Natural selection on genes that underlie human disease susceptibility.

What evolutionary forces shape genes that contribute to the risk of human disease? Do similar selective pressures act on alleles that underlie simple versus complex disorders [1-3]? Answers to these questions will shed light onto the origin of human disorders (e.g., [4]) and help to predict the population frequencies of alleles that contribute to disease risk, with important implications for the efficient design of mapping studies [5-7]. As a first step toward addressing these questions, we created a hand-curated version of the Mendelian Inheritance in Man database (OMIM). We then examined selective pressures on Mendelian-disease genes, genes that contribute to complex-disease risk, and genes known to be essential in mouse by analyzing patterns of human polymorphism and of divergence between human and rhesus macaque. We found that Mendelian-disease genes appear to be under widespread purifying selection, especially when the disease mutations are dominant (rather than recessive). In contrast, the class of genes that influence complex-disease risk shows little signs of evolutionary conservation, possibly because this category includes targets of both purifying and positive selection.

Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery.

BACKGROUND: Studies conducted in adults undergoing surgery reported a beneficial effect of oral melatonin administered before surgery. There is a paucity of such data in children undergoing anesthesia and surgery. METHODS: Children undergoing surgery were randomly assigned to receive preoperatively oral midazolam 0.5 mg/kg or oral melatonin 0.05 mg/kg, 0.2 mg/kg, or 0.4 mg/kg. The primary outcome of the study was preoperative anxiety (Yale Preoperative Anxiety Scale). The secondary outcomes were the children's compliance with induction (Induction Compliance Checklist), emergence behavior (Keegan scale), and parental anxiety (State-Trait Anxiety Inventory). RESULTS: Repeated measures ANOVA showed that children who received melatonin at any of the three doses were more anxious compared with children who received midazolam (P < 0.001). Parental anxiety did not differ on the basis of the experimental condition (P = ns). The melatonin groups showed a dose-response effect on emergence behavior. Children who received melatonin developed less emergence delirium compared with those who received midazolam (P < 0.05), and the effect was dose related; the incidence after 0.05 mg/kg melatonin was 25.0%, incidence after 0.2 mg/kg melatonin was 8.3%, and incidence after 0.4 mg/kg melatonin was 5.4%. CONCLUSIONS: Midazolam is more effective than melatonin in reducing children's anxiety at induction of anesthesia. Melatonin showed a direct dose-dependent effect on emergence delirium.

Eighteen Years of Respiratory Syncytial Virus Surveillance: Changes in Seasonality and Hospitalization Rates in Southwestern Alaska Native Children.

BACKGROUND: Alaska Native infants from the Yukon-Kuskokwim Delta (YKD) experienced respiratory syncytial virus (RSV) hospitalization rates 5 times higher and an RSV season twice as long as the general US infant population. We describe trends in hospitalization rates and seasonality during 18 years of continuous RSV surveillance in this population and explore contributions of climate and sociodemographic factors. METHODS: We abstracted clinical and RSV test information from computerized medical records at YKD Regional Hospital and Alaska Native Medical Center from 1994 to 2012 to determine hospitalization rates and RSV season timing. Descriptive village and weather data were acquired through the US Census and Alaska Climate Research Center, University of Alaska, Fairbanks, respectively. RESULTS: During 1994-2012, YKD infant RSV hospitalization rates declined nearly 3-fold, from 177 to 65 per 1000 infants/yr. RSV season onset shifted later, from mid October to late December, contributing to a significantly decreased season duration, from 30 to 11 weeks. In a multivariate analysis, children from villages with more crowded households and lacking plumbed water had higher rates of RSV hospitalizations (relative rate, 1.17; P = 0.0005 and relative rate, 1.45; P = 0.0003). No association of temperature or dew point was found with the timing or severity of RSV season. CONCLUSIONS: Although the RSV hospitalization rate decreased 3-fold, YKD infants still experience a hospitalization rate 3-fold higher than the general US infant population. Overcrowding and lack of plumbed water were associated with RSV hospitalization. Dramatic changes occurred in RSV seasonality, not explained by changes in climate.