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.

Gimmelife : listening for dialogic voices in the email self-narratives of gifted young adolescents

The art of listening for voices within narrative research is a positive endeavour that has specific value within research design and subsequent approaches to analysis. This paper details an investigation into the dialogic nature of voices among gifted young adolescents who engaged in the co-construction of email-generated self-narratives. Data are drawn from a study involving ten adolescents, aged between ten and fourteen years, diagnosed as gifted according to Australian guidelines. Individual participants were asked to produce self-managed journal entries written and sent as asynchronous emails to the researcher who was the sole recipient and respondent. Within this approach, specific techniques of listening were used to examine a series of multi-vocal narratives generated over a period of six months. This paper proposes that an adaptation of the everyday convenience of email with the traditional journal format as a self-report mechanism creates a synergy that fosters self-disclosure. Individual excerpts are presented to show that the harnessing of personal narratives within an email context has potential to yield valuable insights into the emotions, personal realities and experiences of gifted young adolescents. Furthermore, the co-construction of self-expressive and explanatory narratives supported by a facilitative adult listener appeared to promote healthy self-awareness amongst participants. This paper contributes to narrative exploration in two distinct ways: first, in using online methods for gaining access to the everyday, emotional realities of participants; and, second, in demonstrating the value of listening as a narrative technique for uncovering layers of voices across a body of texts produced over time. These methods represent an innovative attempt to move beyond face-to-face approaches and away from a focus on content and coding techniques that might oversimplify complex emotions.

Notch and NOXA-related pathways in melanoma cells

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

Juvenile justice and truancy legislation : The move towards parental responsibilisation in Queensland

Much current Queensland media rhetoric, government policy and legislation on truancy and youth justice appears to be based on ideas of responsibilisation – of sheeting responsibility for children’s behaviour back onto their parents. This article examines the evidence of parental responsibility provisions in juvenile justice and truancy legislation in Queensland and the drivers behind this approach. It considers recent legislative initiatives as part of an international trend toward making parents ‘responsible’ for the wrongs of their children. It identifies the parental responsibility rhetoric appearing in recent ministerial statements and associated media reports. It then asks the questions – are these legislative provisions being enforced? And if so, are they successful? Are they simply adding to the administrative burdens placed on teachers and schools, and the socioeconomic burdens placed on already disadvantaged parents? Parental responsibility provisions have been discussed at length in the context of juvenile offending and research suggests that punishing parents for the acts of their children does not decrease delinquency. The paper asks how, as a society, we intend to evaluate these punitive measures against parents?

Work-Related Subjective Experiences, Work-Related Self-Efficacy, and Career Learning Among People with Psychiatric Disabilities

Work-related subjective experiences and work-related self-efficacy were investigated as candidate correlates of career learning among people with schizophrenia and schizoaffective disorder. Work-related self-efficacy was expected to mediate any observed relationship between work-related subjective experiences and employment status, after controlling for demographic, vocational, and clinical covariates. Baseline measures (n 1 = 104) were repeated at six months (n 2 = 94) and 12 months (n 3 = 94). Work-related subjective experiences and work-related self-efficacy were consistently associated with current employment after controlling for covariates. The proposed mediator role of work-related self-efficacy remains a viable hypothesis requiring further investigation. Both work-related subjective experiences and work-related self-efficacy appear promising as components of the social cognitive career learning theory to help explain career development among people with psychiatric disabilities.

Classifying Socially-Valued Role Functioning Among Community Residents with Psychiatric Disorders

An increased emphasis on community-based care has not ensured that people recovering from psychiatric disorders return to active and valued roles in their local communities. Although clinical recovery remains a priority for mental health services there is increasing recognition of the need for functional recovery to be attained and demonstrated in roles valued by the wider community. With this need in mind, a method for classifying socially-valued role functioning among people with schizophrenia or schizoaffective disorder was developed and trialed. Participants (n = 104) were recruited via mental health, psychosocial rehabilitation, and other community support services. Socially-valued roles were investigated via participation in five categories: (1) self-care and home duties; (2) caring for others; (3) self-development, voluntary work or rehabilitation; (4) formal education or training; and (5) employment. Activities were classified by primary role type and role status level at baseline, six, and 12 months. Current role status was assessed along with highest and lowest status in the previous year. Preliminary psychometric results were favorable. Research applications are now recommended for monitoring socially-valued role functioning in community settings.

