ABSTRACT
Gallbladder adenocarcinomas from patients in two high-prevalence areas, Niigata (Japan) and Santiago (Chile), were analyzed for acquired mutations in exons 5-8 of the p53 tumor suppressor gene, and the characteristics of p53 alterations in the two groups were compared. Of 42 tumors, 22 (52.4%) harbored 25 alterations identified by PCR amplification and direct sequencing (13 of 22 tumors from Niigata and 12 of 20 tumors from Santiago). All alterations were single base pair substitutions, 20 (80%) leading to an amino acid substitution or a chain-termination signal, and 5 (20%) were silent. Immunohistochemically, 55 of 84 cases (65.5%) showed overexpression of p53 protein, with no significant difference in frequency between the two areas. Missense mutations correlated highly with overexpression of the p53 protein (93.4%). Mutations of p53 occurred in all four exons examined, most commonly in exon 5, but in no particular "hot spot." In base-change spectra, all 12 mutations from Santiago showed transitions, with 4 arising at the CpG dinucleotide (33.3%). In contrast, no such transition was found at CpG sites in Niigata, and 4 of 13 mutations (30.8%) were transversions. The data indicated that p53 mutations are highly important in carcinogenesis in the gallbladder. In addition, the difference in p53 mutational spectra in Niigata and Santiago indicate a likely regional difference in mutagenesis.
Subject(s)
Carcinoma/epidemiology , Carcinoma/genetics , Gallbladder Neoplasms/epidemiology , Gallbladder Neoplasms/genetics , Mutation/genetics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Aged, 80 and over , Carcinoma/pathology , Chile/epidemiology , DNA Mutational Analysis , DNA, Neoplasm/analysis , Female , Gallbladder Neoplasms/pathology , Humans , Immunohistochemistry , Incidence , Japan/epidemiology , Male , Middle Aged , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Protein p53/biosynthesisABSTRACT
Steady-state pharmacokinetics of valproic acid (VPA) with or without other antiepileptic drug (AED) treatment were studied in 37 children. Children (N = 16) receiving multiple AED therapy had a higher clearance (23.5 vs 13.0 ml/hr/kg, P less than 0.001), larger volume of distribution (0.30 vs 0.22 L/kg, P less than 0.01), and shorter half-life (9.4 vs 12.3 hours, P less than 0.01) than did those (n = 21) receiving VPA only. Inverse correlations of age with clearance (R = -0.559, P less than 0.01) and apparent volume of distribution of VPA (r = -0.490, P less than 0.05) were observed in children receiving monotherapy. In determining the dose and dosing interval of VPA, consider a possible alteration in the pharmacokinetics relating to age and other concurrent AED therapy.