No description available.

Mycobacterium abscessus is an emerging pathogen with infections increasing worldwide, especially among Cystic Fibrosis (CF) patients. During my PhD, I studied key aspects of the biology of M. abscessus spp.; particularly, I studied host-pathogen interactions, antimicrobial resistance mechanisms, and genetic determinants of virulence. First, I performed phenotypic characterization of M. abscessus spp. clinical isolates obtained from CF patients classified according to subspecies and clustering. I found clustered isolates, representing probable transmission events, were phenotypically distinct from sporadic isolates and showed adaptation phenotypes associated with chronic lung infection, such as enhanced intracellular survival, increased antibiotic resistance, and metabolic adaptations to the host environment. Second, I assessed the role of an inserted element containing an active methyltransferase in M. a. massiliense. Infection experiments with an isolate containing the inserted element (BIR1049wt) and a knockout strain (BIR1049Δ1809078_1815649) showed decreased survival of BIR1049Δ1809078_1815649 within macrophages. RNAseq analysis showed a distinct gene expression pattern between both isolates, with a number of mycobacterial virulence factors upregulated in BIR1049wt. Third, I studied heritable non-mutational antibiotic resistance mechanisms in M. abscessus to linezolid and clofazimine. For both antibiotics, I found clonal isolates of M. abscessus spp. with varying susceptibilities and different gene expression patterns, suggesting transcriptional regulation of antibiotic resistance. Mutation- mediated resistance to clofazimine was also found due to mutations in two transcriptional regulators predicted to regulate efflux pumps. Last, I evaluated the potential of repurposing a kinase inhibitor (compound H) in clinical trials for the treatment of cancer and CF, to treat M. abscessus infection. I found compound H enhanced killing of intracellular M. abscessus in macrophages through stimulation of autophagy and lysosomal function. I further studied over 60 chemical analogues of compound H in order to find a more active and specific compound for M. abscessus infection.

Objective: To determine if inhaled Hypertonic Saline (7%) improves the Lung Clearance Index in paediatric Cystic Fibrosis patients with FEV1 ≥80% predicted. Methods: In a blinded crossover trial, twenty CF patients received 4 weeks of hypertonic saline (7%) (HS) and 4 weeks of isotonic saline (0.9%) (IS) separated by a 4 week washout period. The primary endpoint was the change in LCI in the HS versus the IS treatment periods. Results: Four weeks of twice daily inhalation of HS significantly improved the LCI as compared to IS by 1.16, 95% CI [0.26, 2.05]; p=0.016. Baseline LCI before IS, 8.71+/-2.10, was not significantly different from baseline LCI before HS inhalation, 8.84+/-1.95 (p=0.73). Randomization order had no significant impact on the treatment effect (p=0.61). Conclusions: Four weeks of twice daily Hypertonic Saline (7%) inhalations improved the LCI and may be a suitable early intervention therapy for CF patients with mild disease.

Objective: To determine if inhaled Hypertonic Saline (7%) improves the Lung Clearance Index in paediatric Cystic Fibrosis patients with FEV1 ≥80% predicted. Methods: In a blinded crossover trial, twenty CF patients received 4 weeks of hypertonic saline (7%) (HS) and 4 weeks of isotonic saline (0.9%) (IS) separated by a 4 week washout period. The primary endpoint was the change in LCI in the HS versus the IS treatment periods. Results: Four weeks of twice daily inhalation of HS significantly improved the LCI as compared to IS by 1.16, 95% CI [0.26, 2.05]; p=0.016. Baseline LCI before IS, 8.71+/-2.10, was not significantly different from baseline LCI before HS inhalation, 8.84+/-1.95 (p=0.73). Randomization order had no significant impact on the treatment effect (p=0.61). Conclusions: Four weeks of twice daily Hypertonic Saline (7%) inhalations improved the LCI and may be a suitable early intervention therapy for CF patients with mild disease.

No description available.

Thesis (M.Med.Sc.)--University of Western Australia, 2007.

Thesis (Ph. D.)--University of Missouri-Columbia, 2005. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on October 18, 2007) Vita. Includes bibliographical references.

Class of 2006 Abstract / Objectives: To develop a new equation to predict creatinine clearance specific for cystic fibrosis patients. Methods: A literature review was performed to capture data on the daily creatinine excretion in CF patients in relation to age, weight, height, and other physiologic variables. Nonlinear mixed effect modeling was then used to develop an equation to estimate creatinine clearance using individual covariates. The performance of the new equation developed was compared to the Cockcroft and Gault method in a CF population (age > 16 years). Results: A database of individual patient data from a previously published study of 19 patients was created. Significant covariates for model development included actual body weight, sex, and serum creatinine. The final candidate model was: 5.62× ABW0.67 CrCl = sCr(mg / dl) × 0.649( female) Conclusions: The results of the mean absolute error and root mean squared error calculations show that the new equation resulted in less bias and better precision than Cockcroft-Gault, Jeliffe I, and Jeliffe II based on the limited data available. However, these conclusions are limited in that the only evaluation data available was the same data that was used for model development.

No description available.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).