Varenicline, an alpha-4 beta-2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Abstract Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.

Long-evans rats acquire operant self-administration of 20% ethanol without sucrose fading

A major obstacle in the development of new medications for the treatment of alcohol use disorders (AUDs) has been the lack of preclinical, oral ethanol consumption paradigms that elicit high consumption. We have previously shown that rats exposed to 20% ethanol intermittently in a two-bottle choice paradigm will consume two times more ethanol than those given continuous access without the use of water deprivation or sucrose fading (5-6 g/kg every 24 h vs 2-3 g/kg every 24 h, respectively). In this study, we have adapted the model to an operant self-administration paradigm. Long-Evans rats were given access to 20% ethanol in overnight sessions on one of two schedules: (1) intermittent (Monday, Wednesday, and Friday) or (2) daily (Monday through Friday). With the progression of the overnight sessions, both groups showed a steady escalation in drinking (3-6 g/kg every 14 h) without the use of a sucrose-fading procedure. Following the acquisition phase, the 20% ethanol groups consumed significantly more ethanol than did animals trained to consume 10% ethanol with a sucrose fade (1.5 vs 0.7 g/kg every 30 min) and reached significantly higher blood ethanol concentrations. In addition, training history (20% ethanol vs 10% ethanol with sucrose fade) had a significant effect on the subsequent self-administration of higher concentrations of ethanol. Administration of the pharmacological stressor yohimbine following extinction caused a significant reinstatement of ethanol-seeking behavior. Both 20% ethanol models show promise and are amenable to the study of maintenance, motivation, and reinstatement. Furthermore, training animals to lever press for ethanol without the use of sucrose fading removes a potential confound from self-administration studies. © 2010 Nature Publishing Group All rights reserved.

Radioactive residues associated with water treatment, use and disposal in Australia

Water resources are known to contain radioactive materials, either from natural or anthropogenic sources. Treatment, including wastewater treatment, of water for drinking, domestic, agricultural and industrial purposes has the potential to concentrate radioactive materials. Inevitably concentrated radioactive material is discharged to the environment as a waste product, reused for soil conditioning, or perhaps recycled as a new potable water supply. This thesis, presented as a collection of peer reviewed scientific papers, explores a number of water / wastewater treatment applications, and the subsequent nature and potential impact of radioactive residues associated with water exploitation processes. The thesis draws together research outcomes for sites predominantly throughout Queensland, Australia, where it is recognised that there is a paucity of published data on the subject. This thesis contributes to current knowledge on the monitoring, assessment and potential for radiation exposure from radioactive residues associated with the water industry.

Integrating efficient filtration and visible-light photocatalysis by loading Ag-doped zeolite Y particles on aluminia nanofiber membrane

Filtration membrane technology has already been employed to remove various organic effluents produced from the textile, paper, plastic, leather, food and mineral processing industries. To improve membrane efficiency and alleviate membrane fouling, an integrated approach is adopted that combines membrane filtration and photocatalysis technology. In this study, alumina nanofiber (AF) membranes with pore size of about 10 nm (determined by the liquid-liquid displacement method) have been synthesized through an in situ hydrothermal reaction, which permitted a large flux and achieved high selectivity. Silver nanoparticles (Ag NPs) are subsequently doped on the nanofibers of the membranes. Silver nanoparticles can strongly absorb visible light due to the surface plasmon resonance (SPR) effect, and thus induce photocatalytic degradation of organic dyes, including anionic, cationic and neutral dyes, under visible light irradiation. In this integrated system, the dyes are retained on the membrane surface, their concentration in the vicinity of the Ag NPs are high and thus can be efficiently decomposed. Meanwhile, the usual flux deterioration caused by the accumulation of the filtered dyes in the passage pores can be avoided. For example, when an aqueous solution containing methylene blue is processed using an integrated membrane, a large flux of 200 L m-2 h-1 and a stable permeating selectivity of 85% were achieved. The combined photocatalysis and filtration function leads to superior performance of the integrated membranes, which have a potential to be used for the removal of organic pollutants in drinking water.

