positive ever, year of HIV diagnosis and incidence of ADI. Parametric models showed a fairly constant mortality risk by year of cART up to 15 years of treatment.
Conclusion
Observed mortality remained fairly constant by duration of cART and was modelled accurately by accepted prognostic factors. These rates did not vary much by duration of treatment. Changes in mortality with age were similar to those in the Australian general population.
doi:10.1371/journal.pone.0048839
PMCID: PMC3492258  PMID: 23144991
24.  A randomised controlled trial of Heparin versus EthAnol Lock THerapY for the prevention of Catheter Associated infecTion in Haemodialysis patients – the HEALTHY-CATH trial 
BMC Nephrology  2012;13:146.
Background
Tunnelled central venous dialysis catheter use is significantly limited by the occurrence of catheter-related infections. This randomised controlled trial assessed the efficacy of a 48 hour 70% ethanol lock vs heparin locks in prolonging the time to the first episode of catheter related blood stream infection (CRBSI).
Methods
Patients undergoing haemodialysis (HD) via a tunnelled catheter were randomised 1:1 to once per week ethanol locks (with two heparin locks between other dialysis sessions) vs thrice per week heparin locks.
Results
Observed catheter days in the heparin (n=24) and ethanol (n=25) groups were 1814 and 3614 respectively. CRBSI occurred at a rate of 0.85 vs. 0.28 per 1000 catheter days in the heparin vs ethanol group by intention to treat analysis (incident rate ratio (IRR) for ethanol vs. heparin 0.17; 95%CI 0.02-1.63; p=0.12). Flow issues requiring catheter removal occurred at a rate of 1.6 vs 1.4 per 1000 catheter days in the heparin and ethanol groups respectively (IRR 0.85; 95% CI 0.20-3.5 p =0.82 (for ethanol vs heparin).
Conclusions
Catheter survival and catheter-related blood stream infection were not significantly different but there was a trend towards a reduced rate of infection in the ethanol group. This study establishes proof of concept and will inform an adequately powered multicentre trial to definitively examine the efficacy and safety of ethanol locks as an alternative to current therapies used in the prevention of catheter-associated blood stream infections in patients dialysing with tunnelled catheters.
Trial Registration
Australian New Zealand Clinical Trials Registry ACTRN12609000493246
doi:10.1186/1471-2369-13-146
PMCID: PMC3531247  PMID: 23121768
Catheter related blood stream infection (CRBSI); Central venous catheter; Ethanol; Lock therapy; Haemodialysis (HD); Prophylaxis
25.  Animal Welfare in Different Human Cultures, Traditions and Religious Faiths 
Animal welfare has become a growing concern affecting acceptability of agricultural systems in many countries around the world. An earlier Judeo-Christian interpretation of the Bible (1982) that dominion over animals meant that any degree of exploitation was acceptable has changed for most people to mean that each person has responsibility for animal welfare. This view was evident in some ancient Greek writings and has parallels in Islamic teaching. A minority view of Christians, which is a widespread view of Jains, Buddhists and many Hindus, is that animals should not be used by humans as food or for other purposes. The commonest philosophical positions now, concerning how animals should be treated, are a blend of deontological and utilitarian approaches. Most people think that extremes of poor welfare in animals are unacceptable and that those who keep animals should strive for good welfare. Hence animal welfare science, which allows the evaluation of welfare, has developed rapidly.
doi:10.5713/ajas.2012.r.02
PMCID: PMC4093044  PMID: 25049508
Animal Welfare; Ancient and Modern Philosophies; Religious Faiths; Ethics

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