Molecular and neurologic responses to chronic alcohol use.

This chapter provides an overview of current knowledge on the molecular and clinical aspects of chronic alcohol effects on the central nervous system. This drug is almost ubiquitous, widely enjoyed socially, but produces a diverse spectrum of neurologic disease when abused. Acutely, alcohol interacts predominantly with γ-aminobutyric acid-A (GABA-A) and N-methyl-d-aspartate (NMDA) receptors, but triggers diverse signaling events within well-defined neural pathways. These events result in adaptive changes in gene expression that ultimately produce two major states: addiction and toxicity. Epigenetic modifications of chromatin could lead to long-lived or even transgenerational changes in gene expression, thus producing aspects of the heritability of alcohol use disorders (AUD) and long-term behaviors such as recidivism. The diverse clinical syndromes produced by chronic alcohol actions in the central nervous system reflect the molecular pathology and predominantly involve aspects of tolerance/withdrawal, selective vulnerability (manifest as central pontine myelinolysis, Marchiafava-Bignami disease), and additional environmental factors (e.g., thiamine deficiency in Wernicke-Korsakoff's syndrome). Additionally, deleterious aspects of chronic alcohol on signaling, synaptic transmission, and cell toxicity lead to primary alcoholic dementia. Genetically determined aspects of myelin structure and alcohol actions on myelin gene expression may be a prominent molecular mechanism resulting in a predisposition to, or causation of, AUD and multiple other neurologic complications of chronic alcohol. The dramatic progress made in understanding molecular actions of alcohol holds great promise for our eventual treatment or prevention of AUD and neurologic complications resulting from chronic alcohol abuse.

Using genome-wide expression profiling to define gene networks relevant to the study of complex traits: from RNA integrity to network topology.

Postgenomic studies of the function of genes and their role in disease have now become an area of intense study since efforts to define the raw sequence material of the genome have largely been completed. The use of whole-genome approaches such as microarray expression profiling and, more recently, RNA-sequence analysis of transcript abundance has allowed an unprecedented look at the workings of the genome. However, the accurate derivation of such high-throughput data and their analysis in terms of biological function has been critical to truly leveraging the postgenomic revolution. This chapter will describe an approach that focuses on the use of gene networks to both organize and interpret genomic expression data. Such networks, derived from statistical analysis of large genomic datasets and the application of multiple bioinformatics data resources, potentially allow the identification of key control elements for networks associated with human disease, and thus may lead to derivation of novel therapeutic approaches. However, as discussed in this chapter, the leveraging of such networks cannot occur without a thorough understanding of the technical and statistical factors influencing the derivation of genomic expression data. Thus, while the catch phrase may be "it's the network … stupid," the understanding of factors extending from RNA isolation to genomic profiling technique, multivariate statistics, and bioinformatics are all critical to defining fully useful gene networks for study of complex biology.

Chloride intracellular channels modulate acute ethanol behaviors in Drosophila, Caenorhabditis elegans and mice.

Identifying genes that influence behavioral responses to alcohol is critical for understanding the molecular basis of alcoholism and ultimately developing therapeutic interventions for the disease. Using an integrated approach that combined the power of the Drosophila, Caenorhabditis elegans and mouse model systems with bioinformatics analyses, we established a novel, conserved role for chloride intracellular channels (CLICs) in alcohol-related behavior. CLIC proteins might have several biochemical functions including intracellular chloride channel activity, modulation of transforming growth factor (TGF)-ß signaling, and regulation of ryanodine receptors and A-kinase anchoring proteins. We initially identified vertebrate Clic4 as a candidate ethanol-responsive gene via bioinformatic analysis of data from published microarray studies of mouse and human ethanol-related genes. We confirmed that Clic4 expression was increased by ethanol treatment in mouse prefrontal cortex and also uncovered a correlation between basal expression of Clic4 in prefrontal cortex and the locomotor activating and sedating properties of ethanol across the BXD mouse genetic reference panel. Furthermore, we found that disruption of the sole Clic Drosophila orthologue significantly blunted sensitivity to alcohol in flies, that mutations in two C. elegans Clic orthologues, exc-4 and exl-1, altered behavioral responses to acute ethanol in worms and that viral-mediated overexpression of Clic4 in mouse brain decreased the sedating properties of ethanol. Together, our studies demonstrate key roles for Clic genes in behavioral responses to acute alcohol in Drosophila, C. elegans and mice.

Fire fighters' exposure to carbon monoxide during Australian bushfires.

Fatal entrapments of Australian bushfire fighters have led to suggestions that carbon monoxide (CO) poisoning could have contributed to these accidents by impairing the fire fighters' judgement. Carboxyhemoglobin saturation (COHb%) levels were assessed from alveolar CO levels in 24 fire fighters working with handtools and in 12 accompanying scientific observers, before and after fire fighting (duration 37-187 min) on 15 experimental bushfires. Carboxyhemoglobin levels increased on average by 0.7% per hour in the fire fighters and by 0.3% per hour in the observers. Nonsmoking fire fighters had lower COHb% after fires than the smokers had before fires. Estimates of environmental CO concentrations (including cigarette smoke) during the fires averaged 31 parts per million (ppm) for the smokers, 17 ppm for the nonsmoking crew members, and 11 ppm for the observers, none of whom smoked. The highest estimates of environmental CO arising solely from bushfire smoke were 40 to 50 ppm. Smokers were exposed to as much CO from their cigarettes as from bushfire smoke. Carboxyhemoglobin levels at the end of 8-hr fire fighting shifts, predicted from these levels of environmental CO, averaged about 5% (maximum 11%) in smokers and about 3% (maximum 7%) in nonsmokers. Acute levels of COHb% of this degree are not considered to have significant effects on health or performance. These results indicate that bushfire fighters are generally unlikely to experience hazardous levels of CO exposure.

Acute symptoms of the aerodigestive tract caused by rapidly enlarging thyroid neoplasms.

Two cases of rapidly enlarging tumors of the thyroid presenting with the sudden onset of symptoms referable to the aerodigestive tract are discussed. Although tumors of the thyroid are known to produce dysfunction of these structures, these cases are highly unusual, since in the vast majority of cases the onset and progression of these symptoms are insidious and rarely recognized by the patient or physician. The diagnostic workup and management of enlarging masses in this area is reviewed.

Bowel stenosis as a late complication of acute necrotizing enterocolitis.

Bowel stricture as a late complication of acute necrotizing enterocolitis in 10 neonates is discussed with respect to time interval to development, number of strictures, location, sexual and racial distribution and possible contributing factors. This is compared with previous reports in the literature. Differences in the distribution of acute and late sites of involvement are discussed.