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The asthmatic airways are highly susceptible to inflammatory injury by air pollutants such as ozone (O 3 ), characterized by enhanced activation of eosinophilic granulocytes and a failure of immune protective mechanisms. Eosinophil activation during asthma exacerbation contributes to the proinflammatory oxidative stress by high levels of nitric oxide (NO) production and extracellular DNA release. Surfactant protein-D (SP-D), an epithelial cell product of the airways, is a critical immune regulatory molecule with a multimeric structure susceptible to oxidative modifications. Using recombinant proteins and confocal imaging, we demonstrate here that SP-D directly bound to the membrane and inhibited extracellular DNA trap formation by human and murine eosinophils in a concentration and carbohydrate-dependent manner. Combined allergic airway sensitization and O 3 exposure heightened eosinophilia and nos2 mRNA (iNOS) activation in the lung tissue and S-nitrosylation related de-oligomerisation of SP-D in the airways. In vitro reproduction of the iNOS action led to similar effects on SP-D. Importantly, S-nitrosylation abolished the ability of SP-D to block extracellular DNA trap formation. Thus, the homeostatic negative regulatory feedback between SP-D and eosinophils is destroyed by the NO-rich oxidative lung tissue environment in asthma exacerbations., (©2018 Society for Leukocyte Biology.)

Aims: Autologous CD34+ (auto-CD34+) cells represent an attractive option for the treatment of refractory angina. Three double-blinded randomized trials (n = 304) compared intramyocardial (IM) auto-CD34+ cells with IM placebo injections to affect total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE). Patient-level data were pooled from the Phase I, Phase II ACT-34, ACT-34 extension, and Phase III RENEW trials to determine the efficacy and safety of auto-CD34+ cells., Methods and Results: Treatment effects for TET were analysed using an analysis of covariance mixed-effects model and for AF using Poisson regression in a log linear model with repeated measures. The Kaplan-Meier rate estimates for MACE were compared using the log-rank test. Autologous CD34+ cell therapy improved TET by 46.6 s [3 months, 95% confidence interval (CI) 13.0 s-80.3 s; P = 0.007], 49.5 s (6 months, 95% CI 9.3-89.7; P = 0.016), and 44.7 s (12 months, 95% CI - 2.7 s-92.1 s; P = 0.065). The relative frequency of angina was 0.78 (95% CI 0.63-0.98; P = 0.032), 0.66 (0.48-0.91; P = 0.012), and 0.58 (0.38-0.88; P = 0.011) at 3-, 6- and 12-months in auto-CD34+ compared with placebo patients. Results remained concordant when analysed by treatment received and when confined to the Phase III dose of 1 × 105 cells/kg. Autologous CD34 + cell therapy significantly decreased mortality (12.1% vs. 2.5%; P = 0.0025) and numerically reduced MACE (38.9% vs. 30.0; P = 0.14) at 24 months., Conclusion: Treatment with auto-CD34+ cells resulted in clinically meaningful durable improvements in TET and AF at 3-, 6- and 12-months, as well as a reduction in 24-month mortality in this patient-level meta-analysis.

