Menthol Enhances the Desensitization of Human α3ß4 Nicotinic Acetylcholine Receptors.

The α3ß4 nicotinic acetylcholine receptor (nAChR) subtype is widely expressed in the peripheral and central nervous systems, including in airway sensory nerves. The nAChR subtype transduces the irritant effects of nicotine in tobacco smoke and, in certain brain areas, may be involved in nicotine addiction and/or withdrawal. Menthol, a widely used additive in cigarettes, is a potential analgesic and/or counterirritant at sensory nerves and may also influence nicotine's actions in the brain. We examined menthol's effects on recombinant human α3ß4 nAChRs and native nAChRs in mouse sensory neurons. Menthol markedly decreased nAChR activity as assessed by Ca(2+) imaging, (86)Rb(+) efflux, and voltage-clamp measurements. Coapplication of menthol with acetylcholine or nicotine increased desensitization, demonstrated by an increase in the rate and magnitude of the current decay and a reduction of the current integral. These effects increased with agonist concentration. Pretreatment with menthol followed by its washout did not affect agonist-induced desensitization, suggesting that menthol must be present during the application of agonist to augment desensitization. Notably, menthol acted in a voltage-independent manner and reduced the mean open time of single channels without affecting their conductance, arguing against a simple channel-blocking effect. Further, menthol slowed or prevented the recovery of nAChRs from desensitization, indicating that it probably stabilizes a desensitized state. Moreover, menthol at concentrations up to 1 mM did not compete for the orthosteric nAChR binding site labeled by [(3)H]epibatidine. Taken together, these data indicate that menthol promotes desensitization of α3ß4 nAChRs by an allosteric action.

Pancreaticoduodenectomy in Florida: do 20-year trends document the salutary benefits of centralization of care?

BACKGROUND: Concentration of care has been promoted as fostering superior outcomes. This study was undertaken to determine if the concentration of care is occurring in Florida for a pancreaticoduodenectomy, and if so, is it having a salutary effect. METHODS: The data for a pancreaticoduodenectomy were obtained from the Florida Agency for Health Care Administration for three 3-year periods:1992-1994, 2001-2003, 2010-2012; data were sorted by surgeon volume of pancreaticoduodenectomy during these periods and correlated with post-operative length of stay (LOS), in-hospital mortality and hospital charges (adjusted to 2012 dollars). RESULTS: Relative to 1992-1994, in 2010-2012 46% fewer surgeons performed 115% more pancreaticoduodenectomies with significant reductions in LOS and in-hospital mortality, and higher charges (P < 0.001 for each). From 1992-1994 to 2010-2012 there was an 18-fold increase in the number of pancreaticoduodenectomies by surgeons completing ≥ 12 per year (n = 45 to n = 806, respectively). During 2010-2012, the more frequently surgeons performed a pancreaticoduodenectomy, the shorter LOS, the lower in-hospital mortality, the greater the likelihood of discharge home and the lower the hospital charges (P < 0.03 for each). CONCLUSIONS: Over the last 20 years, the concentration of care has occurred in Florida with substantially fewer surgeons undertaking many more pancreaticoduodenectomies with dramatic improvements in LOS and in-hospital mortality, albeit with increased hospital charges.

Regional differences for pancreaticoduodenectomy in Florida: Location matters.

INTRODUCTION: Regionalization of care raises potential for differences in cost of care and outcome. This study was undertaken to determine if costs and outcome after pancreaticoduodenectomy vary by region in Florida, and whether costs and outcome are related. METHODS: Inpatient data for pancreaticoduodenectomy in Florida during 2010-2012 were obtained from the Florida Agency for Health Care Administration. Seven geographically different regions were designated based on "cost of living index" and "urban to rural population ratio". Hospital costs, LOS, in-hospital mortality, and the frequency with which surgeons performed pancreaticoduodenectomy were evaluated for these regions. RESULTS: Median hospital costs for pancreaticoduodenectomy by region ranged from $101,436-$214,971. Median hospital costs by region correlated positively with LOS (p < 0.0001) and in-hospital mortality (p < 0.0001), and negatively with the frequency of pancreaticoduodenectomies performed by high-volume surgeons (p < 0.0001). CONCLUSIONS: There are regional differences for hospital costs and outcome with pancreaticoduodenectomy in Florida. Regions with lower costs had more pancreaticoduodenectomies performed by high-volume surgeons, shorter LOS, and lower in-hospital mortality rates. Regional differences in cost and quality-of-care need to be studied and abrogated to provide uniform optimal care.