Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes

Dihalomethanes can produce liver tumors in mice but not in rats, and concern exists about the risk of these compounds to humans. Glutathione (GSH) conjugation of dihalomethanes has been considered to be a critical event in the bioactivation process, and risk assessment is based upon this premise; however, there is little experimental support for this view or information about the basis of genotoxicity. A plasmid vector containing rat GSH S-transferase 5-5 was transfected into the Salmonella typhimurium tester strain TA1535, which then produced active enzyme. The transfected bacteria produced base-pair revertants in the presence of ethylene dihalides or dihalomethanes, in the order CH2Br2 > CH2BrCl > CH2Cl2. However, revertants were not seen when cells were exposed to GSH, CH2Br2, and an amount of purified GSH S-transferase 5-5 (20-fold excess in amount of that expressed within the cells). HCHO, which is an end product of the reaction of GSH with dihalomethanes, also did not produce mutations. S-(1-Acetoxymethyl)GSH was prepared as an analog of the putative S-(1-halomethyl)GSH reactive intermediates. This analog did not produce revertants, consistent with the view that activation of dihalomethanes must occur within the bacteria to cause genetic damage, presenting a model to be considered in studies with mammalian cells. S-(1-Acetoxymethyl)GSH reacted with 2′-deoxyguanosine to yield a major adduct, identified as S-[1-(N2-deoxyguanosinyl)methyl]GSH. Demonstration of the activation of dihalomethanes by this mammalian GSH S-transferase theta class enzyme should be of use in evaluating the risk of these chemicals, particularly in light of reports of the polymorphic expression of a similar activity in humans.

Species differences in the glutathione transferase GSTT1-1 activity towards the model substrates methyl chloride and dichloromethane in liver and kidney

Glutathione transferase (GST) GSTT1-1 is involved in the biotransformation of several chemicals widely used in industry, such as butadiene and dichloro methane DCM. The polymorphic hGSTT1-1 may well play a role in the development of kidney tumours after high and long-term occupational exposure against trichloroethylene. Although several studies have investigated the association of this polymorphism with malignant diseases little is known about its enzyme activity in potential extrahepatic target tissues. The known theta-specific substrates methyl chloride (MC) dichloromethane and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) were used to assay GSTT1-1 activity in liver and kidney of rats, mice, hamsters and humans differentiating the three phenotypes (non-conjugators, low conjugators, high conjugators) seen in humans. In addition GSTT1-1 activity towards MC and DCM was determined in human erythrocytes. No GSTT1-1 activity was found in any tissue of non-conjugators (NC). In all organs high conjugators (HC) showed twofold higher activity towards MC and DCM than low conjugators (LC). The activity in human samples towards EPNP was too close to the detection limit to differentiate between the three conjugator phenotypes. GSTT1-1 activity towards MC was two to seven-times higher in liver cytosol than in kidney cytosol. The relation for MC between species was identical in both organs: mouse > HC > rat > LC > hamster > NC. In rats, mice and hamsters GSTT1-1 activity in liver cytosol towards DCM was also two to seven-times higher than in the kidney cytosol. In humans this activity was twice as high in kidney cytosol than in liver cytosol. The relation between species was mouse > rat > HC > LC > hamster > NC for liver, but mouse > HC > LC/rat > hamster/NC for kidney cytosol. The importance to heed the specific environment at potential target sites in risk assessment is emphasized by these results.

Cartels – What are they and how to avoid being part of one : the implications of University fee deregulation

Universities supply a range of services to students. These include most obviously, tuition services in relation to undergraduate and postgraduate courses; research supervision services in relation to research degrees; as well as consultancy services in relation to Government and industry work. For the purposes of the CCA, universities are trading corporations. They engage in trade or commerce through the provision of a range of services for reward. As such Universities are subject to the same rules and regulations that govern the conduct of other trading corporations, such Coles and Woolworths. As senior officers and managers of a trading corporation you need to acquire some basic understanding of the rules that govern competition in the education sector. In other sectors, companies generally undertake a risk assessment of those areas where they are most at risk of contravening the CCA; to ascertain in advance how problems might arise so that they can put in place strategies to mitigate the risk of inadvertent contraventions.

