Whole-body galactose oxidation as a robust functional assay to assess the efficacy of gene-based therapies in a mouse model of Galactosemia.

Despite the implementation of lifesaving newborn screening programs and a galactose-restricted diet, many patients with classic galactosemia develop long-term debilitating neurological deficits and primary ovarian insufficiency. Previously, we showed that the administration of human GALT mRNA predominantly expressed in the GalT gene-trapped mouse liver augmented the expression of hepatic GALT activity, which decreased not only galactose-1 phosphate (gal-1P) in the liver but also peripheral tissues. Since each peripheral tissue requires distinct methods to examine the biomarker and/or GALT effect, this highlights the necessity for alternative strategies to evaluate the overall impact of therapies. In this study, we established that whole-body galactose oxidation (WBGO) as a robust, noninvasive, and specific method to assess the in vivo pharmacokinetic and pharmacodynamic parameters of two experimental gene-based therapies that aimed to restore GALT activity in a mouse model of galactosemia. Although our results illustrated the long-lasting efficacy of AAVrh10-mediated GALT gene transfer, we found that GALT mRNA therapy that targets the liver predominantly is sufficient to sustain WBGO. The latter could have important implications in the design of novel targeted therapy to ensure optimal efficacy and safety.

Handgun safety: what do consumers learn from gun dealers?

OBJECTIVE: To explore the type and quality of handgun safety information a typical consumer would obtain from a licensed gun dealer. METHODS: Semistructured, interactional on-site interviews were conducted with licensed handgun dealers in 2 metropolitan areas. A variety of dealers (gun shops, pawnshops, general merchandise stores, and sporting goods stores) were visited. Investigators posed as customers interested in buying a handgun. During the interview, investigators expressed concern that as the parent of a 4-year-old child, they needed suggestions about keeping their child safe with a gun in the home. Information collected included basic dealer demographics, opinions on whether a 4-year-old child could pull a handgun trigger, handgun safety advice and recommendations, and the type of safety devices and handgun safety educational materials that were available in the store. RESULTS: There were 96 visits made to gun dealers. The typical salesperson was a man who appeared to be older than 40 years. Trigger locks were the most common safety devices available. When asked what a consumer should know about purchasing a handgun, 85% of salespeople did not mention safe storage. Only 9 (9%) offered advice that included all of the following: keeping the gun securely locked, keeping the gun unloaded, and storing the gun separately from the ammunition. One third answered "no" or "don't know" or "uncertain" when asked if a 4-year-old could pull the trigger. The majority (92%) did not have any handgun safe storage educational materials on site. CONCLUSIONS: Salespeople offered potential buyers little or no education about safe storage of handguns. The information provided was often inconsistent with the recommendations of the American Academy of Pediatrics.