Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

An evaluation of medication review reports across different settings

Background There is a growing body of evidence which supports that a pharmacist conducted medication review increases the health outcomes for patients. A pharmacist integrated into a primary care medical centre may offer many potential advantages in conducting medication reviews in this setting however research describing this is presently limited. Objective To compare medication review reports conducted by pharmacists practicing externally to a medical centre to those medication review reports conducted by an integrated practice pharmacist. The secondary objective was to compare medication review reports conducted by pharmacists in the patient’s home to those conducted in the medical centre. Setting A primary care medical centre, Brisbane, Australia Method A retrospective analysis of pharmacist conducted medication reviews prior to and after the integration of a pharmacist into a medical centre. Main outcome measures Types of drug related problems identified by the Pharma cists, recommended intervention for drug related problems made by the pharmacist, and the extent of implementation of pharmacist recommendations by the general practitioner. Results The primary drug related problem reported in the practice pharmacist phase was Additional therapy required as compared to Precautions in the external pharmacist phase. The practice pharmacist most frequently recommended to add drug with Additional monitoring recommended most often in the external pharmacists. During the practice pharmacist phase 71 % of recommendations were implemented and was significantly higher than the external pharmacist phase with 53 % of recommendations implemented (p\0.0001). Two of the 23 drug related problem domains differed significantly when comparing medication reviews conducted in the patient’s home to those conducted in the medical centre.

Acticoat™ : A cost-effective and evidence-based dressing strategy [Letter to the Editor]

We thank Dr. Burd et al. for taking an interest in our paper [1]. The retrospective cohort study was performed and published for two reasons. Firstly, we wished to compare and contrast the use of Acticoat™ and Silvazine™, and secondly we wished to demonstrate how one's practice can be dramatically altered by a change in dressing used. We found that Acticoat™ was safe and easy to use, caused less trauma to patients, required less frequent dressing changes and enabled treatment to be conducted on an outpatient, rather than an inpatient basis. During the period of Acticoat™ treatment we also saw a dramatic reduction in grafting requirements and also in the need for long-term scar management. Burd et al. correctly state that silver-based dressings are now more widely available, however many burn centres in the world continue to use silver sulphadiazine with daily baths. We therefore feel that a comparison is very relevant and useful. Prospective, randomised clinical trials of a range of silver-based dressings would indeed be useful, and hopefully Dr. Burd and colleagues will take up their own suggestion and perform these studies...

Cataract surgery in eyes with low corneal astigmatism : implantation of the AcrySof IQ Toric SN6AT2 intraocular lens

Purpose The aim of this study is to assess the refractive and visual outcomes following cataract surgery and implantation of the AcrySof IQ Toric SN6AT2 intraolcular lens (IOL) (Alcon Laboratories, Inc) in patients with low corneal astigmatism. Materials and Methods A retrospective, consecutive, single surgeon series of ninety-eight eyes of 88 patients following cataract surgery and implantation of the AcrySof IQ Toric SN6AT2 IOL in eyes with low preoperative corneal astigmatism. Postoperative measurements were obtained at one month post surgery. Main outcome measures were monocular distance visual acuity and residual refractive astigmatism. Results The mean preoperative corneal astigmatic power vector (APV) was 0.38 ± 0.09 D. Following surgery and implantation of the toric IOL, mean postoperative refractive APV was 0.13 ± 0.10 D. Mean postoperative distance uncorrected visual acuity (UCVA) was 0.08 ± 0.09 logMAR. Postoperative spherical equivalent refraction (SER) resulted in a mean of - 0.23 ± 0.22 D, with 96% of eyes falling within 0.50 D of the target SER. Conclusions The AcrySof IQ Toric SN6AT2 IOL is a safe and effective option for eyes undergoing cataract surgery with low amounts of preoperative corneal astigmatism.