Work-related self-efficacy among community residents with psychiatric disabilities

A new measure of work-related self-efficacy for people with psychiatric disabilities is reported. The 37-item scale measures self-efficacy in four relevant activity domains: 1) vocational service access and career planning, 2) job acquisition, 3) work-related social skills, and 4) general work skills. The scale was developed in a 12-month longitudinal survey of urban residents diagnosed with schizophrenia or schizoaffective disorder (n = 104). Results indicate validity of both a four-factor structure differentiating four core skill domains, and a single factor representing total work-related self-efficacy. The favorable psychometric properties support further research and trial applications in supported employment and psychiatric vocational rehabilitation.

Work-related subjective experiences among community residents with schizophrenia or schizoaffective disorder

Objective: To develop a self-report scale of subjective experiences of illness perceived to impact on employment functioning, as an alternative to a diagnostic perspective, for anticipating the vocational assistance needs of people with schizophrenia or schizoaffective disorders. Method: A repeated measures pilot study (n1 = 26, n2 = 21) of community residents with schizophrenia identified a set of work-related subjective experiences perceived to impact on employment functioning. Items with the best psychometric properties were applied in a 12 month longitudinal survey of urban residents with schizophrenia or schizoaffective disorder (n1 = 104; n2 = 94; n3 = 94). Results: Construct validity, factor structure, responsiveness, internal consistency, stability, and criterion validity investigations produced favourable results. Work-related subjective experiences provide information about the intersection of the person, the disorder, and expectations of employment functioning, which suggest new opportunities for vocational professionals to explore and discuss individual assistance needs. Conclusion: Further psychometric investigations of test-retest reliability, discriminant and predictive validity, and research applications in supported employment and vocational rehabilitation, are recommended. Subject to adequate psychometric properties, the new measure promises to facilitate exploring: individuals' specific subjective experiences; how each is perceived to contribute to employment restrictions; and the corresponding implications for specialized treatment, vocational interventions and workplace accommodations.

Quantification of particle emission characteristics and development of an emission model for use in transport microenvironments affected by traffic emissions

