Genes and gene expression in the brain of the alcoholic

Chronic alcoholism leads to localized brain damage, which is prominent in superior frontal cortex but mild in motor cortex. The likelihood of developing alcohol dependence is associated with genetic markers. GABA(A) receptor expression differs between alcoholics and controls, whereas glutamate receptor differences are muted. We determined whether genotype differentiated the localized expression of glutamate and gamma-aminobutyric acid (GABA) receptors to influence the severity of alcohol-induced brain damage. Cerebrocortical tissue was obtained at autopsy from alcoholics without alcohol-related disease, alcoholics with cirrhosis, and matched controls. DRD2A, DRD2B, GABB2, EAAT2, and 5HTT genotypes did not divide alcoholic cases and controls on N-methyl-D-aspartate (NMDA) receptor parameters. In contrast, alcohol dehydrogenase (ADH)3 genotype interacted significantly with NMDA receptor efficacy and affinity in a region-specific manner. EAAT2 genotype interacted significantly with local GABAA receptor subunit mRNA expression, and GABB2 and DRD2B genotypes with p subunit isoform protein expression. Genotype may modulate amino acid transmission locally so as to mediate neuronal vulnerability. This has implications for the effectiveness of pharmacological interventions aimed at ameliorating brain damage and, possibly, dependence. (C) 2004 Elsevier Ltd. All rights reserved

Medication management reviews for people from the former Yugoslavia now resident in Australia

Aim: The objective of this prospective study was to conduct medication management reviews (MMR) in people from a non-English speaking background (NESB) (Bosnian/Serbian/ Croatian, from former Yugoslavia, currently residing in Australia) in their native language in order to identify medication-related problems (needs analysis) and implement appropriate therapeutic interventions, in collaboration with their general practitioners (GPs). Methods: Twenty-five participants entered the study. Each was interviewed and medication-related issues were identified by the health care team. Results: Various interventions (over 150 for the whole group, an average of 6 per participant), based on actual and potentia medication-related problems, were designed to improve the use of medicines. The MMRs introduced effective changes into the participants' health care. Psychological (e.g., feeling depressed) and sociological factors (e.g., costs of medicines, not understanding labels written in English) were identified having significant impacts on medication management. Conclusions: These data confirmed there are avoidable medication-related problems in people from a NESB. GPs and pharmacists working in health care teams with a trained interpreter could greatly improve medication use through regular review and a team approach to problem identification and solving.

Coherent molecular bound states of bosons and fermions near a Feshback resonance

We analyze molecular bound states of atomic quantum gases near a Feshbach resonance. A simple, renormalizable field theoretic model is shown to have exact solutions in the two-body sector, whose binding energy agrees well with observed experimental results in both Bosonic and Fermionic cases. These solutions, which interpolate between BEC and BCS theories, also provide a more general variational ansatz for resonant superfluidity and related problems.

Does health assessment improve health outcomes in Indigenous people? An RCT with 13 years of follow-up

Objective: To examine the impact of a multi-component health assessment on mortality and morbidity in Kimberley Aboriginal residents during a 13-year follow-up. Method. A population-based randomised controlled trial using linked hospital, cancer and death records to evaluate outcomes in 620 intervention and 6,736 control subjects. Results: The intervention group had a higher rate of first-time hospitalisation for any reason (IRR = 1.37; 95 % Cl 1.25-1.50), a higher rate of injury-related hospital episodes (IRR = 1.31; 95 % Cl 1.15-1.48) and a higher notification rate of alcohol-related cancers. There was a smaller difference in the rates of multiple hospitalisations (IRR = 1.14; 95 % Cl 0.751.74) and no improvement in overall mortality compared with controls (IRR = 1.08; 95 % Cl 0.91-1.29). Conclusions: There was no overall mortality benefit despite increased health service contact associated with the intervention. Implications: Although not influencing mortality rates, multi-component health assessment may result in a period of increased health service use in Aboriginal and Torres Strait Islander populations, thus constituting an 'intervention'. However, this should not be confused with systematic and sustained interventions and investment in community development to achieve better health outcomes.

