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WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

to improved population

to improved population health and decreased costs for Medicaid. Recently created TB-related quality measures for primary care may also aid implementation. 12) Bacterial Mn 2+ ATPases and pathogenesis Teresita Padilla-Benavides 1 , Jarukit E. Long 2 , Daniel Raimunda 1 , Christopher M. Sassetti 2,3 , and José M. Argüello 1 1 Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA., USA. 01609; 2 Department of Microbiology and Physiological Systems. University of Massachusetts Medical School. Worcester, MA, USA 01655; 3 Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. 20815 Bacterial P1B-ATPases, responsible for cytoplasmic metal efflux, are important elements in hostpathogen interactions. From these, CtpC, has been found to prevent Zn 2+ toxicity in M. tuberculosis, suggesting a role in Zn 2+ export. However, CtpC is a novel ATPase that lacks welldescribed structures that determine the metal transported by Cu + - and Zn 2+ -ATPases. CtpC contains 8 transmembrane segments with distinct signatures in H6 (CPC), H7 (QN), and H8 (HXXSS). This ATPase is activated with high affinity by Mn 2+ and in less extent with Co 2+ , Cu 2+ , and Zn 2+ . The turnover rate is comparable to the observed in Cu + -ATPases required for metalloprotein assembly. Interestingly, ctpC transcription is induced only by Zn 2+ and ctpC deletion increases sensitivity to Zn 2+ and the redox stressor tert-butyl hydroperoxide. ctpC deletion lead to an increase in cytosolic Mn 2+ level consistent with a decrease on Mn 2+ content in the secreted protein fraction. The ctpC mutant strain was attenuated in the tuberculosis mouse model. We hypothesized that CtpC might be involved in Mn 2+ uploading into secreted Mn 2+ -proteins and the Mn-SodA appears to be the candidate target. In vitro M. tuberculosis SodA is secreted as a Fe-Sod, while M. smegmatis SodA is secreted as a Mn-Sod. To test the role of this Mn 2+ -ATPase, M. smegmatis ctpC gene was deleted and secreted SodA activity determined. A decrease in SodA activity was observed in the ctpC mutant strain. We propose that, in phagosomal Fe 2+ starvation conditions, CtpC is required for the assembly of functional SodA, driving Mn 2+ efflux for loading into the secreted apo-protein. This work was supported by NIH grant 1R21AI082484-01 (J.M.A.) and award F32A1093049 (J.E.L.). 13) Evaluating the effect of GenoType MTBDRplus on time to multidrug-resistant tuberculosis (MDR-TB) therapy initiation in a rural TB hospital, South Africa KR Jacobson, D Theron, EA Kendall, MF Franke, TC Victor, EM Streicher, MB Murray, RM Warren. Infectious Diseases Division, Massachusetts General Hospital, Boston, MA, USA; Brewelskloof Hospital, Worcester, South Africa; Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa Recognition of drug resistance and timely initiation of MDR-TB therapy are essential to reduce transmission and improve outcomes. In mid-2008, the MTBDRplus line probe assay replaced traditional DST in the Western Cape Province, South Africa. Evaluation of the test’s effect on shortening time to MDR-TB treatment and identification of patient characteristics that predict diagnostic delay is essential for implementation success. We conducted a retrospective cohort analysis of 197 MDR-TB patients treated at Brewelskloof, a rural TB hospital, between 2007-2011. 89 patients received conventional DST and 108 the MTBDRplus assay. Mean age was 37.1 years (SD12.2), 55% were men, 30% were known HIV infected. 88% had only pulmonary disease, 38% were smear positive. Median time from sputum taken to MDR therapy initiation was reduced from 80 days (IQ62-100) for conventional DST to 55 days (IQ37.5-78) with MTBDRplus. Reduction in laboratory processing time decreased significantly (p

esistance reporting to when the patient started therapy stayed constant. Laboratory time was still 27 days (IQ20-24) for patients who received MDRTBplus. In multivariate analysis, patients with a MTBDRplus had a reduced risk of starting treatment ≥60 days after sputum collection of 0.53 (p

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