The switch

In this video, text types across the screen one line at a time set to an emotive stock music soundtrack. The text combines two teen film plot descriptions into one story. This work engages with the language of Hollywood narratives. By emphasizing the potentially abstract and convoluted qualities of linguistic communication, it challenges our capacity to assimilate information into conventional narratives. It draws specific attention to the conventions of Hollywood plot development, and questions the mechanisms by which they construct and communicate meaning.

The role of education and awareness in workplace alcohol and drug use in the Australian construction industry : proposed program of research and preliminary results

The main aim of this paper is to outline a proposed program of research which will attempt to quantify the extent of the problem of alcohol and other drugs in the Australian construction industry, and furthermore, develop an appropriate industry-wide policy and cultural change management program and implementation plan to address the problem. This paper will also present preliminary results from the study. The study will use qualitative and quantitative methods (in the form of interviews and surveys, respectively) to evaluate the extent of the problem of alcohol and other drug use in this industry, to ascertain the feasibility of an industry-wide policy and cultural change management program, and to develop an appropriate implementation plan. The study will be undertaken in several construction organisations, at selected sites in South Australia, Victoria and Northern Territory. It is anticipated that approximately 500 employees from the participating organisations across Australia will take part in the study. The World Health Organisation’s Alcohol Use Disorders Identification Test (AUDIT) will be used to measure the extent of alcohol use in the industry. Illicit drug use, ‘‘readiness to change’’, impediments to reducing impairment, feasibility of proposed interventions, and employee attitudes and knowledge regarding workplace AOD impairment, will also be measured through a combination of interviews and surveys. Among the preliminary findings, for 51% (n=127) of respondents, score on the AUDIT indicated alcohol use at hazardous levels. Of the respondents who were using alcohol at hazardous levels, 76% reported (n97) that they do not have a problem with drinking and 54% (n=68) reported that it would be easy to ‘‘cut down’’ or stop drinking. Nearly half (49%) of all respondents (n=122) had used marijuana/cannabis at some time prior to being surveyed. The use of other illicit substances was much less frequently reported. Preliminary interview findings indicated a lack of adequate employee knowledge regarding the physical effects of alcohol and other drugs in the workplace. As for conclusions, the proposed study will address a major gap in the literature with regard to the extent of the problem of alcohol and other drug use in the construction industry in Australia. The study will also develop and implement a national, evidence-based workplace policy, with the aim of mitigating the deleterious effects of alcohol and other drugs in this industry.

What explains the association between socioeconomic status and depression among Vietnamese adults?

