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Ethanol can induce acute stimulant responses in animals and human beings. Moreover, repeated exposure to ethanol may produce increased sensitivity to its acute locomotor stimulant actions, a process referred to as locomotor sensitization. The molecular mechanism of the development of acute stimulant responses and locomotor sensitization by ethanol is not fully understood. Sodium leak channel (NALCN) is widely expressed in central nervous system and controls the basal excitability of neurons. The present study aims to determine whether NALCN is implicated in the ethanol-induced acute responses and locomotor sensitization in mice. Here, our results showed that ethanol caused acute stimulant responses in DBA/2 mice. Locomotor sensitization was successfully induced following the sensitization procedure. Accordingly, the expression levels of NALCN mRNA and protein in the nucleus accumbens (NAc) were markedly increased in the sensitization mice compared to the control mice. Knockdown the expression levels of NALCN in the NAc alleviated both the ethanol-induced acute responses and locomotor sensitization. Our findings indicate that upregulation of NALCN expression in the NAc contributes to the ethanol-induced acute stimulant responses and locomotor sensitization in DBA/2 mice.

Liver fluke infection (fascioliasis) is a parasitic disease which affects the health and welfare of ruminants. It is a concern for the livestock industry and is considered as a growing threat to the industry because changing climatic conditions are projected to be more favorable to increased frequency and intensity of liver fluke outbreaks. Recent reports highlighted that the incidence and geographic range of liver fluke has increased in the UK over the last decade and estimated to increase the average risk of liver fluke in the UK due to increasing temperature and rainfall. This paper explores financial impacts of the disease with and without climate change effects on Scottish livestock farms using a farm-level economic model. The model is based on farming system analysis and uses linear programming technique to maximize farm net profit within farm resources. Farm level data from a sample of 160 Scottish livestock farms is used under a no disease baseline scenario and two disease scenarios (with and without climate change). These two disease scenarios are compared with the baseline scenario to estimate the financial impact of the disease at farm levels. The results suggest a 12% reduction in net profit on an average dairy farm compared to 6% reduction on an average beef farm under standard disease conditions. The losses increase by 2-fold on a dairy farm and 6-fold on a beef farm when climate change effects are included with disease conditions on farms. There is a large variability within farm groups with profitable farms incurring relatively lesser economic losses than non-profitable farms. There is a substantial increase in number of vulnerable farms both in dairy (+20%) and beef farms (+27%) under the disease alongside climate change conditions.

Abstract. The impact of air pollution on human health and the associated external costs in Europe and the United States (U.S.) for the year 2010 is modelled by a multi-model ensemble of regional models in the frame of the third phase of the Air Quality Modelling Evaluation International Initiative (AQMEII3). This is the first study known to use a common health assessment approach across the two continents. The modelled surface concentrations of O3, CO, SO2 and PM2.5 from each model are used as input to the Economic Valuation of Air Pollution (EVA) system to calculate the resulting health impacts and the associated external costs. Along with a base case simulation, additional runs were performed introducing 20 % emission reductions both globally and regionally in Europe, North America and East Asia. Health impacts estimated by different models can vary up to a factor of three in Europe (twelve models) and the United States (three models). In Europe, the multi-model mean number of premature deaths is calculated to be 414 000 while in the U.S., it is estimated to be 160 000, in agreement with previous global and regional studies. In order to estimate the impact of biases coming from each model, two multi-model ensembles were produced, the first attributing an equal weight to each member of the ensemble, and the second where the subset of models that produce the smallest error compared to the surface observations at each time step. The latter results in increase of health impacts by up to 30 % in Europe, thus giving significantly higher mortality estimates compared to available literature. This is mostly due to a 27 % increase in the domain mean PM2.5 levels, along with a slight increase in O3 by ~ 1 %. Over the U.S., the mean PM2.5 and O3 levels decrease by 11 % and 2 %, respectively, when the optimal ensemble mean is used, leading to a decrease in the calculated health impacts by ~ 11 %. These differences encourage the use of optimal-reduced multi-model ensembles over traditional all model-mean ensembles, in particular for policy applications. Finally, the role of domestic versus foreign emission sources on the related health impacts is investigated using the 20 % emission reduction scenarios applied over the source regions as defined in the frame of HTAP2. The differences are calculated based on the models that are common in the basic multi-model ensemble and the perturbation scenarios, resulting in five models in Europe and all three models in the U.S. A 20 % reduction of global anthropogenic emissions avoids 54 000 and 27 500 premature deaths in Europe and the U.S., respectively. A 20 % reduction of North American emissions foreign emissions avoids ~ 1000 premature deaths in Europe and 25 000 premature deaths in the U.S. A 20 % decrease of emissions within the European source region avoids 47 000 premature deaths in Europe. Reducing the East Asian emission by 20 % avoids ~ 2000 premature deaths in the U.S. These results show that the domestic emissions make the largest impacts on premature death, while foreign sources make a minor contributing to adverse impacts of air pollution.

