A novel SNP in COMT is associated with alcohol dependence but not opiate or nicotine dependence: a case control study

Background It is well established that COMT is a strong candidate gene for substance use disorder and schizophrenia. Recently we identified two SNPs in COMT (rs4680 and rs165774) that are associated with schizophrenia in an Australian cohort. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. Association of both rs4680 and rs165774 with substance dependence, a common comorbidity of schizophrenia has not been investigated. Methods To determine whether COMT is important in substance dependence, rs165774 and rs4680 were genotyped and haplotyped in patients with nicotine, alcohol and opiate dependence. Results The rs165774 SNP was associated with alcohol dependence. However, it was not associated with nicotine or opiate dependence. Individuals with alcohol dependence were more than twice as likely to carry the GG or AG genotypes compared to the AA genotype, indicating a dominant mode of inheritance. The rs4680 SNP showed a weak association with alcohol dependence at the allele level that did not reach significance at the genotype level but it was not associated with nicotine or opiate dependence. Analysis of rs165774/rs4680 haplotypes also revealed association with alcohol dependence with the G/G haplotype being almost 1.5 times more common in alcohol-dependent cases. Conclusions Our study provides further support for the importance of the COMT in alcohol dependence in addition to schizophrenia. It is possible that the rs165774 SNP, in combination with rs4680, results in a common molecular variant of COMT that contributes to schizophrenia and alcohol dependence susceptibility. This is potentially important for future studies of comorbidity. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.

A DRD2 and ANKK1 haplotype is associated with nicotine dependence

To test the importance of the dopamine D2 receptor (DRD2) region in nicotine dependence, 150 smokers and 228 controls were genotyped for the DRD2 C957T, -141delC and ANKK1 TaqIA polymorphisms (rs6277, rs1799732 and rs1800497, respectively). The -141delC SNP did not show any association but both the C957T and TaqIA SNPs showed association at the allele, genotype, haplotype and combined genotype levels. The 957C/TaqI A1 haplotype was more than 3.5 times as likely to be associated with nicotine dependence compared with the 957T/TaqI A1 haplotype (P = 0.003). Analysis of the combined genotypes of both SNPs revealed that individuals who were homozygous for the 957C-allele (CC) and had either one or two copies of the TaqI A1-allele were 3.3 times as likely to have nicotine dependence compared to all other genotype combinations (P = 0.0003) and that these genotypes accounted for approximately 13% of the susceptibility to nicotine addiction in our population. Our findings suggest that the DRD2 C957T polymorphism and the ANKK1 TaqIA polymorphism are key contributors to the genetic susceptibility to nicotine dependence.

DRD2 C957T and TaqIA genotyping reveals gender effects and unique low-risk and high-risk genotypes in alcohol dependence

AIMS: As recent conflicting reports describe a genetic association between both the C- and the T-alleles of the dopamine D2 receptor (DRD2) C957T polymorphism (rs6277) in alcohol-dependent subjects, our aim was to examine this polymorphism and TaqIA (rs1800497) in Australian alcohol-dependent subjects. METHODS: The C957T polymorphism was genotyped in 228 patients with alcohol dependence (72 females and 156 males) and 228 healthy controls. RESULTS: The C-allele and C/C genotype of C957T was associated with alcohol dependence, whereas the TaqIA polymorphism was not. When analysed separately for C957T, males showed an even stronger association with the C-allele and females showed no association. The C957T and TaqIA haplotyping revealed a strong association with alcohol dependence and a double-genotype analysis (combining C957T and TaqIA genotypes) revealed that the relative risk of different genotypes varied by up to 27-fold with the TT/A1A2 having an 8.5-fold lower risk of alcohol dependence than other genotypes. CONCLUSION: Decreased DRD2 binding associated with the C-allele of the DRD2 C957T polymorphism is likely to be important in the underlying pathophysiology of at least some forms of alcohol dependence, and this effect appears to be limited to males only.

The intraocular pressure response to dehydration : a pilot study

This study was designed to determine the Intraocular Pressure (IOP) response to differing levels of dehydration. Seven males participated in a 90 minute treadmill walk (5 km/h and 1 % grade) in both a cool (22 °C) and hot (43 °C) climate. At Baseline and at 30 minute intervals measurements of IOP, by tonometery, and indicators of hydration status (nude weight and plasma osmolality (Posm)) were taken. Body temperature and heart rate were also measured at these time points. Statistically significant interactions (time point (4) by trial (2)) were observed for IOP (F = 10.747, p = 0.009) and body weight loss (F = 50.083, p < 0.001) to decrease, and Posm (F = 34.867, p < 0.001) to increase, by a significantly greater amount during the hot trial compared to the cool. A univariate general linear model showed a significant relationship between IOP and body weight loss (F = 37.63, p < 0.001) and Posm (F = 38.53, p < 0.001). A significant interaction was observed for body temperature (F = 20.908, p < 0.001) and heart rate (F = 25.487, p < 0.001) between the trials and time points, but there was negligible association between these variables and IOP (Pearson correlation coefficient < ±0.5). The present study provides evidence to suggest that IOP is influenced by hydration status.

