Partial agonists of the [alpha]3[beta]4[ast] neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats

Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the α3, α5, and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the α3, and β4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at α3β4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations, suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs. Furthermore, the selective α4β2(*) nAChR antagonist, DHβE, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs.

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.

Physical activity, sitting and depression during pregnancy

Aims The aim of this cross sectional study is to explore levels of physical activity and sitting behaviour amongst a sample of pregnant Australian women (n = 81), and investigate whether reported levels of physical activity and/or time spent sitting were associated with depressive symptom scores after controlling for potential covariates. Methods Study participants were women who attended the antenatal clinic of a large Brisbane maternity hospital between October and November 2006. Data relating to participants. current levels of physical activity, sitting behaviour, depressive symptoms, demographic characteristics and exposure to known risk factors for depression during pregnancy were collected; via on-site survey, follow-up telephone interview (approximately one week later) and post delivery access to participant hospital records. Results Participants were aged 29.5 (¡¾ 5.6) years and mostly partnered (86.4%) with a gross household income above $26,000 per annum (88.9%). Levels of physical activity were generally low, with only 28.4 % of participants reporting sufficient total activity and 16% of participants reporting sufficient planned (leisure-time) activity. The sample mean for depressive symptom scores measured by the Hospital Anxiety and Depression Scale (HADS-D) was 6.38 (¡¾ 2.55). The mean depressive symptom scores for participants who reported total moderate-to-vigorous activity levels of sufficient, insufficient, and none, were 5.43 (¡¾ 1.56), 5.82 (¡¾ 1.77) and 7.63 (¡¾ 3.25), respectively. Hierarchical multivariable linear regression modelling indicated that after controlling for covariates, a statistically significant difference of 1.09 points was observed between mean depressive symptom scores of participants who reported sufficient total physical activity, compared with participants who reported they were engaging in no moderate-to-vigorous activity in a typical week (p = 0.05) but this did not reach the criteria for a clinically meaningful difference. Total physical activity was contributed 2.2% to the total 30.3% of explained variance within this model. The other main contributors to explained variance in multivariable regression models were anxiety symptom scores and the number of existing children. Further, a trend was observed between higher levels of planned sitting behaviour and higher depressive symptom scores (p = 0.06); this correlation was not clinically meaningful. Planned sitting contributed 3.2% to the total 31.3 % of explained variance. The number of regression covariates and limited sample size led to a less than ideal ratio of covariates to participants, probably attenuating this relationship. Specific information about the sitting-based activities in which participants engaged may have provided greater insight about the relationship between planned sitting and depressive symptoms, but these data were not captured by the present study. Conclusions The finding that higher levels of physical activity were associated with lower levels of depressive symptoms is consistent with the current body of existing literature in pregnant women, and with a larger body of evidence based in general population samples. Although this result was not considered clinically meaningful, the criterion for a clinically meaningful result was an a priori decision based on quality of life literature in non-pregnant populations and may not truly reflect a difference in symptoms that is meaningful to pregnant women. Further investigation to establish clinically meaningful criteria for continuous depressive symptom data in pregnant women is required. This result may have implications relating to prevention and management options for depression during pregnancy. The observed trend between planned sitting and depressive symptom scores is consistent with literature based on leisure-time sitting behaviour in general population samples, and suggests that further research in this area, with larger samples of pregnant women and more specific sitting data is required to explore potential associations between activities such as television viewing and depressive symptoms, as this may be an area of behaviour that is amenable to modification.

tert-Butylaminium 2-carboxy-4,5-dichlorobenzoate

In the structure of the title anhydrous salt C4H12N+ C8H3Cl2O4-, the 4,5-dichlorophthalate monoanions have the common 'planar' conformation with the carboxyl groups close to coplanar with the benzene ring and with a short intramolecular carboxylic acid O-H...O hydrogen bond. A two-dimensional sheet structure is formed through aminium N-H...O(carboxyl) hydrogen-bonding associations.

High frequency of BRAF mutations in nevi

To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.