Background Depression is a major public health problem worldwide and is currently ranked second to heart disease for years lost due to disability. For many decades, international research has found that depressive symptoms occur more frequently among low socioeconomic (SES) individuals than their more-advantaged peers. However, the reasons as to why those of low socioeconomic groups suffer more depressive symptoms are not well understood. Studies investigating the prevalence of depression and its association with SES emanate largely from developed countries, with little research among developing countries. In particular, there is a serious dearth of research on depression and no investigation of its association with SES in Vietnam. The aims of the research presented in this Thesis are to: estimate the prevalence of depressive symptoms among Vietnamese adults, examine the nature and extent of the association between SES and depression and to elucidate causal pathways linking SES to depressive symptoms Methods The research was conducted between September 2008 and November 2009 in Hue city in central Vietnam and used a combination of qualitative (in-depth interviews) and quantitative (survey) data collection methods. The qualitative study contributed to the development of the theoretical model and to the refinement of culturally-appropriate data collection instruments for the quantitative study. The main survey comprised a cross-sectional population–based survey with randomised cluster sampling. A sample of 1976 respondents aged between 25-55 years from ten randomly-selected residential zones (quarters) of Hue city completed the questionnaire (response rate 95.5%). Measures SES was classified using three indicators: education, occupation and income. The Center for Epidemiologic Studies-Depression (CES-D) scale was used to measure depressive symptoms (range0-51, mean=11.0, SD=8.5). Three cut-off points for the CES-D scores were applied: ‘at risk for clinical depression’ (16 or above), ‘depressive symptoms’ (above 21) and ‘depression’ (above 25). Six psychosocial indicators: life time trauma, chronic stress, recent life events, social support, self esteem, and mastery were hypothesized to mediate the association between SES and depressive symptoms. Analyses The prevalence of depressive symptoms were analysed using bivariate analyses. The multivariable analytic phase comprised of ordinary least squares regression, in accordance with Baron and Kenny’s three-step framework for mediation modeling. All analyses were adjusted for a range of confounders, including age, marital status, smoking, drinking and chronic diseases and the mediation models were stratified by gender. Results Among these Vietnamese adults, 24.3% were at or above the cut-off for being ‘at risk for clinical depression’, 11.9% were classified as having depressive symptoms and 6.8% were categorised as having depression. SES was inversely related to depressive symptoms: the least educated those with low occupational status or with the lowest incomes reported more depressive symptoms. Socioeconomicallydisadvantaged individuals were more likely to report experiencing stress (life time trauma, chronic stress or recent life events), perceived less social support and reported fewer personal resources (self esteem and mastery) than their moreadvantaged counterparts. These psychosocial resources were all significantly associated with depressive symptoms independent of SES. Each psychosocial factor showed a significant mediating effect on the association between SES and depressive symptoms. This was found for all measures of SES, and for males and females. In particular, personal resources (mastery, self esteem) and chronic stress accounted for a substantial proportion of the variation in depressive symptoms between socioeconomic groups. Social support and recent life events contributed modestly to socioeconomic differences in depressive symptoms, whereas lifetime trauma contributed the least to these inequalities. Conclusion This is the first known study in Vietnam or any developing country to systematically examine the extent to which psychosocial factors mediate the relationship between SES and depression. The study contributes new evidence regarding the burden of depression in Vietnam. The findings have practical relevance for advocacy, for mental health promotion and health-care services, and point to the need for programs that focus on building a sense of personal mastery and self esteem. More broadly, the work presented in this Thesis contributes to the international scientific literature on the social determinants of depression.

On the significance of omitted variables in intersection crash modeling

Advances in safety research—trying to improve the collective understanding of motor vehicle crash causes and contributing factors—rest upon the pursuit of numerous lines of research inquiry. The research community has focused considerable attention on analytical methods development (negative binomial models, simultaneous equations, etc.), on better experimental designs (before-after studies, comparison sites, etc.), on improving exposure measures, and on model specification improvements (additive terms, non-linear relations, etc.). One might logically seek to know which lines of inquiry might provide the most significant improvements in understanding crash causation and/or prediction. It is the contention of this paper that the exclusion of important variables (causal or surrogate measures of causal variables) cause omitted variable bias in model estimation and is an important and neglected line of inquiry in safety research. In particular, spatially related variables are often difficult to collect and omitted from crash models—but offer significant opportunities to better understand contributing factors and/or causes of crashes. This study examines the role of important variables (other than Average Annual Daily Traffic (AADT)) that are generally omitted from intersection crash prediction models. In addition to the geometric and traffic regulatory information of intersection, the proposed model includes many spatial factors such as local influences of weather, sun glare, proximity to drinking establishments, and proximity to schools—representing a mix of potential environmental and human factors that are theoretically important, but rarely used. Results suggest that these variables in addition to AADT have significant explanatory power, and their exclusion leads to omitted variable bias. Provided is evidence that variable exclusion overstates the effect of minor road AADT by as much as 40% and major road AADT by 14%.

