The results of this study indicate that 6 weeks of voluntary alcohol intake are sufficient for the development of physical dependence upon alcohol in the alcohol-preferring P rats as measured by susceptibility to bicuculline-induced seizures. This time is much shorter than the 15-20 weeks reported earlier. Development of physical dependence to alcohol was associated with an increase in daily alcohol intake (40% over the baseline), an increase in alcohol intake during each drinking bout (90% over the baseline), and elevated anxiety during alcohol withdrawal.

CINCH (Consortium for the Immunization of Norfolk's Children) is an urban coalition that was developed in 1993 to improve childhood immunization rates in Norfolk, Virginia. CINCH involves diverse citizens and institutions in effective community-based assessment, planning, and action. A needs assessment from 1993 found that only 49% of Norfolk 2-year-olds were adequately immunized. Using this data, CINCH developed a plan focused on education and communication, support for at-risk families, increased access to immunizations, and improved immunization delivery. After federal funding ended in 1995, members voted to expand the scope of the coalition to address additional child health needs and to broaden the membership. CINCH is a model for a sustainable city-citizen learning environment that intervenes to "help families help themselves to better health." The coalition is presented as an organization that focuses on community empowerment and development. The stages of coalition development and implications for coalition implementation in other sites are discussed.

A strong association has been observed between [3H]zolpidem binding and the presence of gamma-aminobutyric acid (GABAA) receptor mRNA for alpha 1-, beta 2-, and gamma 2-subunits in specific brain regions. This correlates with observed sensitivity of individual neurons to zolpidem and ethanol in these same regions. Previous studies using homogenate binding approaches showed small alterations in [3H]zolpidem binding levels after chronic ethanol exposure. This study was undertaken to ascertain if there is regional specificity of the effects of chronic ethanol administration on [3H]zolpidem binding levels. Chronic ethanol administration induced small, but significant alterations in [3H]zolpidem (5 nM) binding in the inferior colliculus, substantia nigra, and the medial septum. [3H]Zolpidem binding was increased in the inferior colliculus and substantia nigra, and decreased in the medial septum. No significant differences in [3H]zolpidem binding were noted in any other brain area analyzed, including the cortex and cerebellum. These findings show that chronic ethanol administration has small effects on [3H]zolpidem binding, although they occur in a site-specific and bidirectional manner. Moreover, there is no correlation between changes in [3H]zolpidem binding and alterations in GABAA receptor subunit expression.

Coalition development is a major strategy to increase immunization rates. However, if local and state coalitions are to succeed, their staffs need training and technical assistance in coalition development, community planning, and program implementation. The National Coalition Training Institute trains key health agency staff in 87 state, territorial, and urban sites to perform needs assessments, use data to guide planning, plan comprehensive strategies, and evaluate their coalitions. The curriculum is based on training needs that are identified by a national survey of immunization coalitions, effective approaches, and participant evaluation. According to evaluations conducted during its first year, the National Coalition Training Institute is meeting the needs of participants.

The development of targeted treatment options for precision medicine is hampered by a slow and costly process of drug screening. While small molecule docking simulations are often applied in conjunction with cheminformatic methods to reduce the number of candidate molecules to be tested experimentally, the current approaches suffer from high false positive rates and are computationally expensive. Here, we present a novel in silico approach for drug discovery and repurposing, dubbed connectivity enhanced Structure Activity Relationship (ceSAR) that improves on current methods by combining docking and virtual screening approaches with pharmacogenomics and transcriptional signature connectivity analysis. ceSAR builds on the landmark LINCS library of transcriptional signatures of over 20,000 drug-like molecules and ~5,000 gene knock-downs (KDs) to connect small molecules and their potential targets. For a set of candidate molecules and specific target gene, candidate molecules are first ranked by chemical similarity to their ‘concordant’ LINCS analogs that share signature similarity with a knock-down of the target gene. An efficient method for chemical similarity search, optimized for sparse binary fingerprints of chemical moieties, is used to enable fast searches for large libraries of small molecules. A small subset of candidate compounds identified in the first step is then re-scored by combining signature connectivity with docking simulations. On a set of 20 DUD-E benchmark targets with LINCS KDs, the consensus approach reduces significantly false positive rates, improving the median precision 3-fold over docking methods at the extreme library reduction. We conclude that signature connectivity and docking provide complementary signals, offering an avenue to improve the accuracy of virtual screening while reducing run times by multiple orders of magnitude.

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