Bayesian network analysis of resistance pathways against HIV-1 protease inhibitors.

Interpretation of Human Immunodeficiency Virus 1 (HIV-1) genotypic drug resistance is still a major challenge in the follow-up of antiviral therapy in infected patients. Because of the high degree of HIV-1 natural variation, complex interactions and stochastic behaviour of evolution, the role of resistance mutations is in many cases not well understood. Using Bayesian network learning of HIV-1 sequence data from diverse subtypes (A, B, C, F and G), we could determine the specific role of many resistance mutations against the protease inhibitors (PIs) nelfinavir (NFV), indinavir (IDV), and saquinavir (SQV). Such networks visualize relationships between treatment, selection of resistance mutations and presence of polymorphisms in a graphical way. The analysis identified 30N, 88S, and 90M for nelfinavir, 90M for saquinavir, and 82A/T and 46I/L for indinavir as most probable major resistance mutations. Moreover we found striking similarities for the role of many mutations against all of these drugs. For example, for all three inhibitors, we found that the novel mutation 89I was minor and associated with mutations at positions 90 and 71. Bayesian network learning provides an autonomous method to gain insight in the role of resistance mutations and the influence of HIV-1 natural variation. We successfully applied the method to three protease inhibitors. The analysis shows differences with current knowledge especially concerning resistance development in several non-B subtypes.

Analysis of HIV-1 pol sequences using Bayesian Networks: implications for drug resistance.

Human Immunodeficiency Virus-1 (HIV-1) antiviral resistance is a major cause of antiviral therapy failure and compromises future treatment options. As a consequence, resistance testing is the standard of care. Because of the high degree of HIV-1 natural variation and complex interactions, the role of resistance mutations is in many cases insufficiently understood. We applied a probabilistic model, Bayesian networks, to analyze direct influences between protein residues and exposure to treatment in clinical HIV-1 protease sequences from diverse subtypes. We can determine the specific role of many resistance mutations against the protease inhibitor nelfinavir, and determine relationships between resistance mutations and polymorphisms. We can show for example that in addition to the well-known major mutations 90M and 30N for nelfinavir resistance, 88S should not be treated as 88D but instead considered as a major mutation and explain the subtype-dependent prevalence of the 30N resistance pathway.

Identification of toxicologically predictive gene sets using cDNA microarrays.

We have developed an approach to classify toxicants based upon their influence on profiles of mRNA transcripts. Changes in liver gene expression were examined after exposure of mice to 24 model treatments that fall into five well-studied toxicological categories: peroxisome proliferators, aryl hydrocarbon receptor agonists, noncoplanar polychlorinated biphenyls, inflammatory agents, and hypoxia-inducing agents. Analysis of 1200 transcripts using both a correlation-based approach and a probabilistic approach resulted in a classification accuracy of between 50 and 70%. However, with the use of a forward parameter selection scheme, a diagnostic set of 12 transcripts was identified that provided an estimated 100% predictive accuracy based on leave-one-out cross-validation. Expansion of this approach to additional chemicals of regulatory concern could serve as an important screening step in a new era of toxicological testing.

A long-term randomized prospective trial of the Nissen procedure versus a modified Toupet technique.

Thirty-one patients about to undergo surgery for gastroesophageal reflux were randomized into either a Nissen fundoplication group (12) or a modified Toupet semifundoplication group (19). All patients were followed on a long-term basis for 5 years with a standard questionnaire, endoscopy, and manometry. Ninety-five percent of the patients in the modified Toupet group had good or excellent results versus 67% for the Nissen group. However both procedures are effective in curtailing esophagitis with an improvement of the endoscopic grading in the Nissen group by 91% and 89% in the group undergoing the modified Toupet procedure. A significant improvement in symptoms (acid regurgitation, heartburn, retrosternal pain) was noted in both groups, except for dysphagia in the Nissen group. Three patients with a Nissen fundoplication had a slipped Nissen requiring reoperation and two had gas-bloat syndrome. These specific complications of the Nissen procedure were not found in the modified Toupet group.

A "nondislodgeable" endoprosthesis for nonsurgical drainage of the biliary tract.

In patients with obstructive jaundice, biliary decompression can be achieved by an endoprosthesis inserted by a percutaneous transhepatic approach. The prosthesis sometimes becomes dislodged and thus additional percutaneous transhepatic procedures may be required. To avoid this problem, a nondislodgeable endoprosthesis has been developed. The prosthesis is constructed with a layer of biocompatible material (hydrogel) on its surface. The hydrogel is located in grooves around the endoprosthesis and has the ability to absorb liquid, which increases its size. By placing the rings of hydrogel on either side of the obstruction, dislodgement of the prosthesis can be prevented. The nondislodgeable endoprosthesis has been inserted into 11 patients with biliary obstructions due to malignant strictures. No dislodgement has occurred and the established internal drainage reduced serum bilirubin levels without any major complications.

Cadmium concentrations in human liver, blood, and bile: comparison with a metabolic model.

Cadmium concentrations in liver biopsies, blood, and bile were measured by atomic absorption spectrophotometry in 23 patients in connection with routine gallstone operations. On a group basis cadmium in blood was a good indicator of cadmium in liver, and the estimated linear relationship agreed well with calculations from a formerly proposed metabolic model. Cadmium in bile was also analyzed, and an average of about 2.5 ng of Cd/g wet weight was found. This is about 10 times more than would have been expected form the metabolic model and suggests that bile might be an important excretion route for cadmium. Definite conclusions cannot be drawn, however, since the results could not be cross-checked with neutron activation analysis, due to insufficient sensitivity of the latter method.