Heavy tails, importance sampling and cross-entropy

We consider the problem of estimating P(Yi + (...) + Y-n > x) by importance sampling when the Yi are i.i.d. and heavy-tailed. The idea is to exploit the cross-entropy method as a toot for choosing good parameters in the importance sampling distribution; in doing so, we use the asymptotic description that given P(Y-1 + (...) + Y-n > x), n - 1 of the Yi have distribution F and one the conditional distribution of Y given Y > x. We show in some specific parametric examples (Pareto and Weibull) how this leads to precise answers which, as demonstrated numerically, are close to being variance minimal within the parametric class under consideration. Related problems for M/G/l and GI/G/l queues are also discussed.

The pathophysiology of 'brain shrinkage' in alcoholics - Structural and molecular changes and clinical implications

This article represents a symposium of the 2004 ISBRA Congress held in Mannheim. The presentations were: Review of the neuropathological and neurochemical changes seen in alcohol-related ' brain shrinkage ' by Clive Harper; In Vivo Detection of Macrostructural and Microstructural Markers of Brain Integrity in Human Alcoholism and a Rodent Model of Alcoholism by Adolf Pfefferbaum, Elfar Adalsteinsson and Edith Sullivan; Gene and Protein Changes in the Brains of Alcoholics with ' Brain Shrinkage ' by Joanne Lewohl and Peter Dodd; Cross sectional and longitudinal MR spectroscopy studies of chronic adult alcoholics by Michael Taylor; Brain Atrophy Associated with Impairment on a Simulated Gambling Task in Long-Term Abstinent Alcoholics by George Fein and Bennett Landman.

Stress in veterinary science students: A study at the University of Queensland

This paper reports on the results of a survey of selected University of Queensland (UQ) veterinary students aimed at elucidating factors causing stress during the five undergraduate years of the program. Students from each of the five years were asked to form six- or seven-member focus groups. Each focus group was then interviewed and their opinions sought on causes of ongoing stress and the ranking of those causes into predetermined categories. They were also asked to give their opinions on counseling services available within the university and what, if any, services they would like to see in place to help students with stress-related problems. Students in the first, third, and fourth years of the program rated academic issues as the most likely causes of ongoing stress, while students in the second and fifth years of the program ranked lifestyle and financial issues as more likely to cause ongoing stress. in most cases, students coped well with these causes of stress and tended not to use counseling services available to all UQ students. When faced with stressful issues, students looked to their classmates or family members for help and not to university counseling services. Students were also happy to approach staff members in the Veterinary School when faced with a problem. The authors nevertheless conclude that mechanisms set in place at the undergraduate level to help veterinary students cope with stress should particularly benefit those students when they become new graduates and are faced with the stresses of veterinary practice.

Drinking refusal self-efficacy questionnaire-revised (DRSEQ-R): a new factor structure with confirmatory factor analysis

The drinking refusal self-efficacy questionnaire (DRSEQ: Young, R.M., Oei, T.P.S., 1996. Drinking expectancy profile: test manual. Behaviour Research and Therapy Centre, University of Queensland, Australia Young, R.M., Oei, T.P.S., Crook, G.M., 1991. Development of a drinking refusal self-efficacy questionnaire. J. Psychopathol. Behav. Assess., 13, 1-15) assesses a person's belief in their ability to resist alcohol. The DRSEQ is a sound psychometric instrument based on exploratory factor analyses, but has not been subjected to confirmatory factor analysis. In total 2773 participants were used to confirm the factor structure of the DRSEQ. Initial analyses revealed that the original structure was not confirmed in the current study. Subsequent analyses resulted in a revised factor structure (DRSEQ-R) being confirmed in community, student and clinical samples. The DRSEQ-R was also found to have good construct and concurrent validity. The factor structure of the DRSEQ-R is more stable than the original structure of the DRSEQ and the revised scale has considerable potential in future alcohol-related research. (c) 2004 Elsevier Ireland Ltd. All rights reserved.

