Hyperammonemia following intravenous valproate loading.

BACKGROUND: Valproic acid (VPA) has been associated with hyperammonemia with and without encephalopathy. We report the frequent but transient nature of hyperammonemia following intravenous (IV) administration of loading doses of VPA. METHODS: Forty participants received a VPA loading dose (20 or 30 mg/kg) at 6 or 10mg/kg/min. All participants were monitored for signs of systemic and local intolerance. Serum VPA level, ammonia, complete blood count, bilirubin, transaminases, pancreatic enzymes, and level of consciousness were obtained at baseline, 1 and 24h after administration. Changes in ammonia levels were assessed using repeated-measures ANOVA. RESULTS: Asymptomatic hyperammonemia occurred in 30 of 40 participants at 1h post-VPA infusion. Majority of the participants (66%) demonstrated decreasing ammonia concentrations at 24h post-infusion. Multivariable repeated-measures analysis indicates the lack of influence of VPA dose (p=0.8), VPA levels (p>0.24, all time points), infusion rate (p=0.41) and gender (0.68) on ammonia levels across time. Age (p=0.015), time since dosing (p=0.017) and co-therapy with enzyme-inducing antiepileptic drugs (p=0.035) were significant predictors of changes in ammonia levels. CONCLUSIONS: Hyperammonemia is a frequent but transient finding following intravenous administration of loading doses of VPA. Hyperammonemia was not associated with alteration in consciousness or hepatic transaminases.

An adaptive alpha spending algorithm improves the power of statistical inference in microarray data analysis.

The adaptive alpha-spending algorithm incorporates additional contextual evidence (including correlations among genes) about differential expression to adjust the initial p-values to yield the alpha-spending adjusted p-values. The alpha-spending algorithm is named so because of its similarity with the alpha-spending algorithm in interim analysis of clinical trials in which stage-specific significance levels are assigned to each stage of the clinical trial. We show that the Bonferroni correction applied to the alpha-spending adjusted p-values approximately controls the Family Wise Error Rate under the complete null hypothesis. Using simulations we also show that the use of the alpha spending algorithm yields increased power over the unadjusted p-values while controlling FDR. We found the greater benefits of the alpha spending algorithm with increasing sample sizes and correlation among genes. The use of the alpha spending algorithm will result in microarray experiments that make more efficient use of their data and may help conserve resources.

Influences of calorie restriction and age on energy expenditure in the rhesus monkey.

Caloric restriction (CR) is known to retard the aging process, and a marker of aging is decreased energy expenditure (EE). To assess longitudinal effects of CR on EE in rhesus monkeys (Macaca mulatta), data from 41 males (M) and 26 females (F) subjected to 9 or 15 yr of CR were studied. EE and body composition of monkeys 11-28 yr of age were measured using indirect calorimetry and dual X-ray absorptiometry. Total EE (24-h EE) was divided into daytime (day EE), nighttime (night EE), and daytime minus nighttime (D - N EE). M calorie-restricted monkeys showed a lower 24-h EE (means +/- SD = 568 +/- 96 kcal/day, P < 0.0001) than controls (C; 630 +/- 129 kcal/day). Calorie-restricted M had a lower night EE (difference = 36 kcal P < 0.0001) compared with C M, but after adjusting for FFM and FM, night EE was not different between calorie-restricted and C males (P = 0.72). The 24-h EE decreased with age (13 kcal decrease/yr, P < 0.0001), but there was no difference between CR and C. Adjusted for FFM and FM, D - N EE decreased with age (9 kcal/yr, P < 0.0001), with no interaction with age (P = 0.72). The F were compared with age-matched M selected from the male cohort. F had a lower 24-h EE (496 +/- 84 kcal/day) than M (636 +/- 139 kcal/day) (P < 0.0001). Adjusting for FFM and FM, night EE was lower in F compared with M (difference = 18 kcal, P = 0.077). Night EE did not differ between calorie-restricted and C younger monkeys after adjusting for FFM and FM. In conclusion, CR did not alter the age-related decrease in EE with CR.