Cholesterol regulates Syntaxin 6 trafficking at trans-Golgi network endosomal boundaries.

Inhibition of cholesterol export from late endosomes causes cellular cholesterol imbalance, including cholesterol depletion in the trans-Golgi network (TGN). Here, using Chinese hamster ovary (CHO) Niemann-Pick type C1 (NPC1) mutant cell lines and human NPC1 mutant fibroblasts, we show that altered cholesterol levels at the TGN/endosome boundaries trigger Syntaxin 6 (Stx6) accumulation into VAMP3, transferrin, and Rab11-positive recycling endosomes (REs). This increases Stx6/VAMP3 interaction and interferes with the recycling of αVβ3 and α5β1 integrins and cell migration, possibly in a Stx6-dependent manner. In NPC1 mutant cells, restoration of cholesterol levels in the TGN, but not inhibition of VAMP3, restores the steady-state localization of Stx6 in the TGN. Furthermore, elevation of RE cholesterol is associated with increased amounts of Stx6 in RE. Hence, the fine-tuning of cholesterol levels at the TGN-RE boundaries together with a subset of cholesterol-sensitive SNARE proteins may play a regulatory role in cell migration and invasion.

A review of the effects of sedation on thermoregulation : insights for the cardiac catheterisation laboratory

Purpose To examine the effects that the sedative and analgesic medications which are commonly used in the cardiac catheterisation laboratory have on thermoregulation. Design A structured review strategy was used. Methods Medline and CINAHL were searched for published studies and reference lists of retrieved studies were scrutinized for further research. Data were extracted using a standardised extraction tool. Results A total of nine studies examined the effect that sedative and analgesic medications have on thermoregulation. Midazolam has minimal impact on thermoregulation while opioids, dexmedetomidine and propofol markedly decrease vasoconstriction and shivering thresholds. Conclusions Patients who receive sedation in the cardiac catheterisation laboratory may be at risk of hypothermia, due to the use of medications that impair thermoregulation. Further research is required to identify the prevalence of unplanned hypothermia during sedation in the cardiac catheterisation laboratory.

Optimism : what it is and its relevance in the school context

"For myself, I am an optimist - it does not seem to be much use to be anything else". Winston Churchill Optimism has its modern roots in philosophy dating back to the 17th century in the writings of philosophers such as Descartes and Voltaire (Domino & Conway, 2001). Previous to these philosophical writings, the concept of optimism was revealed in the teaching of many of the great spiritual traditions such as Buddhism and Christianity (Miller, Richards, & Keller, 2001). In the 20th century, optimism became defined in juxtaposition to pessimism, sometimes conceptualized as a bipolar unidimensional construct and by others as two related but separate constructs (Garber, 2000). Contemporary models (Scheier & Carver, 1985; Seligman, 1991) have increasingly focused on distinguishing optimism-pessimism as a general dispositional orientation, as described by expectancy theory, and as an explanatory process, described by explanatory style theory.

Pasture Degradation and Recovery in Australia's Rangelands : Learning from History

"The extended drought periods in each degradation episode have provided a test of the capacity of grazing systems (i.e. land, plants, animals, humans and social structure) to handle stress. Evidence that degradation was already occurring was identified prior to the extended drought sequences. The sequence of dry years, ranging from two to eight years, exposed and/or amplified the degradation processes. The unequivocal evidence was provided by: (a) the physical 'horror' of bare landscapes, erosion scalds and gullies and dust storms; (b) the biological devastation of woody weeds and animal suffering/deaths or forced sales, and; (c) the financial and emotional plight of graziers and their families due to reduced production in some cases leading to abandonment of properties or, sadly, deaths (e.g. McDonald 1991, Ker Conway 1989)."--Publisher website

Xenome--a tool for classifying reads from xenograft samples

Motivation Shotgun sequence read data derived from xenograft material contains a mixture of reads arising from the host and reads arising from the graft. Classifying the read mixture to separate the two allows for more precise analysis to be performed. Results We present a technique, with an associated tool Xenome, which performs fast, accurate and specific classification of xenograft-derived sequence read data. We have evaluated it on RNA-Seq data from human, mouse and human-in-mouse xenograft datasets.

The prevention, detection and management of cancer treatment-induced cardiotoxicity: a meta-review