Assessment of tumor prevention in Type 1 Neurofibromatosis using a nitroxide compound

Background Type 1 Neurofibromatosis (NF1) is a genetic disorder linked to mutations of the NF1 gene. Clinical symptoms are varied, but hallmark features of the disease include skin pigmentation anomalies (café au lait macules, skinfold freckling) and dermal neurofibromas. Method These dermal manifestations of NF1 have previously been reported in a mouse model where Nf1+/− mice are topically treated with dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). We adopted this mouse model to test the protective effects of a nitroxide antioxidant, 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO). Antioxidants have previously been shown to increase longevity in nf1-deficient fruitflies. Doses of 4 μM and 40 μM CTMIO provided ad libitum in drinking water were given to Nf1-deficient mice. Results Consistent with previous reports, Nf1-deficient mice showed a 4.7-fold increase in papilloma formation (P < 0.036). However, neither dose of CTMIO had any significant affect on papilloma formation. A non-significant decrease in skin pigmentation abnormalities was seen with 4 μM but not 40 μM CTMIO. Subsequent analysis of genomic DNA isolated from papillomas indicated that DMBA/TPA induced tumors did not exhibit a local loss of heterozygosity (LOH) at the Nf1 locus. Conclusion These data reveal that oral antioxidant therapy with CTMIO does not reduce tumor formation in a multistage cancer model, but also that this model does not feature LOH for Nf1.

Removal of toxic metals in a multi metal system using sorbents for potential application to urban stormwater treatment

In the context of increasing demand for potable water and the depletion of water resources, stormwater is a logical alternative. However, stormwater contains pollutants, among which metals are of particular interest due to their toxicity and persistence in the environment. Hence, it is imperative to remove toxic metals in stormwater to the levels prescribed by drinking water guidelines for potable use. Consequently, various techniques have been proposed, among which sorption using low cost sorbents is economically viable and environmentally benign in comparison to other techniques. However, sorbents show affinity towards certain toxic metals, which results in poor removal of other toxic metals. It was hypothesised in this study that a mixture of sorbents that have different metal affinity patterns can be used for the efficient removal of a range of toxic metals commonly found in stormwater. The performance of six sorbents in the sorption of Al, Cr, Cu, Pb, Ni, Zn and Cd, which are the toxic metals commonly found in urban stormwater, was investigated to select suitable sorbents for creating the mixtures. For this purpose, a multi criteria analytical protocol was developed using the decision making methods: PROMETHEE (Preference Ranking Organisation METHod for Enrichment Evaluations) and GAIA (Graphical Analysis for Interactive Assistance). Zeolite and seaweed were selected for the creation of trial mixtures based on their metal affinity pattern and the performance on predetermined selection criteria. The metal sorption mechanisms employed by seaweed and zeolite were defined using kinetics, isotherm and thermodynamics parameters, which were determined using the batch sorption experiments. Additionally, the kinetics rate-limiting steps were identified using an innovative approach using GAIA and Spearman correlation techniques developed as part of the study, to overcome the limitation in conventional graphical methods in predicting the degree of contribution of each kinetics step in limiting the overall metal removal rate. The sorption kinetics of zeolite was found to be primarily limited by intraparticle diffusion followed by the sorption reaction steps, which were governed mainly by the hydrated ionic diameter of metals. The isotherm study indicated that the metal sorption mechanism of zeolite was primarily of a physical nature. The thermodynamics study confirmed that the energetically favourable nature of sorption increased in the order of Zn < Cu < Cd < Ni < Pb < Cr < Al, which is in agreement with metal sorption affinity of zeolite. Hence, sorption thermodynamics has an influence on the metal sorption affinity of zeolite. On the other hand, the primary kinetics rate-limiting step of seaweed was the sorption reaction process followed by intraparticle diffusion. The boundary layer diffusion was also found to limit the metal sorption kinetics at low concentration. According to the sorption isotherm study, Cd, Pb, Cr and Al were sorbed by seaweed via ion exchange, whilst sorption of Ni occurred via physisorption. Furthermore, ionic bonding is responsible for the sorption of Zn. The thermodynamics study confirmed that sorption by seaweed was energetically favourable in the order of Zn < Cu < Cd < Cr . Al < Pb < Ni. However, this did not agree with the affinity series derived for seaweed suggesting a limited influence of sorption thermodynamics on metal affinity for seaweed. The investigation of zeolite-seaweed mixtures indicated that mixing sorbents have an effect on the kinetics rates and the sorption affinity. Additionally, the theoretical relationships were derived to predict the boundary layer diffusion rate, intraparticle diffusion rate, the sorption reaction rate and the enthalpy of mixtures based on that of individual sorbents. In general, low coefficient of determination (R2) for the relationships between theoretical and experimental data indicated that the relationships were not statistically significant. This was attributed to the heterogeneity of the properties of sorbents. Nevertheless, in relative terms, the intraparticle diffusion rate, sorption reaction rate and enthalpy of sorption had higher R2 values than the boundary layer diffusion rate suggesting that there was some relationship between the former set of parameters of mixtures and that of sorbents. The mixture, which contained 80% of zeolite and 20% of seaweed, showed similar affinity for the sorption of Cu, Ni, Cd, Cr and Al, which was attributed to approximately similar sorption enthalpy of the metal ions. Therefore, it was concluded that the seaweed-zeolite mixture can be used to obtain the same affinity for various metals present in a multi metal system provided the metal ions have similar enthalpy during sorption by the mixture.

