Georges-Etienne Rivard

Absence of Association of Thrombophilia Polymorphisms with Intrauterine Growth Restriction

BACKGROUND Previous data have demonstrated associations between thrombophilia polymorphisms in pregnant women and an increased risk of intrauterine growth restriction in their offspring, but this finding remains uncertain. METHODS We performed a hospital-based case-control study and a family-based study including 493 newborns with intrauterine growth restriction (defined by birth weight below the 10th percentile for gestational age and sex according to Canadian norms) and 472 controls (with birth weight at or above the 10th percentile). We determined the presence or absence in newborns and their parents of the following polymorphisms: methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, factor V Leiden G1691A, and prothrombin G20210A. Mothers were interviewed to obtain information on other risk factors for intrauterine growth restriction. RESULTS The risk of intrauterine growth restriction was not increased among mothers carrying a polymorphism associated with thrombophilia. In the case-control study, the odds ratios associated with two copies of the variant, after adjustment for newborn genotype and other risk factors, were 1.55 for MTHFR C677T (95 percent confidence interval, 0.83 to 2.90) and 0.49 for MTHFR A1298C (95 percent confidence interval, 0.25 to 0.93); heterozygotes for factor V Leiden had an odds ratio of 1.18 (95 percent confidence interval, 0.54 to 2.55), and heterozygotes for prothrombin G20210A had an odds ratio of 0.92 (95 percent confidence interval, 0.36 to 2.35). These polymorphisms in the newborn were not associated with an increased risk. Newborns who were homozygous for the MTHFR C677T variant had a decreased risk of intrauterine growth restriction (odds ratio after adjustment for mothers genotype and other confounders, 0.52 [95 percent confidence interval, 0.29 to 0.94]). The results of the family-based study supported those of the case-control study. CONCLUSIONS Our findings do not indicate that there are associations between maternal or newborn polymorphisms associated with thrombophilia and an increased risk of intrauterine growth restriction.

Lupus Anticoagulants, Anticardiolipin Antibodies, and Fetal Loss: A Case–Control Study

Abstract Background. Lupus anticoagulants and anticardiolipin antibodies are antiphospholipid antibodies that have been associated with fetal loss, but they have not been shown unequivocally to be a risk factor for this event. Methods. To estimate the risk of fetal loss in association with these antibodies, we conducted a hospital-based case–control study of 331 women with spontaneous abortion or fetal death (case patients) and 993 controls. The subjects were included in the study only if they reported that they had had no previous spontaneous fetal loss. Each control was a pregnant woman who, in the same period of pregnancy as a case patient, had not had a fetal loss. Lupus anticoagulants were identified in blood samples through a series of coagulation tests, and IgG anticardiolipins by an enzyme-linked immunosorbent assay. Each subject was interviewed in person to obtain information on potential confounding variables, such as sociodemographic characteristics and medical conditions. Results. Lupus antico...

Periostin, a Member of a Novel Family of Vitamin K-dependent Proteins, Is Expressed by Mesenchymal Stromal Cells

The modification of glutamic acid residues to γ-carboxyglutamic acid (Gla) is a post-translational modification catalyzed by the vitamin K-dependent enzyme γ-glutamylcarboxylase. Despite ubiquitous expression of the γ-carboxylation machinery in mammalian tissues, only 12 Gla-containing proteins have so far been identified in humans. Because bone tissue is the second most abundant source of Gla-containing proteins after the liver, we sought to identify Gla proteins secreted by bone marrow-derived mesenchymal stromal cells (MSCs). We used a proteomics approach to screen the secretome of MSCs with a combination of two-dimensional gel electrophoresis and tandem mass spectrometry. The most abundant Gla-containing protein secreted by MSCs was identified as periostin, a previously unrecognized γ-carboxylated protein. In silico amino acid sequence analysis of periostin demonstrated the presence of four consensus γ-carboxylase recognition sites embedded within fasciclin-like protein domains. The carboxylation of periostin was confirmed by immunoprecipitation and purification of the recombinant protein. Carboxylation of periostin could be inhibited by warfarin in MSCs, demonstrating its dependence on the presence of vitamin K. We were able to demonstrate localization of carboxylated periostin to bone nodules formed by MSCs in vitro, suggesting a role in extracellular matrix mineralization. Our data also show that another fasciclin I-like protein, βig-h3, contains Gla. In conclusion, periostin is a member of a novel vitamin K-dependent γ-carboxylated protein family characterized by the presence of fasciclin domains. Furthermore, carboxylated periostin is produced by bone-derived cells of mesenchymal lineage and is abundantly found in mineralized bone nodules in vitro.

