Epidemiology of vertically transmitted HIV-1 infection in Switzerland: Results of a nationwide prospective study

A nationwide study involving 286 children of human immunodeficiency virus (HIV)-infected mothers living in Switzerland has been performed with the participation of all paediatricians interested in HIV infection in the country. Of these children 201 could be followed up prospectively from birth up to a median age of 22 months. Prevalence of HIV infection in Swiss parturients was estimated at 0.1% and apparently remained stable from 1986 to 1989. Vertical transmission rate was estimated at 14%–20%. Variables of maternal or perinatal history were not associated with transmission rate. Transmission to pairs of siblings of the same mothers was discordant in 33% (6 of 18), with always the elder sibling being infected. Postneonatal mortality in infants of HIV-infected mothers followed up from birth was increased 15-fold over the general population with a very high incidence (2 in 100) of sudden infant death apparently unrelated to HIV infection.A complete list of all the participants in the study is available on request     

Conversion of Laparoscopic Cholecystectomy to Open Cholecystectomy in Acute Cholecystitis: Artificial Neural Networks Improve the Prediction of Conversion

Laparoscopic cholecystectomy is now also performed for acute cholecystitis. In the presence of inflammatory conditions, technical difficulties leading to conversion to open cholecystectomy may occur and overshadow the advantages of the laparoscopic approach. Factors associated with these undue events combined with techniques capable of learning from them may help in determining when to completely avoid the laparoscopic procedure. In this study we determined predictors of conversion in acute cholecystitis and tested their predictive ability by means of statistical multivariate analysis and artificial neural networks. Between January 1994 and February 1997, 225 patients underwent laparoscopic cholecystectomy for acute cholecystitis. Preoperative and operative data were prospectively collected on standardized forms. The first 180 laparoscopically approached cases entered the training set, which was learned by both the statistical and the artificial neural networks methods. Conversion was first studied in relation to a set of preoperative data. Prediction models were then fitted by both of these methods. The last 45 operated cases, which remained unknown to the learning systems, served for testing the fitted models. The forward stepwise logistic regression technique, the forward stepwise linear discriminant analysis, and the artificial neural networks method enabled positive prediction of conversion in 0%, 27%, and 100% of the cases, and a negative prediction in 80%, 85.5%, and 97% respectively, in the training set. A positive prediction of conversion in 0%, 25%, and 67% of the cases, and a negative prediction in 82%, 88%, and 94%, respectively, in the untrained, validation set of patients. An artificial neural networks based model provides a practical tool for the prediction of successful laparoscopic cholecystectomies and their conversion. The high degree of certainty of prediction in untrained cases reveals its potential, and justifies, under appropriate conditions, the complete avoidance of laparoscopy and turning directly to open cholecystectomy.     

Structural requirements for inhibition of the neuronal nitric oxide synthase (NOS-I): 3D-QSAR analysis of 4-oxo- and 4-amino-pteridine-based inhibitors

The family of homodimeric nitric oxide synthases (NOS I-III) catalyzes the generation of the cellular messenger nitric oxide (NO) by oxidation of the substrate L-arginine. The rational design of specific NOS inhibitors is of therapeutic interest in regulating pathological NO levels associated with sepsis, inflammatory, and neurodegenerative diseases. The cofactor (6R)-5,6,7,8-tetrahydrobiopterin (H(4)Bip) maximally activates all NOSs and stabilizes enzyme quaternary structure by promoting and stabilizing dimerization. Here, we describe the synthesis and three-dimensional (3D) quantitative structure-activity relationship (QSAR) analysis of 65 novel 4-amino- and 4-oxo-pteridines (antipterins) as inhibitors targeting the H(4)Bip binding site of the neuronal NOS isoform (NOS-I). The experimental binding modes for two inhibitors complexed with the related endothelial NO synthase (NOS-III) reveal requirements of biological affinity and form the basis for ligand alignment. Different alignment rules were derived by building other compounds accordingly using manual superposition or a genetic algorithm for flexible superposition. Those alignments led to 3D-QSAR models (comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA)), which were validated using leave-one-out cross-validation, multiple analyses with two and five randomly chosen cross-validation groups, perturbation of biological activities by randomization or progressive scrambling, and external prediction. An iterative realignment procedure based on rigid field fit was used to improve the consistency of the resulting partial least squares models. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which correspond to experimentally determined NOS-II and -III H(4)Bip binding site topologies as well as to the NOS-I homology model binding site in terms of steric, electrostatic, and hydrophobic complementarity. These models provide clear guidelines and accurate activity predictions for novel NOS-I inhibitors.