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Choudary S.K.,Tufts University | Qiu J.,Clinical Translational Research Institute | Plaut A.G.,Clinical Translational Research Institute | Kritzer J.A.,Tufts University
ChemBioChem | Year: 2013

Bacterial meningitis is a severe infectious disease with high mortality. Gram-positive and Gram-negative bacteria that cause meningitis secrete immunoglobulin A1 (IgA1) proteases to assist in mucosal colonization, invasion, and immune evasion. IgA1 proteases have unique selectivity, with few reported substrates other than IgA1 from human tissue. Here we describe the design, characterization, and application of peptide substrates for diverse IgA1 proteases from Neisseria, Haemophilus, and Streptococcus bacteria. IgA1 proteases from diverse strains showed unexpected selectivity profiles among peptide substrates derived from autoproteolytic sites. A fluorescence probe derived from one of these peptides was used to quantitate IgA1 protease activity in buffer and in human cerebrospinal fluid; it was able to detect recombinant Haemophilus influenzae type 1 IgA1 protease at less than 1 μgmL-1. We also used the probe to establish the first high-throughput screen for IgA1 protease inhibitors. This work provides tools that will help investigate the roles of IgA1 proteases in bacterial colonization, immune evasion, and infection. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Ilfeld B.M.,University of California at San Diego | Madison S.J.,University of California at San Diego | Suresh P.J.,University of California at San Diego | Sandhu N.S.,University of California at San Diego | And 6 more authors.
Regional Anesthesia and Pain Medicine | Year: 2014

BACKGROUND: We aimed to determine with this randomized, triple-masked, placebo-controlled study if benefits are afforded by adding a multiple-day, ambulatory, continuous ropivacaine paravertebral nerve block to a single-injection ropivacaine paravertebral block after mastectomy. METHODS: Preoperatively, 60 subjects undergoing unilateral (n = 24) or bilateral (n = 36) mastectomy received either unilateral or bilateral paravertebral perineural catheter(s), respectively, inserted between the third and fourth thoracic transverse process(es). All subjects received an initial bolus of ropivacaine 0.5% (15 mL) via the catheter(s). Subjects were randomized to receive either perineural ropivacaine 0.4% or normal saline using portable infusion pump(s) [5 mL/h basal; 300 mL reservoir(s)]. Subjects remained hospitalized for at least 1 night and were subsequently discharged home where the catheter(s) were removed on postoperative day (POD) 3. Subjects were contacted by telephone on PODs 1, 4, 8, and 28. The primary end point was average pain (scale, 0-10) queried on POD 1. RESULTS: Average pain queried on POD 1 for subjects receiving perineural ropivacaine (n = 30) was a median (interquartile) of 2 (0-3), compared with 4 (1-5) for subjects receiving saline (n = 30; 95% confidence interval difference in medians, -4.0 to -0.3; P = 0.021]. During this same period, subjects receiving ropivacaine experienced a lower severity of breakthrough pain (5 [3-6] vs 7 [5-8]; P = 0.046) as well. As a result, subjects receiving perineural ropivacaine experienced less pain-induced physical and emotional dysfunction, as measured with the Brief Pain Inventory (lower score = less dysfunction): 14 (4-37) versus 57 (8-67) for subjects receiving perineural saline (P = 0.012). For the subscale that measures the degree of interference of pain on 7 domains, such as general activity and relationships, subjects receiving perineural saline reported a median score 10 times higher (more dysfunction) than those receiving ropivacaine (3 [0-24] vs 33 [0-44]; P = 0.035). In contrast, after infusion discontinuation, there were no statistically significant differences detected between treatment groups. CONCLUSIONS: After mastectomy, adding a multiple-day, ambulatory, continuous ropivacaine infusion to a single-injection ropivacaine paravertebral nerve block results in improved analgesia and less functional deficit during the infusion. However, no benefits were identified after infusion discontinuation. Copyright © 2014 by American Society of Regional Anesthesia and Pain. Source

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