Timmermans, S.

Myelin-Derived Lipids Modulate Macrophage Activity by Liver X Receptor Activation (Article)

2012-09-12T00:00:00Z

Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions. Recent studies have described an altered macrophage phenotype after myelin internalization. However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation. Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor β. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis.

Liver X receptors regulate cholesterol homeostasis in oligodendrocytes (Article)

2012-01-01T00:00:00Z

Cholesterol synthesis and transport in oligodendrocytes are essential for optimal myelination and remyelination in pathological conditions such as multiple sclerosis. However, little is known about cholesterol homeostasis in the myelin-forming oligodendrocytes. Liver X receptors (LXRs) are nuclear oxysterol receptors that regulate genes involved in cholesterol homeostasis and may therefore play an important role in de- and remyelination. We investigated whether LXRs regulate cholesterol homeostasis in oligodendrocytes. mRNA expression of genes encoding LXR-α and LXR-β and their target genes (ABCA1, ABCG1, ABCG4, apoE, and LDLR) was detected in oligodendrocytes derived from both neonatal and adult rats using quantitative real-time PCR. The expression of LXR-β and several target genes was increased during oligodendrocyte differentiation. We further demonstrated that treatment of primary neonatal rat oligodendrocytes with the synthetic LXR agonist T0901317 induced the expression of several established LXR target genes, including ABCA1, ABCG1, apoE, and LDLR. Treatment of oligodendrocytes with T0901317 resulted in an enhanced cholesterol efflux in the presence of apolipoprotein A-I or high-density lipoprotein particles. These data show that LXRs are involved in regulating cholesterol homeostasis in oligodendrocytes.

Folic acid supplements modify the adverse effects of maternal smoking on fetal growth and neonatal complications (Article)

2011-12-01T00:00:00Z

Maternal smoking during pregnancy leads to increased risks of neonatal complications. The use of folic acid supplements might reduce the adverse effects of smoking. We examined whether folic acid supplement use modifies the associations of maternal smoking with first trimester plasma homocysteine concentrations, fetal growth characteristics, and risks of neonatal complications. The associations were studied in 6294 mothers participating in a prospective population-based cohort study in The Netherlands. Main outcomes measurements were first trimester plasma homocysteine concentrations, fetal growth characteristics, and neonatal complications, including preterm birth, low birth weight, and small-sizefor-gestational-age. Continued maternal smoking was associated with higher first trimester plasma homocysteine concentrations [difference 0.52 μmol/L (95% range = 0.20, 2.14)], lower third trimester fetal weight (difference -44 g (95% CI = -57, -31)], and birth weight [difference -148 g (95% CI = -179, -118)]. There were significant interactions between maternal smoking and folic acid supplements on all outcome measures (all P-interaction <0.040). Among mothers who continued smoking during pregnancy, those who did not use folic acid supplements had the highest risk of delivering a child with low birth weight [OR = 3.45 (95% CI = 1.25, 9.54)] compared to those who did use periconceptional folic acid supplements. No significant effects were observed for the risks of preterm birth and small-size-for-gestationalage at birth. Our results suggest that some adverse effects of maternal smoking on fetal growth and neonatal outcomes might be reduced by the use of folic acid supplements. The observed interaction seems to be mainly driven by smoking in the first trimester only.

Major dietary patterns and blood pressure patterns during pregnancy: the Generation R Study (Article)

2011-08-18T00:00:00Z

Objective: We sought to evaluate associations between dietary patterns and systolic blood pressure (SBP) and diastolic blood pressure during pregnancy. Study design: This was a prospective study of 3187 pregnant women. Participants completed a food-frequency questionnaire in early pregnancy. The Mediterranean dietary pattern, comprising high intake of vegetables, vegetable oils, pasta, fish, and legumes, and the Traditional dietary pattern, comprising high intake of meat and potatoes, were identified using factor analysis. Results: A higher SBP was observed among mothers with high Traditional pattern adherence. Low adherence to the Mediterranean pattern was also associated with higher SBP but only in early and mid pregnancy. A higher diastolic blood pressure throughout pregnancy was observed in mothers with high adherence to the Traditional pattern and low adherence to the Mediterranean pattern. These effect estimates were most pronounced in mid pregnancy. Conclusion: Low adherence to a Mediterranean and high adherence to a Traditional dietary pattern is associated with a higher blood pressure in pregnancy.