Pregnancy loss and work schedule during pregnancy.

Shift work has been associated with many health complaints, but its relation with pregnancy loss has rarely been studied. We compared the work schedule during pregnancy of 331 women with a pregnancy loss with that of 993 pregnant women matched on gestational age. The risk of pregnancy loss was four times higher among women with fixed evening work schedules in comparison with women on a fixed day schedule (odds ratio = 4.17; 95% confidence interval = 2.19-7.92), and more than twice as high among those on a fixed night schedule (odds ratio = 2.68; 95% confidence interval = 0.53-13.43).

Low-dose ASA Response Using the PFA-100 in Women With High-risk Pregnancy

OBJECTIVES To study the platelet function response to low-dose ASA with the Platelet Function Analyzer (PFA-100) in pregnant women and to identify maternal characteristics associated with non-responsiveness. METHODS We conducted a prospective cohort study involving 87 pregnant women on ASA. The platelet function response to ASA was measured as the closure time obtained with epinephrine cartridges (CT-EPI) by the PFA-100. Non-response to ASA was defined as a CT-EPI < or =150 seconds after four weeks of therapy. Non-responders were given an escalating dose of ASA and their CT-EPI was tested again. RESULTS After four weeks of enteric-coated ASA 81 mg daily, 25/87 women (28.7%) were non-responders (95% CI 16.1 to 41.4). Among these women, a CT-EPI < or =150 seconds was found in 8/24 women (33.3%) after another four weeks of alternating ASA 81 mg and 162 mg daily. After a further four-week course of ASA 162 mg daily, a CT-EPI < or =150 seconds was found in 3/6 women (50.0%). Among the women who initially responded and who were reassessed at 24-32 weeks of pregnancy, the CT-EPI was < or =150 seconds in 9/36 (25.0%). There was no statistical difference in maternal characteristics between ASA responders and non-responders. CONCLUSION A significant number of pregnant women showed a lack of platelet function response to ASA 81 mg that was in most cases overcome with higher dosing. Furthermore, the prevalence of non-responsiveness increased with advancing pregnancy.

Unexpected Relationship between Plasma Homocysteine and Intrauterine Growth Restriction

BACKGROUND Moderate hyperhomocysteinemia is considered a risk factor for thrombosis and atherosclerosis. We hypothesized that higher maternal and newborn homocysteine concentrations in plasma would increase the risk of intrauterine growth restriction through placental thrombosis. METHODS We carried out a case-control study that included all cases born at our institution over a 2-year period whose birthweight was below the 10th percentiles for gestational age and sex according to Canadian norms; controls were born at the same period and institution at or above the 10th percentiles and were matched on gestational age, race, and sex. Homocysteine was measured in cord and maternal blood. The analysis included 483 case and 468 control mothers and 409 case and 438 control newborns. RESULTS Homocysteine values were largely <15 micromol/L. Contrary to expectation, within that range of values, increased plasma homocysteine, particularly in the mother, was protective against intrauterine growth restriction. With the case/control status as the outcome, the estimated odds ratio was 0.37 (95% confidence interval, 0.24-0.58) for a 5 micromol/L unit difference on the maternal homocysteine scale. With birthweight as the outcome, the estimated increase was 178.1 g (95% confidence interval, 92.5-263.7 g) for every 5 micromol/L unit increase in maternal homocysteine. Results were similar using newborn homocysteine concentrations. CONCLUSIONS The data suggest that, in contrast to the proposed hypothesis, mothers with small babies have lower homocysteine concentrations than those giving birth to larger ones.

Oxidative tyrosylation of high density lipoproteins impairs cholesterol efflux from mouse J774 macrophages: role of scavenger receptors, classes A and B

Studies were designed to test whether tyrosylation of high-density lipoprotein (HDLT) modifies its metabolic features. HDLT was less effective than native HDL in promoting cholesterol efflux from J774-AI macrophages. Cell association with fluorescent HDLT-apolipoprotein and the uptake of HDLT-[3H]cholesteryl hexadecyl ether were enhanced by 50% in comparison with native HDL. In addition, neutral cholesterol ester hydrolase (nCEH) activity in J774-AI, which controls the hydrolysis of cholesteryl ester stores to provide free cholesterol for cellular release, declined in the presence of HDLT. In vitro displacement experiments revealed the ability of HDLT to compete with oxidized and acetylated LDL, known as ligands of scavenger receptor (SR) class B type I/II. Similarly, treatment with a blocking antibody to SR-BI/II reduced the cell association of HDLT and native HDL by 50%. The addition of polyinosinic acid, an inhibitor of SR class A, reduced the cell association of HDLT without affecting that of native HDL. These findings provide evidence that HDLT can compete with modified LDL, bind SR-BI/BII and internalize cholesterol ester. Furthermore, the impaired capacity of HDLT in promoting cholesterol efflux from J774-AI was accompanied by diminished nCEH and enhanced recognition by SR-AI/II, which appears to involve the transport of cholesterol into cells.

