Duration and magnitude of hypotension and monocyte deactivation in patients with community-acquired pneumonia

The objective was to examine the relationship of duration and magnitude of arterial hypotension to subsequent cellular immune suppression and cytokinemia in patients hospitalized with community-acquired pneumonia (CAP). We studied an observational cohort of 525 subjects hospitalized after presenting to the emergency department with radiographic and clinical signs of CAP. We compared the duration and magnitude of hypotension, using the cardiovascular Sequential Organ Failure Assessment (CV SOFA) subscore, to day 3 monocyte expression of human leukocyte antigen-DR (mHLA-DR), a previously validated marker of cellular immune suppression. A significant association of CV SOFA with decreased mHLA-DR expression was present in univariate analysis (P < 0.001) and persisted after adjustment for illness severity and other covariates (P = 0.01). With CV SOFA separated into components of magnitude and duration, after covariate adjustment, only duration was associated with day 3 mHLA-DR expression (P = 0.03). Levels of key proinflammatory and anti-inflammatory cytokines (interleukin 6 [IL-6], IL-10, tumor necrosis factor) increased with hypotension exposure and were also associated with mHLA-DR expression. In patients admitted with CAP, arterial hypotension over the first 3 days is associated with markers of monocyte deactivation. The duration of exposure to hypotension may be more important than the magnitude, and monocyte deactivation correlates with IL-6 and IL-10 release. These results suggest that persistent hypotension might contribute to immunosuppression following septic shock.     

Discoloration of Teeth after Avulsion and Replantation: Results from a Multicenter Randomized Controlled Trial

Introduction

There is evidence to suggest that Ledermix, placed as an intervisit root canal dressing, might improve periodontal healing after replantation of avulsed teeth. As a part of a multicenter randomized controlled trial, we aimed to compare the effect of 2 root canal medicaments, Ledermix and Ultracal XS, on the discoloration of replanted teeth.

Methods

Discoloration was investigated by using 3 methods: patient satisfaction with the color of replanted teeth, clinical photographs taken at baseline and 12-month reviews, and estimation of color change by using CIELAB scores for baseline and 12-month photographs.

Results

Twenty-two patients (27 teeth) were recruited. Ten patients (12 teeth) were randomized to the Ledermix group and 12 patients (15 teeth) to the Ultracal XS group. At 12 months, 8 patients were concerned with the discoloration of their teeth. Seven came from the Ledermix group and 1 from the Ultracal XS group. This difference was significant (Fisher exact test, P = .009). Standardized photographs were taken for the patients recruited at one center only (17 patients). There was significant discoloration of teeth from baseline with Ledermix, causing a darkening and gray-brown discoloration (mean change from baseline to 12 months, L∗ = -5.1, a∗ = 0.3, b∗ = -1.2, and ΔE = 8.1) and Ultracal XS, causing a yellowing and lightening of teeth (L∗ = 1.9, a∗ = 0.3, b∗ = 3.3, and ΔE = 5.4). There was a significant difference for the L∗ and b∗ variables (independent t test) between the 2 groups.

Conclusions

Both root canal medicaments cause discoloration, with Ledermix proving less acceptable to patients.     

Looking back through the MIST: a perspective of evolving strategies and key focus areas for metabolite safety analysis

The publication of the US FDA MIST guidance document in 2008 reignited the debate around the most appropriate strategies to underwrite metabolite safety for novel compounds. Whilst some organizations have suggested that the guidelines necessitate a paradigm shift to more thorough metabolite analysis during early development, an evaluation of historical practices shows that the principles of the guidelines have always largely underpinned metabolism studies within the pharmaceutical industry. Therefore, it is argued that existing practices, when coupled to appropriate emerging analytical tools and a case-by-case consideration of the relevance of the generated metabolism data in terms of structure, physicochemisty, abundance and activity, represent a fit-for-purpose approach to metabolite-safety assessments.     

Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes

Cognitive deficits may index genetic liability for schizophrenia and are candidate endophenotypes for the illness. In order to compare the degree of sensitivity among cognitive tasks to group differences between healthy relatives and controls and the influence of moderator variables, this review reports mean effect sizes for 43 cognitive test scores from 58 studies of cognitive performance in the unaffected adult relatives of schizophrenia patients. Results indicate reliable relative-control differences, in the small to medium effect size range, over a diverse array of tasks, with the largest effect sizes seen in complex versions of continuous performance tasks, auditory verbal learning, design copy tests, and category fluency. Three study design features were found to have significant effects on overall effect size magnitude: groups unmatched on education, groups unmatched on age, and asymmetric psychiatric exclusion criteria. After excluding studies with the latter 2 design features, reliable performance differences were still observed over a smaller subset of cognitive test variables, with the largest effect sizes seen in Trails B (d = 0.50) and performance measures from both simple (d = 0.56) and complex (d = 0.60-0.66) versions of continuous performance tasks. Four of the 6 largest effect sizes reflect tasks with high executive control demands in common, such as working memory demands, set shifting, and inhibition of prepotent responses. Cognitive deficits, particularly those tapping such executive control functions, should continue to prove valuable as endophenotypes of interest in the search for specific genetic factors related to schizophrenia.     

Early treatment failure in severe malaria resulting from abnormally low plasma quinine concentrations

A patient admitted with severe Plasmodium falciparum malaria in western Thailand had an early treatment failure with quinine, despite full dosing. Plasma quinine concentrations were subtherapeutic. Abnormal quinine pharmacokinetics may explain sporadic reports of quinine treatment failures in severe malaria.     

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.