The pharmacokinetics and protein-binding of fusidic acid in patients with severe renal failure requiring either haemodialysis or continuous ambulatory peritoneal dialysis

Antibiotic treatment options for Burkholderia cepacia infection are limited because of high intrinsic resistance. The problem is complicated by development of cross-resistance between antibiotics of different classes. We isolated antibiotic-resistant mutants by stepwise exposure to chloramphenicol (Chlor) and to trimethoprim/sulphamethoxazole (T/S) for four B. cepacia strains: ATCC13945, Per (clinical isolate), Cas and D4 (environmental isolates). Chlor(r) mutants did not produce chloramphenicol acetyl-transferase. Cross-resistance, defined as greater than four-fold increase in MIC by microtitre dilution method, was consistently seen in both types of mutants. For chloramphenicol-resistant (Chlor[r]) and trimethoprim/sulphamethoxazole-resistant (Tr/Sr) mutants of B. cepacia ATCC13945 and Cas, no MIC change was seen for piperacillin, ceftazidime, rifampicin, gentamicin, tobramycin, polymyxin B or azithromycin. B. cepacia-Per and -D4 mutants showed cross-resistance to ceftazidime and to piperacillin. Comparison of outer membrane protein (OMP) profiles of B. cepacia and their mutants by SDS-PAGE revealed Tr/Sr) mutants to be deficient in a major OMP (molecular weight 39-47 kDa). Tr/Sr mutants also expressed additional OMPs not found in wild type strains at 75-77 kDa for B. cepacia-ATCC13945 and -Cas, and 20-21 kDa in B. cepacia-D4 and -Per. No OMP changes occurred in Chlor(r) mutants. Lipopolysaccharide (LPS) profiles of each type of mutant showed new high and low molecular weight LPS bands. Cross-resistance seems to be mediated by alterations in porin and LPS for Tr/Sr mutants, but only by LPS in Chlor(r) mutants.     

Substrate-induced conformational change in a trimeric ornithine transcarbamoylase

The crystal structure of Escherichia coli ornithine transcarbamoylase (OTCase, EC 2.1.3.3) complexed with the bisubstrate analog N-(phosphonacetyl)-L-ornithine (PALO) has been determined at 2.8-A resolution. This research on the structure of a transcarbamoylase catalytic trimer with a substrate analog bound provides new insights into the linkages between substrate binding, protein-protein interactions, and conformational change. The structure was solved by molecular replacement with the Pseudomonas aeruginosa catabolic OTCase catalytic trimer (Villeret, V., Tricot, C., Stalon, V. & Dideberg, O. (1995) Proc. Natl. Acad. Sci. USA 92, 10762-10766; Protein Data Bank reference pdb 1otc) as the model and refined to a crystallographic R value of 21.3%. Each polypeptide chain folds into two domains, a carbamoyl phosphate binding domain and an L-ornithine binding domain. The bound inhibitor interacts with the side chains and/or backbone atoms of Lys-53, Ser-55, Thr-56, Arg-57, Thr-58, Arg-106, His-133, Asn-167, Asp-231, Met-236, Leu-274, Arg-319 as well as Gln-82 and Lys-86 from an adjacent chain. Comparison with the unligated P. aeruginosa catabolic OTCase structure indicates that binding of the substrate analog results in closure of the two domains of each chain. As in E. coli aspartate transcarbamoylase, the 240s loop undergoes the largest conformational change upon substrate binding. The clinical implications for human OTCase deficiency are discussed.     

Data collection: evaluation of a pilot model

The overall purpose of this study was to explore nurses' feelings about the applicability and adequacy of a pilot model of nursing assessment (PMNA) developed for coronary care units (CCU) in order to obtain data that could help in establishing a definitive model. The evaluation, performed by 11 CCU nurses, showed that they considered the development and implementation of PMNA as valuable, and that its design was adequate for interviewing cardiac patients. These results will be employed in the elaboration of a definitive model of nursing assessment.     

The Role of Network Topologies in the Optical Core of IP-over-WDM Networks with Static Wavelength Routing

In this paper, we present a performance analysis of network topologies for the optical core of IP-over-WDM networks with static wavelength routing. The performance analysis is focused on regular degree four topologies, and, for comparison purposes, degree three topologies are also considered. It is shown that the increase of the nodal degree from three (degree three topology with smallest diameter) to four (degree four topology with smallest diameter) improves the network performance if a larger number of wavelengths per link is available. However, the influence of wavelength interchange on the nodal degree gain is small. The performance of regular degree four topologies with smallest diameter is also compared with the performance of mesh–torus topologies (which are also degree four topologies), and it is shown that the blocking probability of degree four topologies with smallest diameter is about two orders of magnitude lower than the blocking probability of mesh–torus topologies. It is also presented a performance comparison of WDM-based networks with nodal degrees ranging from two to five and it is shown that the increase of the nodal degree from two to three leads to high nodal degree gains, while de increase of the nodal degree from four to five leads to low nodal degree gains. These results show that degree three and degree four topologies are very attractive for use in the optical core of IP-over-WDM networks.