Improving national hospice/palliative care service symptom outcomes systematically through point-of-care data collection, structured feedback and benchmarking

PURPOSE Every health care sector including hospice/palliative care needs to systematically improve services using patient-defined outcomes. Data from the national Australian Palliative Care Outcomes Collaboration aims to define whether hospice/palliative care patients' outcomes and the consistency of these outcomes have improved in the last 3 years. METHODS Data were analysed by clinical phase (stable, unstable, deteriorating, terminal). Patient-level data included the Symptom Assessment Scale and the Palliative Care Problem Severity Score. Nationally collected point-of-care data were anchored for the period July-December 2008 and subsequently compared to this baseline in six 6-month reporting cycles for all services that submitted data in every time period (n = 30) using individual longitudinal multi-level random coefficient models. RESULTS Data were analysed for 19,747 patients (46 % female; 85 % cancer; 27,928 episodes of care; 65,463 phases). There were significant improvements across all domains (symptom control, family care, psychological and spiritual care) except pain. Simultaneously, the interquartile ranges decreased, jointly indicating that better and more consistent patient outcomes were being achieved. CONCLUSION These are the first national hospice/palliative care symptom control performance data to demonstrate improvements in clinical outcomes at a service level as a result of routine data collection and systematic feedback.

One-step homogeneous C-reactive protein assay for saliva

Background: Cardiovascular disease is the leading cause of death in the world. Human C-reactive protein (CRP) has been used in the risk assessment of coronary events. Human saliva mirrors the body's health and well-being and is non-invasive, easy to collect and ideal for third world countries as well as for large patient screening. The aim was to establish a saliva CRP reference range and to demonstrate the clinical utility of salivary CRP levels in assessing the coronary events in a primary health care setting. Methods: We have used a homogeneous bead based assay to detect CRP levels in human saliva. We have developed a rapid 15 min (vs 90 min), sequential, one-step assay to detect CRP in saliva. Saliva was collected from healthy volunteers (n = 55, ages 20-70 years) as well as from cardiac patients (n = 28, ages 43-86 years). Results: The assay incubation time was optimised from 90 min to 15 mm and generated a positive correlation (n = 29, range 10-2189 pg/mL, r2 = 0.94; Passing Bablok slope 0.885. Intercept 0, p>0.10), meaning we could decrease the incubation time and produce equivalent results with confidence. The mean CRP level in the saliva of healthy human volunteers was 285 pg/mL and in cardiac patients was 1680 pg/mL (p<0.01). Analysis of CRP concentrations in paired serum and saliva samples from cardiac patients gave a positive correlation (r2 = 0.84, p<0.001) and the salivary CRP concentration capable of distinguishing healthy from diseased patients. Conclusions: The results suggest that this minimally invasive, rapid and sensitive assay will be useful in large patient screening studies for risk assessment of coronary events. (C) 2011 Elsevier B.V. All rights reserved.

2nd ESMO consensus conference on lung cancer : early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, earlystage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Building the safety case for UAS operations in support of natural disaster response

A framework supporting the systematic development of safety cases for Unmanned Aircraft System (UAS) operations in a broad range of civil and commercial applications is presented. The case study application is the use of UAS for disaster response. In those States where regulations do not preclude UAS operations altogether, approvals for UAS operations can be granted on a case-by-case basis contingent on the provision of a safety case acceptable to the relevant National Airworthiness Authority (NAA). A safety case for UAS operations must show how the risks associated with the hazards have been managed to an acceptable level. The foundational components necessary for structuring and assessing these safety cases have not yet been proposed. Barrier-bow-tie models are used in this paper to structure the safety case for the two primary hazards of 1) a ground impact, and 2) a Mid-Air Collision (MAC). The models establish the set of Risk Control Variables (RCVs) available to reduce the risk. For the ground-impact risk model, seven RCVs are identified which in combination govern the probability of an accident. Similarly, ten RCVs are identified within the MAC model. The effectiveness of the RCVs and how they can implemented in terms of processes, policies, devices, practices, or other actions for each of the case-study applications are discussed. The framework presented can provide for the more systematic and consistent regulation of UAS through a "safety target" approach.

Gray matter deficits, mismatch negativity, and outcomes in schizophrenia

Reduced mismatch negativity (MMN) in response to auditory change is a well-established finding in schizophrenia and has been shown to be correlated with impaired daily functioning, rather than with hallmark signs and symptoms of the disorder. In this study, we investigated (1) whether the relationship between reduced MMN and impaired daily functioning is mediated by cortical volume loss in temporal and frontal brain regions in schizophrenia and (2) whether this relationship varies with the type of auditory deviant generating MMN. MMN in response to duration, frequency, and intensity deviants was recorded from 18 schizophrenia subjects and 18 pairwise age- and gender-matched healthy subjects. Patients’ levels of global functioning were rated on the Social and Occupational Functioning Assessment Scale. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex and temporal lobe models using cortical pattern matching. This technique allows accurate statistical comparison and averaging of cortical measures across subjects, despite wide variations in gyral patterns. MMN amplitude was reduced in schizophrenia patients and correlated with their impaired day-to-day function level. Only in patients, bilateral gray matter reduction in Heschl’s gyrus, as well as motor and executive regions of the frontal cortex, correlated with reduced MMN amplitude in response to frequency deviants, while reduced gray matter in right Heschl’s gyrus also correlated with reduced MMN to duration deviants. Our findings further support the importance of MMN reduction in schizophrenia by linking frontotemporal cerebral gray matter pathology to an automatically generated event-related potential index of daily functioning.

