pi-Face selectivities in nucleophilic additions to 2-endo aryl-norbornan-7-ones: The role of through-space electrostatic interactions

Experimental diastereoselectivities in hydride reduction of 2-endo-arylnorbornan-7-ones and computed transition state energetics reveal that the facial selectivity in these systems is predominantly determined by repulsions between the approaching nucleophile and the electron cloud of the aryl ring

Cellular mechanisms underlying the increased disease severity seen for patients with long QT syndrome caused by compound mutations in KCNQ1

The KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) gene encodes the Kv7.1 potassium channel which forms a complex with KCNE1 (potassium voltage-gated channel Isk-related family member 1) in the human heart to produce the repolarizing IKs (slow delayed rectifier potassium current). Mutations in KCNQ1 can perturb IKs function and cause LQT1 (long QT syndrome type 1). In LQT1, compound mutations are relatively common and are associated with increased disease severity. LQT1 compound mutations have been shown to increase channel dysfunction, but whether other disease mechanisms, such as defective channel trafficking, contribute to the increase in arrhythmic risk has not been determined. Using an imaging-based assay we investigated the effects of four compound heterozygous mutations (V310I/R594Q, A341V/P127T, T391I/Q530X and A525T/R518X), one homozygous mutation (W248F) and one novel compound heterozygous mutation (A178T/K422fs39X) (where fs denotes frameshift) on channel trafficking. By analysing the effects in the equivalent of a homozygous, heterozygous and compound heterozygous condition, we identify three different types of behaviour. A341V/P127T and W248F/W248F had no effect, whereas V310I/R594Q had a moderate, but not compound, effect on channel trafficking. In contrast, T391I/Q530X, A525T/R518X and A178T/K422fs39X severely disrupted channel trafficking when expressed in compound form. In conclusion, we have characterized the disease mechanisms for six LQT1 compound mutations and report that, for four of these, defective channel trafficking underlies the severe clinical phenotype.</jats:p

Maternal health in pregnancy and associations with adverse birth outcomes: evidence from Growing Up in New Zealand

Objective: To examine prospectively multiple indicators of pregnancy health and associations with adverse birth outcomes within a large, diverse sample of contemporary women.Design: A cohort of pregnant women who gave birth during 2009–10.Population: We enrolled a sample of 6822 pregnant New Zealand (NZ) women: 11% of all births in NZ during the recruitment period.Methods: We analysed a number of maternal health indicators and behaviours during pregnancy in relation to birth outcomes using multivariable logistic regression. Associations were described using adjusted odds ratios and 95% confidence intervals.Main outcome measures: Three birth outcomes, low birth weight (LBW), pre-term birth (PTB) and delivery type, were measured via linkage with maternity hospital perinatal databases. Small for gestational age (SGA) was then defined as below the 10th percentile by week of gestation.Results: Modelling of birth outcomes after adjusting for confounders indicated patterns of increased risk of LBW and PTB for women who smoke, have elevated pre-pregnancy body mass index (BMI), or with insufficient pregnancy weight gain. SGA was associated with maternal smoking, alcohol use, insufficient weight gain and nausea and vomiting during pregnancy. Risk of caesarean section was associated with having a diagnosed illness before pregnancy, elevated BMI, greater pregnancy weight gain and less pregnancy exercise. Number of risk factor variables were then used to model birth outcomes. Women with multiple risk factors were at increased risk compared with those who had no risk factors.Conclusions: Women with multiple health risks are at particular risk of adverse birth outcomes