Maternal fish consumption, fetal growth and the risks of neonatal complications: The Generation R Study (Article)

2011-03-28T00:00:00Z

Maternal fish consumption during pregnancy has been suggested to affect birth outcomes. Previous studies mainly focused on birth outcomes and did not study fetal growth during pregnancy. In a prospective cohort study from early pregnancy onwards in The Netherlands, we assessed the associations of first-trimester maternal total-fish, lean-fish, fatty-fish and shellfish consumption with fetal growth characteristics in the second and third trimesters, growth characteristics at birth and the risks of neonatal complications, including pre-term birth, low birth weight and small for gestational age. In total, 3380 mothers completed a 293-item semi-quantitative FFQ to obtain information about fish consumption during the first trimester of pregnancy. Head circumference, femur length and fetal weight were estimated in the second and third trimesters by ultrasound. Information about birth anthropometrics and neonatal complications was available from hospital and midwife registries. Maternal older age, higher educational level, folic acid supplement use, alcohol use and not smoking were associated with higher fish consumption (P < 0.01). After adjustment, we observed no consistent associations of maternal total-fish consumption or specific consumption of lean fish, fatty fish or shellfish with fetal growth characteristics in the second and third trimesters and at birth. Likewise, total-fish consumption or specific consumption of any type of fish was not consistently associated with the risks of neonatal complications. These findings suggest that in a population with a relatively low fish intake, consumption of lean fish, fatty fish or shellfish in the first trimester is not associated with fetal growth or the risks of neonatal complications.

Individual accumulation of heterogeneous risks explains perinatal inequalities within deprived neighbourhoods (Article)

2011-02-01T00:00:00Z

Dutch' figures on perinatal mortality and morbidity are poor compared to EU-standards. Considerable within-country differences have been reported too, with decreased perinatal health in deprived urban areas. We investigated associations between perinatal risk factors and adverse perinatal outcomes in 7,359 pregnant women participating in population-based prospective cohort study, to establish the independent role, if any, for living within a deprived urban neighbourhood. Main outcome measures included perinatal death, intrauterine growth restriction (IUGR), prematurity, congenital malformations, Apgar at 5 min < 7, and pre-eclampsia. Information regarding individual risk factors was obtained from questionnaires, physical examinations, ultrasounds, biological samples, and medical records. The dichotomous Dutch deprivation indicator was additionally used to test for unexplained deprived urban area effects. Pregnancies from a deprived neighbourhood had an increased risk for perinatal death (RR 1.8, 95% CI [1.1; 3.1]). IUGR, prematurity, Apgar at 5 min < 7, and pre-eclampsia also showed higher prevalences (P < 0.05). Residing within a deprived neighbourhood was associated with increased prevalence of all measured risk factors. Regression analysis showed that the observed neighbourhood related differences in perinatal outcomes could be attributed to the increased risk factor prevalence only, without a separated role for living within a deprived neighbourhood. Women from a deprived neighbourhood had significantly more 'possibly avoidable' risk factors. To conclude, women from a socioeconomically deprived neighbourhood are at an increased risk for adverse pregnancy outcomes. Differences regarding possibly avoidable risk factors imply that preventive strategies may prove effective.

Folic Acid, Dietary Patterns and Perinatal Health: The Generation R Study (Doctoral Thesis)

2010-09-15T00:00:00Z

The perinatal mortality rate in The Netherlands is among the highest in the European Union, with one in 100 babies dying during pregnancy, at birth or shortly thereafter. Low birth weight, preterm birth, congenital anomalies, perinatal asphyxia, and pre-eclampsia are major contributors to perinatal mortality. Moreover, pre-eclampsia is not only a major driver for perinatal mortality but plays a significant role in maternal mortality as well.