A new approach to spatial data interpolation using higher-order statistics

Interpolation techniques for spatial data have been applied frequently in various fields of geosciences. Although most conventional interpolation methods assume that it is sufficient to use first- and second-order statistics to characterize random fields, researchers have now realized that these methods cannot always provide reliable interpolation results, since geological and environmental phenomena tend to be very complex, presenting non-Gaussian distribution and/or non-linear inter-variable relationship. This paper proposes a new approach to the interpolation of spatial data, which can be applied with great flexibility. Suitable cross-variable higher-order spatial statistics are developed to measure the spatial relationship between the random variable at an unsampled location and those in its neighbourhood. Given the computed cross-variable higher-order spatial statistics, the conditional probability density function (CPDF) is approximated via polynomial expansions, which is then utilized to determine the interpolated value at the unsampled location as an expectation. In addition, the uncertainty associated with the interpolation is quantified by constructing prediction intervals of interpolated values. The proposed method is applied to a mineral deposit dataset, and the results demonstrate that it outperforms kriging methods in uncertainty quantification. The introduction of the cross-variable higher-order spatial statistics noticeably improves the quality of the interpolation since it enriches the information that can be extracted from the observed data, and this benefit is substantial when working with data that are sparse or have non-trivial dependence structures.

Workforce-related risks in projects with a contingent workforce

Our research examined how projects can draw together the fields of human resource management (HRM) and risk management (RM) to consider workforce-related risks on projects; particularly those with a large contingent workforce. It is argued that RM frameworks could be enhanced by a more comprehensive understanding of the specific potential non-technical “people risks” in projects. The study focussed on the Oil and Gas industry and undertook interviews with experts in the field. The findings are considered within the framework of key HRM areas; Management Practices, General Employment Practices, Staffing, HR Development, and Compensation and Benefits, along with Project Completion. Drawing together RM and HRM in a project environment, our research provides a unique opportunity to identify critical workforce-related risks. Such identification is the first step towards a more comprehensive approach to risk assessment and planning for mitigation of such risks in projects.

A clarion call for action based on refined DALY estimates for South Africa

Initial estimates of the burden of disease in South Africa in 20001 have been revised on the basis of additional data to estimate the disability-adjusted life-years (DALYs) for single causes for the first time in South Africa. The findings highlight the fact that despite uncertainty in the estimates, they provide important information to guide public health responses to improve the health of the nation...

The global epidemiology and contribution of cannabis use and dependence to the global burden of disease: results from the GBD 2010 study

Aim Estimate the prevalence of cannabis dependence and its contribution to the global burden of disease. Methods Systematic reviews of epidemiological data on cannabis dependence (1990-2008) were conducted in line with PRISMA and meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Culling and data extraction followed protocols, with cross-checking and consistency checks. DisMod-MR, the latest version of generic disease modelling system, redesigned as a Bayesian meta-regression tool, imputed prevalence by age, year and sex for 187 countries and 21 regions. The disability weight associated with cannabis dependence was estimated through population surveys and multiplied by prevalence data to calculate the years of life lived with disability (YLDs) and disability-adjusted life years (DALYs). YLDs and DALYs attributed to regular cannabis use as a risk factor for schizophrenia were also estimated. Results There were an estimated 13.1 million cannabis dependent people globally in 2010 (point prevalence0.19% (95% uncertainty: 0.17-0.21%)). Prevalence peaked between 20-24 yrs, was higher in males (0.23% (0.2-0.27%)) than females (0.14% (0.12-0.16%)) and in high income regions. Cannabis dependence accounted for 2 million DALYs globally (0.08%; 0.05-0.12%) in 2010; a 22% increase in crude DALYs since 1990 largely due to population growth. Countries with statistically higher age-standardised DALY rates included the United States, Canada, Australia, New Zealand and Western European countries such as the United Kingdom; those with lower DALY rates were from Sub-Saharan Africa-West and Latin America. Regular cannabis use as a risk factor for schizophrenia accounted for an estimated 7,000 DALYs globally. Conclusion Cannabis dependence is a disorder primarily experienced by young adults, especially in higher income countries. It has not been shown to increase mortality as opioid and other forms of illicit drug dependence do. Our estimates suggest that cannabis use as a risk factor for schizophrenia is not a major contributor to population-level disease burden.

