Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2 300Q transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2 300Q transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment.rologic disorder caused by a CAG repeat expansion within the coding region of the HD gene (Htt), resulting in a mutant protein (htt) with a lengthened polyglutamine tract (1). Mutant htt protein has been shown to disrupt transcription by multiple mechanisms, but it is unclear which are most important to pathology (2-4). By interacting with specific transcription factors, htt can alter the expression of clusters of genes controlled by those factors. For example, several genes driven by Sp1, which has been shown to interact with htt (5, 6), show decreased mRNA expression in human HD and in mouse models of HD (7). Alternatively, htt may have more global effects on transcription by disrupting core transcriptional machinery (8, 9) or by altering posttranslational modifications of histones, resulting in condensed chromatin structure (10-13). Understanding the basis for transcriptional dysregulation is important for choosing appropriate drug-discovery strategies.Manifestations of transcriptional dysregulation are evident from several gene-profiling studies, which have revealed alterations in the expression of large numbers of genes in the brains of different HD mouse models and in human subjects with HD (7, 14-16). Many of the expression changes in mouse models are observed in early stages of illness before the onset of symptoms, suggesting that gene expression alterations may be pathogenic.Because o...

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Allergic contact dermatitis (ACD) used to be considered a rarity in children, but recently has been estimated to effect 4.4 million children in the USA alone, with a notable rise in investigative research in the field of pediatric ACD. Researchers have shown that patch testing is safe and effective in afflicted children and that those with atopic dermatitis (AD) have similar sensitization rates, although they have a higher sensitization to certain allergens, thought to be related to the inflammatory (IL-4) milieu. Patch testing assessment guidelines in children include five key considerations: if a patient's dermatitis worsens, changes distribution, fails to improve with topical therapy, or immediately rebounds after removal of topical treatments; if a patient has a particular distribution of dermatitis; if a working patient has hand eczema that fails to improve with therapy; if the patient has AD that started in adolescence or adulthood with definitely no history of childhood eczema; and importantly, if a patient has severe or widespread atopic dermatitis that will require immunosuppressive systemic medication.

Background/Objectives To determine the initial efficacy of a mailed screening and brief intervention to reduce at-risk drinking among persons aged 50 years and older. Design Pilot randomized controlled trial. Setting UCLA Department of Medicine Community Offices and Primary Care Network. Participants: 86 adults aged 50 years and above who were identified as at-risk drinkers by the Comorbidity Alcohol Risk Evaluation Tool (CARET). Intervention Participants were assigned randomly to receive personalized mailed feedback outlining their specific risks associated with alcohol use, an educational booklet on alcohol and aging, and the NIH Rethinking Drinking: Alcohol and Your Health booklet (intervention group) or nothing (control group). Measurements Alcohol-related assessments at baseline and at 3 months. CARET assessed at-risk drinking, number of risks, and types of risks. Results At 3 months, relative to controls, fewer intervention group participants were: at-risk drinkers (66% versus 88%), binge drinking (45% versus 68%), used alcohol with a medical or psychiatric condition (3% versus 17%) or with symptoms of such a condition (29% versus 49%). Conclusion A mailed brief intervention may be an effective approach to intervening with at-risk drinkers aged 50 and older.

Objectives To understand characteristics of and reasons why older at-risk drinkers decide to change or maintain their alcohol consumption. Design Secondary analysis of data from a randomized controlled trial to reduce drinking among at-risk drinkers. Setting Three primary care sites in southern California. Participants Six-hundred and thirty one adults aged 55 years and older who were at-risk drinkers at baseline and five hundred twenty-one of them who completed a 12 month assessment. Measurements Sociodemographic and alcohol-related characteristics were compared using descriptive statistics between 12 month assessment completers and non-completers, and among those completing the 12 month assessment by telephone or mail. Reasons why respondents maintained or changed average alcohol consumption were asked among those who completed a 12 month assessment by telephone. Factors that might motivate at-risk drinkers to reduce drinking were asked and frequencies were calculated for these responses. Results Participants were primarily male, White, highly educated and in good health. Those who responded to the 12 month assessment by mail were more likely than to be working, in the intervention arm, and to drink more. Most who reduced alcohol consumption and heavy drinking did so because they thought it would be of benefit to them. Those who did not thought it was not a problem for them. Both groups cited their environment and circumstances as influencing their drinking. Remaining at-risk drinkers reported that medical evidence that alcohol was harming them would motivate them to reduce drinking. Conclusion Older adults report they make reductions in drinking when they recognize their drinking habits may be causing them harm and one’s environment can hinder or help one to make reductions in drinking.