Interleukin 6 Influences Germinal Center Development and Antibody Production via a Contribution of C3 Complement Component

Mice rendered deficient for interleukin (IL) 6 by gene targeting were evaluated for their response to T cell–dependent antigens. Antigen-specific immunoglobulin (Ig)M levels were unaffected whereas all IgG isotypes showed varying degrees of alteration. Germinal center reactions occurred but remained physically smaller in comparison to those in the wild-type mice. This concurred with the observations that molecules involved in initial signaling events leading to germinal center formation were not altered (e.g., B7.2, CD40 and tumor necrosis factor R1). T cell priming was not impaired nor was a gross imbalance of T helper cell (Th) 1 versus Th2 cytokines observed. However, B7.1 molecules, absent from wild-type counterparts, were detected on germinal center B cells isolated from the deficient mice suggesting a modification of costimulatory signaling. A second alteration involved impaired de novo synthesis of C3 both in serum and germinal center cells from IL-6–deficient mice. Indeed, C3 provided an essential stimulatory signal for wild-type germinal center cells as both monoclonal antibodies that interrupted C3-CD21 interactions and sheep anti–mouse C3 antibodies caused a significant decrease in antigen-specific antibody production. In addition, germinal center cells isolated from C3–deficient mice produced a similar defect in isotype production. Low density cells with dendritic morphology were the local source of IL-6 and not the germinal center lymphocytes. Adding IL-6 in vitro to IL-6–deficient germinal center cells stimulated cell cycle progression and increased levels of antibody production. These findings reveal that the germinal center produces and uses molecules of the innate immune system, evolutionarily pirating them in order to optimally generate high affinity antibody responses.     

What Factors in Early Pregnancy Indicate that the Mother Will Be Hit by Her Partner during the Year after Childbirth?A Nationwide Swedish Survey

Abstract: Background : To be hit by one's intimate partner during the first year after childbirth may affect a woman's health and ability to take care of her newborn. The purpose of this study was to document the prevalence and indicators in early pregnancy of a woman being hit by her partner during the year after childbirth. Method : Information was collected by a postal questionnaire in early pregnancy and 12 months after childbirth from the approximately 5,550 women in Sweden who visited an antenatal care clinic for the first time during one of three chosen weeks in 1999 and 2000. Results : Of the 3,266 recruited women, 2,563 returned the follow‐up questionnaire. Being hit during the first year after childbirth was reported by 52 of the 2,563 (2%) women: 32 (61%) had been hit by their partner once, 12 (23%) twice, and 8 (15%) three or more times. Risk increased in women who were age 24 years or younger (3.9% had been hit), unmarried (7.1%), born in countries outside Europe (6.8%), with a partner born outside Europe (5.4%), had a low level of education (8.9%), and were unemployed (5.0%). In early pregnancy, women with back pain (4.0%), a chronic illness (4.1%), coital pain (6.1%), frequent depression‐related symptoms (8.1%), stomach pain (3.8%), or a urinary tract problem (6.3%) were hit more often than others after childbirth. Conclusions : At least 2 percent of Swedish women giving birth in 2000 were hit by their partner during the year after childbirth. Using identified predictors during antenatal care may increase the likelihood of finding women at risk, thereby enhancing the possibility of interventions to prevent this crime and health hazard.     

Sample size considerations when groups are the appropriate unit of analysis.

This article discusses issues to be considered by nurse researchers when groups should be used as the unit of randomization. Advantages and disadvantages are presented, with statistical calculations needed to determine the effective sample size. Examples of these concepts are presented using data from the Black Cosmetologists Promoting Health Program. Different hypothetical scenarios and their impact on sample size are also presented. Given the complexity of calculating the sample size when using groups as the unit of randomization, it is advantageous for researchers to work closely with statisticians when designing and implementing studies that anticipate the use of groups as the unit of randomization.     

Effect of prolonged inhibition of neutral endopeptidase on cardiac hypertrophy in rats with myocardial infarction

Summary Myocardial infarction was induced in rats by ligation of the left coronary artery. Treatment with TM1, a prodrug of SQ 28,603, an inhibitor of neutral endopeptidase (NEP, EC 3.4.24.11), was started 18–20 hours after ligation and was continued for 4 weeks (100 mg/kg, orally, twice daily). Morphological and biochemical parameters were assessed at the end of therapy. The treatment resulted in a significant reduction of heart hypertrophy, which was restricted to the parts of myocardium hemodynamically upstream of the infarcted left ventricle. The weights of the right ventricle and atria were reduced by 15–20%, whereas the treatment had no effect on the left ventricle and septum weights. Treatment led to an almost complete inhibition of plasma NEP activity and to a slight decrease (-14%, p<0.05) in plasma ACE activity. Plasma ANF level increased 3.8-fold after ligation, and treatment resulted in a slight (+29%) and nonsignificant additional increase in the ANF level. The amount of hydroxyproline in the right ventricle was enhanced by +207% in control ligated rats and by +140% (NS) in treated rats. These data indicate that prolonged NEP inhibition exerts a favorable effect in heart failure by reducing the development of right ventricular and atrial hypertrophy. These effects may result from an improvement in hemodynamic conditions, leading to a reduction in cardiac preload.     