Periconception folic acid supplementation, fetal growth and the risks of low birth weight and preterm birth: The Generation R Study (Article)

2009-09-01T00:00:00Z

Countries worldwide, including the Netherlands, recommend that women planning pregnancy use a folic acid supplement during the periconception period. Some countries even fortify staple foods with folic acid. These recommendations mainly focus on the prevention of neural tube defects, despite increasing evidence that folic acid may also influence birth weight. We examined whether periconception folic acid supplementation affects fetal growth and the risks of low birth weight, small for gestational age (SGA) and preterm birth, in the Generation R Study in Rotterdam, the Netherlands. Main outcome measures were fetal growth measured in mid- and late pregnancy by ultrasound, birth weight, SGA and preterm birth in relation to periconception folic supplementation (0.4-0.5mg). Data on 6353 pregnancies were available. Periconception folic acid supplementation was positively associated with fetal growth. Preconception folic acid supplementation was associated with 68g higher birth weight (95% CI 37.2, 99.0) and 13g higher placental weight (95% CI 1.1, 25.5), compared to no folic acid supplementation. In these analyses parity significantly modified the effect estimates. Start of folic acid supplementation after pregnancy confirmation was associated with a reduced risk of low birth weight (OR 0.61, 95% CI 0.40, 0.94). Similarly, reduced risks for low birth weight and SGA were observed for women who started supplementation preconceptionally, compared to those who did not use folic acid (OR 0.43, 95% CI 0.28, 0.69 and OR 0.40, 95% CI 0.22, 0.72). In conclusion, periconception folic acid supplementation is associated with increased fetal growth resulting in higher placental and birth weight, and decreased risks of low birth weight and SGA.

Folic acid is positively associated with uteroplacental vascular resistance: The Generation R Study (Article)

2009-01-01T00:00:00Z

Background and aims: Periconception folic acid supplementation may influence early placentation processes and thereby the occurrence of hypertensive pregnancy disorders. For this reason we examined the associations between periconception folic acid supplementation and uteroplacental vascular resistance, blood pressure, and the risks of gestational hypertension and preeclampsia, in 5993 pregnant women, participating in a population-based cohort study. Methods and results: Folic acid supplementation was assessed by questionnaire. Mean pulsatility index (PI) and resistance index (RI) of the uterine (UtA) and umbilical arteries (UmA) were measured by Doppler ultrasound in mid- and late pregnancy. Systolic and diastolic blood pressures (SBP, DBP) were measured in early, mid- and late pregnancy. Compared to women who did not use folic acid, preconception folic acid users had a slightly lower UtA-RI in mid-pregnancy [β -0.02, 95% confidence interval (CI) -0.03, -0.01] and late pregnancy [β -0.02, 95% CI -0.03, -0.001], a lower UtA-PI in mid-pregnancy [β -0.06, 95% CI -0.1, -0.03] and late pregnancy [β -0.03, 95% CI -0.05, -0.01], as well as tendencies towards a lower UmA-PI in mid-pregnancy [β -0.02, 95% CI -0.04, -0.001] and late pregnancy [β -0.01, 95% CI -0.02, 0.01]. Additionally, these women had slightly higher SBP and DBP throughout pregnancy. Neither the patterns of blood-pressure change during pregnancy, nor the risk of gestational hypertension and preeclampsia differed between the folic acid categories. Conclusion: Periconception folic acid supplementation is associated with lower uteroplacental vascular resistance and higher blood pressures during pregnancy. The effects are small and within physiologic ranges and seem not associated with the risk of hypertensive pregnancy disorders.

Determinants of folic acid use in early pregnancy in a multi-ethnic urban population in The Netherlands: The Generation R study (Article)

