Citations

Aging and hypertension lead to arterial remodeling and tandem increases in arterial (Ea) and ventricular (LV) systolic stiffness (ventricular-arterial [VA] coupling). Age and hypertension also predispose to heart failure with normal ejection fraction (HFnlEF), where symptoms during hypertensive urgencies or exercise are common. We hypothesized that: (1) chronic VA coupling also occurs in diastole, (2) acute changes in Ea are coupled with shifts in the diastolic and systolic pressure-volume relationships (PVR), and (3) diastolic VA coupling reflects changes in LV diastolic stiffness rather than external forces or relaxation. Old chronically hypertensive (OHT, n=8) and young normal (YNL, n=7) dogs underwent assessment of PVR (caval occlusion) and of aortic pressure, dimension, and flow, at baseline and during changes in afterload and preload. Concomitant changes in the slope/position of PVR were accounted for by calculating systolic (ESV 200 ) and diastolic (EDV 20 ) volumes at common pressures (capacitance). OHT displayed marked vascular remodeling. Indices reflecting the pulsatile component of Ea (aortic stiffness and systemic arterial compliance) were more impaired in OHT at any distending pressure. In both groups, acute increases in Ea were associated with decreases in ESV 200 and EDV 20 . However, at any load, OHT had lower ESV 200 and EDV 20 , associated with LV remodeling and myocardial endothelin activation. Acute changes in EDV 20 were not mediated by changes in relaxation or external forces. These observations provide insight into the mechanisms whereby arterial remodeling and acute and chronic VA coupling in both systole and diastole may predispose to and interact with increases in load to cause HFnlEF.

Purpose Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. Patients and Methods In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. Results One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. Conclusion Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.

ABSTRACT Staphylococcus lugdunensis is an atypically virulent coagulase-negative staphylococcal species associated with acute and destructive infections that often resemble Staphylococcus aureus infections. Several types of infection caused by S. lugdunensis (e.g., native valve endocarditis, prosthetic joint infection, and intravascular catheter infection) are associated with biofilm formation, which may lead to an inability to eradicate the infection due to the intrinsic nature of biofilms to resist high levels of antibiotics. In this study, planktonic MICs and MBCs and biofilm bactericidal concentrations of 10 antistaphylococcal antimicrobial agents were measured for 15 S. lugdunensis isolates collected from patients with endocarditis, medical device infections, or skin and soft tissue infections. Planktonic isolates were susceptible to all agents studied, but biofilms were resistant to high concentrations of most of the drugs. However, moxifloxacin was able to kill 73% of isolates growing in biofilms at ≤0.5 μg/ml. Relative to the effect on cell density, subinhibitory concentrations of nafcillin substantially stimulated biofilm formation of most isolates, whereas tetracycline and linezolid significantly decreased biofilm formation in 93 and 80% of isolates, respectively. An unexpected outcome of MBC testing was the observation that vancomycin was not bactericidal against 93% of S. lugdunensis isolates, suggesting widespread vancomycin tolerance in this species. These data provide insights into the response of S. lugdunensis isolates when challenged with various levels of antimicrobial agents in clinical use.

ABSTRACT Staphylococci, common orthopedic pathogens, form antibiotic-resistant biofilms. Polymethylmethacrylate (PMMA) beads loaded with the quorum-sensing inhibitor RNAIII-inhibiting peptide (RIP) were implanted in rats and shown to prevent methicillin-resistant Staphylococcus aureus infection. RIP release was bimodal, typical of previously-tested antibiotics. These results suggest that RIP-PMMA warrants further evaluation for management of orthopedic infections caused by staphylococci.

ABSTRACT Conjunctival exposure to the Staphylococcus aureus superantigen staphylococcal enterotoxin B (SEB) may occur accidentally, as a result of bioterrorism, or during colonization or infection of the external eye. Using human leukocyte antigen class II transgenic mice, we show for the first time that conjunctival exposure to SEB can cause robust systemic immune activation.

Abstract Fracture risk among patients diagnosed with asthma in childhood is greater in males and oral corticosteroid users, but most fractures are of the appendicular skeleton and may relate to impaired skeletal development. Introduction: There are no population-based data on fracture outcomes among the growing number of patients with asthma diagnosed in childhood. Materials and Methods: We conducted a population-based retrospective (historical) cohort study among 279 Rochester, Minnesota, residents who were <35 years of age (mean, 6.2 years) when first diagnosed with asthma. Fractures were ascertained by review of comprehensive community medical records, and cases were compared directly with age- and sex-matched controls in a stratified proportional hazards model. Risk factors for fractures among the asthma cases were assessed using Andersen-Gill time-to-fracture regression models. Results: During 6649 person-years of follow-up (median, 24.3 years/subject), 107 asthma patients experienced 189 fractures, for a crude fracture incidence rate of 2.8 per 100 person-years. The actuarially estimated cumulative fracture incidence after 20 years was 40% compared with 34% among controls (p = 0.122). There was no significant increase in overall fracture risk among cases compared to their age- and sex-matched controls (hazard ratio [HR], 1.3; 95% CI, 0.9-1.9), but males with asthma had a 2.6-fold greater risk of hand and finger fractures than control males. The independent predictors of overall fracture risk among the asthma patients included male gender (HR, 2.2; 95% CI, 1.5-3.2) and use of oral corticosteroids (HR, 2.0; 95% CI, 1.2-3.1) or anti-cholinergic agents (HR, 3.9; 95% CI, 1.5-10). Conclusions: Rather than osteoporotic fractures of the axial skeleton, oral corticosteroid therapy was associated here with limb fractures, suggesting a relationship with impaired development of a biomechanically competent skeleton. Additional studies are needed to assess this possibility.

ABSTRACT The activity of garenoxacin was compared to that of levofloxacin or penicillin in a rabbit model of Streptococcus mitis group (penicillin MIC, 0.125 μg/ml) and Streptococcus sanguinis group (penicillin MIC, 0.25 μg/ml) endocarditis. Garenoxacin and levofloxacin had MICs of 0.125 and 0.5 μg/ml, respectively, for both study isolates. Rabbits with catheter-induced aortic valve endocarditis were given no treatment, penicillin at 1.2 × 10 6 IU/8 h intramuscularly, garenoxacin at 20 mg/kg of body weight/12 h intravenously, or levofloxacin at 40 mg/kg/12 h intravenously. For both isolates tested, garenoxacin area under the curve (AUC)/MIC and maximum concentration of drug in serum ( C max )/MIC ratios were 368 and 91, respectively. Rabbits were sacrificed after 3 days of treatment; cardiac valve vegetations were aseptically removed and quantitatively cultured. For S. mitis group experimental endocarditis, all studied antimicrobial agents were more active than no treatment ( P < 0.001), whereas for S. sanguinis group endocarditis, no studied antimicrobial agents were more active than no treatment. We conclude that AUC/MIC and C max /MIC ratios may not predict activity of some quinolones in experimental viridans group endocarditis and that garenoxacin and levofloxacin may not be ideal choices for serious infections caused by some quinolone-susceptible viridans group streptococci.