Aims: Evidence from randomized controlled trials (RCTs) evaluating possible benefits of endovascular therapy (EVT) for acute ischaemic stroke has shown conflicting results. The purpose of this meta-analysis was to systematically examine clinical outcomes in RCTs comparing the use of intravenous (IV) fibrinolysis alone to IV fibrinolysis plus EVT, for the treatment of acute ischaemic stroke., Methods and Results: We selected English language RCTs, comparing EVT plus IV tissue-type plasminogen activator (tPA) (if eligible) with IV tPA alone in eligible patients for the treatment of acute ischaemic stroke. The primary endpoint was good functional outcome [modified Rankin Scale (mRS) of 0-2]. Other major endpoints of interest were all-cause mortality and symptomatic intracerebral haemorrhage (sICH). The meta-analysis included 8 RCTs that randomized 2423 patients with large-vessel, anterior-circulation stroke. EVT significantly improved the rate of functional independence (90-day mRS of 0-2) when compared with IV fibrinolysis [odds ratio (OR) 1.73, 95% confidence interval (CI) 1.18-2.53, number needed to treat (NNT) = 9.3]. The all-cause mortality was lower with EVT compared with the control group; however, the result did not reach statistical significance (OR 0.89, 95% CI 0.68-1.15). The rate of sICH was not higher with EVT (OR 1.07, 95% CI 0.73-1.56). Analyses from only the recent trials (reported in 2014-15) showed further benefit (OR of mRS 0-2: 2.42, 95% CI 1.91-3.08, NNT = 5) with similar safety results., Conclusion: In centres with advanced systems of stroke care, EVT significantly improved functional outcomes (without compromising safety) in patients with acute ischaemic stroke due to anterior circulation, large artery occlusion, compared with standard therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Dotter first described percutaneous revascularization of peripheral vascular disease (PVD) in 1964. In 1974, Gruentzig developed a balloon catheter for dilation of vascular lesions. Currently, percutaneous transluminal angioplasty (PTA) employs a variety of devices ranging from implantable stents to endovascular radiation devices for re-stenosis and is recognized as a safe and effective alternative to surgery for selected patients. In addition to the general efficacy of peripheral angioplasty, which is comparable to that of bypass surgery for selected lesions, angioplasty offers several distinct advantages over surgery. It is performed under local anaesthesia, making it feasible to treat patients who are at high risk for general anaesthesia. When compared to surgical revascularization, the morbidity from angioplasty is low, generally related to problems at the vascular access site, and mortality is extremely rare. Unlike vascular surgery, there is no recovery period after angioplasty, and most patients can return to normal activity within 24-48 h of an uncomplicated procedure. Finally, angioplasty can be repeated if necessary usually without increased difficulty or increased patient risk compared to the first procedure, and does not preclude surgery as adjunctive or definitive therapy.

Eight hundred and twelve children, 12 months to 3.5 years of age, were enrolled in two clinical studies to evaluate the safety and immunogenicity of a live, attenuated combination vaccine for measles, mumps, rubella, and varicella (MMRV). Children were enrolled in one of two randomized, multicenter studies, involving administration of (1) MMRV and placebo vs. measles, mumps, and rubella vaccine (M-M-R(II)) and varicella-zoster virus vaccine (VARIVAX), given at separate anatomic sites at the same office visit; or (2) MMRV, DTaP (diphtheria, tetanus, and acellular pertussis vaccine) and OPV (oral polio vaccine) vs. M-M-R(II), DTaP, and OPV, with VARIVAX given 6 weeks later. All vaccine regimens were generally well tolerated. More than 95% of vaccinees seroconverted for measles, mumps, rubella, and varicella, regardless of the vaccine or regimen used. In each study, the level of antibody titer to varicella virus was significantly lower in vaccinees receiving MMRV than in those who received VARIVAX in a separate syringe.

To approximate the effect of prolonged storage on safety and immunogenicity, healthy children were given a single dose of the currently marketed live attenuated varicella vaccine (3625 pfu) or of a partially heat-inactivated vaccine (1125 or 439 pfu). The 3 doses had similar antigen content (attenuated plus inactive virus particles). The vaccine was well tolerated. No significant differences in adverse reactions were observed. Although the seroconversion rates were excellent at each dose (> or = 98%), the higher doses resulted in significantly greater geometric mean antibody titers at 6 weeks (10.5 and 10.6 ELISA U/mL) compared with the 439 pfu dose (5.7 ELISA U/mL), P < or = .01. One year after immunization, differences in antibodies were similar to the 6-week postimmunization results. Results indicate that until the date of expiry, the vaccine's immunogenicity will be preserved and there will be no clinically important changes in type or frequency of adverse events.

An investigational tetravalent combined measles, mumps, rubella, and varicella vaccine and measles-mumps-rubella and varicella vaccines at separate injection sites given at the same visit were evaluated with respect to safety and cell-mediated and humoral immune responses at 6 weeks and 1 year after vaccination. Varicella seroconversion rates and lymphocyte proliferation responses were 100% for both vaccine groups at 6 weeks and 1 year. However, the antibody titer to varicella was lower in the combined vaccine group at 6 weeks, but there was no statistical difference in cell-mediated immune responses. One-year geometric mean titers were not statistically different. Seroconversion rates for measles, mumps, and rubella were 100% for both vaccine at 6 weeks and 1 year. Long-term follow-up of these immune responses is planned.

