E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators

Context  Knowledge and understanding of gram-negative sepsis have grown over the past 20 years, but the ability to treat severe sepsis successfully has not. Objective  To assess the efficacy and safety of E5 in the treatment of patients with severe gram-negative sepsis. Design  A multicenter, double-blind, randomized, placebo-controlled trial conducted at 136 US medical centers from April 1993 to April 1997, designed with 90% power to detect a 25% relative risk reduction, incorporating 2 planned interim analyses. Setting  Intensive care units at university medical centers, Veterans Affairs medical centers, and community hospitals. Patients  Adults aged 18 years or older, with signs and symptoms consistent with severe sepsis and documented or probable gram-negative infection. Intervention  Patients were assigned to receive 2 doses of either E5, a murine monoclonal antibody directed against endotoxin (n = 550; 2 mg/kg per day by intravenous infusion 24 hours apart) or placebo (n = 552). Main Outcome Measures  The primary end point was mortality at day 14; secondary end points were mortality at day 28, adverse event rates, and 14-day and 28-day mortality in the subgroup without shock at presentation. Results  The trial was stopped after the second interim analysis. A total of 1090 patients received study medication and 915 had gram-negative infection confirmed by culture. There were no statistically significant differences in mortality between the E5 and placebo groups at either day 14 (29.7% vs 31.1%; P = .67) or day 28 (38.5% vs 40.3%; P = .56). Patients presenting without shock had a slightly lower mortality when treated with E5 but the difference was not significant (28.9% vs 33.0% for the E5 and placebo groups, respectively, at day 28; P = .32). There was a similar profile of adverse event rates between E5 and placebo. Conclusions  Despite adequate sample size and high enrollment of patients with confirmed gram-negative sepsis, E5 did not improve short-term survival. Current study rationale and designs should be carefully reviewed before further large-scale studies of patients with sepsis are conducted.      

Circulating serum xenoestrogens and mammographic breast density

Introduction

Humans are widely exposed to estrogenically active phthalates, parabens, and phenols, raising concerns about potential effects on breast tissue and breast cancer risk. We sought to determine the association of circulating serum levels of these chemicals (reflecting recent exposure) with mammographic breast density (a marker of breast cancer risk).

Methods

We recruited postmenopausal women aged 55 to 70 years from mammography clinics in Madison, Wisconsin (N = 264). Subjects completed a questionnaire and provided a blood sample that was analyzed for mono-ethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, butyl paraben, propyl paraben, octylphenol, nonylphenol, and bisphenol A (BPA). Percentage breast density was measured from mammograms by using a computer-assisted thresholding method.

Results

Serum BPA was positively associated with mammographic breast density after adjusting for age, body mass index, and other potentially confounding factors. Mean percentage density was 12.6% (95% confidence interval (CI), 11.4 to 14.0) among the 193 women with nondetectable BPA levels, 13.7% (95% CI, 10.7 to 17.1) among the 35 women with detectable levels below the median (<0.55 ng/ml), and 17.6% (95% CI, 14.1 to 21.5) among the 34 women with detectable levels above the median (>0.55 ng/ml; P_trend = 0.01). Percentage breast density was also elevated (18.2%; 95% CI, 13.4 to 23.7) among the 18 women with serum mono-ethyl phthalate above the median detected level (>3.77 ng/ml) compared with women with nondetectable BPA levels (13.1%; 95% CI, 11.9 to 14.3; P_trend = 0.07). No other chemicals demonstrated associations with percentage breast density.

Conclusions

Postmenopausal women with high serum levels of BPA and mono-ethyl phthalate had elevated breast density. Further investigation of the impact of BPA and mono-ethyl phthalate on breast cancer risk by using repeated serum measurements or other markers of xenoestrogen exposure are needed.     

Rinderpest Virus Sequestration and Use in Posteradication Era

After the 2011 declaration of rinderpest disease eradication, we surveyed 150 countries about rinderpest virus stocks. Forty-four laboratories in 35 countries held laboratory-attenuated strains, field strains, or diagnostic samples. Vaccine and reagent production and laboratory experiments continued. Rigorous standards are necessary to ensure that stocks are kept under safe conditions.     

Spinal injuries in motorcycle crashes: patterns and outcomes

BACKGROUND: The purpose of this study was to determine patterns of spinal injury and clinical outcomes resulting from motorcycle crashes. METHODS: We analyzed data collected on 1,121 motorcyclists involved in road traffic accidents (from 1993-2000) and identified those who had sustained a spinal injury. RESULTS: Spinal injury occurred in 126 (11.2%) riders (112 male riders [88.9%] and 14 female riders [11.1%]), with a mean age of 30.2 years (range, 16-61 years) and Injury Severity Score of 18.8 (range, 4-66). Isolated injuries to the spine occurred in 30 (23.8%) riders. The thoracic spine was injured in 69 (54.8%), the lumbar spine in 37 (29.4%), and the cervical spine in 34 (27.0%) cases. Multiple vertebral levels were affected in 54 (42.9%). Neurologic injury occurred in 25 riders (19.8%), with complete distal neurologic injury in 14 (4 cervical, 9 thoracic, and 1 lumbar). Eleven (8.7%) patients required spinal surgery. There were 13 (10.3%) deaths. CONCLUSION: The thoracic spine is the most commonly injured spinal region in motorcycle crashes. Multiple level injuries are common. Protocols concentrating on the radiographic clearance of the cervical region may miss a significant number of spinal injuries. Vigilance is required in assessing these patients, who often have multiple injuries.     

