The α5 subunit regulates the expression and function of α4*-containing neuronal nicotinic acetylcholine receptors in the ventral-tegmental area

Human genetic association studies have shown gene variants in the α5 subunit of the neuronal nicotinic receptor (nAChR) influence both ethanol and nicotine dependence. The α5 subunit is an accessory subunit that facilitates α4* nAChRs assembly in vitro. However, it is unknown whether this occurs in the brain, as there are few research tools to adequately address this question. As the α4*-containing nAChRs are highly expressed in the ventral tegmental area (VTA) we assessed the molecular, functional and pharmacological roles of α5 in α4*-containing nAChRs in the VTA. We utilized transgenic mice α5+/+(α4YFP) and α5-/-(α4YFP) that allow the direct visualization and measurement of α4-YFP expression and the effect of the presence (α5+/+) and absence of α5 (-/-) subunit, as the antibodies for detecting the α4* subunits of the nAChR are not specific. We performed voltage clamp electrophysiological experiments to study baseline nicotinic currents in VTA dopaminergic neurons. We show that in the presence of the α5 subunit, the overall expression of α4 subunit is increased significantly by 60% in the VTA. Furthermore, the α5 subunit strengthens baseline nAChR currents, suggesting the increased expression of α4* nAChRs to be likely on the cell surface. While the presence of the α5 subunit blunts the desensitization of nAChRs following nicotine exposure, it does not alter the amount of ethanol potentiation of VTA dopaminergic neurons. Our data demonstrates a major regulatory role for the α5 subunit in both the maintenance of α4*-containing nAChRs expression and in modulating nicotinic currents in VTA dopaminergic neurons. Additionally, the α5α4* nAChR in VTA dopaminergic neurons regulates the effect of nicotine but not ethanol on currents. Together, the data suggest that the α5 subunit is critical for controlling the expression and functional role of a population of α4*-containing nAChRs in the VTA.

Matrix metalloproteinases during wound healing - a double edged sword

The extracellular matrix (ECM) provides a framework for cells and gives skin its tensile strength and elasticity. Loss of its integrity necessitates the clearing of damaged components and the deposition of firstly a provisional matrix and later remodelling of the ECM to support a functionally intact tissue. Matrix metalloproteinases (MMPs) are an important family of enzymes that function in the breakdown of the ECM and modulate the function of many biologically active molecules housed in the ECM. Through their enzymatic actions MMPs play a role in fundamental processes such as immune cell infiltration and ECM remodelling during wound repair. Their tight control is necessary for timely wound healing and excessive MMP activity participates in the development and persistence of chronic wounds, while reduced activity contributes to fibrosis. A number of inhibitors have been designed to target this activity and improve wound healing with limited success. Novel strategies are currently being investigated to improve wound healing by targeting MMP modulating molecules.

Development and validation of a pregnancy symptoms inventory

Background Physical symptoms are common in pregnancy and are predominantly associated with normal physiological changes. These symptoms have a social and economic cost, leading to absenteeism from work and additional medical interventions. There is currently no simple method for identifying common pregnancy related problems in the antenatal period. A validated tool, for use by pregnancy care providers would be useful. The aim of this study was to develop and validate a Pregnancy Symptoms Inventory for use by health professionals. Methods A list of symptoms was generated via expert consultation with health professionals. Focus groups were conducted with pregnant women. The inventory was tested for face validity and piloted for readability and comprehension. For test-re-test reliability, the tool was administered to the same women 2 to 3 days apart. Finally, midwives trialled the inventory for 1 month and rated its usefulness on a 10cm visual analogue scale (VAS). Results A 41-item Likert inventory assessing how often symptoms occurred and what effect they had, was developed. Individual item test re-test reliability was between .51 to 1, the majority (34 items) scoring ≥0.70. The top four “often” reported symptoms were urinary frequency (52.2%), tiredness (45.5%), poor sleep (27.5%) and back pain (19.5%). Among the women surveyed, 16.2% claimed to sometimes or often be incontinent. Referrals to the incontinence nurse increased > 8 fold during the study period. Conclusions The PSI provides a comprehensive inventory of pregnancy related symptoms, with a mechanism for assessing their effect on function. It was robustly developed, with good test re-test reliability, face validity, comprehension and readability. This provides a validated tool for assessing the impact of interventions in pregnancy.

Dynamic Micromapping of CO2 Sorption in Coal

We have applied X-ray and neutron small-angle scattering techniques (SAXS, SANS, and USANS) to study the interaction between fluids and porous media in the particular case of subcritical CO2 sorption in coal. These techniques are demonstrated to give unique, pore-size-specific insights into the kinetics of CO2 sorption in a wide range of coal pores (nano to meso) and to provide data that may be used to determine the density of the sorbed CO2. We observed densification of the adsorbed CO2 by a factor up to five compared to the free fluid at the same (p, T) conditions. Our results indicate that details of CO2 sorption into coal pores differ greatly between different coals and depend on the amount of mineral matter dispersed in the coal matrix: a purely organic matrix absorbs more CO2 per unit volume than one containing mineral matter, but mineral matter markedly accelerates the sorption kinetics. Small pores are filled preferentially by the invading CO2 fluid and the apparent diffusion coefficients have been estimated to vary in the range from 5 × 10-7 cm2/min to more than 10-4 cm2/min, depending on the CO2 pressure and location on the sample.