Epidemiology of open- and closed-globe trauma presenting to Cairns Base Hospital, Queensland

Purpose: To review the epidemiology of serious ocular trauma presenting to Cairns Base Hospital, from the far north Queensland health districts. Methods: A retrospective study of cases from January 1995 to November 2002 inclusive. Cases were analysed with respect to demographics, cause and nature of injury, method of transport and time to and type of ophthalmic treatment, and visual outcomes. Results: There were 226 cases identified, including 71 open-globe and 155 closed-globe injuries. The annual rate of injury was 3.7 per 100 000 for open-globe and 11.8 per 100 000 in total. The Aboriginal and Torres Strait Islander population from the far north Queensland districts showed a disproportionate incidence, with 38% of the total number of injuries, despite representing only 12.3% of the population. Assault in the Aboriginal and Torres Strait Islander population resulted in 69.6% of injuries in men and 75.8% of injuries in women. Of all assaults 76.2% were alcohol-related. The majority (71.5%) of injuries in the Caucasian population were due to accidental blunt and sharp trauma. In total, 77.4% of injuries occurred in men, with an average age of 31 years. Of all open and closed injuries in the study, a final visual acuity of 6/12 or better was achieved in 47.8% of eyes and a final visual acuity of 6/60 or less occurred in 17.7% of patients, 20.8% patients were lost to follow up. In total, 14.1% of open injuries required enucleation/evisceration. Conclusions: The incidence of ocular trauma in far north Queensland is equal to other Australian populations. However, there is a disproportionately high incidence in the Aboriginal and Torres Strait Islander population. Alcohol-related assault is a significant cause of visual loss in the Aboriginal and Torres Strait Islander population. Closed-globe injuries are more common than open globe; however, the latter have poorer visual prognosis. Initial visual acuity of all injuries correlated with final visual acuity.

Course of substance misuse and daily tobacco use in first-episode psychosis

Background: Study of the course of substance misuse and daily tobacco use in first-episode psychosis may enhance detection and treatment of these substance-related problems. Methods: This 15-month follow-up study examined the course of substance misuse and daily tobacco use in 103 individuals treated for first-episode psychosis. Results: Three-quarters (72.6%) of patients with lifetime substance misuse, or half (51.5%) of all patients, continued substance misuse (primarily cannabis) during the 15-month follow-up period. There was a significant reduction in the rate of any substance misuse (70.9% versus 53.4%) but not daily tobacco use (76.7% versus 75.7%) between baseline and 15-month follow-up. Patients who continued substance misuse showed a significant reduction in the severity and frequency of substance use between baseline and follow-up. Patients who continued substance misuse were more likely to be younger, male and single, less likely to have completed secondary school, and more likely to have had more severe cannabis use prior to entry to treatment compared to patients who ceased substance misuse. Discussion: A significant proportion of young patients treated for first-episode psychosis are at risk of mental and physical health problems associated with substance misuse and/or regular tobacco use. (c) 2005 Elsevier B.V. All rights reserved.

Lipoprotein lipase and lipolysis in milk

Bovine milk contains a lipoprotein lipase that accounts for most, if not all, of its lipolytic activity. The total lipase activity in raw milk is sufficient to cause rapid hydrolysis of a large proportion of the fat. However, in reality this does not happen, because the lipase is prevented from accessing the fat by the milkfat globule membrane. Physical damage to this membrane in raw milk initiates lipolysis. Furthermore, simply cooling certain individual milks soon after secretion can initiate the so-called spontaneous lipolysis. The biochemical basis of spontaneous lipolysis is still poorly understood, but it appears to be related to a balance between activating and inhibiting factors in the milk. Lipolysis in milk and milk products causes rancid off-flavours and other problems, and is a constant concern in the dairy industry. A thorough understanding of the mechanism of lipolysis and constant vigilance by operatives is required to minimize lipase-related problems. (c) 2006 Elsevier Ltd. All rights reserved.

