The Flagellum of Pseudomonas aeruginosa Is Required for Resistance to Clearance by Surfactant Protein A

Surfactant protein A (SP-A) is an important lung innate immune protein that kills microbial pathogens by opsonization and membrane permeabilization. We investigated the basis of SP-A-mediated pulmonary clearance of Pseudomonas aeruginosa using genetically-engineered SP-A mice and a library of signature-tagged P. aeruginosa mutants. A mutant with an insertion into flgE, the gene that encodes flagellar hook protein, was preferentially cleared by the SP-A(+/+) mice, but survived in the SP-A(-/-) mice. Opsonization by SP-A did not play a role in flgE clearance. However, exposure to SP-A directly permeabilized and killed the flgE mutant, but not the wild-type parental strain. P. aeruginosa strains with mutation in other flagellar genes, as well as mucoid, nonmotile isolates from cystic fibrosis patients, were also permeabilized by SP-A. Provision of the wild-type fliC gene restored the resistance to SP-A-mediated membrane permeabilization in the fliC-deficient bacteria. In addition, non-mucoid, motile revertants of CF isolates reacquired resistance to SP-A-mediated membrane permeability. Resistance to SP-A was dependent on the presence of an intact flagellar structure, and independent of flagellar-dependent motility. We provide evidence that flagellar-deficient mutants harbor inadequate amounts of LPS required to resist membrane permeabilization by SP-A and cellular lysis by detergent targeting bacterial outer membranes. Thus, the flagellum of P. aeruginosa plays an indirect but important role resisting SP-A-mediated clearance and membrane permeabilization

Efficacy of oral diltiazem to control ventricular response in chronic atrial fibrillation at rest and during exercise

Although digpxin is often the first choice for control of ventricular response in chronic atrial fibrillation, it fails to slow exercise rates. Diltiazem, a calcium channel antagonist that slows atrioventricular conduction, was administered to 16 patients who failed to achieve adequate rate control on low level exercise testing despite digoxin therapy. Therapeutic response to diltiazem was assessed with submaximal and maximal exercise tests and 24 hour ambulatory electrocardiographic monitoring. During the diltiazem treatment phase, ventricular response at rest diminished (96 ± 17 versus 69 ± 10 beats/min, p \u3c 0.001) as did rate during submaximal exercise (155 ± 28 versus 116 ± 26, p \u3c 0.001), maximal exercise (163 ± 14 versus 133 ± 26, p \u3c 0.001) and average ventricular response during 24 hour monitoring (87 ± 13 versus 69 ± 10, p \u3c 0.001). Rate at rest decreased 26 ± 15% and submaximal exercise rate diminished 24 ± 12%. Thirteen (81%) of the 16 patients exhibited at least 15% slowing of rate at rest and during submaximal exercise. Eleven patients (69%) reported alleviation of symptoms. There was no change in serum digoxin levels during diltiazem treatment (1.3 ± 0.5 versus 1.3 ± 0.6 ng/ml, p = NS). On withdrawal of diltiazem, ventricular response returned to baseline values. Diltiazem is an effective agent for control of ventricular response, both at rest and during exercise, in digoxin-treated patients with chronic atrial fibrillation. © 1987, American College of Cardiology Foundation. All rights reserved

Independent and interactive effects of digoxin and quinidine on the atrial fibrillation threshold in dogs

To assess the effects of digoxin as single therapy and in combination with quinidine in the treatment of atrial fibrillation, the atrial fibrillation threshold was determined from the right atrial appendage and Bachmann\u27s bundle in 11 open chest dogs. In group 1 (six dogs), the atrial fibrillation threshold was determined at baseline, post-quinidine (10 mg/kg intravenously) and then post-digoxin (50 µg/kg intravenously). In group 2 (five dogs), the order of drug administration was reversed. The results of this study were: 1) Digoxin had no significant effect on the atrial fibrillation threshold when given alone. 2) Quinidine significantly increased the atrial fibrillation threshold (p \u3c 0.002) and the addition of digoxin resulted in a further increase in threshold (p \u3c 0.002). 3) Quinidine produced greater suppression of atrial fibrillation induction at the right atrial site than at the Bachmann\u27s bundle site, suggesting differential effects of quinidine on atrial fibers. © 1985, American College of Cardiology Foundation. All rights reserved

Temporal evolution of the human coronary collateral circulation after myocardial infarction