The once-and-for-all withdrawal of the Liverpool Care Pathway in the UK : what are the implications for Australia?

This Perspective reflects on the withdrawal of the Liverpool Care Pathway in the UK, and its implications for Australia. Integrated care pathways are documents which outline the essential steps of multidisciplinary care in addressing a specific clinical problem. They can be used to introduce best clinical practice, to ensure that the most appropriate management occurs at the most appropriate time and that it is provided by the most appropriate health professional. By providing clear instructions, decision support and a framework for clinician-patient interactions, care pathways guide the systematic provision of best evidence-based care. The Liverpool Care Pathway (LCP) is an example of an integrated care pathway, designed in the 1990s to guide care for people with cancer who are in their last days of life and are expected to die in hospital. This pathway evolved out of a recognised local need to better support non-specialist palliative care providers’ care for patients dying of cancer within their inpatient units. Historically, despite the large number of people in acute care settings whose treatment intent is palliative, dying patients receiving general hospital acute care tended to lack sufficient attention from senior medical staff and nursing staff. The quality of end-of-life care was considered inadequate, therefore much could be learned from the way patients were cared for by palliative care services. The LCP was a strategy developed to improve end-of-life care in cancer patients and was based on the care received by those dying in the palliative care setting.

Overview of the ShARe/CLEF eHealth Evaluation Lab 2014

This paper reports on the 2nd ShARe/CLEFeHealth evaluation lab which continues our evaluation resource building activities for the medical domain. In this lab we focus on patients' information needs as opposed to the more common campaign focus of the specialised information needs of physicians and other healthcare workers. The usage scenario of the lab is to ease patients and next-of-kins' ease in understanding eHealth information, in particular clinical reports. The 1st ShARe/CLEFeHealth evaluation lab was held in 2013. This lab consisted of three tasks. Task 1 focused on named entity recognition and normalization of disorders; Task 2 on normalization of acronyms/abbreviations; and Task 3 on information retrieval to address questions patients may have when reading clinical reports. This year's lab introduces a new challenge in Task 1 on visual-interactive search and exploration of eHealth data. Its aim is to help patients (or their next-of-kin) in readability issues related to their hospital discharge documents and related information search on the Internet. Task 2 then continues the information extraction work of the 2013 lab, specifically focusing on disorder attribute identification and normalization from clinical text. Finally, this year's Task 3 further extends the 2013 information retrieval task, by cleaning the 2013 document collection and introducing a new query generation method and multilingual queries. De-identified clinical reports used by the three tasks were from US intensive care and originated from the MIMIC II database. Other text documents for Tasks 1 and 3 were from the Internet and originated from the Khresmoi project. Task 2 annotations originated from the ShARe annotations. For Tasks 1 and 3, new annotations, queries, and relevance assessments were created. 50, 79, and 91 people registered their interest in Tasks 1, 2, and 3, respectively. 24 unique teams participated with 1, 10, and 14 teams in Tasks 1, 2 and 3, respectively. The teams were from Africa, Asia, Canada, Europe, and North America. The Task 1 submission, reviewed by 5 expert peers, related to the task evaluation category of Effective use of interaction and targeted the needs of both expert and novice users. The best system had an Accuracy of 0.868 in Task 2a, an F1-score of 0.576 in Task 2b, and Precision at 10 (P@10) of 0.756 in Task 3. The results demonstrate the substantial community interest and capabilities of these systems in making clinical reports easier to understand for patients. The organisers have made data and tools available for future research and development.

From bench to bedside : immunotherapy for prostate cancer

The mainstay therapeutic strategy for metastatic castrate-resistant prostate cancer (CRPC) continues to be androgen deprivation therapy usually in combination with chemotherapy or androgen receptor targeting therapy in either sequence, or recently approved novel agents such as Radium 223. However, immunotherapy has also emerged as an option for the treatment of this disease following the approval of sipuleucel-T by the FDA in 2010. Immunotherapy is a rational approach for prostate cancer based on a body of evidence suggesting these cancers are inherently immunogenic and, most importantly, that immunological interventions can induce protective antitumour responses. Various forms of immunotherapy are currently being explored clinically, with the most common being cancer vaccines (dendritic-cell, viral, and whole tumour cell-based) and immune checkpoint inhibition. This review will discuss recent clinical developments of immune-based therapies for prostate cancer that have reached the phase III clinical trial stage. A perspective of how immunotherapy could be best employed within current treatment regimes to achieve most clinical benefits is also provided.