Breastfeeding self-efficacy of women using second-line strategies for healthy term infants in the first week postpartum : an Australian observational study

Background Breastfeeding self-efficacy (BFSE) supports breastfeeding initiation and duration. Challenges to breastfeeding may undermine BFSE, but second-line strategies including nipple shields, syringe, cup, supply line and bottle feeding may support breastfeeding until challenges are resolved. The primary aim of this study was to examine BFSE in a sample of women using second-line strategies for feeding healthy term infants in the first week postpartum. Methods A retrospective self-report study was conducted using the Breastfeeding Self-Efficacy Scale - Short Form (BSES-SF), demographic and infant feeding questionnaires. Breastfeeding women who gave birth to a singleton healthy term infant at one private metropolitan birthing facility in Australia from November 2008 to February 2009 returned anonymous questionnaires by mail. Results A total of 128 (73 multiparous, 55 primiparous) women participated in the study. The mean BSES-SF score was 51.18 (Standard deviation, SD: 12.48). The median BSES-SF score was 53. Of women using a second-line strategy, 16 exceeded the median, and 42 were below. Analyses using Kruskal-Wallis tests confirmed this difference was statistically significant (H = 21.569, p = 0.001). The rate of second-line strategy use was 48%. The four most commonly used second-line strategies were: bottles with regular teats (77%); syringe feeding (44%); bottles with wide teats (34%); and nipple shields (27%). Seven key challenges were identified that contributed to the decision to use second-line strategies, including: nipple pain (40%); unsettled infant (40%); insufficient milk supply (37%); fatigue (37%); night nursery care (25%); infant weight loss > 10% (24%); and maternal birth associated pain (20%). Skin-to-skin contact at birth was commonly reported (93%). At seven days postpartum 124 women (97%) were continuing to breastfeed. Conclusions The high rate of use of second-line strategies identified in this study and high rate of breastfeeding at day seven despite lower BFSE indicate that such practices should not be overlooked by health professionals. The design of this study does not enable determination of cause-effect relationships to identify factors which contribute to use of second-line strategies. Nevertheless, the significantly lower BSES-SF score of women using a second-line strategy highlights this group of women have particular needs that require attention.

The judgments of Justice Lionel Murphy

Member of High Court Bench; includes references to Aboriginal voting rights; protection of Aboriginal sites in Franklin Dam Case; authors statements from cases - Onus v Alcoa of Australia Ltd, Portland; Neal v Queen, Yarrabah, Koowarta v BjelkePeterson, and Racial Discrimination Act 1975, Archer River; Queen v Toohey (Kenbi, Cox Peninsula); Coe v Commonwealth; Veen v Queen.

The Politics and Legality of Prisoner Disenfranchisement in Australian Federal Elections

To remove the right of prisoners to vote does many things. … It signals that whatever the prisoner says is not of interest to those at the top, that you are not interested in talking to them or even listening to them, that you want to exclude them and that you have no interest in knowing about them. INTRODUCTION In June 2006, Australia passed legislation disenfranchising all prisoners serving full-time custodial sentences from voting in federal elections. This followed a succession of changes dating from 1983 that alternately extended and restricted the prisoner franchise. In 1989 and 1995, the Australian Labor Party (ALP) federal government prepared draft legislation removing any restrictions on prisoner voting rights in federal elections; the measures were defeated and withdrawn. With the 2006 legislation, the Howard Coalition government (composed of the Liberal and National parties) successfully achieved the total disenfranchisement it first sought in 1998. This chapter examines the politics and legality of the 2006 disenfranchisement. This will be approached, first, by briefly outlining the key provisions of the Commonwealth Electoral Act 1918, offering a short legislative history of prisoner franchise, and examining some of the key constitutional issues. Second, the 2006 disenfranchisement introduced in the Electoral and Referendum (Electoral Integrity and Other Measures) Act 2006 will be examined in greater detail, particularly in terms of the manner in which it was achieved and the arguments that were mobilized both in support of and against the change.

How much geological detail is needed for gasifier success?

