Markers of genetic susceptibility in human environmental hygiene and toxicology : the role of selected CYP, NAT and GST genes

Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1 *0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology.

Twitter data: what do they represent?

Scholarly research into the uses of social media has become a major area of growth in recent years, as the adoption of social media for public communication itself has continued apace. While social media platforms provide ready avenues for data access through their Application Programming interfaces, it is increasingly important to think through exactly what these data represent, and what conclusions about the role of social media in society the research which is based on such data therefore enables. This article explores these issues especially for one of the currently leading social media platforms: Twitter.

Tetraspanins as regulators of the tumour microenvironment : implications for metastasis and therapeutic strategies

One of the hallmarks of cancer is the ability to activate invasion and metastasis (Hanahan et al., 2011). Cancer morbidity and mortality are largely related to the spread of the primary, localised tumour to adjacent and distant sites (Pantel et al., 2004). Appropriate management and treatment decisions of predicting metastatic disease at the time of diagnosis is thus crucial, which supports better understanding of the metastatic process. There are common events that occur during metastasis: dissociation from the primary tumour mass, reorganisation/remodelling of extracellular matrix, cell migration, recognition and transversal of endothelial cells and the vascular circulation and lodgement and proliferation within ectopic stroma (Wells, 2006). One of the key and initial events is the increased capability of cancer cells to move, escaping the regulation of normal physiological control. The cellular cytoskeleton plays an important role in cancer cell motility and active cytoskeletal rearrangement can result in metastatic disease. This active change in cytoskeletal dynamics results in manipulation of plasma membrane and cellular balance between cellular adhesion and motility which in turn determines cancer cell movement. Members of the tetraspanins play important roles in regulation of cancer migration and cancer-endothelial cell interactions, which are critical for cancer invasion and metastasis. Their involvements in active cytoskeletal dynamics, cancer metastasis and potential clinical application will be discussed in this review. In particular, tetraspanin member, CD151, is highlighted for its major role in cancer invasion and metastasis

Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens

BACKGROUND AND PURPOSE Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*-containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline’s effects on ethanol consumption. EXPERIMENTAL APPROACH Rats were trained to consume ethanol using the intermittent-access two-bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core-shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast-scan cyclic voltammetry (FSCV). KEY RESULTS Microinfusion of varenicline into the NAc core and core-shell border, but not into the NAc shell or VTA, reduced ethanol intake following long-term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc. CONCLUSION AND IMPLICATIONS Following long-term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline’s effects on ethanol consumption.

Homing by path integration when a locomotion trajectory crosses itself

Path integration is a process with which navigators derive their current position and orientation by integrating self-motion signals along a locomotion trajectory. It has been suggested that path integration becomes disproportionately erroneous when the trajectory crosses itself. However, there is a possibility that this previous finding was confounded by effects of the length of a traveled path and the amount of turns experienced along the path, two factors that are known to affect path integration performance. The present study was designed to investigate whether the crossover of a locomotion trajectory truly increases errors of path integration. In an experiment, blindfolded human navigators were guided along four paths that varied in their lengths and turns, and attempted to walk directly back to the beginning of the paths. Only one of the four paths contained a crossover. Results showed that errors yielded from the path containing the crossover were not always larger than those observed in other paths, and the errors were attributed solely to the effects of longer path lengths or greater degrees of turns. These results demonstrated that path crossover does not always cause significant disruption in path integration processes. Implications of the present findings for models of path integration are discussed.

Children's emotions and multimodal appraisal of places : walking with the camera

This sensory ethnography explores the affordances and constraints of multimodal design to represent emotions and appraisal associated with experiencing local places. Digital video production, walking with the camera, and the use of a think-aloud protocol to reflect on the videos, provided an opportunity for the primary school children to represent their emotions and appraisal of places multimodally. Applying a typology from Martin and White's (2005) framework for the Language of Evaluation, children's multimodal emotional responses to places in this study tended toward happiness, security, and satisfaction. The findings demonstrate an explicit connection between children's emotions in response to local places through video, while highlighting the potential for teachers to use digital filmmaking to allow children to reflect actively on their placed experiences and represent their emotional reactions to places through multiple modes.