Small babies receive the cardiovascular protective apolipoprotein ε2 allele less frequently than expected

A newborn whose weight for gestational age and sex is less than expected, based on population standards, is considered as having intrauterine growth restriction (IUGR); a cut off at less than the 10th centile is often used to define IUGR. Causes of IUGR remain unclear although a number of fetal and maternal risk factors have been identified.1,2 Increased early morbidity and mortality, as well as, possibly, less than optimal neuropsychological development, have been reported as consequences of IUGR.2,3 In addition, small size at birth has been associated with health problems in adulthood such as coronary heart disease and dyslipidaemia.4,5 The association between restricted fetal growth and adult chronic diseases (often referred to as the Barker hypothesis) is now considered robust and possibly causal.6 Apolipoprotein E (apoE) is one of the key regulators of plasma lipid levels as it affects hepatic binding, uptake, and catabolism of several classes of lipoproteins.7 The apolipoprotein E gene (APOE) codes for the apoE protein; in animal models, underexpression of the APOE gene and lack of the apoE protein result in increased susceptibility to atherosclerosis,8,9 whereas gene overexpression displays anti-inflammatory, antiproliferative, and atheroprotective properties.10 ApoE has also emerged as a central factor in various biological processes such as immunoregulation, control of cell growth and differentiation,11 and brain development.12 The three common allelic variants at the APOE locus (e2, e3, e4) code for three major apoE protein isoforms (E2, E3, E4). These isoforms differ from one another only by single amino acid substitutions, yet these changes exhibit functional consequences at both the cellular and molecular levels.13,14 In previous studies, children who carry the e4 allele and those who carry the e2 allele have been shown to have, respectively, higher and lower total …

Thrombophilic polymorphisms and intrauterine growth restriction.

Background: The relationship between thrombophilic polymorphisms and intrauterine growth restriction remains unclear. Whereas a subset of these polymorphims have received some attention, others have not. Methods: We conducted a case–control study of 493 cases of intrauterine growth restriction (birthweight less than the 10th percentile for gestational age and sex) and 472 controls (greater than the 10th percentile). We also conducted a family study including approximately 250 case trios (affected newborn, mother, and father) for each studied gene. Plasminogen activator inhibitor-1(PAI-1) 4G/5G and Factor XIII Val134Leu variants were compared between maternal and newborn cases and controls. Relative risks for newborn and maternal PAI-1 and Factor XIII genotypes in case trios were estimated using a log-linear model. Transmission of MTHFR C677T and 1298C haplotypes was analyzed in case trios, and the estimated haplotype distribution compared between cases and controls. Finally, we explored pairwise gene-gene interactions between all measured polymorphisms, including Factor V Leiden G1691A and Prothrombin G20210A. Results: PAI-1 and Factor XIII polymorphisms were not associated with an increased risk of intrauterine growth restriction in the case–control analysis, and the case–parent analysis showed no newborn or maternal excess genotype relative risk. No excess transmission of the MTHFR haplotypes was observed in case newborns, and the distribution of MTHFR haplotypes was similar between cases and controls. Some results were suggestive of interactions between genes. Conclusions: Overall, there seems to be little or no indication that thrombophilic genes, at least individually, have an effect on intrauterine growth restriction.

Folate deficiency among institutionalized elderly. Public health impact.

All patients 65 years and older who had been living in an institution for at least six months had a measurement of red blood cell folate (RBCF), serum folate (SF), vitamin B12, hemoglobin, and mean corpuscular volume. Twenty‐two percent of the 97 studied subjects were found deficient in RBCF, although only 6% had anemia. Length of stay at the institution was significantly associated with deficiency in RBCF and this association was uncon‐founded by age. The proportion of RBCF deficiency among the studied subjects attributable to length of stay is 80%. The prophylactic administration of folate among long‐term nursing home type of patients should be considered.