The incipient Underground Coal Gasification (UCG) industry in Queensland, Australia, undertook three trial projects in two Mesozoic basins of southeast Queensland. The experiences of these three operations provide useful retrospective insight into gasifier productivity. This paper identifies key output measures of gasifier ‘success’ including output gas composition, presence of contaminants in groundwater and consistency of chamber operation. Likewise, a review of the geological and hydrogeological understanding of each site prior to gasifier commissioning was undertaken. Productivity parameters from gasification were then correlated against the level of baseline geological/hydrogeological understanding for each site. The aim of the study was to identify the optimum scope of geological and hydrogeological understanding required at the site assessment phase to ensure safe, maximum gasifier output during production phase. This approach allows identification of poor or unexpected performance that is attributable to pre-existing uncertainty. A historical review of gasifier conditions inferred from the three trial projects is presented. Hence from the Queensland experiences it is possible to identify what aspects of baseline geological understanding should be clearly understood at the site selection phase in order to limit anomalous gasifier performance and undesirable deviations, and maximise production output.

BDNF and TNF-α polymorphisms in memory

Here, we investigate the genetic basis of human memory in healthy individuals and the potential role of two polymorphisms, previously implicated in memory function. We have explored aspects of retrospective and prospective memory including semantic, short term, working and long-term memory in conjunction with brain derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-alpha). The memory scores for healthy individuals in the population were obtained for each memory type and the population was genotyped via restriction fragment length polymorphism for the BDNF rs6265 (Val66Met) SNP and via pyrosequencing for the TNF-alpha rs113325588 SNP. Using univariate ANOVA, a significant association of the BDNF polymorphism with visual and spatial memory retention and a significant association of the TNF-alpha polymorphism was observed with spatial memory retention. In addition, a significant interactive effect between BDNF and TNF-alpha polymorphisms was observed in spatial memory retention. In practice visual memory involves spatial information and the two memory systems work together, however our data demonstrate that individuals with the Val/Val BDNF genotype have poorer visual memory but higher spatial memory retention, indicating a level of interaction between TNF-alpha and BDNF in spatial memory retention. This is the first study to use genetic analysis to determine the interaction between BDNF and TNF-alpha in relation to memory in normal adults and provides important information regarding the effect of genetic determinants and gene interactions on human memory.

Why are there Different Age Related Trends for Different Chemicals?

Persistent organic pollutants (POPs) such as dioxins, PCBs, persistent organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs) as well as perfluorinated compounds (PFCs) and triclosan are ubiquitous in the human population. In Australia, we have pooled and subsequently analysed over 10 000 human serum samples for the determination of these chemicals by age group (0–0.5; 0.6–1; 1.1–1.5; 1.6–2; 2.1–2.5; 2.6–3; 3.1–3.5; 3.6–4; 4.1–6; 6.1–9; 9.1–12; 12.1–15; 16–30; 31–45; 46–60 and >60 years) and gender. The results of this analysis were then used to assess the trends of these different chemicals as a function of age, gender and to a lesser extent region. Our data demonstrate clear chemical specific age trends. In particular we demonstrate that for the traditional POPs there is an increase in body burden with age whereas the opposite is true for chemicals such as PBDEs. For PFCs we find chemical specific age trends that vary from compound to compound. For triclosan we show that no apparent age trend is observable. The results of the study and its implications to the collection and archiving of samples for retrospective analysis are discussed.

Learning and teaching epidemiology with audience response technology

Background The learning and teaching of epidemiology is core to many public health programs. Many students find the content of epidemiology, and specifically risk of bias assessment, challenging to learn. Howbeit, learning is enhanced when knowledge is able to be acquired from an active-learning, hands-on experience. Methods The innovative use of wireless audience response technology “clickers” was incorporated into the lectures of the university’s post-graduate epidemiology units and the tailored epidemiological modules delivered for professional disciplines (e.g. optometry). Clickers were used to apply several pedagogical approaches of active learning including peer-instruction and real-world simulation. Students were also assessed for their gain in knowledge within the lecture (pre-post) and their perceptions of how the use of clickers helped them learn. The routine university-wide end of semester Insight Survey provided further information of the student’s satisfaction with the approach. Results The technology was useful in identifying deficits of knowledge of key concepts either before or after instruction. Where key concepts were re-tested post-lecture, as expected, knowledge increased significantly and provided immediate feed-back to students. Across the lecture series, typically 85% of students identified the technology helped them learn, increased their opportunity to interact with the lecturer, and recommend their use for future classes. The Insight Survey report identified 93% of respondents identified the unit in which clickers were consistently used provided good learning opportunities. Numerous student comments supported the teaching method. Conclusions Epidemiological subject matter lends itself to incorporation of audience response technology. The use of the technology to facilitate interactive voting provides an instant response and participation of everyone to enhance the classroom experience. The pedagogical approach increases students’ knowledge and increases their satisfaction with the unit.