Vehicle emitted particles are of significant concern based on their potential to influence local air quality and human health. Transport microenvironments usually contain higher vehicle emission concentrations compared to other environments, and people spend a substantial amount of time in these microenvironments when commuting. Currently there is limited scientific knowledge on particle concentration, passenger exposure and the distribution of vehicle emissions in transport microenvironments, partially due to the fact that the instrumentation required to conduct such measurements is not available in many research centres. Information on passenger waiting time and location in such microenvironments has also not been investigated, which makes it difficult to evaluate a passenger’s spatial-temporal exposure to vehicle emissions. Furthermore, current emission models are incapable of rapidly predicting emission distribution, given the complexity of variations in emission rates that result from changes in driving conditions, as well as the time spent in driving condition within the transport microenvironment. In order to address these scientific gaps in knowledge, this work conducted, for the first time, a comprehensive statistical analysis of experimental data, along with multi-parameter assessment, exposure evaluation and comparison, and emission model development and application, in relation to traffic interrupted transport microenvironments. The work aimed to quantify and characterise particle emissions and human exposure in the transport microenvironments, with bus stations and a pedestrian crossing identified as suitable research locations representing a typical transport microenvironment. Firstly, two bus stations in Brisbane, Australia, with different designs, were selected to conduct measurements of particle number size distributions, particle number and PM2.5 concentrations during two different seasons. Simultaneous traffic and meteorological parameters were also monitored, aiming to quantify particle characteristics and investigate the impact of bus flow rate, station design and meteorological conditions on particle characteristics at stations. The results showed higher concentrations of PN20-30 at the station situated in an open area (open station), which is likely to be attributed to the lower average daily temperature compared to the station with a canyon structure (canyon station). During precipitation events, it was found that particle number concentration in the size range 25-250 nm decreased greatly, and that the average daily reduction in PM2.5 concentration on rainy days compared to fine days was 44.2 % and 22.6 % at the open and canyon station, respectively. The effect of ambient wind speeds on particle number concentrations was also examined, and no relationship was found between particle number concentration and wind speed for the entire measurement period. In addition, 33 pairs of average half-hourly PN7-3000 concentrations were calculated and identified at the two stations, during the same time of a day, and with the same ambient wind speeds and precipitation conditions. The results of a paired t-test showed that the average half-hourly PN7-3000 concentrations at the two stations were not significantly different at the 5% confidence level (t = 0.06, p = 0.96), which indicates that the different station designs were not a crucial factor for influencing PN7-3000 concentrations. A further assessment of passenger exposure to bus emissions on a platform was evaluated at another bus station in Brisbane, Australia. The sampling was conducted over seven weekdays to investigate spatial-temporal variations in size-fractionated particle number and PM2.5 concentrations, as well as human exposure on the platform. For the whole day, the average PN13-800 concentration was 1.3 x 104 and 1.0 x 104 particle/cm3 at the centre and end of the platform, respectively, of which PN50-100 accounted for the largest proportion to the total count. Furthermore, the contribution of exposure at the bus station to the overall daily exposure was assessed using two assumed scenarios of a school student and an office worker. It was found that, although the daily time fraction (the percentage of time spend at a location in a whole day) at the station was only 0.8 %, the daily exposure fractions (the percentage of exposures at a location accounting for the daily exposure) at the station were 2.7% and 2.8 % for exposure to PN13-800 and 2.7% and 3.5% for exposure to PM2.5 for the school student and the office worker, respectively. A new parameter, “exposure intensity” (the ratio of daily exposure fraction and the daily time fraction) was also defined and calculated at the station, with values of 3.3 and 3.4 for exposure to PN13-880, and 3.3 and 4.2 for exposure to PM2.5, for the school student and the office worker, respectively. In order to quantify the enhanced emissions at critical locations and define the emission distribution in further dispersion models for traffic interrupted transport microenvironments, a composite line source emission (CLSE) model was developed to specifically quantify exposure levels and describe the spatial variability of vehicle emissions in traffic interrupted microenvironments. This model took into account the complexity of vehicle movements in the queue, as well as different emission rates relevant to various driving conditions (cruise, decelerate, idle and accelerate), and it utilised multi-representative segments to capture the accurate emission distribution for real vehicle flow. This model does not only helped to quantify the enhanced emissions at critical locations, but it also helped to define the emission source distribution of the disrupted steady flow for further dispersion modelling. The model then was applied to estimate particle number emissions at a bidirectional bus station used by diesel and compressed natural gas fuelled buses. It was found that the acceleration distance was of critical importance when estimating particle number emission, since the highest emissions occurred in sections where most of the buses were accelerating and no significant increases were observed at locations where they idled. It was also shown that emissions at the front end of the platform were 43 times greater than at the rear of the platform. The CLSE model was also applied at a signalled pedestrian crossing, in order to assess increased particle number emissions from motor vehicles when forced to stop and accelerate from rest. The CLSE model was used to calculate the total emissions produced by a specific number and mix of light petrol cars and diesel passenger buses including 1 car travelling in 1 direction (/1 direction), 14 cars / 1 direction, 1 bus / 1 direction, 28 cars / 2 directions, 24 cars and 2 buses / 2 directions, and 20 cars and 4 buses / 2 directions. It was found that the total emissions produced during stopping on a red signal were significantly higher than when the traffic moved at a steady speed. Overall, total emissions due to the interruption of the traffic increased by a factor of 13, 11, 45, 11, 41, and 43 for the above 6 cases, respectively. In summary, this PhD thesis presents the results of a comprehensive study on particle number and mass concentration, together with particle size distribution, in a bus station transport microenvironment, influenced by bus flow rates, meteorological conditions and station design. Passenger spatial-temporal exposure to bus emitted particles was also assessed according to waiting time and location along the platform, as well as the contribution of exposure at the bus station to overall daily exposure. Due to the complexity of the interrupted traffic flow within the transport microenvironments, a unique CLSE model was also developed, which is capable of quantifying emission levels at critical locations within the transport microenvironment, for the purpose of evaluating passenger exposure and conducting simulations of vehicle emission dispersion. The application of the CLSE model at a pedestrian crossing also proved its applicability and simplicity for use in a real-world transport microenvironment.