A case-control study of multiple myeloma and occupation

Lifetime job histories from a population-based, case-control study were analyzed to investigate the relationship between multiple myeloma and employment in various occupations and industries. Interviews were obtained from 89% (692) of eligible incident cases and 83% (1683) of eligible controls. An elevated risk was observed among persons ever employed as painters [odds ratio (OR) + 2.1, 95% confidence interval (CI) + 1.2–3.6], particularly for those employed for 10 or more years (OR + 4.1, 95% CI + 1.8–10.4). A small excess risk was observed among agricultural workers employed for 10 or more years (OR + 1.3, 95% CI + 1.0–2.2), with a higher relative risk observed among farm laborers (OR + 1.8, 95% CI + 1.0–4.0). Among agricultural workers who reported having been highly exposed to pesticides, the OR was 5.2 (95% CI + 1.6–21.1). Some evidence, based on smaller numbers, was also found to support an association with firefighting and employment in the petroleum- and coal-products manufacturing industries. Little evidence was found to support the previously noted association with wood exposure, and no evidence for an association with employment in the rubber or petroleum refining industries was found. This study lends further support to previously reported associations between multiple myeloma and employment among painters and agricultural workers. © 1993 Wiley-Liss, Inc.     

Baraitser–Winter cerebrofrontofacial syndrome: Report of two adult siblings

Baraitser–Winter cerebrofrontofacial syndrome (BWCS) is a rare, autosomal dominant condition that is characterized by intellectual disability, distinctive craniofacial features, structural brain abnormalities, seizures, microcephaly, hearing loss, and ocular colobomas. The first three cases were described in 1988 by Baraitser and Winter and included two siblings and an unrelated third patient. Subsequently, causative missense variants in the ACTB and ACTG1 genes were identified, with de novo occurrence in patients with the condition. Herein, we describe two adult siblings who were born to unaffected parents and who were diagnosed with BWCS in their fourth and sixth decade of life following exome sequencing performed for intellectual disability. We review the literature reports of adult patients with BWCS to document the clinical features and phenotypic variability that can occur later in life. This is the first molecularly confirmed report of germline mosaicism in BWCS and one of only a few reports to describe two BWCS patients belonging to the same family.     

Functional characterization of a Ca2+-activated non-selective cation channel in human atrial cardiomyocytes

Cardiac arrhythmias, which occur in a wide variety of conditions where intracellular calcium is increased, have been attributed to the activation of a transient inward current ( I _ti). I _ti is the result of three different [Ca]_i-sensitive currents: the Na⁺–Ca²⁺ exchange current, a Ca²⁺-activated chloride current and a Ca²⁺-activated non-selective cationic current. Using the cell-free configuration of the patch-clamp technique, we have characterized the properties of a Ca²⁺-activated non-selective cation channel (NSC_Ca) in freshly dissociated human atrial cardiomyocytes. In excised inside-out patches, the channel presented a linear I–V relationship with a conductance of 19 ± 0.4 pS. It discriminated poorly among monovalent cations (Na⁺ and K⁺) and was slightly permeable to Ca²⁺ ions. The channel's open probability was increased by depolarization and a rise in internal calcium, for which the K _d for [Ca²⁺]_i was 20.8 μ m . Channel activity was reduced in the presence of 0.5 m m ATP or 10 μ m glibenclamide on the cytoplasmic side to 22.1 ± 16.8 and 28.5 ± 8.6%, respectively, of control. It was also inhibited by 0.1 m m flufenamic acid. The channel shares several properties with TRPM4b and TRPM5, two members of the 'TRP melastatin' subfamily. In conclusion, the NSC_Ca channel is a serious candidate to support the delayed after-depolarizations observed in [Ca²⁺] overload and thus may be implicated in the genesis of arrhythmias.     

Potent inhibition of SARS-associated coronavirus (SCOV) infection and replication by type I interferons (IFN-alpha/beta) but not by type II interferon (IFN-gamma).

We sought to investigate the anti-severe acute respiratory syndrome (SARS)-associated coronavirus (SCoV) activities of type I (alpha and beta) and type II (gamma) interferons (IFN) in vitro. Type I IFNs protected cells from cytopathic effects (CPE) induced by SCoV, and inhibited viral genomic RNA replication in FRhk-4 cells (measured by quantitative RT-PCR) in a dose-dependent manner. Intracellular viral RNA copies were reduced 50% by IFN-alpha at a concentration of 25 U/ml and by IFN-beta at a concentration of 14 U/ml. IFN-gamma had fewer effects on inhibition of viral infection and replication. The type I IFN receptor signaling pathway in host cells is mainly involved in the inhibition of SCoV infection and replication. Type I IFNs could be used as potential agents for anti-SARS treatment.     

Quantitative evaluation of recall and precision of CAT Crawler,a search engine specialized on retrieval of Critically Appraised Topics

Background

Critically Appraised Topics (CATs) are a useful tool that helps physicians to make clinical decisions as the healthcare moves towards the practice of Evidence-Based Medicine (EBM). The fast growing World Wide Web has provided a place for physicians to share their appraised topics online, but an increasing amount of time is needed to find a particular topic within such a rich repository.

Methods

A web-based application, namely the CAT Crawler, was developed by Singapore's Bioinformatics Institute to allow physicians to adequately access available appraised topics on the Internet. A meta-search engine, as the core component of the application, finds relevant topics following keyword input. The primary objective of the work presented here is to evaluate the quantity and quality of search results obtained from the meta-search engine of the CAT Crawler by comparing them with those obtained from two individual CAT search engines. From the CAT libraries at these two sites, all possible keywords were extracted using a keyword extractor. Of those common to both libraries, ten were randomly chosen for evaluation. All ten were submitted to the two search engines individually, and through the meta-search engine of the CAT Crawler. Search results were evaluated for relevance both by medical amateurs and professionals, and the respective recall and precision were calculated.

Results

While achieving an identical recall, the meta-search engine showed a precision of 77.26% (±14.45) compared to the individual search engines' 52.65% (±12.0) (p < 0.001).

Conclusion

The results demonstrate the validity of the CAT Crawler meta-search engine approach. The improved precision due to inherent filters underlines the practical usefulness of this tool for clinicians.