A genetic model to investigate drug-target interactions at the ribosomal decoding site.

Recent advances in X-ray crystallography have greatly contributed to the understanding of the structural interactions between aminoglycosides and the ribosomal decoding site. Efforts to genetically probe the functional relevance of proposed drug-nucleotide contacts have in part been hampered by the presence of multiple rRNA operons in most bacteria. A derivative of the Gram-positive Mycobacterium smegmatis was rendered single rRNA operon allelic by means of gene inactivation techniques. In this system, genetic manipulation of the single chromosomal rRNA operon results in cells carrying homogeneous populations of mutant ribosomes. An exhaustive mutagenesis study of the ribosomal A site has been performed to define the importance of individual drug-nucleotide contacts. Mutational alterations in the M. smegmatis decoding site are discussed here, comparing the results with those obtained in other organisms. Implications for the selectivity of antimicrobial agents and for the fitness cost of resistance mutations are addressed.

Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects.

We examined the relation of multivitamin intake in general, and folic acid in particular, to the risk of neural tube defects in a cohort of 23,491 women undergoing maternal serum alpha-fetoprotein screening or amniocentesis around 16 weeks of gestation. Complete questionnaires and subsequent pregnancy outcome information was obtained in 22,776 pregnancies, 49 of which ended in a neural tube defect. The prevalence of neural tube defect was 3.5 per 1000 among women who never used multivitamins before or after conception or who used multivitamins before conception only. The prevalence of neural tube defects for women who used folic acid-containing multivitamins during the first 6 weeks of pregnancy was substantially lower--0.9 per 1000 (prevalence ratio, 0.27; 95% confidence interval, 0.12 to 0.59 compared with never users). For women who used multivitamins without folic acid during the first 6 weeks of pregnancy and women who used multivitamins containing folic acid beginning after 7 or more weeks of pregnancy, the prevalences were similar to that of the nonusers and the prevalence ratios were close to 1.0.

Predictive values, relative risks, and overall benefits of high and low maternal serum alpha-fetoprotein screening in singleton pregnancies: new epidemiologic data.

In a prospective study of maternal serum alpha-fetoprotein screening for both high and low values, we assessed the overall predictive value, sensitivity, specificity and relative risks for congenital defects and complications of pregnancy. Among 13,486 women with singleton pregnancies interviewed at the time of screening (15 to 20 weeks of gestation), 3.9% had high and 3.4% had low values. A high maternal serum alpha-fetoprotein value was associated with the following adverse outcomes: neural tube defects (relative risk = 224), other major congenital defects (relative risk = 4.7), fetal deaths (relative risk = 8.1), neonatal death (relative risk = 4.7), low birth weight (relative risk = 4.0), newborn complications (relative risk = 3.6), oligohydramnios (relative risk = 3.4), abruptio placentae (relative risk = 3.0) and preeclamptic toxemia (relative risk = 2.3). A low maternal serum alpha-fetoprotein value was associated with chromosomal defects (relative risk = 11.6) for fetal death (relative risk = 3.3). Either high or low maternal serum alpha-fetoprotein values were associated with 34.2% of all major congenital defects, 19.1% of all stillbirths and fetal-neonatal deaths, 11.0% of major pregnancy complications, and 15.9% of serious newborn complications. Maternal serum alpha-fetoprotein screening provides an important adjunctive tool for the identification of high-risk pregnancy and adverse neonatal outcome.