Attitudes of employees and employers towards older workers in a climate of anti-discrimination

Attitudes and practices towards older workers were surveyed in Brisbane with 525 employees randomly sampled from the electoral roll and executives of 104 companies obtained by stratified random sampling from the Register of Workplaces (response rates, 60% and 80% respectively). The results indicated that “older workers” are young in terms of contemporary life expectancy, and younger for employers than employees; they have some desirable personal qualities (eg. loyalty), but are not perceived as adaptable; workers aged 25–39 were preferred on qualities held to be important in the workplace and there was minimal interest in recruiting anyone over 45 years.

Mixed convection laminar flow along a horizontal plate subject to streamwise sinusoidal surface temperature

Mixed convection of a two-dimensional laminar incompressible flow along a horizontal flat plate with streamwise sinusoidal surface temperature has been numerically investigated for different values of Rayleigh number and Reynolds number for constant values of Prandtl number, amplitude and frequency of periodic temperature. The numerical scheme is based on the finite element method adapted to rectangular non-uniform mesh elements by a non-linear parametric solution algorithm. The fluid considered in this study is air. The results are obtained for the Rayleigh number and Reynolds number ranging from 102 to 104 and 1 to 100, respectively, with constant physical properties for the fluid medium considered. Velocity and temperature profiles, streamlines, isotherms, and average Nusselt numbers are presented to observe the effect of the investigating parameters on fluid flow and heat transfer characteristics. The present results show that the convective phenomena are greatly influenced by the variation of Rayleigh numbers and Reynolds number.

The association between maternal infant feeding practices and child weight at 11-17 months in first-time Australian mothers

Introduction: Emerging evidence reveals that early feeding practices are associated with child food intake, eating behaviour and weight status. This cross-sectional analysis examined the association between maternal infant feeding practices/beliefs and child weight in Australian infants aged 11-17 months. Methods: Participants were 293 first-time mothers of healthy term infants (144 boys, mean age 14±1 months) enrolled in the NOURISH RCT. Mothers self-reported infant feeding practices and beliefs using the Infant Feeding Questionnaire (Baughcum, 2001). Anthropometric data were also measured at baseline (infants aged 4 months). Multiple regression analysis was used, adjusting for infant age, gender, birth weight, infant feeding mode (breast vs. formula), maternal perceptions of infant weight status, pre-pregnancy weight, weight concern, age and education. Results: The average child weight-for-age z-score (WAZ) was 0.62±0.83 (range:-1.56 to 2.94) and the mean change in WAZ (WAZ change) from 4 to 14 months was 0.62±0.69 (range:-1.50 to 2.76). Feeding practices/beliefs partly explained child WAZ (R2=0.28) and WAZ change (R2=0.13) in the adjusted models. While child weight status at 14 months was inversely associated with responsive feeding (e.g. baby feeds whenever she wants, feeding to stop baby being unsettled) (β=-0.104, p=0.06) and maternal concern about the child becoming underweight (β=-0.224, p<0.001), it was positively associated with mother’s concern about child overweight (β=0.197, p<0.05). Birth weight, infant’s age, maternal weight concern and perceiving her child as overweight were significant covariates. WAZ change was only significantly associated with responsive feeding (β=-0.147, p<0.05). Conclusion: Responsive feeding may be an important strategy to promote healthy child weight.

Childbirth and the development of acute trauma symptoms : incidence and contributing factors

Background: Little is known about the relationship between women's birthing experiences and the development of trauma symptoms. This study aimed to determine the incidence of acute trauma symptoms and posttraumatic stress disorder in women as a result of their labor and birth experiences, and to identify factors that contributed to the women's psychological distress. Method: Using a prospective, longitudinal design, women in their last trimester of pregnancy were recruited from four public hospital antenatal clinics. Telephone interviews with 499 participants were conducted at 4 to 6 weeks postpartum to explore the medical and midwifery management of the birth, perceptions of intrapartum care, and the presence of trauma symptoms. Results: One in three women (33%) identified a traumatic birthing event and reported the presence of at least three trauma symptoms. Twenty-eight women (5.6%) met DSM-IV criteria for acute posttraumatic stress disorder. Antenatal variables did not contribute to the development of acute or chronic trauma symptoms. The level of obstetric intervention experienced during childbirth (β= 0.351, p < 0.0001)and the perception of inadequate intrapartum care (β= 0.319, p < 0.0001) during labor were consistently associated with the development of acute trauma symptoms. Conclusions: Posttraumatic stress disorder after childbirth is a poorly recognized phenomenon. Women who experienced both a high level of obstetric intervention and dissatisfaction with their intrapartum care were more likely to develop trauma symptoms than women who received a high level of obstetric intervention or women who perceived their care to be inadequate. These findings should prompt a serious review of intrusive obstetric intervention during labor and delivery, and the care provided to birthing women.