Error and variance bounds on sigmoidal neurons with weight and input errors

Bounds on the expectation and variance of errors at the output of a multilayer feedforward neural network with perturbed weights and inputs are derived. It is assumed that errors in weights and inputs to the network are statistically independent and small. The bounds obtained are applicable to both digital and analogue network implementations and are shown to be of practical value.

Strange and stranger ruralities: Social constructions of rural crime in Australia

Rural crime has largely been understood through social disorganization theory. The dominance of this perspective has meant that most research into rural crime has tried to resolve perceived strains in communities, rather than analyze how social problems are constituted in rural places. Using Elias and Scotson's (1994) account of established-outsider relations, the paper examines how the organizational capacity of specific social groups is significant in determining the quality of crime-talk and responses to crime in isolated and rural settings. In particular social 'oldness' and notions of what constitutes 'community' are significant in determining what activities and individuals or groups are marked as features of crime-talk in these settings.

Global, regional, and national age–sex specifi c all-cause and cause-specifi c mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background Up-to-date evidence on levels and trends for age-sex-specific all-cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. Methods We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions. Findings Global life expectancy for both sexes increased from 65·3 years (UI 65·0–65·6) in 1990, to 71·5 years (UI 71·0–71·9) in 2013, while the number of deaths increased from 47·5 million (UI 46·8–48·2) to 54·9 million (UI 53·6–56·3) over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25–39 years and older than 75 years and for men aged 20–49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10·7%, from 4·3 million deaths in 1990 to 4·8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100 000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions. Interpretation For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade.

Australian nurses volunteering for the Sumatra-Andaman earthquake and tsunami of 2004 : a review of experience and analysis of data collected by the Tsunami Volunteer Hotline

This paper provides an outline of the work undertaken by nurses who participated in the relief effort as members of Australian medical teams during the Sumatra-Andaman earthquake and tsunami response. This profile is contrasted with the information provided by nurses who registered their interest in volunteering to help via the Australian Tsunami Hotline. The paper provides an overview of the skills and background of the nurses who provided information to the hotline and describes the range and extent of experience among this cohort of potential volunteers. This data is compared to nursing workforce data and internal rates of volunteering in Australia. The paper concludes that further research is necessary to examine the motivations of and disincentives for nurses to volunteer for overseas (disaster) work and, to develop an improved understanding within the discipline of the skills and experience required of volunteer responders. Further, it is argued that the development of standards for the collection of disaster health volunteer data would assist future responses and provide better tools for developing an improved understanding of disaster volunteering.

'Genuine' refugees or illegitimate 'boat people' : political constructions of asylum seekers and refugees in the Malaysia Deal debate

Immigration to Australia has long been the focus of negative political interest. In recent times, the proposal of exclusionary policies such as the Malaysia Deal in 2011 has fuelled further debate. In these debates, Federal politicians often describe asylum seekers and refugees as ‘illegal’, ‘queue jumpers’, and ‘boat people’. This article examines the political construction of asylum seekers and refugees during debates surrounding the Malaysia Deal in the Federal Parliament of Australia. Hansard parliamentary debates were analysed to identify the underlying themes and constructions that permeate political discourse about asylum seekers and refugees. We argue that asylum seekers arriving in Australia by boat were constructed as threatening to Australia’s national identity and border security, and were labelled as ‘illegitimate’. A dichotomous characterisation of legitimacy pervades the discourse about asylum seekers, with this group constructed either as legitimate humanitarian refugees or as illegitimate ‘boat arrivals’. Parliamentarians apply the label of legitimacy based on implicit criteria concerning the mode of arrival of asylum seekers, their respect for the so-called ‘queue’, and their ability to pay to travel to Australia. These constructions result in the misrepresentation of asylum seekers as illegitimate, undermining their right to protection under Australia’s laws and international obligations.