2008-10-01T00:00:00Z

Objective: Recommendations on folic acid use to prevent neural tube defects have been launched in several countries. Adequate folic acid use seems to be low. This study assesses the prevalence of folic acid use and identifies its determinants. Methods: The study was embedded in the Generation R Study Rotterdam, the Netherlands, a population-based prospective cohort study between 2002 and 2006. Complete information of 6940 women was available. Information on folic acid use and potential determinants was obtained by questionnaires and physical examination. Results: Of all women 37% adequately used folic acid during the preconception period. Most important risk factors for inadequate use were unplanned pregnancy (OR 9.5, CI 7.2-12.4, p < 0.001), low educational level (OR 2.5, CI 1.8-3.6, p < 0.001) and non-western ethnicity, (OR 3.5, CI 2.9-4.3, p < 0.001). After stratification for ethnicity, unplanned pregnancy remained the most important risk factor for inadequate use. Other risk factors for inadequate use were younger age, single marital status, smoking, multiparity (all p < 0.001) and alcohol use (p < 0.05). In contrast, previous spontaneous abortion decreased the risk of inadequate folic acid use (p < 0.001). Conclusion: Adequate preconception folic acid supplementation is still too low. Implementation of preconception programs and other public health strategies are strongly needed.

Conservative management of abnormally invasive placentation (Article)

2007-08-01T00:00:00Z

Due to the growing number of cesarean deliveries, the frequency of abnormally invasive placentation is increasing. The optimal management of this condition remains unclear. This article reviews the efficacy and safety of conservative management of abnormally invasive placentation. We performed a MEDLINE and Embase search and reviewed all articles on conservative management of abnormally invasive placentation published from 1985 through 2006. Over the past 20 years, 48 reports have described outcomes of 60 women who were treated conservatively for abnormally invasive placentation. Twenty-six women were managed without any additional interventions. In most of these patients (19/26), the placenta had been partially removed. In 4 of these 26, conservative therapy failed. Twenty-two women received adjuvant methotrexate. In most of these women (19/22), the entire placenta was left in situ. In 5, therapy failed. Twelve women were managed with arterial embolization. In most of these (9/12), the diagnosis was made antepartum and the placenta was completely left in situ. In 3, therapy failed. Overall, 11 women experienced infection (11/60), 21 women experienced vaginal bleeding (21/60), and 4 suffered disseminated intravascular coagulopathy (4/60). Spontaneous loss of placental tissue was noted in 16 women. Subsequent pregnancies were reported in 8 women. Conservative management of abnormally invasive placentation can be effective and fertility can be preserved. It should only be considered in highly selected cases when blood loss is minimal and there is desire for fertility preservation. Whether adjuvant methotrexate or selective arterial embolization is beneficial is uncertain. Undetectable hCG values do not seem to guarantee complete resorption of retained placental tissue. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader should be able to explain that there are methods to successfully treat abnormal placentation with conservative means, but these methods must be applied only in highly selected cases and recall that no one method is superior to the other.

The AmRo study: Pregnancy outcome in HIV-1-infected women under effective highly active antiretroviral therapy and a policy of vaginal delivery (Article)

2007-02-01T00:00:00Z

Objective: To explore pregnancy outcome in HIV-1-positive and HIV-negative women, and mother-to-child transmission (MTCT) according to mode of delivery under effective highly active antiretroviral therapy (HAART). Design: Cohort of 143 pregnant HIV-1-infected women including a matched case-control study in a 2:1 ratio of controls to cases (n = 98). Setting: Academic Medical Center in Amsterdam and Erasmus Medical Center in Rotterdam, the Netherlands. Population: Consecutive referred HIV-1 infected pregnant women treated with HAART and matched control not infected pregnant women. Main outcome measures: MTCT, preterm delivery, low birthweight, pre-eclampsia. Results: MTCT was 0% (95% CI 0-2.1%). Seventy-eight percent of HIV-1-infected women commenced and 62% completed vaginal delivery. The calculated number of caesarean sections needed to prevent a single MTCT was 131 or more. Preterm delivery rates were 18% (95% CI 11-27) in women infected with HIV-1 and 9% (95% CI 5-13) in controls (P = 0.03). HAART used at <13 weeks of gestation was associated with a 44% preterm delivery rate compared with 21% when HAART was started at or after 13 weeks and 14% in controls. (Very) low birthweight and incidence of pre-eclampsia were not different between HIV-1 and controls. Conclusions: We have not demonstrated any MTCT after vaginal delivery in women effectively treated by HAART. The HAART-associated increase in preterm delivery rate is mainly seen after first trimester HAART use.