Maintenance optimisation of a multi-state series-parallel system considering economic dependence and state-dependent inspection intervals

This paper presents a maintenance optimisation method for a multi-state series-parallel system considering economic dependence and state-dependent inspection intervals. The objective function considered in the paper is the average revenue per unit time calculated based on the semi-regenerative theory and the universal generating function (UGF). A new algorithm using the stochastic ordering is also developed in this paper to reduce the search space of maintenance strategies and to enhance the efficiency of optimisation algorithms. A numerical simulation is presented in the study to evaluate the efficiency of the proposed maintenance strategy and optimisation algorithms. The simulation result reveals that maintenance strategies with opportunistic maintenance and state-dependent inspection intervals are more cost-effective when the influence of economic dependence and inspection cost is significant. The study further demonstrates that the optimisation algorithm proposed in this paper has higher computational efficiency than the commonly employed heuristic algorithms.

KPNA3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence

KPNA3 is a gene that has been linked to schizophrenia susceptibility. In this study we investigated the possible association between KPNA3 variation and schizophrenia. To investigate a wider role of KPNA3 across psychiatric disorders we also analysed major depression, PTSD, nicotine dependent, alcohol dependent and opiate dependent cohorts. Using a haplotype block-based gene-tagging approach we genotyped six KPNA3 single nucleotide polymorphisms (SNPs) in 157 schizophrenia patients, 121 post-traumatic stress disorder patients, 120 opiate dependent patients, 231 alcohol dependent patients, 147 nicotine dependent patients and 266 major depression patients. One SNP rs2273816 was found to be significantly associated with schizophrenia, opiate dependence and alcohol dependence at the genotype and allele level. Major depression was also associated with rs2273816 but only at the allele level. Our study suggests that KPNA3 may contribute to the genetic susceptibility to schizophrenia as well as other psychiatric disorders.

Cost effectiveness of nutrition support in the prevention of pressure ulcer in hospitals

Background/objectives This study estimates the economic outcomes of a nutrition intervention to at-risk patients compared with standard care in the prevention of pressure ulcer. Subjects/methods Statistical models were developed to predict ‘cases of pressure ulcer avoided’, ‘number of bed days gained’ and ‘change to economic costs’ in public hospitals in 2002–2003 in Queensland, Australia. Input parameters were specified and appropriate probability distributions fitted for: number of discharges per annum; incidence rate for pressure ulcer; independent effect of pressure ulcer on length of stay; cost of a bed day; change in risk in developing a pressure ulcer associated with nutrition support; annual cost of the provision of a nutrition support intervention for at-risk patients. A total of 1000 random re-samples were made and the results expressed as output probability distributions. Results The model predicts a mean 2896 (s.d. 632) cases of pressure ulcer avoided; 12 397 (s.d. 4491) bed days released and corresponding mean economic cost saving of euros 2 869 526 (s.d. 2 078 715) with a nutrition support intervention, compared with standard care. Conclusion Nutrition intervention is predicted to be a cost-effective approach in the prevention of pressure ulcer in at-risk patients.

Near-Wall Turbulent Pressure Diffusion Modeling and Influence in Three-Dimensional Secondary Flows

The purpose of this paper is to develop a second-moment closure with a near-wall turbulent pressure diffusion model for three-dimensional complex flows, and to evaluate the influence of the turbulent diffusion term on the prediction of detached and secondary flows. A complete turbulent diffusion model including a near-wall turbulent pressure diffusion closure for the slow part was developed based on the tensorial form of Lumley and included in a re-calibrated wall-normal-free Reynolds-stress model developed by Gerolymos and Vallet. The proposed model was validated against several one-, two, and three-dimensional complex flows.

Open design of high pressure ratio radial-inflow turbine for academic validation

Computational Fluid Dynamics (CFD) simulations are widely used in mechanical engineering. Although achieving a high level of confidence in numerical modelling is of crucial importance in the field of turbomachinery, verification and validation of CFD simulations are very tricky especially for complex flows encountered in radial turbines. Comprehensive studies of radial machines are available in the literature. Unfortunately, none of them include enough detailed geometric data to be properly reproduced and so cannot be considered for academic research and validation purposes. As a consequence, design improvements of such configurations are difficult. Moreover, it seems that well-developed analyses of radial turbines are used in commercial software but are not available in the open literature especially at high pressure ratios. It is the purpose of this paper to provide a fully open set of data to reproduce the exact geometry of the high pressure ratio single stage radial-inflow turbine used in the Sundstrand Power Systems T-100 Multipurpose Small Power Unit. First, preliminary one-dimensional meanline design and analysis are performed using the commercial software RITAL from Concepts-NREC in order to establish a complete reference test case available for turbomachinery code validation. The proposed design of the existing turbine is then carefully and successfully checked against the geometrical and experimental data partially published in the literature. Then, three-dimensional Reynolds-Averaged Navier-Stokes simulations are conducted by means of the Axcent-PushButton CFDR CFD software. The effect of the tip clearance gap is investigated in detail for a wide range of operating conditions. The results confirm that the 3D geometry is correctly reproduced. It also reveals that the turbine is shocked while designed to give a high-subsonic flow and highlight the importance of the diffuser.