Our study aims at comparing in C57/Bl male mice, the impact of repeated injections of baclofen (an agonist of GABAB receptor) or diazepam (a benzodiazepine acting through a positive allosteric modulation of GABAA receptor) administered during the alcohol-withdrawal period on hippocampus-dependent memory impairments and brain regional glucocorticoid dysfunction after a short (1-week) or a long (4-week) abstinence. Hence, mice were submitted to a 6-month alcohol consumption (12%v/v) and were progressively withdrawn to water. Then, after a 1- or 4-weeks abstinence, they were submitted to a contextual memory task followed by measurements of corticosterone concentrations in the dorsal hippocampus (dHPC), the ventral hippocampus (vHPC) and the prefrontal cortex (PFC). Results showed that 1- and 4-week withdrawn mice exhibited a severe memory deficit and a significant abnormal rise of the test-induced increase of corticosterone (TICC) in the dHPC, as compared to water-controls or to mice still under alcohol consumption. Repeated daily systemic administrations of decreasing doses of diazepam (ranged from 0.5 to 0.12 mg/kg) or baclofen (ranged from 1.5 to 0.37 mg/kg) during the last 15 days of the withdrawal period, normalized both memory and TICC scores in the dHPC in 1-week withdrawn animals; in contrast, only baclofen-withdrawn mice showed both normal memory performance and TICC scores in the dHPC after a 4-week withdrawal period. In conclusion, the memory improvement observed in 4-week withdrawn mice administered with baclofen stem from the protracted normalization of glucocorticoid activity in the dHPC, a phenomenon encountered only transitorily in diazepam-treated withdrawn mice.

Ethanol and drugs can affect each other's absorption, distribution, metabolism, and excretion. When ingested together, ethanol can increase drug absorption by enhancing the gastric solubility of drugs and by increasing gastrointestinal blood flow. However, high concentrations of ethanol induce gastric irritation causing a pyloric spasm which in turn may delay drug absorption and/or reduce bioavailability. The 'quality' of the alcoholic beverage, independent of its ethanol content, can contribute to altered absorption of a drug. Ethanol is not bound to plasma proteins extensively enough to modify drug distribution. However, serum albumin levels in chronic alcoholics may be abnormally low so that some drugs, e.g. diazepam, have an increased volume of distribution. In addition to the amount ingested, the duration of regular intake determines the effect of ethanol on drug metabolism. Acute intake of ethanol inhibits the metabolism of many drugs but long term intake of ethanol at a high level (greater than 200g of pure ethanol per day) can induce liver enzymes to metabolise drugs more efficiently. At the present time there are no accurate means, with the possible exception of liver biopsy, to clinically predict the capacity of an alcoholic to metabolise drugs. Several drugs can inhibit the metabolism of ethanol at the level of alcohol dehydrogenase. Individual predisposition determines the severity of this drug-ethanol interaction. During its absorption phase, ethanol inhibits the secretion of antidiuretic hormone and is also able to induce increased excretion of a drug through the kidneys. However, chronic alcoholics with water retention may show reduced excretion of drugs via this route. At the pharmacodynamic level, ethanol can enhance the deleterious effects of sedatives, certain anxiolytics, sedative antidepressants and antipsychotics and anticholinergic agents, on performance. Mechanisms of lethal interactions between moderate overdoses of ethanol and anxiolytics/opiates/sedatives are poorly understood. On the other hand, certain peptides, 'nonspecific' stimulants, dopaminergic agents and opiate antagonists can antagonise alcohol-induced inebriation to a significant degree.

Alcohol-induced liver damage is a major burden for most societies, and murine studies can provide a means to better understand its pathogenesis and test new therapies. However, there are many models reported with widely differing phenotypes, not all of which fully regenerate the spectrum of human disease. Thus, it is important to understand the implications of these variations to efficiently model human disease. This review critically appraises key articles in the field, detailing the spectrum of liver damage seen in different models, and how they relate to the phenotype of disease seen in patients. A range of different methods of alcohol administration have been studied, ranging from ad libitum consumption of alcohol and water to modified diets (eg, Lieber deCarli liquid diet). Other feeding regimens have taken more invasive routes using intragastric feeding tubes to infuse alcohol directly into the stomach. Notably, models using wild-type mice generally produce a milder phenotype of liver damage than those using genetically modified mice, with the exception of the chronic binge-feeding model. We recommend panels of tests for consideration to standardize end points for the evaluation of the severity of liver damage-key for comparison of models of injury, testing of new therapies, and subsequent translation of findings into clinical practice.

Although the beneficial effects of mild to moderate ethanol consumption have been implied with respect to heart, alcohol abuse has proven to be a major cause of nonischemic cardiomyopathy in Western society. However, the biochemical and molecular mechanisms, which mediate the pathologic cardiac effects of ethanol, remain largely unknown. The aim of the present study was to explore the effects of chronic ethanol exposure on cardiac apoptosis and expression of some of the genes associated with cardiac remodeling in vivo.Alcohol-avoiding Alko Non Alcohol rats of both sexes were used. The ethanol-exposed rats (females, n=6; males, n=8) were given 12% (v/v) ethanol as the only available fluid from age of three to 24 months of age. The control rats (females, n=7; males, n=5) had only water available. At the end of the experiment, free walls of left ventricles of hearts were immediately frozen. Cytosolic DNA fragmentation, reflecting apoptosis, was measured using a commercial quantitative sandwich enzyme-linked immunosorbent assay kit, and mRNA levels were analyzed using a quantitative reverse transcriptase-polymerase chain reaction method.Ethanol treatment for two years increased cardiac left ventricular p53 mRNA levels significantly (p=0.014) compared with control rats. The gene expression was also dependent on the gender (p=0.001), so that male rats had higher left ventricular p53 mRNA levels than female rats. However, no significant differences in levels of DNA fragmentation were detected.Chronic ethanol exposure in vivo induces rat cardiac left ventricular p53 gene expression. Expression of p53 is also gender-dependent, males having higher p53 mRNA levels than females. This preliminary finding suggests a role for the p53 gene in ethanol-induced cardiac remodeling. The results might also have some relevance for the known gender-dependent differences in propensity to cardiovascular disease.