The association between playgroup participation, learning competence and social-emotional wellbeing for children aged 4-5 years in Australia

Data from Growing Up in Australia: The Longitudinal Study of Australian Children is used to examine the associations between playgroup participation and the outcomes for children aged 4 to 5 years. Controlling for a range of socio-economic and family characteristics, playgroup participation across the ages of 0-3 years was used to predict learning competence and social-emotional functioning outcomes at age 4-5 years. For learning competence, both boys and girls from disadvantaged families scored 3-4% higher if they attended playgroup when aged 0-1 and 2-3 years compared to boys and girls from disadvantaged families who did not attend playgroup. For social and emotional functioning, girls from disadvantaged families who attended playgroup when they were aged 0-1 and 2-3 years scored nearly 5% higher than those who did not attend. Demographic characteristics also showed that disadvantaged families were the families least likely to access these services. Despite data limitations, this study provides evidence that continued participation in playgroups is associated with better outcomes for children from disadvantaged families.

The structure of the mineral leogangite Cu10(OH)6(SO4)(AsO4)4•8H2O–implications for arsenic accumulation and removal

The objective of this research is to determine the molecular structure of the mineral leogangite. The formation of the types of arsenosulphate minerals offers a mechanism for arsenate removal from soils and mine dumps. Raman and infrared spectroscopy have been used to characterise the mineral. Observed bands are assigned to the stretching and bending vibrations of (SO4)2- and (AsO4)3- units, stretching and bending vibrations of hydrogen bonded (OH)- ions and Cu2+-(O,OH) units. The approximate range of O-H...O hydrogen bond lengths is inferred from the Raman spectra. Raman spectra of leogangite from different origins differ in that some spectra are more complex, where bands are sharp and the degenerate bands of (SO4)2- and (AsO4)3- are split and more intense. Lower wavenumbers of  H2O bending vibration in the spectrum may indicate the presence of weaker hydrogen bonds compared with those in a different leogangite samples. The formation of leogangite offers a mechanism for the removal of arsenic from the environment.

A Raman spectroscopic study of the mono-hydrogen phosphate mineral dorfmanite Na2(PO3OH)•2H2O – and in comparison with brushite

Aspects of the molecular structure of the mineral dorfmanite Na2(PO3OH)•2H2O were determined by Raman spectroscopy. The mineral originated from the Kedykverpakhk Mt., Lovozero, Kola Peninsula, Russia. Raman bands are assigned to the hydrogen phosphate units. The intense Raman band at 949 cm-1 and the less intense band at 866 cm-1 are assigned to the PO3 and POH stretching vibrations. Bands at 991, 1066 and 1141 cm-1 are assigned to the ν3 antisymmetric stretching modes. Raman bands at 393, 413 and 448 cm-1 and 514, 541 and 570 cm-1 are attributed to the ν2 and ν4 bending modes of the HPO4 units, respectively. Raman bands at 3373, 3443 and 3492 cm-1 are assigned to water stretching vibrations. POH stretching vibrations are identified by bands at 2904, 3080 and 3134 cm-1. Raman spectroscopy has proven very useful for the study of the structure of the mineral dorfmanite.

Investigating literacy years 4-9 : a pilot. Final report.

Investigating Literacy Years 4-9: A pilot acknowledges that the literacy required of students in the middle years of schooling changes as they begin to read and write to learn across the subject areas using various resources and media. Teachers begin to look for evidence of understanding of concepts, content details, appropriate genre uses and the capacity to work with extended and complex texts. Yet, in comparison to the early years, there has been relatively little research conducted during this period of schooling, especially Years 4-7 of primary schooling (Comber et al, 2002). However, evidence suggests that gaps between those who perform highly and those who perform poorly on standardised measures of literacy increase rather than decrease, and these gaps relate to social background. Hence there is a need to investigate how different school communities with diverse student populations design rich curriculum at these stages of schooling and explicitly teach young people to handle new and changing literacy demands.

4-Aminopyridinium cis-2-carboxycyclohexane-1-carboxylate

In the structure of the title compound, C5H7N2+ C8H11O4-, the cis-monoanions associate through short carboxylic acid-carboxyl O-H...O hydrogen bonds [graph set C(7)], forming zigzag chains which extend along c and are inter-linked through pyridinium and amine N-H...O(carboxyl) hydrogen bonds giving a three-dimensional network structure.

Ethane-1,2-diaminium 4,4'-sulfonyldibenzoate

In the title compound 2(C2H10N2+) C14H8O6S2-, both the ethylenediaminium cations and the 4,4'-sulfonyldibenzoate dianions have crystallographic two-fold rotational symmetry and are interlinked by aminium N-H...O(carboxyl) hydrogen-bonding associations giving sheets which extend along (101) and are further linked down b forming a three-dimensional structure.