Burden of depressive disorders by country, sex, age, and year : findings from the Global Burden of Disease Study 2010

Background Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000 studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity proportions, burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease. Methods and Findings Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data quantified the severity of health loss from depressive disorders. These weights were used to calculate years lived with disability (YLDs) and disability adjusted life years (DALYs). Separate DALYs were estimated for suicide and ischemic heart disease attributable to depressive disorders.Depressive disorders were the second leading cause of YLDs in 2010. MDD accounted for 8.2% (5.9%-10.8%) of global YLDs and dysthymia for 1.4% (0.9%-2.0%). Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause. MDD accounted for 2.5% (1.9%-3.2%) of global DALYs and dysthymia for 0.5% (0.3%-0.6%). There was more regional variation in burden for MDD than for dysthymia; with higher estimates in females, and adults of working age. Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained 16 million suicide DALYs and almost 4 million ischemic heart disease DALYs. This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%-3.8%) to 3.8% (3.0%-4.7%) of global DALYs. Conclusions GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden allocated to suicide and ischemic heart disease. These findings emphasize the importance of including depressive disorders as a public-health priority and implementing cost-effective interventions to reduce its burden.Please see later in the article for the Editors' Summary.

Estimating the burden of disease attributable to smoking in South Africa in 2000

Objectives To quantify the burden of disease attributable to smoking in South Africa for 2000. Design The absolute difference between observed lung cancer death rate and the level in non-smokers, adjusted for occupational and indoor exposure to lung carcinogens, was used to estimate the proportion of lung cancer deaths attributable to smoking and the smoking impact ratio (SIR). The SIR was substituted for smoking prevalence in the attributable fraction formula for chronic obstructive pulmonary disease (COPD) and cancers to allow for the long lag between exposure and outcome. Assuming a shorter lag between exposure and disease, the current prevalence of smoking was used to estimate the population-attributable fractions (PAF) for the other outcomes. Relative risks (RR) from the American Cancer Society cancer prevention study (CPS-II) were used to calculate PAF. Setting South Africa. Outcome measures Deaths and disability-adjusted life years (DALYs) due to lung and other cancers, COPD, cardiovascular conditions, respiratory tuberculosis, and other respiratory and medical conditions. Results Smoking caused between 41 632 and 46 656 deaths in South Africa, accounting for 8.0 - 9.0% of deaths and 3.7 - 4.3% of DALYs in 2000. Smoking ranked third (after unsafe sex/sexually transmitted disease and high blood pressure) in terms of mortality among 17 risk factors evaluated. Three times as many males as females died from smoking. Lung cancer had the largest attributable fraction due to smoking. However, cardiovascular diseases accounted for the largest proportion of deaths attributed to smoking. Conclusion Cigarette smoking accounts for a large burden of preventable disease in South Africa. While the government has taken bold legislative action to discourage tobacco use since 1994, it still remains a major public health priority.

Estimating the burden of disease attributable to excess body weight in South Africa in 2000

Objective. To estimate the burden of disease attributable to excess body weight using the body mass index (BMI), by age and sex, in South Africa in 2000. Design. World Health Organization comparative risk assessment (CRA) methodology was followed. Re-analysis of the 1998 South Africa Demographic and Health Survey data provided mean BMI estimates by age and sex. Populationattributable fractions were calculated and applied to revised burden of disease estimates. Monte Carlo simulation-modelling techniques were used for the uncertainty analysis. Setting. South Africa. Subjects. Adults 30 years of age. Outcome measures. Deaths and disability-adjusted life years (DALYs) from ischaemic heart disease, ischaemic stroke, hypertensive disease, osteoarthritis, type 2 diabetes mellitus, and selected cancers. Results. Overall, 87% of type 2 diabetes, 68% of hypertensive disease, 61% of endometrial cancer, 45% of ischaemic stroke, 38% of ischaemic heart disease, 31% of kidney cancer, 24% of osteoarthritis, 17% of colon cancer, and 13% of postmenopausal breast cancer were attributable to a BMI 21 kg/m2. Excess body weight is estimated to have caused 36 504 deaths (95% uncertainty interval 31 018 - 38 637) or 7% (95% uncertainty interval 6.0 - 7.4%) of all deaths in 2000, and 462 338 DALYs (95% uncertainty interval 396 512 - 478 847) or 2.9% of all DALYs (95% uncertainty interval 2.4 - 3.0%). The burden in females was approximately double that in males. Conclusions. This study shows the importance of recognising excess body weight as a major risk to health, particularly among females, highlighting the need to develop, implement and evaluate comprehensive interventions to achieve lasting change in the determinants and impact of excess body weight.