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. 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Accurate placement of a pelvic binder improves reduction of unstable fractures of the pelvic ring

The aim of this study was to assess the accuracy of placement of pelvic binders and to determine whether circumferential compression at the level of the greater trochanters is the best method of reducing a symphyseal diastasis. Patients were identified by a retrospective review of all pelvic radiographs performed at a military hospital over a period of 30 months. We analysed any pelvic radiograph on which the buckle of the pelvic binder was clearly visible. The patients were divided into groups according to the position of the buckle in relation to the greater trochanters: high, trochanteric or low. Reduction of the symphyseal diastasis was measured in a subgroup of patients with an open-book fracture, which consisted of an injury to the symphysis and disruption of the posterior pelvic arch (AO/OTA 61-B/C). We identified 172 radiographs with a visible pelvic binder. Five cases were excluded due to inadequate radiographs. In 83 (50%) the binder was positioned at the level of the greater trochanters. A high position was the most common site of inaccurate placement, occurring in 65 (39%). Seventeen patients were identified as a subgroup to assess the effect of the position of the binder on reduction of the diastasis. The mean gap was 2.8 times greater (mean difference 22 mm) in the high group compared with the trochanteric group (p < 0.01). Application of a pelvic binder above the level of the greater trochanters is common and is an inadequate method of reducing pelvic fractures and is likely to delay cardiovascular recovery in these seriously injured patients.

Vote with your feet : local community polling on urban screens

Falling prices have led to an ongoing spread of public displays in urban areas. Still, they mostly show passive content such as commercials and digital signage. At the same time, technological advances have enabled the creation of interactive displays potentially increasing their attractiveness for the audience, e.g. through providing a platform for civic discourse. This poses considerable challenges, since displays need to communicate the opportunity to engage, motivate the audience to do so, and be easy to use. In this paper we present Vote With Your Feet, a hyperlocal public polling tool for urban screens allowing users to express their opinions. Similar to vox populi interviews on TV or polls on news websites, the tool is meant to reflect the mindset of the community on topics such as current affairs, cultural identity and local matters. It is novel in that it focuses on a situated civic discourse and provides a tangible user interface, tackling the mentioned challenges. It shows one Yes/No question at a time and enables users to vote by stepping on one of two tangible buttons on the ground. This user interface was introduced to attract people’s attention and to lower participation barriers. Our field study showed that Vote With Your Feet is perceived as inviting and that it can spark discussions among co-located people.

Modelling the economic benefits of gold standard care for chronic wounds in a community setting

Chronic leg ulcers are costly to manage for health service providers. Although evidence-based care leads to improved healing rates and reduced costs, a significant evidence-practice gap is known to exist. Lack of access to specialist skills in wound care is one reason suggested for this gap. The aim of this study was to model the change to total costs and health outcomes under two versions of health services for patients with leg ulcers: routine health services for community-living patients; and care provided by specialist wound clinics. Mean weekly treatment and health services costs were estimated from participants’ data (n=70) for the twelve months prior to their entry to a study specialist wound clinic, and prospectively for 24 weeks after entry. For the retrospective phase mean weekly costs of care were $AU130.30 (SD $12.64) and these fell to $AU53.32 (SD $6.47) for the prospective phase. Analysis at a population level suggests if 10,000 individuals receive 12 weeks of specialist evidence-based care, the cost savings are likely to be AU$9,238,800. Significant savings could be made by the adoption of evidence-based care such as that provided by the community and outpatient specialist wound clinics in this study.