Trends in morphine prescriptions, illicit morphine use and associated harms among regular injecting drug users in Australia

This paper examines population trends in morphine prescriptions in Australia, and contrasts them with findings from annual surveys with regular injecting drug users (IDU). Data on morphine prescriptions from 1995 to 2003 were obtained from the Drug Monitoring System (DRUMS) run by the Australian Government Department of Health and Ageing. Data collected from regular IDU as part of the Australian Illicit Drug Reporting System (IDRS) were analysed (2001-2004). The rate of morphine prescription per person aged 15-54 years increased by 89% across Australia between 1995 and 2003 (from 46.3 to 85.9 mg per person). Almost half (46%) of IDU surveyed in 2004 reported illicit morphine use, with the highest rates in jurisdictions where heroin was less available. Recent morphine injectors were significantly more likely to be male, unemployed, out of treatment and homeless in comparison to IDU who had not injected morphine. They were also more likely to have injected other pharmaceutical drugs and to report injection related problems. Among those who had injected morphine recently, the most commonly reported injecting harms were morphine dependence (38%), difficulty finding veins into which to inject (36%) and scarring or bruising (27%). Morphine use and injection is a common practice among regular IDU in Australia. In some cases, morphine may be a substitute for illicit heroin; in others, it may be being used to treat heroin dependence where other pharmacotherapies, such as methadone and buprenorphine, are perceived as being unavailable or undesirable by IDU. Morphine injection appears to be associated with polydrug use, and with it, a range of problems related to drug injection. Further research is required to monitor and reduce morphine diversion and related harms by such polydrug injectors.

Estimating cause-specfic mortality from community- and facility-based data sources in the United Republic of Tanzania: options and implications for mortality burden estimates

Objective To compare mortality burden estimates based on direct measurement of levels and causes in communities with indirect estimates based on combining health facility cause-specific mortality structures with community measurement of mortality levels. Methods. Data from sentinel vital registration (SVR) with verbal autopsy (VA) were used to determine the cause-specific mortality burden at the community level in two areas of the United Republic of Tanzania. Proportional cause-specific mortality structures from health facilities were applied to counts of deaths obtained by SVR to produce modelled estimates. The burden was expressed in years of life lost. Findings. A total of 2884 deaths were recorded from health facilities and 2167 recorded from SVR/VAs. In the perinatal and neonatal age group cause-specific mortality rates were dominated by perinatal conditions and stillbirths in both the community and the facility data. The modelled estimates for chronic causes were very similar to those from SVR/VA. Acute febrile illnesses were coded more specifically in the facility data than in the VA. Injuries were more prevalent in the SVR/VA data than in that from the facilities. Conclusion. In this setting, improved International classification of diseases and health related problems, tenth revision (ICD-10) coding practices and applying facility-based cause structures to counts of deaths from communities, derived from SVR, appears to produce reasonable estimates of the cause-specific mortality burden in those aged 5 years and older determined directly from VA. For the perinatal and neonatal age group, VA appears to be required. Use of this approach in a nationally representative sample of facilities may produce reliable national estimates of the cause-specific mortality burden for leading causes of death in adults.

