Context.-Human neurodevelopmental consequences of exposure to methylmercury (MeHg) from eating fish remain a question of public health concern. Objective.-To study the association between MeHg exposure and the developmental outcomes of children in the Republic of Seychelles at 66 months of age. Design.-A prospective longitudinal cohort study. Participants.-A total of 711 of 779 cohort mother-child pairs initially enrolled in the Seychelles Child Development Study in 1989. Setting.-The Republic of Seychelles, an archipelago in the Indian Ocean where 85% of the population consumes ocean fish daily. Main Outcome Measures.-Prenatal and postnatal MeHg exposure and 6 age-appropriate neurodevelopmental tests: the McCarthy Scales of Children's Abilities, the Preschool Language Scale, the Woodcock-Johnson Applied Problems and Letter and Word Recognition Tests of Achievement, the Bender Gestalt test, and the Child Behavior Checklist. Results.-The mean maternal hair total mercury level was 6.8 ppm and the mean child hair total mercury level at age 66 months was 6.5 ppm. No adverse outcomes at 66 months were associated with either prenatal or postnatal MeHg exposure. Conclusion.-In the population studied, consumption of a diet high in ocean fish appears to pose no threat to developmental outcomes through 66 months of age.

No abstract

Background-The efficacy of nitroglycerin (NTG) as a vasodilator is limited by tolerance, which develops shortly after treatment begins. In vascular smooth muscle cells (VSMCs), NTG is denitrated to form nitric oxide (NO), which activates guanylyl cyclase and generates cGMP. cGMP plays a key role in nitrate-induced vasodilation by reducing intracellular Ca 2ϩ concentration. Therefore, one possible mechanism for development of nitrate tolerance would be increased activity of the cGMP phosphodiesterase (PDE), which decreases cGMP levels. Methods and Results-To test this hypothesis, rats were made tolerant by continuous infusion of NTG for 3 days (10 g · kg Ϫ1 · min Ϫ1 SC) with an osmotic pump. Analysis of PDE activities showed an increased function of Ca 2ϩ /calmodulin (CaM)-stimulated PDE (PDE1A1), which preferentially hydrolyzes cGMP after NTG treatment. Western blot analysis for the Ca 2ϩ /CaM-stimulated PDE revealed that PDE1A1 was increased 2.3-fold in NTG-tolerant rat aortas. Increased PDE1A1 was due to mRNA upregulation as measured by relative quantitative reverse transcription-polymerase chain reaction. The PDE1-specific inhibitor vinpocetine partially restored the sensitivity of the tolerant vasculature to subsequent NTG exposure. In cultured rat aortic VSMCs, angiotensin II (Ang II) increased PDE1A1 activity, and vinpocetine blocked the effect of Ang II on decrease in cGMP accumulation. Conclusions-Induction of PDE1A1 in nitrate-tolerant vessels may be one mechanism by which NO/cGMP-mediated vasodilation is desensitized and Ca 2ϩ -mediated vasoconstriction is supersensitized. Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic approach to limit nitrate tolerance.