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Summary. The relationships of three measurements of the factor VIII/von Willebrand factor (VWF) complex (factor VIII activity, FVIIIc (one-stage assay); VWF antigen, VWF Ag (ELISA); and VWF activity, VWF act, measured by a recentlydeveloped ELISA) to major ischaemic heart disease (IHD) events were studied in 1997 men aged 49-65 years, in the second phase of the Caerphilly Heart Study. These variables were related using logistic regression analysis to myocardial infarction or IHD death, which occurred in 129 men during an average follow-up period of 61 months. All three measurements were highly correlated (r ¼ 0·63-0·77), and each was significantly associated with incident major IHD on univariate analyses (relative odds in highest fifth compared to lowest fifth, 1·68-1·90; P ¼ 0·028-0·006) and on multivariate analyses adjusting for major IHD risk factors and for baseline IHD. Neither FVIIIc nor VWF act was significantly related to incident IHD following adjustment for VWF Ag. We therefore suggest that the associations between these three measurements of the factor VIII/VWF complex and incident IHD might have at least three explanations: VWFAg is a marker of arterial endothelial disturbance; VWF act promotes platelet adhesion/aggregation and hence the platelet component of arterial thrombosis; and FVIIIc promotes fibrin formation and hence the fibrin component of arterial thrombosis.

AimsNeuropilins 1 and 2 (NRP1 and NRP2) play crucial roles in endothelial cell migration contributing to angiogenesis and vascular development. Both NRPs are also expressed by cultured vascular smooth muscle cells (VSMCs) and are implicated in VSMC migration stimulated by PDGF-BB, but it is unknown whether NRPs are relevant for VSMC function in vivo. We investigated the role of NRPs in the rat carotid balloon injury model, in which endothelial denudation and arterial stretch induce neointimal hyperplasia involving VSMC migration and proliferation.Methods and resultsNRP1 and NRP2 mRNAs and proteins increased significantly following arterial injury, and immunofluorescent staining revealed neointimal NRP expression. Down-regulation of NRP1 and NRP2 using shRNA significantly reduced neointimal hyperplasia following injury. Furthermore, inhibition of NRP1 by adenovirally overexpressing a loss-of-function NRP1 mutant lacking the cytoplasmic domain (ΔC) reduced neointimal hyperplasia, whereas wild-type (WT) NRP1 had no effect. NRP-targeted shRNAs impaired, while overexpression of NRP1 WT and NRP1 ΔC enhanced, arterial re-endothelialization 14 days after injury. Knockdown of either NRP1 or NRP2 inhibited PDGF-BB-induced rat VSMC migration, whereas knockdown of NRP2, but not NRP1, reduced proliferation of cultured rat VSMC and neointimal VSMC in vivo. NRP knockdown also reduced the phosphorylation of PDGFα and PDGFβ receptors in rat VSMC, which mediate VSMC migration and proliferation.ConclusionNRP1 and NRP2 play important roles in the regulation of neointimal hyperplasia in vivo by modulating VSMC migration (via NRP1 and NRP2) and proliferation (via NRP2), independently of the role of NRPs in re-endothelialization.

OBJECTIVE-To examine associations of fasting C-peptide, BMI, and maternal glucose with risk of preeclampsia, in a multicenter multinational study.STUDY DESIGN-Secondary analysis of blinded observational cohort study. Subjects underwent a 75-g OGTT at 24-32 weeks gestation. Associations of preeclampsia with fasting C-peptide, BMI, and maternal glucose were assessed using multiple logistic regression analyses, adjusting for potential confounders.RESULTS-Of 21,364 women included in analyses, 5.2% developed preeclampsia. Adjusted odds ratios (OR) for preeclampsia for 1 SD higher fasting C-peptide (0.87 ug/L), BMI (5.1 kg/m 2 ), fasting (6.9 mg/dl), 1-hour (30.9 mg/dl), and 2-hour plasma glucose (23.5 mg/dl) were 1.28 (1.20, 1.36), 1.60 (95% CI 1.60-1.71), 1.08 (95% CI 1.00-1.16), 1.19 (95% CI 1.11-1.28), and 1.21 (1.13-1.30), respectively. CONCLUSION-Resultsindicate strong, independent associations of fasting C-peptide and BMI with preeclampsia. Maternal glucose levels (below diabetes) had weaker associations with preeclampsia, particularly after adjustment for fasting C-peptide and BMI.Keywords preeclampsia associations; BMI; C-peptide; glucose INTRODUCTIONPreeclampsia complicates 2-8% of pregnancies worldwide and is associated with increased risk of adverse outcomes for mother and baby (1). It is a systemic disease characterized by increased vascular resistance, endothelial dysfunction, proteinuria and coagulopathy, in addition to hypertension (2). The pathophysiology is not completely defined but probably includes immune, genetic, and placental abnormalities. Insulin resistance and secretion rise during normal pregnancy; there is growing evidence that preeclampsia is related to increased insulin resistance during pregnancy (3-9). There is also strong evidence that women with Corresponding Author and Reprint Requests: Boyd E. Metzger, MD, Northwestern University Feinberg School of Medicine, Endocrinology, 645 N Michigan Ave, Chicago, IL 60611, bem@northwestern.edu NIH Public Access Author ManuscriptAm J Obstet Gynecol. Author manuscript; available in PMC 2011 March 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript higher pre-pregnancy body mass index (BMI) are more likely to develop preeclampsia (10-13).Most observational studies of GDM and preeclampsia included adjustment for maternal BMI (14-16), but none included adjustment for insulin resistance. Nordin, et al (17) showed that lesser degrees of glucose intolerance are associated with risk of preeclampsia; however, it is not clear if there was an independent association as this study did not include adjustment for BMI or other potential confounders. Another study looked at the association with preeclampsia across quartiles of glucose values below those diagnostic of GDM and found a positive association that became non-significant after adjustment for confounders (18). Thus, the nature of the association between lesser degrees of hyperglycemia and preeclampsia remains uncertain.The objective of the Hyperglycemia and Advers...

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