Neurobiological alterations in the human alcoholic brain: effect of genotype

Long-term alcohol abuse by human subjects leads to selective brain damage that is restricted in extent and variable in severity. Within the cerebral cortex, neuronal loss is most marked in the superior frontal cortex and relatively mild in motor cortex. Cirrhotic alcoholics and subjects with alcohol-related Wernicke-Korsakoff syndrome show more severe and more extensive damage than do uncomplicated cases. Accumulating evidence suggests that the likelihood of developing alcohol dependency is associated with one or more genetic markers. In previous work we showed that GABAA receptor functionality, and the subunit isoform expression that underlies this, differed in region- and disease-specific ways between alcoholics and controls. By contrast, glutamate receptor (NMDA, KA, AMPA) differences were muted or absent. Here we asked if genotype differentiated the form, pharmacology, or expression of glutamate and GABA receptors in pathologically vulnerable and spared cortical regions, with a view to determining whether such subject factors might influence the severity of alcohol-induced brain damage. Cerebrocortical tissue was obtained at autopsy under informed, written consent from uncomplicated and alcoholic-cirrhotic Caucasian (predominantly Anglo-Celtic) cases, together with matched controls and cases with cirrhosis of non-alcoholic origin. All subjects had pathological confirmation of liver and brain diagnosis; none had been polydrug abusers. Samples were processed for synaptic membrane receptor binding, mRNA analysis by quantitative RT-PCR, and protein analysis by Western blot. Genotyping was performed by PCR methods, in the main using published primers. Several genetic markers differentiated between our alcoholic and control subjects, including the GABAA receptor 2 subunit (GABB2) gene ( 2 (3) 10.329, P 0.01), the dopamine D2 receptor B1 (DRD2B) allele ( 2 (3) 10.109, P 0.01) and a subset of the alcohol dehydrogenase-3 (ADH3) alleles ( 2 (2) 4.730, P 0.05). Although neither the type-2 glutamate transporter (EAAT2) nor the serotonin transporter (5HTT) genes were significantly associated with alcoholism, only EAAT2 heterozygotes showed a significant association between ADH3 genotype and alcoholism ( 2 (3) 7.475, P 0.05). Other interactions between genotypes were also observed. DRD2A, DRD2B, GABB2, EAAT2 and 5HTT genotypes did not divide alcoholic cases and controls on NMDA receptor parameters, although in combined subjects there was a significant DRD2B X Area Interaction with glutamateNMDA receptor efficacy (F(1,57) 4.67; P 0.05), measured as the extent of glutamate-enhanced MK801 binding. In contrast, there was a significant Case-group X ADH3 X Area Interaction with glutamateNMDA receptor efficacy (F(3,57) 2.97; P 0.05). When GABAA receptor subunit isoform expression was examined, significant Case-group X Genotype X Area X Isoform interactions were found for EAAT2 with subunit mRNA (F(1,37) 4.22; P0.05), for GABB2 with isoform protein (F(1,37) 5.69; P 0.05), and for DRD2B with isoform protein (F(2,34)5.69; P0.05). The results suggest that subjects’ genetic makeup may modulate the effectiveness of amino acid-mediated transmission in different cortical regions, and thereby influence neuronal vulnerability to excitotoxicity.

Noisy fitness evaluation in genetic algorithms and the dynamics of learning

A theoretical model is presented which describes selection in a genetic algorithm (GA) under a stochastic fitness measure and correctly accounts for finite population effects. Although this model describes a number of selection schemes, we only consider Boltzmann selection in detail here as results for this form of selection are particularly transparent when fitness is corrupted by additive Gaussian noise. Finite population effects are shown to be of fundamental importance in this case, as the noise has no effect in the infinite population limit. In the limit of weak selection we show how the effects of any Gaussian noise can be removed by increasing the population size appropriately. The theory is tested on two closely related problems: the one-max problem corrupted by Gaussian noise and generalization in a perceptron with binary weights. The averaged dynamics can be accurately modelled for both problems using a formalism which describes the dynamics of the GA using methods from statistical mechanics. The second problem is a simple example of a learning problem and by considering this problem we show how the accurate characterization of noise in the fitness evaluation may be relevant in machine learning. The training error (negative fitness) is the number of misclassified training examples in a batch and can be considered as a noisy version of the generalization error if an independent batch is used for each evaluation. The noise is due to the finite batch size and in the limit of large problem size and weak selection we show how the effect of this noise can be removed by increasing the population size. This allows the optimal batch size to be determined, which minimizes computation time as well as the total number of training examples required.