An analysis of the coronary collateral circulation in a consecutive series of 116 postinfarction angiograms from patients with persistent 100% occlusion of their infarct artery is reported. Patients were classified into four groups according to the interval between acute infarction and angiography. Of 42 patients studied within 6 hours of infarction (Group I), 52% had no evidence of any coronary collateral development as compared with only 8% (1 of 16 patients) studied 1 day to 2 weeks after infarction (Group II). Virtually all patients studied beyond 2 weeks after myocardial infarction (14 to 45 days, Group III) and later than 45 days (Group IV) had visible collateral flow. Angiographically “well developed” collateral channels were seen in only 16% of Group I patients compared with 62, 75 and 84% of patients in Groups II to IV, respectively. Of six patients studied twice, on the day of the infarction and 2 weeks later, only one patient had collateral vessels on the day of infarction, whereas all six patients did at follow-up study. Group I patients were studied as part of a randomized acute myocardial infarction reperfusion trial, whereas the other patients were referred for angiography primarily because of postinfarction ischemia. Within the limitations imposed by the patient selection process, it is concluded that well developed coronary collateral vessels are rarely present at the time of infarction. After infarction, they develop rapidly and are generally demonstrable within 2 weeks. It may also be inferred that the preservation of ischemic myocardium by well developed coronary collateral vessels at the time of myocardial infarction may be an uncommon occurrence. © 1984, American College of Cardiology Foundation. All rights reserved

A randomized, angiographically controlled trial of intracoronary streptokinase in acute myocardial infarction

Fifty-five patients with acute myocardial infarction evaluated within 4 hours of the onset of symptoms were entered into an angiographically controlled trial of intracoronary Streptokinase (IC STK). Forty-three patients with total occlusion of their infarct artery were randomized to either IC STK or intracoronary nitroglycerin (IC NTG), and 12 patients with lessthan-complete occlusion received only IC NTG. Reperfusion of a totally occluded vessel was achieved in 69% of STK patients and 17% of IC NTG patients. Time from onset of symptoms to peak CK activity was significantly shorter in reperfused patients and patients with subtotal occlusion on initial angiography than in patients with total occlusion who were not reperfused (p \u3c0.0001). Comparison of radionuclide ejection fractions (EF) determined acutely and 10 to 14 days after infarction failed to show improvement in either the STK or IC NTG group (mean decrease of 2.8% and 0.4%, respectively). In contrast, patients with subtotal occlusion on baseline angiography demonstrated a significant (p = 0.05) spontaneous improvement in EF over 2 weeks (7.3% increase). © 1984

Detection of left ventricular wall motion abnormalities for the diagnosis of coronary artery disease: A comparison of exercise radionuclide and pacing intravenous digital ventriculography

Intravenous digital ventriculography before and after pacing was compared with equilibrium gated nuclear ventriculography at rest and after exercise. Specifically, the relative abilities of the 2 techniques to detect resting and stress-related wall motion abnormalities were tested. Twelve normal patients and 28 patients with coronary artery disease (CAD) were tested. Neither technique produced a new wall motion abnormality in a patient with normal coronary arteries. Six patients with CAD had a history of a myocardial infarction (MI); an abnormality at rest was present in all 6 by both techniques. Of the 22 patients with CAD and a normal baseline ventriculogram, a wall motion abnormality developed in 18 during digital ventriculography with pacing; a wall motion abnormality developed in 15 with exercise nuclear ventriculography. Wall motion abnormalities by nuclear ventriculography (performed in the left anterior oblique projection) tended to be apical; digital ventriculography (performed in the right anterior oblique projection) more often produced an abnormality of the anterior or inferior wall, which could be predictive of coronary anatomy. Thus, the 2 techniques are substantially equivalent for the detection of wall motion abnormalities in CAD. © 1984

Recurrent early ischemic events after thrombolysis for acute myocardial infarction

Myocardium salvaged by early thrombolysis and then perfused through a residual stenosis may be at risk for ischemic events. To investigate this possibility, the short-term (2-week) clinical course of 81 consecutive patients managed within a randomized intracoronary thrombolysis trial was reviewed. All patients underwent coronary anglography within 5 hours of symptoms of acute myocardial infarction and were stratified into the following 3 outcome groups: patients with initially subtotal occlusion (subtotal group, n= 17), those with initial total occlusion and infarct artery reperfusion (reperfused group, n = 24) and those with continued infarct artery occlusion (occluded group, n = 40). Recurrent ischemic events were defined as spontaneous typical angina, provokable angina on predischarge exercise testing, and reinfarction. Eleven of 17 patients (65%) in the subtotal and 11 of 23 patients (48%) in the reperfused groups had an ischemic event (difference not significant). In contrast, 4 of 37 patients (11%) with occlusion had an ischemic event (p \u3c0.01 compared with patients in the subtotal or reperfused groups). Four patients were excluded because of early (within 72 hours) elective coronary bypass surgery or death from pump failure. To eliminate the impact of multivessel coronary artery disease (CAD), 39 patients with 1-vessel CAD were analyzed separately. Five of 9 patients (56%) in the subtotal group, 3 of 10 (30%) in the reperfused group and only 2 of 20 (10%) in the occluded group had an ischemic event. These observations suggest the need for a more definitive revascularization strategy for acute myocardial infarction. © 1987