Background The benefits associated with some cancer treatments do not come without risk. A serious side effect of some common cancer treatments is cardiotoxicity. Increased recognition of the public health implications of cancer treatment-induced cardiotoxicity has resulted in a proliferation of systematic reviews in this field to guide practice. Quality appraisal of these reviews is likely to limit the influence of biased conclusions from systematic reviews that have used poor methodology related to clinical decision-making. The aim of this meta-review is to appraise and synthesise evidence from only high quality systematic reviews focused on the prevention, detection or management of cancer treatment-induced cardiotoxicity. Methods Using Cochrane methodology, we searched databases, citations and hand-searched bibliographies. Two reviewers independently appraised reviews and extracted findings. A total of 18 high quality systematic reviews were subsequently analysed, 67 % (n = 12) of these comprised meta-analyses. Results One systematic review concluded that there is insufficient evidence regarding the utility of cardiac biomarkers for the detection of cardiotoxicity. The following strategies might reduce the risk of cardiotoxicity: 1) The concomitant administration of dexrazoxane with anthracylines; 2) The avoidance of anthracyclines where possible; 3) The continuous administration of anthracyclines (>6 h) rather than bolus dosing; and 4) The administration of anthracycline derivatives such as epirubicin or liposomal-encapsulated doxorubicin instead of doxorubicin. In terms of management, one review focused on medical interventions for treating anthracycline-induced cardiotoxicity during or after treatment of childhood cancer. Neither intervention (enalapril and phosphocreatine) was associated with statistically significant improvement in ejection fraction or mortality. Conclusion This review highlights the lack of high level evidence to guide clinical decision-making with respect to the detection and management of cancer treatment-associated cardiotoxicity. There is more evidence with respect to the prevention of this adverse effect of cancer treatment. This evidence, however, only applies to anthracycline-based chemotherapy in a predominantly adult population. There is no high-level evidence to guide clinical decision-making regarding the prevention, detection or management of radiation-induced cardiotoxicity.

Depth of anaesthesia monitoring during procedural sedation and analgesia: A systematic review protocol

Background Procedural sedation and analgesia (PSA) is used to attenuate the pain and distress that may otherwise be experienced during diagnostic and interventional medical or dental procedures. As the risk of adverse events increases with the depth of sedation induced, frequent monitoring of level of consciousness is recommended. Level of consciousness is usually monitored during PSA with clinical observation. Processed electroencephalogram-based depth of anaesthesia (DoA) monitoring devices provide an alternative method to monitor level of consciousness that can be used in addition to clinical observation. However, there is uncertainty as to whether their routine use in PSA would be justified. Rigorous evaluation of the clinical benefits of DoA monitors during PSA, including comprehensive syntheses of the available evidence, is therefore required. One potential clinical benefit of using DoA monitoring during PSA is that the technology could improve patient safety by reducing sedation-related adverse events, such as death or permanent neurological disability. We hypothesise that earlier identification of lapses into deeper than intended levels of sedation using DoA monitoring leads to more effective titration of sedative and analgesic medications, and results in a reduction in the risk of adverse events caused by the consequences of over-sedation, such as hypoxaemia. The primary objective of this review is to determine whether using DoA monitoring during PSA in the hospital setting improves patient safety by reducing the risk of hypoxaemia (defined as an arterial partial pressure of oxygen below 60 mmHg or percentage of haemoglobin that is saturated with oxygen [SpO2] less than 90 %). Other potential clinical benefits of using DoA monitoring devices during sedation will be assessed as secondary outcomes. Methods/design Electronic databases will be systematically searched for randomized controlled trials comparing the use of depth of anaesthesia monitoring devices with clinical observation of level of consciousness during PSA. Language restrictions will not be imposed. Screening, study selection and data extraction will be performed by two independent reviewers. Disagreements will be resolved by discussion. Meta-analyses will be performed if suitable. Discussion This review will synthesise the evidence on an important potential clinical benefit of DoA monitoring during PSA within hospital settings.

Inadvertent hypothermia after procedural sedation and analgesia in a cardiac catheterisation laboratory: A prospective observational study

Objective To identify the prevalence of and risk factors for inadvertent hypothermia after procedures performed with procedural sedation and analgesia in a cardiac catheterisation laboratory. Design Single-centre, prospective observational study. Setting Tertiary care private hospital in Australia. Participants A convenience sample of 399 patients undergoing elective procedures with procedural sedation and analgesia were included. Propofol infusions were used when an anaesthetist was present. Otherwise, bolus doses of either midazolam or fentanyl or a combination of these medications was used. Interventions None Measurements and main results Hypothermia was defined as a temperature <36.0° Celsius. Multivariate logistic regression was used to identify risk factors. Hypothermia was present after 23.3% (n=93; 95% confidence interval [CI] 19.2%-27.4%) of 399 procedures. Sedative regimens with the highest prevalence of hypothermia were any regimen that included propofol (n=35; 40.2%; 95% CI 29.9%-50.5%) and the use of fentanyl combined with midazolam (n=23; 20.3%; 95% CI 12.9%-27.7%). Difference in mean temperature from pre to post-procedure was -0.27°C (Standard deviation [SD] 0.45). Receiving propofol (odds ratio [OR] OR 4.6 95% CI 2.5-8.6), percutaneous coronary intervention (OR 3.2 95% CI 1.7-5.9), body mass index <25 (OR 2.5 95% CI 1.4-4.4) and being hypothermic prior to the procedure (OR 4.9; 95% CI 2.3-10.8) were independent predictors of post-procedural hypothermia. Conclusions A moderate prevalence of hypothermia was observed. The small absolute change in temperature observed may not be a clinically important amount. More research is needed to increase confidence in our estimates of hypothermia in sedated patients and its impact on clinical outcomes.

