Faulty measurement substitution and control reconfiguration by using a multivariate flow control loop.

A two-tank multivariate loop was designed and built to support research related to instrumentation and control, equipment and sensor monitoring. This test bed provides the framework necessary to investigate and test control strategies and fault detection methods applicable to sensors, equipment, and actuators, and was used to experimentally develop and demonstrate a fault-tolerant control strategy using six correlated variables in a single-tank configuration. This work shows the feasibility of using data-based empirical models to perform fault detection and substitute faulty measurements with predictions and to perform control reconfiguration in the presence of actuator failure in a real system. These experiments were particularly important because they offered the opportunity to prove that a system, such as the multivariate control loop, could survive degraded conditions, provided the empirical models used were accurate and representative of the process dynamics.

Expression and cellular localization of Trypanosoma cruzi type II DNA topoisomerase.

Topoisomerases are enzymes that participate in many cellular functions involving topological manipulation of DNA strands. There are two types of topoisomerases in the cell: (a) type I topoisomerases; and (b) type II topoisomerases (topo II). Previously we have cloned and sequenced the gene encoding Trypanosoma cruzi topo II (TcTOP2). This study group has raised an antiserum against recombinant type II DNA topoisomerase (TctopoII) to study the expression of this gene during T. cruzi differentiation and to determine the cellular location of the enzyme. Western blot analysis showed that T. cruzi TctopoII is expressed in the replicative epimastigotes but not in the infective and non-replicative trypomastigotes. However, slot blot analysis of RNAs extracted from epimastigotes and metacyclic trypomastigotes showed that the mRNA encoding the enzyme is present in both developmental stages of the parasite. Confocal laser microscopy using the antiserum raised against recombinant TctopoII showed that the enzyme is located exclusively in the nucleus of the parasite. Similar results were obtained by immunofluorescence analysis of Crithidia fasciculata. However, monoclonal antisera against the corresponding enzyme extracted from C. fasciculata recognizes a kinetoplast protein in both T. cruzi and Crithidia.

Phase I trial of 5-fluorouracil by 24-hour infusion weekly.

A novel schedule of 5-fluorouracil administration has been developed for biochemical modulation studies. In combination with the pyrimidine synthesis inhibitor PALA, 5-fluorouracil has been given as a 24-hour infusion, repeated weekly: a dose of 2600 mg/m2 is well tolerated. To identify a suitable dose of 5-fluorouracil as a single agent on this schedule, we treated 26 patients at doses ranging from 2800 to 3400 mg/m2 per week. Two-thirds of the patients had failed previous therapy, and most were symptomatic from their disease. Over half of the patients had metastatic colorectal cancer. The dose-limiting toxicity was diarrhea: Grade 3 or 4 toxicity occurred at every level tested. Twenty-two of the 26 patients required therapy interruption because of toxicity. The severity of this toxicity indicated that escalation of 5-fluorouracil on this schedule beyond the 2600 mg/m2 known to be tolerated in the PALA-containing regimen, would be impractical. Two patients, both with previously untreated colorectal cancer, had partial remissions lasting three and five months respectively. This dose-intense schedule of 5-fluorouracil administration will be explored further in large-scale randomized trials.