UI - 97479605 TI - Higher neonatal cerebral blood flow correlates with worse childhood neurologic outcome. AB - Cerebral blood flow (CBF) in newborn infants is often below levels necessary to sustain brain viability in adults. Controversy exists regarding the effects of such low CBF on subsequent neurologic function. We determined the current childhood neurologic status and IQ in 26 subjects who had measurements of CBF performed with PET in the neonatal period between 1983 and 1989 as part of a study of hypoxic-ischemic encephalopathy. Follow-up information at ages 4 to 12 years was obtained on all 26 subjects. Ten subjects had died. All 16 survivors underwent clinical neurologic evaluation, and 14 also underwent intelligence testing. Eight had abnormal clinical neurologic evaluations; eight were normal. The mean neonatal CBF in those with abnormal childhood neurologic outcome was significantly higher than in those with normal childhood neurologic outcome (35.64 +/- 11.80 versus 18.26 +/- 8.62 mL 100 g(-1) min(-1), t = 3.36, p = 0.005). A significant negative correlation between neonatal CBF and childhood IQ was demonstrated (Spearman rank correlation r = -0.675, p = 0.008). Higher CBF was associated with lower IQ. The higher CBF in subjects with worse neurologic and intellectual outcome may reflect greater loss of cerebrovascular autoregulation or other vascular regulatory mechanisms due to more severe brain damage. UI - 98018928 TI - Bupivacaine inhibition of L-type calcium current in ventricular cardiomyocytes of hamster. AB - BACKGROUND: The local anesthetic bupivacaine is cardiotoxic when accidentally injected into the circulation. Such cardiotoxicity might involve an inhibition of cardiac L-type Ca2+ current (ICa,L). This study was designed to define the mechanism of bupivacaine inhibition of ICa,L. METHODS: Cardiomyocytes were enzymatically dispersed from hamster ventricles. Certain voltage- and time-dependencies of ICa,L were recorded using the whole-cell patch clamp method in the presence and absence of different concentrations of bupivacaine. RESULTS: Bupivacaine, in a concentration-dependent manner (10-300 microM), tonically inhibited the peak amplitude of ICa,L. The inhibition was characterized by an increase in the time of recovery from inactivation and a negative-voltage shift of the steady-state inactivation curve. The inhibition was shown to be voltage-dependent, and the peak amplitude of ICa,L could not be restored to control levels by a wash from bupivacaine. CONCLUSIONS: The inhibition of ICa,L appears, in part, to result from bupivacaine predisposing L-type Ca channels to the inactivated state. Data from washout suggest that there may be two mechanisms of inhibition at work. Bupivacaine may bind with low affinity to the Ca channel and also affect an unidentified metabolic component that modulates Ca channel function. UI - 97443327 TI - Formation of formate and hydrogen, and flux of reducing equivalents and carbon in Ruminococcus flavefaciens FD-1. AB - A pathway for conversion of the metabolic intermediate phosphoenolpyruvate (PEP) and the formation of acetate, succinate, formate, and H2 in the anaerobic cellulolytic bacterium Ruminococcus flavefaciens FD-1 was constructed on the basis of enzyme activities detected in extracts of cells grown in cellulose- or cellobiose-limited continuous culture. PEP was converted to acetate and CO2 (via pyruvate kinase, pyruvate dehydrogenase, and acetate kinase) or carboxylated to form succinate (via PEP carboxykinase, malate dehydrogenase, fumarase, and fumarate reductase). Lactate was not formed even during rapid growth (batch culture, mu = 0.35/h). H2 was formed by a hydrogenase rather than by cleavage of formate, and 13C-NMR and 14C-exchange reaction data indicated that formate was produced by CO2 reduction, not by a cleavage of pyruvate. The distribution of PEP into the acetate and succinate pathways was not affected by changing extracellular pH and growth rates within the normal growth range. However, increasing growth rate from 0.017/h to 0.244/h resulted in a shift toward formate production, presumably at the expense of H2. This shift suggested that reducing equivalents could be balanced through formate or H2 production without affecting the yields of the major carbon-containing fermentation endproducts. UI - 97408530 TI - Approximate confidence intervals for heritability from method R estimates. AB - Method R estimates of heritability (h2) and associated confidence intervals (CI) were obtained from simulated data using a single trait, direct effects, full animal model, with 50% subsampling. Five hundred data sets were simulated for each of five levels of h2 (.10, .20, .30, .40, and .50) and two types of pedigree structure (random pedigree structure [N = 2,000] that varied over simulations, or the pedigree structure from a real data set [N = 2,644] that was constant for all simulations). The first 10, 20, and all 50 h2 estimates were used to obtain 80, 90, 95, and 99% CI for each data set. The variance of h2 estimates within data sets approximated the sampling variance of the h2 estimates. The Box-Cox transformation was used to normalize the distribution of estimates from each data set. Confidence intervals were computed on the transformed scale as CI = mu +/- (T x sigma), where mu and sigma = the mean and SD of the N transformed h2 estimates, respectively, and T = the critical value from the T distribution for a 1-alpha CI, with df = N-1. Upper and lower CI bounds were converted back to the original scale by reversing the transformation. The percentages of CI containing the true h2 value, pooled across all levels of h2, types of pedigree, and number of estimates used to obtain CI, for 80, 90, 95, and 99% CI were 81.14, 90.96, 95.27, and 98.76%, respectively. These results suggested that Method R h2 estimates can be used to obtain reliable CI. UI - 97453431 TI - rhDNase as an example of recurrent event analysis. AB - We consider counting process methods for analysing time-to-event data with multiple or recurrent outcomes, using the models developed by Anderson and Gill, Wei, Lin and Weissfeld and Prentice, Williams and Peterson. We compare the methods, and show how to implement them using popular statistical software programs. By analysing three data sets, we illustrate the strengths and pitfalls of each method. The first example is simulated and involves the effect of a hidden covariate. The second is based on a trial of gamma interferon, and behaves remarkably like the first. The third and most interesting example involves both multiple events and discontinuous intervals at risk, and the three approaches give dissimilar answers. We recommend the AG and marginal models for the analysis of this type of data.