Annually, for 4 years after a live attenuated varicella-zoster virus (VZV) vaccine was administered to 202 elderly (55 to > 87 years old) VZV-immune persons, the immune response of vaccinees was evaluated. Anti-VZV antibody levels were enhanced by vaccination for just 1 year. However, VZV-specific proliferating T cells in peripheral blood were increased in frequency from 1 in 68,000 to 1 in 40,000 at 1 year; VZV-responding T cells were still 1 in 51,000 4 years after vaccination. The calculated half-life of this enhanced immunity was 54 months. Age had little effect on response to the vaccine, but larger doses were associated with longer duration of enhanced immunity. Immunity in approximately 10%-15% of vaccinees, independent of dose, failed to increase with the vaccine. This might complicate the use of this vaccine for prevention or attenuation of herpes zoster in the elderly.

The purpose of the study was to establish the minimum immunizing dose of stored Oka/Merck varicella vaccine and mimic effects of prolonged storage of vaccine at freezer temperatures. Ninety children were randomized to one of three groups: group A (1770 pfu/dose), group B (400-500 pfu/dose), or group C (80-160 pfu/dose). Seroconversion rates for groups A-C were 97%, 96%, and 92%, respectively. Group A and B vaccinees had higher antibody titers at 1 year than did group C subjects (P = .01). The difference between groups B and C approached significance (P = .058). At 1 year after immunization, 73%, 83%, and 80% in groups A-C, respectively, demonstrated cell-mediated responses. Since freshly reconstituted vaccine contains 1770 pfu/dose, vaccine failure from loss of potency is unlikely if vaccine is stored properly and administered promptly after reconstitution.

The Oka strain live attenuated varicella-zoster virus (VZV) vaccine was administered subcutaneously to 202 VZV-immune individuals who were 55 to greater than 87 years old. The dose administered varied from 1100 to 12,000 pfu. One cohort received 3000 pfu with a 3000 pfu booster 3 months later. The vaccine was well tolerated. VZV-specific immunologic responses were evaluated over a 24-month period. The mean anti-VZV antibody level was significantly increased for 12 months after vaccination. Interferon-gamma production in vitro by peripheral blood mononuclear cells (PBMC) of vaccinees was also increased for 6 months after vaccination. Most significantly, VZV-specific proliferating T cells in PBMC of vaccinees were increased in frequency from 1 in 68,000 to 1 in 40,000. This vaccine-enhanced frequency of VZV-responding T cells is similar to the frequency observed in 35- to 40-year-old adults. Dose and age of the vaccinees did not significantly influence the magnitude of the mean cell-mediated immune response. The data indicate that VZV immunity in the elderly can be boosted by active immunization. If the increased incidence of herpes zoster that accompanies aging results from the natural waning of immunity, active immunization may prevent or attenuate zoster in the elderly.

Aspergillus nidulans var. echinulatus was the sole agent cultured from the left lung, a paraspinal abscess, left ribs, and thoracic vertebral bodies from a patient with chronic granulomatous disease. Hyphal elements were present in histologic sections of lung, vertebral bodies, and infected ribs along with granuloma formation. The patient was treated with two debridement procedures and insertion of a Harrington rod followed by a long course of amphotericin B, flucytosine, and daily white blood cell transfusions.

Normal volunteers were infected with hookworm larvae Necator americanus. Peripheral blood counts showed a mean of 524 +/- 29 eosinophils/mm3 of blood before infection and a mean of 3,008 +/- 456 eosinophils/mm3 of blood during infection (P less than .01). Absolute numbers of neutrophils did not change. Eosinophils and neutrophils from the infected period were compared with the noninfected state in each subject. The percentage of hypodense eosinophils increased from a mean of 34% +/- 13% to 80% +/- 7% during infection (P less than .05). Superoxide production of eosinophils increased from a mean of 56 +/- 9 to 97 +/- 12 nmol of O2-./10(6) cells per 60 min (P less than .05) during infection. Chemotaxis of eosinophils to Escherichia coli endotoxin-activated serum increased from a mean average distance migrated of 19 +/- 2 micron (P less than .05), whereas neutrophil responsiveness did not change. This is the first report of changes in eosinophil density and stimulation of eosinophil function in normal hosts experimentally infected with hookworm. The data indicate that hookworm infection preferentially increases eosinophil production and activity with little effect on neutrophils.