Some of the design considerations in power generation from offshore wind farms

The global efforts to reduce carbon emissions from power generation have favoured renewable energy resources such as wind and solar in recent years. The generation of power from the renewable energy resources has become attractive because of various incentives provided by government policies supporting green power. Among the various available renewable energy resources, the power generation from wind has seen tremendous growth in the last decade. This article discusses various advantages of the upcoming offshore wind technology and associated considerations related to their construction. The conventional configuration of the offshore wind farm is based on the alternative current internal links. With the recent advances of improved commercialised converters, voltage source converters based high voltage direct current link for offshore wind farms is gaining popularity. The planning and construction phases of offshore wind farms, including related environmental issues, are discussed here.

A theoretical approach to segmenting children’s walking behaviour

Childhood obesity is a leading public health concern globally. This study aimed to extend research applying the principle of market segmentation to gain insight into changing the physical activity behaviour of children, particularly their walk to/from school behaviour. It further examined the utility of employing theory, specifically the Theory of Planned Behaviour (TPB), for this purpose. The study demonstrates the usefulness of behavioural, geographic and psychographic variables, as measured by the TPB, in distinguishing segments, offering an important contrast to prior segmentation studies emphasising demographic variables. This result provides empirical evidence of the value of employing the four segmentation bases, extending beyond a demographic focus, and the importance of incorporating behavioural theory in market segmentation. In so doing, this research provides key insights into changing children’s walking behaviour.

Energy use assessment of educational buildings: Toward a campus-wide sustainable energy policy

The purpose of this article is to assess the viability of blanket sustainability policies, such as Building Rating Systems in achieving energy efficiency in university campus buildings. We analyzed the energy consumption trends of 10 LEED-certified buildings and 14 non-LEED certified buildings at a major university in the US. Energy Use Intensity (EUI) of the LEED buildings was significantly higher (EUILEED= 331.20 kBtu/sf/yr) than non-LEED buildings (EUInon-LEED=222.70 kBtu/sf/yr); however, the median EUI values were comparable (EUILEED= 172.64 and EUInon-LEED= 178.16). Because the distributions of EUI values were non-symmetrical in this dataset, both measures can be used for energy comparisons—this was also evident when EUI computations exclude outliers, EUILEED=171.82 and EUInon-LEED=195.41. Additional analyses were conducted to further explore the impact of LEED certification on university campus buildings energy performance. No statistically significant differences were observed between certified and non-certified buildings through a range of robust comparison criteria. These findings were then leveraged to devise strategies to achieve sustainable energy policies for university campus buildings and to identify potential issues with portfolio level building energy performance comparisons.

Working on the edge : Exploring the creative tensions experienced by practitioners facilitating participatory media projects with refugees and asylum seekers in Australia

This paper aims to provide a contextualised and embedded exploration of how the notions of "practice" and "participation", key concepts in the study of culture and media, are manifest in an example of a complex creative project. This project aimed to engage with refugees and asylum seekers through the co-creation of cultural material and is an outcome of an? ethnographic action research (Tacchi et al. 2003) partnership involving a community development worker in a settlement support agency and a storytelling/community media researcher (the author), along with other project collaborators. The discussion of this project focuses on the role of the facilitator and illustrates the processes of orchestrating a complex project involving a series of linked stages with cumulative effect. As practitioners at this site we are working in the space where personal narratives, participatory arts and media, and the staging of intercultural, civic dialogue events, intersect. Co-creative media facilitation in these contexts involves both managing hybrid communicative spaces and (re)combining the "integrative practices" (Schatzki 1996) of a range of professional approaches and creative roles. This is liminal work, located on the boundaries of several disciplines and practices. Drawing on reflections gathered from collaborative ethnographic descriptions (Bhattacharya 2008), this paper traces moments of practitioner uncertainty that can be linked to the way "practice" and “participation” is problematised within the community cultural development field in a way that is at times an uneasy fit with conventional ways of operating in social service roles. These moments of tension also indicate where this project pushed practitioners into spaces of improvisation and new learning. Keywords: Youth, refugees, community cultural development, co-creative media facilitation, ethnographic action research, intercultural dialogue.