The culture wars of climate change

Of late, there has been a growth in cultural expression about climate change – with the rise of climate fiction (‘cli-fi’); art and photography responding to changes in nature; musical anthems about climate change; plays and dramas about climate change; and environmental documentaries, and climate cinema. Drawing comparisons to past controversies over cultural funding, this paper considers the cultural wars over climate change. This article considers a number of cultural fields. Margaret Atwood made an important creative and critical contribution to the debate over climate change. The work examines Ian McEwan's novel, Solar, a tragi-comedy about authorship, invention, intellectual property, and climate science. After writing a history of Merchants of Doubt, Naomi Oreskes and Erik Conway have experimented with fiction – as well as history. This article focuses upon artistic works about climate change. It analyses James Balog’s work with the Extreme Ice Survey, which involved photography of glaciers under retreat in a warming world. The work was turned into a documentary called Chasing Ice. It also considers the artistic project of 350.org 'to transform the human rights and environmental issues connected to climate change into powerful art that gets people to stop, think and act.' The paper examines musical storytelling in respect of climate change. The paper explores dramatic works about climate change including Steve Waters' The Contingency Plan, Stephen Emmott's Ten Billion, and Andrew Bovell's When the Rain Stops Falling and Hannie Rayson’s Extinction. The paper also examines the role of documentary film-making. It also considers the cinematographic film, Beasts of the Southern Wild. Such a survey will enable a consideration of the larger question of whether creative art about climate change matters; and whether it is deserving of public funding.

Capnography monitoring during procedural sedation and analgesia: A systematic review protocol

Background An important potential clinical benefit of using capnography monitoring during procedural sedation and analgesia (PSA) is that this technology could improve patient safety by reducing serious sedation-related adverse events, such as death or permanent neurological disability, which are caused by inadequate oxygenation. The hypothesis is that earlier identification of respiratory depression using capnography leads to a change in clinical management that prevents hypoxaemia. As inadequate oxygenation/ventilation is the most common reason for injury associated with PSA, reducing episodes of hypoxaemia would indicate that using capnography would be safer than relying on standard monitoring alone. Methods/design The primary objective of this review is to determine whether using capnography during PSA in the hospital setting improves patient safety by reducing the risk of hypoxaemia (defined as an arterial partial pressure of oxygen below 60 mmHg or percentage of haemoglobin that is saturated with oxygen [SpO2] less than 90 %). A secondary objective of this review is to determine whether changes in the clinical management of sedated patients are the mediating factor for any observed impact of capnography monitoring on the rate of hypoxaemia. The potential adverse effect of capnography monitoring that will be examined in this review is the rate of inadequate sedation. Electronic databases will be searched for parallel, crossover and cluster randomised controlled trials comparing the use of capnography with standard monitoring alone during PSA that is administered in the hospital setting. Studies that included patients who received general or regional anaesthesia will be excluded from the review. Non-randomised studies will be excluded. Screening, study selection and data extraction will be performed by two reviewers. The Cochrane risk of bias tool will be used to assign a judgment about the degree of risk. Meta-analyses will be performed if suitable. Discussion This review will synthesise the evidence on an important potential clinical benefit of capnography monitoring during PSA within hospital settings. Systematic review registration: PROSPERO CRD42015023740

Genome-wide association study identifies eight loci associated with blood pressure

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N 71,225 European ancestry, N 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10 24), CYP1A2 (P = 1 × 10 23), FGF5 (P = 1 × 10 21), SH2B3 (P = 3 × 10 18), MTHFR (P = 2 × 10 13), c10orf107 (P = 1 × 10 9), ZNF652 (P = 5 × 10 9) and PLCD3 (P = 1 × 10 8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

Methodology for developing competency standards for dietitians in Australia

Competency standards document the knowledge, skills, and attitudes required for competent performance. This study develops competency standards for dietitians in order to substantiate an approach to competency standard development. Focus groups explored the current and emerging purpose, role, and function of the profession, which were used to draft competency standards. Consensus was then sought using two rounds of a Delphi survey. Seven focus groups were conducted with 28 participants (15 employers/practitioners, 5 academics, 8 new graduates). Eighty-two of 110 invited experts participated in round one and 67 experts completed round two. Four major functions of dietitians were identified: being a professional, influencing the health of individuals, groups, communities, and populations through evidence-based nutrition practice, and working collaboratively in teams. Overall there was a high level of consensus on the standards: 93% achieved agreement by participants in round one and all revised standards achieved consensus on round 2. The methodology provides a framework for other professions wishing to embark on competency standard review or development.

A systematic review of capnography for sedation

We included six trials with 2524 participants. Capnography reduced hypoxaemic episodes, relative risk (95% CI) 0.71 (0.56-0.91), but the quality of evidence was poor due to high risks of performance bias and detection bias and substantial statistical heterogeneity. The reduction in hypoxaemic episodes was statistically homogeneous in the subgroup of three trials of 1823 adults sedated for colonoscopy, relative risk (95% CI) 0.59 (0.48-0.73), although the risks of performance and detection biases were high. There was no evidence that capnography affected other outcomes, including assisted ventilation, relative risk (95% CI) 0.58 (0.26-1.27), p = 0.17.