Delta opioid-receptor function in the dorsal striatum plays a role in high levels of ethanol consumption in rats

Binge-like patterns of excessive drinking during young adulthood increase the propensity for alcohol use disorders (AUDs) later in adult life; however, the mechanisms that drive this are not completely understood. Previous studies showed that the δ-opioid peptide receptor (DOP-R) is dynamically regulated by exposure to ethanol and that the DOP-R plays a role in ethanol-mediated behaviors. The aim of this study was to determine the role of the DOP-R in high ethanol consumption from young adulthood through to late adulthood by measuring DOP-R-mediated [(35)S]GTPγS binding in brain membranes and DOP-R-mediated analgesia using a rat model of high ethanol consumption in Long Evans rats. We show that DOP-R activity in the dorsal striatum and DOP-R-mediated analgesia changes during development, being highest during early adulthood and reduced in late adulthood. Intermittent access to ethanol but not continuous ethanol or water from young adulthood leads to an increase in DOP-R activity in the dorsal striatum and DOP-R-mediated analgesia into late adulthood. Multiple microinfusions of naltrindole into the dorsal striatum or multiple systemic administration of naltrindole reduces ethanol consumption, and following termination of treatment, DOP-R activity in the dorsal striatum is attenuated. These findings suggest that DOP-R activity in the dorsal striatum plays a role in high levels of ethanol consumption and suggest that targeting the DOP-R is an alternative strategy for the treatment of AUDs.

The α5 neuronal nicotinic acetylcholine receptor subunits plays an important role in the sedative effects of ethanol but does not modulate consumption in mice

Alcohol use disorders (AUDs) are a major public health problem, and the few treatment options available to those seeking treatment offer only modest success rates. There remains a need to identify novel targets for the treatment of AUDs. The neuronal nicotinic acetylcholine receptors (nAChRs) represent a potential therapeutic target in the brain, as recent human genetic studies have implicated gene variants in the α5 nAChR subunit as high risk factors for developing alcohol dependence. Here, we evaluate the role of 5* nAChR for ethanol-mediated behaviors using α5+/+ and α5-/- mice. We characterized the effect of hypnotic doses of ethanol and investigated drinking behavior using an adapted Drinking-in-the Dark (DID) paradigm that has been shown to induce high ethanol consumption in mice. We found the α5 subunit to be critical in mediating the sedative effects of ethanol. The α5-/- mice showed slower recovery from ethanol-induced sleep, as measured by loss of righting reflex. Additionally the α5-/- mice showed enhanced impairment to ethanol-induced ataxia. We found the initial sensitivity to ethanol and ethanol metabolism to be similar in both α5+/+ and α5-/- mice. Hence the enhanced sedation is likely due to a difference in the acute tolerance of ethanol in mice deficient of the α5 subunit. However the α5 subunit did not play a role in ethanol consumption for ethanol concentrations ranging from 5% to 30% in the DID paradigm. Additionally, varenicline (Chantix®) was effective in reducing ethanol intake in α5-/- mice. Together, our data suggest that the α5 nAChR subunit is important for the sedative hypnotic doses of ethanol but does not play a role in ethanol consumption. Varenicline can be a treatment option even when there is loss of function of the α5 nAChR subunit.

