Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Pharmacokinetics of Clindamycin in Pregnant Women in the Peripartum Period ▿

The study presented here was performed to determine the pharmacokinetics of intravenously administered clindamycin in pregnant women. Seven pregnant women treated with clindamycin were recruited. Maternal blood and arterial and venous umbilical cord blood samples were obtained. Maternal clindamycin concentrations were analyzed by nonlinear mixed-effects modeling with the NONMEM program. The data were best described by a linear three-compartment model. The clearance and the volume of distribution at steady state were 10.0 liters/h and 6.32 × 103 liters, respectively. Monte Carlo simulations were performed to determine the area under the concentration curve (AUC) for the free (unbound) drug (f) in maternal serum for 24 h divided by the MIC (fAUC0-24/MIC). At a MIC of 0.5 mg/liter, which is the EUCAST breakpoint, the attainment at the lower 95% confidence interval (CI) was 24.6 if the level of protein binding was 65%, and this value concurred well with the target value of 27. However, for higher degrees of protein binding, as has been described in the literature, the attainment was lower, down to 10.2 for a protein binding level of 85% (lower 95% CI). The concentrations in umbilical cord blood were lower than those in maternal blood. The concentration-time profiles in maternal serum indicate that the level of exposure to clindamycin may be too low in these patients. Together with the lower concentrations in umbilical cord blood, this finding suggests that the current dosing regimen may not be adequate to protect all neonates from group B streptococcal disease

Timing of group b streptococcus screening in pregnancy: A systematic review

Background: Group B streptococcus (GBS) is an important cause of neonatal sepsis. Guidelines advise to collect cultures at 35-37 weeks' gestation and to administer intrapartum antibiotic prophylaxis in case of GBS-positive cultures, as well as in all preterm deliveries. Improved effectiveness of antenatal cultures might help to further decrease GBS early-onset disease. Objective: To determine the best timing of antenatal cultures, which may help establish optimal prevention of perinatal GBS infection in both term and preterm neonates. Methods: PubMed and EMBASE databases were searched for relevant articles published from 1966 to February 2009. Nine articles were included. Information about study features and predictive values of antenatal cultures were abstracted. Results: Positive predictive values for antenatal GBS cultures ranged from 43 to 100% (mean 69%) and negative predictive values from 80 to 100% (mean 94%). GBS cultures collected in late pregnancy had high positive predictive values for colonization during delivery. The negative predictive value was high and relatively constant regardless of GA. Conclusions: This systematic review confirms recommendations to screen pregnant women for colonization of GBS at 35-37 weeks' gestation, but one should be aware of the limitations of screening, with 6% of GBS carriers remaining undetected in antenatal cultures

Prevalence of colonisation with group B Streptococci in pregnant women of a multi-ethnic population in the Netherlands

Objective: This study was performed to determine the prevalence of GBS and to identify GBS colonisation risk factors in a multicultural population of pregnant women in The Netherlands. We calculated predictive values of cultures in pregnancy for intrapartum GBS carriage. Study design: From a total of 1702 women visiting several antenatal outpatient departments, rectovaginal swabs were collected at 35-37 weeks' gestation. In 761 women swabs were repeated at time of delivery. Carriage of GBS late in third trimester and at time of delivery was analysed in relation to age, parity, ethnicity and socio-economic status. Results: Twenty-one percent was GBS carrier late in pregnancy. Compared to Europeans, African women were at a higher risk (29%, RR 1.4, CI 1.1-1.7) and Asian women were at lower risk (13%, RR 0.6, CI 0.4-0.8) for GBS carriage. No differences in colonisation were found between women with respect to age, parity or socio-economic background. Positive predictive value of GBS carriage at 35-37 weeks' gestation for carriage at time of parturition was 79% and negative predictive value was 93%. Conclusions: It was not possible to identify a group of pregnant women at high risk for GBS colonisation. Predictive values of antenatal genital group B streptococci cultures at 35-37 weeks' gestation for intrapartum GBS carriage are lower than previously reported