Impact of second-line drug resistance on tuberculosis treatment outcomes in the United States: MDR-TB is bad enough.

SETTING: The worldwide emergence of extensively drug-resistant tuberculosis (TB) has focused attention on treatment with second-line drugs (SLDs). OBJECTIVE: To determine the impact on outcomes of resistance to individual SLDs, we analyzed successful treatment completion and death among drug-resistant TB cases in the US national TB surveillance system, 1993-2007 (N = 195 518). DESIGN: We defined four combinations of first-line drug (FLD) resistance based on isoniazid (INH) and rifamycin, and three patterns of SLD resistance: fluoroquinolones, injectable SLDs and other oral SLDs. We compared treatment outcomes of cases by FLD resistance, with and without each pattern of SLD resistance. RESULTS: In all but one instance, cases with FLD resistance but no SLD resistance had better outcomes than cases with SLD resistance. Rifamycin resistance, alone or with INH, resulted in a greater decline in treatment completion and greater increase in deaths than resistance to SLDs. Among patients with multidrug-resistant TB, additional resistance to injectable SLDs was statistically significant. Outcomes were better for human immunodeficiency virus (HIV) negative than HIV-positive cases for all resistance patterns, but improved among HIV-infected cases after 1998, when highly active antiretroviral treatment became widely available. CONCLUSION: These results suggest that the effect of rifamycin resistance may outweigh the more modest effects of resistance to specific SLDs.

Comparison of tuberculosis surveillance systems in low-incidence industrialised countries.

The comparative analysis of National Tuberculosis Control Programmes (NTPs) in industrialised, low-tuberculosis-incidence countries is limited. Analysis of applied methods, function and accumulated experience contributes to improving global tuberculosis control. A questionnaire addressing NTP surveillance infrastructure and characteristics was completed in 19 industrialised countries, with populations of >3 million and annual notified tuberculosis incidence rates of <16 cases per 100,000 population (2003 data). All European countries surveyed adopted World Health Organization Collaborating Centre for the Surveillance of Tuberculosis in Europe (EuroTB) definitions. Surveillance information, which usually includes names, was transferred electronically to the national level in 17 out of the 19 countries. Surveillance systems capture process and social determinants. Case notification to the central level occurred within a median period of 7 days, independent of mandatory notification requirements. The mean completeness of tuberculosis case-reporting was estimated to be 93.5% (range 65-100%). Integration between HIV and tuberculosis registries was performed in two countries, and, in seven others, both databases were cross-matched periodically. National Tuberculosis Control Programme function in industrialised low-incidence countries utilises well-established infrastructure and relies upon centralised operations. Approaches are consistent with current World Health Organization surveillance recommendations. The present study lays collaborative groundwork for additional multinational analyses for the enhancement of global tuberculosis surveillance, which may assist policy-makers in countries moving from medium to low rates of incidence.

Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity.

Little is known of the molecular mechanisms that trigger oligodendrocyte death and demyelination in many acute central nervous system insults. Since oligodendrocytes express functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-type glutamate receptors, we examined the possibility that oligodendrocyte death can be mediated by glutamate receptor overactivation. Oligodendrocytes in primary cultures from mouse forebrain were selectively killed by low concentrations of AMPA, kainate or glutamate, or by deprivation of oxygen and glucose. This toxicity could be blocked by the AMPA/kainate receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX). In vivo, differentiated oligodendrocytes in subcortical white matter expressed AMPA receptors and were selectively injured by microstereotaxic injection of AMPA but not NMDA. These data suggest that oligodendrocytes share with neurons a high vulnerability to AMPA/kainate receptor-mediated death, a mechanism that may contribute to white matter injury in CNS disease.

Isolation, DNA sequence analysis, and mutagenesis of a proline dehydrogenase gene (putA) from Bradyrhizobium japonicum.

We report here the cloning and sequencing of the gene for proline dehydrogenase (putA) of Bradyrhizobium japonicum. An open reading frame coding for 1,016 amino acids was identified. The B. japonicum gene codes for a bifunctional protein with proline dehydrogenase and pyrroline-5-carboxylate (P5C) dehydrogenase activities, as it does in Escherichia coli and Salmonella typhimurium. Comparison of the sequences of these proteins with other proline and P5C dehydrogenase sequences identified proline dehydrogenase and P5C dehydrogenase catalytic domains. Within the proline dehydrogenation domain, several areas of high identity were observed between B. japonicum, E. coli, S. typhimurium, Saccharomyces cerevisiae put1, and Drosophila melanogaster slgA. Within the P5C dehydrogenase domain, several areas of high identity were observed between B. japonicum, E. coli, S. typhimurium, Bacillus subtilis ipa76d, and S. cerevisiae put2. A consensus catalytic site for semialdehyde dehydrogenase was observed in the P5C dehydrogenase domain. This suggests that the substrate for this domain may be the open-chain gamma-glutamylsemialdehyde, not its cyclized form, P5C. Unlike the gene isolated from E. coli, S. typhimurium, and K. pneumoniae, the B. japonicum putA gene does not appear to be part of an operon with the proline porter gene (putP). Additionally, the B. japonicum gene lacks the putative C-terminal regulatory domain present in the E. coli and S. typhimurium genes. The gene was disrupted by insertion of antibiotic resistance gene cassettes, which were then recombined into the bacterial chromosome. Symbiotically active mutant strains that were devoid of putA activity were isolated. With this proline dehydrogenase clone, we will test the hypothesis that putA in symbiotic nitrogen-fixing B. japonicum bacteroids is transcriptionally regulated by drought and other stresses.