Secondary cell death via gap junctions (GJs) plays a role in the propagation of neuronal loss under a number of degenerative disorders.Here, we examined the role of GJs in neuronal death in the retina, which has arguably the most diverse expression of GJs in the CNS. Initially, we induced apoptotic death by injecting single retinal ganglion cells and glia with cytochrome C and found that this resulted in the loss of neighboring cells to which they were coupled via GJs. We next found that pharmacological blockade of GJs eradicated nearly all amacrine cell loss and reduced retinal ganglion cell loss by ϳ70% after induction of either excitotoxic or ischemic insult conditions. These data indicate that the GJ-mediated secondary cell death was responsible for the death of most cells. Whereas genetic deletion of the GJ subunit Cx36 increased cell survivability by ϳ50% under excitotoxic condition, cell loss in Cx45 knock-out mouse retinas was similar to that seen in wild-type mice. In contrast, ablation of Cx45 reduced neuronal loss by ϳ50% under ischemic insult, but ablation of Cx36 offered no protection. Immunolabeling of the connexins showed differential changes in protein expression consistent with their differing roles in propagating death signals under the two insults. These data indicate that secondary cell death is mediated by different cohorts of GJs dependent on the connexins they express and the type of initial insult. Our results suggest that targeting specific connexins offers a novel therapeutic strategy to reduce progressive cell loss under different neurodegenerative conditions.
Background: Although serum measures of micronutrients are more specific than questionnaires in quantifying nutritional status, the reliability of serum measures depends on between- and within-person variability of circulating micronutrient levels. The extent to which multiple samples per person might improve reliability is useful information for planning studies and interpreting results. Methods: We analyzed levels of 25 micronutrients in serum samples taken from 381 Hawaii women at 4-month intervals. For all subjects and for subjects at the low and high end of the micronutrient distributions, we calculated inter- and intraindividual variability, reliability coefficients, and the number of measurements required to limit attenuation in estimated parameters (ie, to keep estimates close to their true values). Results: For 18 of the 25 micronutrients, a single measurement provided an estimate within 20% of the true value. For regression coefficients, 2 measurements were needed to limit attenuation to no more than 20% for nearly half of the micronutrients. To achieve no more than 10% attenuation, the number of measurements required ranged from 2 to 10 for correlation and from 3 to 20 for regression coefficients. To achieve no more than 5% attenuation, the corresponding ranges were 3 to 21 for correlation and 6 to 42 regression coefficients. In general, more measurements were required for adequate characterization of subjects with relatively high levels of micronutrients than for subjects with lower levels. Conclusions: Our analysis suggests that 2 or 3 blood measurements are enough to limit attenuation of regression coefficients within 20% of the true value for most carotenoids and tocopherols. For 10% attenuation or less, 4 or more micronutrient measurements may be needed.
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