Hormone and Metabolite Profiles in Nesting Green and Flatback Turtles: Turtle Species with Different Life Histories

Herbivorous turtle, Chelonia mydas, inhabiting the south China Sea and breeding in Peninsular Malaysia, and Natator depressus, a carnivorous turtle inhabiting the Great Barrier Reef and breeding at Curtis Island in Queensland, Australia, differ both in diet and life history. Analysis of plasma metabolites levels and six sex steroid hormones during the peak of their nesting season in both species showed hormonal and metabolite variations. When compared with results from other studies progesterone levels were the highest whereas dihydrotestosterone was the plasma steroid hormone present at the lowest concentration in both C. mydas and N. depressus plasma. Interestingly, oestrone was observed at relatively high concentrations in comparison to oestradiol levels recorded in previous studies suggesting that it plays a significant role in nesting turtles. Also, hormonal correlations between the studied species indicate unique physiological interactions during nesting. Pearson correlation analysis showed that in N. depressus the time of oviposition was associated with elevations in both plasma corticosterone and oestrone levels. Therefore, we conclude that corticosterone and oestrone may influence nesting behaviour and physiology in N. depressus. To summarise, these two nesting turtle species can be distinguished based on the hormonal profile of oestrone, progesterone, and testosterone using discriminant analysis.

Cultural and linguistic localization of games to bridge the digital and cultural divide in indigenous populations

Localization of technology is now widely applied to the preservation and revival of the culture of indigenous peoples around the world, most commonly through the translation into indigenous languages, which has been proven to increase the adoption of technology. However, this current form of localization excludes two demographic groups, which are key to the effectiveness of localization efforts in the African context: the younger generation (under the age of thirty) with an Anglo- American cultural view who have no need or interest in their indigenous culture; and the older generation (over the age of fifty) who are very knowledgeable about their indigenous culture, but have little or no knowledge on the use of a computer. This paper presents the design of a computer game engine that can be used to provide an interface for both technology and indigenous culture learning for both generations. Four indigenous Ugandan games are analyzed and identified for their attractiveness to both generations, to both rural and urban populations, and for their propensity to develop IT skills in older generations.

Osteoporosis and fragility fractures

The prevalence of osteoporosis is expected to increase with the ageing of the world’s population. This article reviews the epidemiology, risk factors and health burden of osteoporosis. In the Global Burden of Disease (GBD) Study 2005, osteoporosis is studied as a risk factor for fracture by considering the bone-mineral-density (BMD) measurement as the continuous exposure variable. We have performed a systematic review seeking population-based studies with BMD data measured by dual-X-ray absorptiometry (DXA). The femoral neck was selected as the unique location and all values were converted into Hologic® to enable inclusion of worldwide data for analysis. Provisional results on mean BMD values for different world regions are shown in age breakdowns for males and females 50 years or over, as well as mean T-scores using the young, white, female reference of National Health and Nutrition Examination Survey (NHANES) III. Results show remarkable geographical differences and a time trend towards improvement of the BMD values in Asian and European populations.

SHA-3 Design and Cryptanalysis Report

The competition to select a new secure hash function standard SHA-3 was initiated in response to surprising progress in the cryptanalysis of existing hash function constructions that started in 2004. In this report we survey design and cryptanalytic results of those 14 candidates that remain in the competition, about 1.5 years after the competition started with the initial submission of the candidates in October 2008. Implementation considerations are not in the scope of this report. The diversity of designs is also reflected in the great variety of cryptanalytic techniques and results that were applied and found during this time. This report gives an account of those techniques and results.

The Games Concept Approach (GCA) as a mandated practice : views of Singaporean teachers

This paper reports on the views of Singaporean teachers of a mandated curriculum innovation aimed at changing the nature of games pedagogy within the physical education curriculum framework in Singapore. Since its first appearance over 20 years ago, Teaching Games for Understanding (TGfU), as an approach to games pedagogy has gathered support around the world. Through a process of evolution TGfU now has many guises and one of the latest of these is the Games Concept Approach (GCA) a name given to this pedagogical approach in Singapore. As part of a major national curricular reform project the GCA was identified as the preferred method of games teaching and as a result was mandated as required professional practice within physical education teaching. To prepare teachers for the implementation phase, a training program was developed by the National Institute of Education in conjunction with the Ministry of Education and well known experts in the field from the United States. For this part of the study, 22 teachers from across Singapore were interviewed. The data were used to create three fictional narratives, a process described by Sparkes (2002a) and used more recently by Ryan (2005) in the field of literacy. The stories were framed using Foucault’s (1980/1977) notion of governmentality and Bernstein’s (1996) notion of regulative discourse. The narratives reveal tales of confusion, frustration but also of hope and enthusiasm.