Loss of the pro-apoptotic BH3-only Bcl-2 family member Bim inhibits BCR stimulation-induced apoptosis and deletion of autoreactive B cells

During development, the stochastic process assembling the genes encoding antigen receptors invariably generates B and T lymphocytes that can recognize self-antigens. Several mechanisms have evolved to prevent the activation of these cells and the concomitant development of autoimmune disease. One such mechanism is the induction of apoptosis in developing or mature B cells by engagement of the B cell antigen receptor (BCR) in the absence of T cell help. Here we report that B lymphocytes lacking the pro-apoptotic Bcl-2 family member Bim are refractory to apoptosis induced by BCR ligation in vitro. The loss of Bim also inhibited deletion of autoreactive B cells in vivo in two transgenic systems of B cell tolerance. Bim loss prevented deletion of autoreactive B cells induced by soluble self-antigen and promoted accumulation of self-reactive B cells developing in the presence of membrane-bound self-antigen, although their numbers were considerably lower compared with antigen-free mice. Mechanistically, we determined that BCR ligation promoted interaction of Bim with Bcl-2, inhibiting its survival function. These findings demonstrate that Bim is a critical player in BCR-mediated apoptosis and in B lymphocyte deletion.     

Recovery of a hypothermic drowned child after resuscitation with cardiopulmonary bypass followed by prolonged extracorporeal membrane oxygenation

Drowning is a leading cause of death in children worldwide. However, there is uncertainty about the initiation and the extent of adequate therapeutic interventions after drowning accidents. As prediction of outcome in drowned children remains difficult, initial maximum life support appears to be generally justified. We present the case of a 3-year-old drowned girl in refractory cardiorespiratory arrest who was resuscitated successfully with cardiopulmonary bypass (CPB) followed by extracorporeal membrane oxygenation (ECMO) for 4 days. After a prolonged period in a vegetative state eventually she made an almost complete neurological recovery. We do not have knowledge of any case of drowning reported with a favourable neurological outcome after such a prolonged period of ECMO.     

Crystal structure of the yeast eIF4A-eIF4G complex: an RNA-helicase controlled by protein-protein interactions

Translation initiation factors eIF4A and eIF4G form, together with the cap-binding factor eIF4E, the eIF4F complex, which is crucial for recruiting the small ribosomal subunit to the mRNA 5' end and for subsequent scanning and searching for the start codon. eIF4A is an ATP-dependent RNA helicase whose activity is stimulated by binding to eIF4G. We report here the structure of the complex formed by yeast eIF4G's middle domain and full-length eIF4A at 2.6-A resolution. eIF4A shows an extended conformation where eIF4G holds its crucial DEAD-box sequence motifs in a productive conformation, thus explaining the stimulation of eIF4A's activity. A hitherto undescribed interaction involves the amino acid Trp-579 of eIF4G. Mutation to alanine results in decreased binding to eIF4A and a temperature-sensitive phenotype of yeast cells that carry a Trp579Ala mutation as its sole source for eIF4G. Conformational changes between eIF4A's closed and open state provide a model for its RNA-helicase activity.     

Chairside CAD/CAM materials. Part 1: Measurement of elastic constants and microstructural characterization

Objective

A deeper understanding of the mechanical behavior of dental restorative materials requires an insight into the materials elastic constants and microstructure. Here we aim to use complementary methodologies to thoroughly characterize chairside CAD/CAM materials and discuss the benefits and limitations of different analytical strategies.

Self-adhesive resin cements: pH-neutralization,hydrophilicity, and hygroscopic expansion stress

Clinical Oral Investigations - The objective of the study was to investigate the relationship between pH-neutralization, hydrophilicity, and free hygroscopic expansion stress of self-adhesive resin...     

Systemic lupus erythematosus in an African Caribbean population: Incidence,clinical manifestations,and survival in the Barbados National Lupus Registry

Objective

To assess the epidemiology, clinical features, and outcomes of systemic lupus erythematosus (SLE) in the predominantly African Caribbean population of Barbados.

Methods

A national registry of all patients diagnosed with SLE was established in 2007. Complete case ascertainment was facilitated by collaboration with the island's sole rheumatology service, medical practitioners, and the lupus advocacy group. Informed consent was required for inclusion.

Results

Between January 1, 2000 and December 31, 2009, there were 183 new cases of SLE (98% African Caribbean) affecting 172 women and 11 men for unadjusted annual incidence rates of 12.21 (95% confidence interval [95% CI] 10.46–14.18) and 0.84 (95% CI 0.42–1.51) per 100,000 person‐years, respectively. Excluding pediatric cases (ages <18 years), the unadjusted incidence rate among women was 15.14 per 100,000 person‐years. The principal presenting manifestations were arthritis (84%), nephritis (47%), pleuritis (41.5%), malar rash (36.4%), and discoid lesions (33.1%). Antinuclear antibody positivity was 95%. The overall 5‐year survival rate was 79.9% (95% CI 69.6–87.1), decreasing to 68% in patients with nephritis. A total of 226 persons with SLE were alive at the end of the study for point prevalences of 152.6 (95% CI 132.8–174.5) and 10.1 (95% CI 5.4–17.2) per 100,000 among women and men, respectively.

Conclusion

Rates of SLE in Barbadian women are among the highest reported to date, with clinical manifestations similar to African American women and high mortality. Further study of this population and similar populations of West African descent might assist our understanding of environmental, genetic, and health care issues underpinning disparities in SLE.     

Conducting a meta-analysis: basics and good practices

Meta-analysis is a statistical method to compare and combine effect sizes from a pool of relevant empirical studies. It is now a standard approach to synthesize research findings in many disciplines, including medical and healthcare research. This paper is the third paper of a mini-series introducing systematic review and meta-analysis. First, common effect sizes used in meta-analysis are presented. Fixed-, random- and mixed-effects models are then introduced. Next, a real data set from a published meta-analysis will be used to illustrate the procedures and interpretations. Last, software packages that may be used to conduct meta-analyses will be highlighted.