Browsing by Subject "cystic fibrosis"

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    Effects of deletion mutations in aguA on fitness and survival of Pseudomonas aeruginosa cystic fibrosis isolates
    (2018-08) McCurtain, Jennifer
    Pseudomonas aeruginosa is a pathogen commonly associated with the disease cystic fibrosis (CF) due to the bacterium’s ability to adapt to numerous environments. These adaptations include mutations that benefit the pathogen such as antibiotic resistance and host immune evasion. Five P. aeruginosa isolates from CF sputum were found to have deletion mutations in aguA that encodes the agmatine deiminase for this species. These mutations cause the cationic molecule agmatine to accumulate both within and outside the cell. The purpose of this thesis was to determine the effects of agmatine accumulation on fitness and survival of P. aeruginosa in the context of CF. Compared to the isogenic strains with a native aguA, the mutations led to decreased susceptibility to cationic antibiotics (aminoglycosides and polymyxins). At sub-minimal inhibitory concentrations (MIC) of these antibiotics, growth of the aguA+ strains was delayed and stunted more than the aguA mutants. This growth phenotype at these sub-MICs was also seen when Mg2+ and Ca2+ concentrations in the growth medium were reduced. In an acute pneumonia the aguA mutant recruited fewer neutrophils to the murine lungs relative to the aguA+ strain. When testing the ex vivo bronchial epithelial cell response to LPS, agmatine caused reduced IL-8 production in response to LPS in a dose-dependent manner, with the higher concentration of agmatine (100 μM) eliciting a response similar to the negative control without LPS. Together, these data show that the mutations in aguA that prevent the bacteria from breaking down agmatine may be beneficial to the P. aeruginosa isolates while colonizing the CF airways.
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    Estimates Of Central Hemodynamics Using Gas Exchange In Patients With Cystic Fibrosis
    (2016-07) Kasak, Alexander
    Pulmonary artery capacitance (PVCAP) is the ability of the pulmonary artery to accept a volume of blood at a given pressure. Traditionally measured invasively with heart catheterization; PaCAP may be estimated non-invasively through the measurement of end-tidal CO2 (PETCO2) and stroke volume (SV), known as gas-exchange capacitance (GXCAP) where a higher capacitance means improved pulmonary vasodilation. The degree of pulmonary vascular dysfunction at rest and during exercise remains unclear in patients with cystic fibrosis (CF). PURPOSE: To determine the effects of exercise on GXCAP in patients with CF, when compared to healthy subjects. METHODS: 19 patients with CF (age=22±2yrs, BMI=23±1kg/m2, VO2=56±6%pred., FVC=83±5%pred., FEV1=72±6%pred., FEV1/FVC=0.72±0.02) and 17 healthy subjects (age=22±1yrs, BMI=23±1kg/m2, VO2=81±5%pred., FVC=93±3%pred., FEV1=89±2%pred., FEV1/FVC=0.81±0.02) were recruited for this study. Exercise testing was performed on a cycle ergometer. PETCO2 was assessed using a metabolic cart, SV was assessed using the acetylene rebreathe technique and GXCAP was calculated from the product of PETCO2 and SV. RESULTS: At rest, SV and GXCAP were higher in healthy subjects when compared to CF (SV=72±6 vs. 54±5ml, GXCAP=22±2 vs. 17±2, for healthy and CF, respectively. PETCO2 remained unchanged between healthy and CF subjects (PETCO2 30±1 and 30±1 respectively). Healthy subjects exercised at a higher absolute intensity, but intensity expressed as a percentage of max was similar between healthy and CF (watts=159±10 vs. 102±8, watts/max watts=96±3 vs. 95±5% for healthy and CF, respectively). At peak exercise, SV and GXCAP increased in both healthy and CF but remained higher in healthy subjects when compared to CF (SV=108±5 vs. 84±6ml, GXCAP=40±3 vs. 29±2, for healthy and CF, respectively, p<0.05). When matched for a workload designed to match for SV, there was no difference in percent of max watts (%MaxW=63±4 vs. 66±5W), Q (11±1 vs. 13±1L/min), or SV (89±4 vs. 90±4ml/beat). When matched, the previous difference in GXCAP in healthy and CF was abolished (GXCAP=32±2 vs. 32±2mL/BEAT ∙ min). CONCLUSION: Gas exchange capacitance is lower in patients with CF at rest and through peak exercise. However, when matched for SV and workload, GXCAP was statistically similar between healthy and CF. This lower GXCAP is likely due to lower SV at rest and with peak exercise in CF patients, when compared to healthy subjects. Therefore, these findings suggest that there is no evidence of pulmonary vasculature dysfunction in these CF patients. Future, more invasive studies are warranted to confirm the lack of difference in pulmonary vascular function in patients with CF.