The taxing effects of the advance pricing arrangement program: A review of APAs and their impact on stakeholders

The current transfer pricing rules contained in Australia’s taxation regime are designed to counter the underpayment of tax by businesses engaged in international related-party dealings. Currently, these transactions must take place at an arm’s length price, a requirement which is becoming increasingly difficult to demonstrate. This results in an increased risk of an audit by the Australian Taxation Office. If a taxpayer wishes to avoid the risk of an audit, and any ensuing penalties, there is one option: an advance pricing arrangement (‘APA’). An APA is an agreement whereby the future transfer pricing methodology to be used to determine the arm’s length price is agreed to by the taxpayer and the relevant tax authority or authorities. This article investigates the use of APAs as a solution to the problem of transfer pricing and considers their impact on stakeholders. It is argued that while APAs provide a valuable practical tool for multinational entities facing the challenges of the taxation of global trading under the current regime, they may not be a practical long term solution.

Risk of Human Papillomavirus-Associated Cancers Among Persons With AIDS

Background Although risk of human papillomavirus (HPV)–associated cancers of the anus, cervix, oropharynx, penis, vagina, and vulva is increased among persons with AIDS, the etiologic role of immunosuppression is unclear and incidence trends for these cancers over time, particularly after the introduction of highly active antiretroviral therapy in 1996, are not well described. Methods Data on 499 230 individuals diagnosed with AIDS from January 1, 1980, through December 31, 2004, were linked with cancer registries in 15 US regions. Risk of in situ and invasive HPV-associated cancers, compared with that in the general population, was measured by use of standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). We evaluated the relationship of immunosuppression with incidence during the period of 4–60 months after AIDS onset by use of CD4 T-cell counts measured at AIDS onset. Incidence during the 4–60 months after AIDS onset was compared across three periods (1980–1989, 1990–1995, and 1996–2004). All statistical tests were two-sided. Results Among persons with AIDS, we observed statistically significantly elevated risk of all HPV-associated in situ (SIRs ranged from 8.9, 95% CI = 8.0 to 9.9, for cervical cancer to 68.6, 95% CI = 59.7 to 78.4, for anal cancer among men) and invasive (SIRs ranged from 1.6, 95% CI = 1.2 to 2.1, for oropharyngeal cancer to 34.6, 95% CI = 30.8 to 38.8, for anal cancer among men) cancers. During 1996–2004, low CD4 T-cell count was associated with statistically significantly increased risk of invasive anal cancer among men (relative risk [RR] per decline of 100 CD4 T cells per cubic millimeter = 1.34, 95% CI = 1.08 to 1.66, P = .006) and non–statistically significantly increased risk of in situ vagina or vulva cancer (RR = 1.52, 95% CI = 0.99 to 2.35, P = .055) and of invasive cervical cancer (RR = 1.32, 95% CI = 0.96 to 1.80, P = .077). Among men, incidence (per 100 000 person-years) of in situ and invasive anal cancer was statistically significantly higher during 1996–2004 than during 1990–1995 (61% increase for in situ cancers, 18.3 cases vs 29.5 cases, respectively; RR = 1.71, 95% CI = 1.24 to 2.35, P < .001; and 104% increase for invasive cancers, 20.7 cases vs 42.3 cases, respectively; RR = 2.03, 95% CI = 1.54 to 2.68, P < .001). Incidence of other cancers was stable over time. Conclusions Risk of HPV-associated cancers was elevated among persons with AIDS and increased with increasing immunosuppression. The increasing incidence for anal cancer during 1996–2004 indicates that prolonged survival may be associated with increased risk of certain HPV-associated cancers.