Persistent Depression of Contractility and Vasodilation with Propofol but Not with Sevoflurane or Desflurane in Rabbits

Background: Propofol, sevoflurane, and desflurane may cause hemodynamic compromise during anesthesia and critical care management. The aim of the study was to compare these anesthetics during increased dose and recovery to maintenance level.

Methods: Anesthetized, open-chest New Zealand White rabbits were used to acquire dose-response curves with sevoflurane, desflurane, and propofol, followed by reduction to baseline infusion. Simultaneous high-fidelity left ventricular pressure and volume data were acquired during caval occlusion with a dual-field conductance catheter inserted via an apical stab. The preload recruitable stroke work and the end-diastolic pressure-volume relationship were used as the primary measures of contractility and diastolic function.

Results: The time-matched controls were stable over time. Propofol and desflurane but not sevoflurane caused dose-dependent reductions in myocardial contractility, although sevoflurane reduced contractility more at 1 minimal alveolar concentration. All anesthetics reduced mean arterial pressure, and significant recovery occurred for sevoflurane and desflurane but not for propofol. The end-diastolic pressure-volume relationship was increased by sevoflurane. Ejection fraction decreased with sevoflurane only. All anesthetics caused dose-dependent vasodilation, with recovery for desflurane and sevoflurane but not propofol. Heart rate was decreased with propofol without significant recovery. Propofol plasma concentrations remained elevated after dose return to baseline infusion rate, suggestive of distribution compartment saturation.     

Destructive index: a measurement of lung parenchymal destruction in smokers

Destruction of alveolar walls is considered by most observers to be the most important part in the definition of emphysema, yet it has never been precisely defined and quantitated. We therefore attempted to devise a reliable microscopic technique to quantitate alveolar destruction that would be both sensitive to disease and easy to perform. Using a point-count system, we obtained an index of parenchymal destruction that represents the percentage of destroyed space as a fraction of the total alveolar and duct space. We have called this measurement the destructive index (DI). In the lungs of 8 nonsmokers and 23 smokers, we quantitated the DI and compared it with the mean linear intercept (Lm) and with pulmonary function in smokers. Although Lm was not significantly different in the 2 groups, significant differences between the DI of smokers and nonsmokers (p less than 0.005) were found. In addition, the DI correlated with FEV1(-0.43, p less than 0.05), MMEF (r = -0.44, p less than 0.05), and recoil pressure at 90% TLC (r = -0.61, p less than 0.05) in smokers. These findings suggest that the destructive component of emphysema can be easily quantitated microscopically, occurs in smokers before dimensional changes are evident (i.e., increased Lm), and influences lung function. Therefore, the quantitation of this destruction (DI) could add greatly to the microscopic definition of emphysema, complementing the information given by the dimensional component of emphysema (Lm).     

Differential modulation of CD4 and CD8 T-cell proliferation by induction of nitric oxide synthesis in antigen presenting cells

BACKGROUND: On antigenic stimulation, CD4 T cells generally proliferate more readily than CD8 T cells. The purpose of the present experiments was to determine whether nitric oxide (NO) might differentially modulate CD4 vs. CD8 T-cell proliferation. METHODS: Various concentrations of C57BL/6 iNOS +/+ and -/- bone marrow (BM)-derived antigen presenting cells (APC) (obtained by culture in granulocyte-macrophage colony-stimulating factor [GM-CSF] and interleukin [IL]-4) were cultured with purified BALB/c CD4 or CD8 T cells. RESULTS: Proliferation of CD4 T cells was similar in the presence of both NO synthase (iNOS) +/+ and -/- APC, whereas CD8 T cell proliferation was inhibited at the higher concentrations of iNOS +/+ dendritic cells (DC), coincident with increased levels of NO in the culture supernatant. Analysis of cytokine levels revealed that more interferon (IFN)-gamma, a potent inducer of NO synthesis in many cell types, was present in CD8 T cell than in CD4 T-cell-APC cultures. Addition of IFN-gamma to CD4 T-cell-APC cultures resulted in induction of NO synthesis and inhibition of proliferation at higher levels of NO than that required to inhibit CD8 T cell proliferation. However, CD4 T-cell proliferation was moderately inhibited in the presence of lipopolysaccharide (LPS)-stimulated CD11c DC, coincident with production of IFN-gamma and induction of NO synthesis. CONCLUSIONS: These findings indicate that CD8 T-cell proliferation can be inhibited by lesser amounts of APC-derived NO than is necessary to inhibit CD4 T cell proliferation. NO synthesis was not initiated in CD4 T cell-DC cultures unless costimulatory molecules were up-regulated and IFN-gamma was produced.