Family-based programmes for preventing smoking by children and adolescents

BACKGROUND: There is evidence that children's decisions to smoke are influenced by family and friends. OBJECTIVES: To assess the effectiveness of interventions to help family members to strengthen non-smoking attitudes and promote non-smoking by children and other family members. SEARCH STRATEGY: We searched 14 electronic bibliographic databases, including the Cochrane Tobacco Addiction Group specialized register, MEDLINE, EMBASE, PsycINFO and CINAHL. We also searched unpublished material, and the reference lists of key articles. We performed both free-text Internet searches and targeted searches of appropriate websites, and we hand-searched key journals not available electronically. We also consulted authors and experts in the field. The most recent search was performed in July 2006. SELECTION CRITERIA: Randomized controlled trials (RCTs) of interventions with children (aged 5-12) or adolescents (aged 13-18) and family members to deter the use of tobacco. The primary outcome was the effect of the intervention on the smoking status of children who reported no use of tobacco at baseline. Included trials had to report outcomes measured at least six months from the start of the intervention. DATA COLLECTION AND ANALYSIS: We reviewed all potentially relevant citations and retrieved the full text to determine whether the study was an RCT and matched our inclusion criteria. Two authors independently extracted study data and assessed them for methodological quality. The studies were too limited in number and quality to undertake a formal meta-analysis, and we present a narrative synthesis. MAIN RESULTS: We identified 19 RCTs of family interventions to prevent smoking. We identified five RCTs in Category 1 (minimal risk of bias on all counts); nine in Category 2 (a risk of bias in one or more areas); and five in Category 3 (risks of bias in design and execution such that reliable conclusions cannot be drawn from the study).Considering the fourteen Category 1 and 2 studies together: (1) four of the nine that tested a family intervention against a control group had significant positive effects, but one showed significant negative effects; (2) one of the five RCTs that tested a family intervention against a school intervention had significant positive effects; (3) none of the six that compared the incremental effects of a family plus a school programme to a school programme alone had significant positive effects; (4) the one RCT that tested a family tobacco intervention against a family non-tobacco safety intervention showed no effects; and (5) the one trial that used general risk reduction interventions found the group which received the parent and teen interventions had less smoking than the one that received only the teen intervention (there was no tobacco intervention but tobacco outcomes were measured). For the included trials the amount of implementer training and the fidelity of implementation are related to positive outcomes, but the number of sessions is not. AUTHORS' CONCLUSIONS: Some well-executed RCTs show family interventions may prevent adolescent smoking, but RCTs which were less well executed had mostly neutral or negative results. There is thus a need for well-designed and executed RCTs in this area.

A systematic review of psychological interventions for excessive alcohol consumption among people with psychotic disorders

Objective: Excessive alcohol consumption is common among people with psychotic disorders. While there is an extensive literature on the efficacy of psychological treatments for excessive drinking, few studies have examined interventions addressing this issue among people with psychotic disorders. Method: Systematic searches in PubMed and PsycINFO were conducted to identify randomized controlled trials comparing manual guided psychological interventions for excessive alcohol consumption among individuals with psychotic disorders. Of the 429 articles identified, 7 met inclusion criteria. Data were extracted from each study regarding study sample characteristics, design, results, clinical significance of alcohol consumption results, and methodological limitations. Results: Assessment interviews, brief motivational interventions and lengthier cognitive behavior therapy have been associated with reductions in alcohol consumption among people with psychosis. While brief interventions (i.e., 1-2 sessions) were generally as effective as longer duration psychological interventions (i.e., 10 session) for reducing alcohol consumption, longer interventions provided additional benefits for depression, functioning and other alcohol outcomes. Conclusion: Excessive alcohol consumption among people with psychotic disorders is responsive to psychological interventions. It is imperative that such approaches are integrated within standard care for people with psychosis.