Visser, W.

Importance of cysteine residues in the thyroid hormone transporter MCT8 (Article)

2013-05-01T00:00:00Z

The thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) is crucial for brain development as demonstrated by the severe psychomotor retardation in patients with MCT8 mutations. MCT8 contains 10 residues of the reactive amino acid cysteine (Cys) whose functional roles were studied using the Cys-specific reagent p-chloromercurybenzenesulfonate (pCMBS) and by site-directed mutagenesis. Pretreatment of JEG3 cells with pCMBS resulted in a dose- and time-dependent decrease of subsequent T3 uptake. Pretreatment with dithiothreitol did not affect TH transport or its inhibition by pCMBS. However, pCMBS inhibition of MCT8 was reversed by dithiothreitol. Inhibition of MCT8 by pCMBS was prevented in the presence of T3. The single and double mutation of C481A and C497A did not affect T3 transport, but the single mutants were less sensitive and the double mutant was completely insensitive to pCMBS. Similar effects on MCT8 were obtained using HgCl2 instead of pCMBS. In conclusion, we have identified Cys481 and Cys497 inMCT8as the residues modified bypCMBSor HgCl2. These residues are probably located at or near the substrate-recognition site in MCT8. It remains to be investigated whether MCT8 function is regulated by modification of these Cys residues under pathophysiological conditions. Copyright

Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: The generation r study (Article)

2012-02-01T00:00:00Z

Background: Maternal thyroid status and autoimmunity during pregnancy have been associated with impaired development of the offspring in animal and human studies. Our objective was to examine whether elevated titers of maternal thyroid peroxidase antibodies (TPOAbs) in early pregnancy increased the risk of cognitive impairment and problem behavior in preschool children. Second, we aimed at exploring to what extent any effect on child behavior was mediated by maternal thyroid parameters during pregnancy. Methods: In the Generation R Study, a population-based cohort of 3139 children and their mothers, we measured maternal thyroid parameters (thyrotropin [TSH], free Thyroxine, and TPOAbs) at 13.5±1.8 weeks of gestation. Children's verbal and nonverbal cognitive functioning was measured at 2.5 years using the Language Development Survey and the Parent Report of Children Abilities. At 3 years, children's behavior was assessed using the Child Behavior Checklist. Results: Elevated titers of TPOAbs during pregnancy did not predict the verbal and nonverbal cognitive functioning of the children. However, elevated titers of TPOAbs in mothers were associated with externalizing problems in children (odds ratio [OR]=1.64, 95% confidence interval [CI]: 1.17-2.29, p=0.004). In particular, children of TPOAb-positive mothers were at a higher risk of attention deficit/hyperactivity problems (OR=1.77, 95% CI: 1.15-2.72, p=0.01). To explore whether the effect of maternal TPOAbs on child problem behavior was mediated by maternal thyroid parameters, we added maternal TSH to the model. After correcting for TSH, the effect of TPOAbs on externalizing problems was attenuated slightly but remained significant (OR=1.56, 95% CI: 1.14, 2.14, p=0.005). Conclusions: Our findings imply that the elevated titers of TPOAbs during pregnancy impact children's risk of problem behavior, in particular, attention deficit/hyperactivity. The observed effect is only partially explained by maternal TSH levels. These findings may point to a specific mechanism of Attention Deficit/Hyperactivity Disorder in children. Nevertheless, we can only speculate about public health implication of the study, as there is no specific treatment for TPOAb-positive pregnant women with normal thyroid function. Further investigation is needed to explore whether TPOAb-positive pregnant women and their children can benefit from close monitoring and early detection of developmental delay in populations at risk.

Postpartum fepression after mild and severe preeclampsia (Article)

2011-10-01T00:00:00Z

Objective: To describe the prevalence of postpartum depressive symptoms after preeclampsia, to assess the extent to which the prevalence of postpartum depressive symptoms differs after mild and severe preeclampsia, and to investigate which factors contribute to such differences. Methods: Women diagnosed with preeclampsia (n=161) completed the Edinburgh Postnatal Depression Scale (EPDS) at 6, 12, or 26 weeks postpartum. Multiple logistic regression analysis was used to investigate the association between severity of preeclampsia, contributing factors and postpartum depression (PPD) (1) at any time during the first 26 weeks postpartum and (2) accounting for longitudinal observations at three time points. Results: After mild preeclampsia, 23% reported postpartum depressive symptoms at any time up to 26 weeks postpartum compared to 44% after severe preeclampsia (unadjusted odds ratio [OR] 2.65, 95% confidence interval [CI] 1.16-6.05) for depression at any time up to 26 weeks postpartum (unadjusted OR 2.57, 95% CI, 1.14-5.76) while accounting for longitudinal observations. Admission to the neonatal intensive care unit (NICU) (adjusted OR 3.19, 95% CI 1.15-8.89) and perinatal death (adjusted OR 2.96, 95% CI 1.09-8.03) contributed to this difference. Conclusions: It appears that not the severity of preeclampsia itself but rather the consequences of the severity of the disease (especially admission to the NICU and perinatal death) cause postpartum depressive symptoms. Obstetricians should be aware of the high risk of postpartum depressive symptoms after severe preeclampsia, particularly among women whose infant has been admitted to the NICU or has died.

Thyroid status in a large cohort of patients with mental retardation: The TOP-R (Thyroid Origin of Psychomotor Retardation) study (Article)

2011-09-01T00:00:00Z

Objective Abnormalities in thyroid state may affect development and function of the brain and result in mental retardation (MR). Thyroid parameters have not been systematically investigated in institutionalized MR subjects. The objective is to measure thyroid parameters in a novel cohort of 946 institutionalized subjects. Design The TOP-R (Thyroid Origin of Psychomotor Retardation) study is a cross-sectional nation-wide multicentre study. Patients Subjects with unexplained MR. Results The majority of the MR subjects had thyroid parameters within the reference range used in our laboratory. Antiepileptic drugs (AEDs) use affected thyroid hormones (T4: 102·1 ± 1·2 vs 83·9 ± 1·2 nmol/l, P < 1 × 10-24; FT4: 18·0 ± 0·2 vs 16·1 ± 0·2 pmol/l, P < 1 × 10-9; T3: 1·72 ± 0·02 vs 1·57 ± 0·02 nmol/l, P < 1 × 10-9; and rT3: 0·37 ± 0·01 vs 0·27 ± 0·01 nmol/l, P < 1 × 10-28in subjects without vs with AEDs). The prevalence of unrecognized primary hypothyroidism and hyperthyroidism was 5·2% and 2·8%, respectively. Conclusions We report thyroid parameters in a cohort of institutionalized subjects with MR. Our findings substantiate the fact that AEDs affect thyroid hormone levels. Future studies will be employed to investigate genetic causes of MR related to abnormalities in thyroid hormone homeostasis.

Preeclampsia is associated with increased cytotoxic T-cell capacity to paternal antigens (Article)

2010-11-01T00:00:00Z

Objective: During an uncomplicated pregnancy the conceptus is a semiallogeneic entity in which rejection is prevented by suppression of the maternal immune system. We hypothesized that this suppression is disturbed in patients with preeclampsia and that a maternal immune response to fetal (foreign/paternal) antigens in the fetal-maternal interface may be responsible for local inflammation, with subsequent endothelial dysfunction and systemic disease. Study design: Blood samples were obtained from 14 women with preeclampsia (cases), 14 gestational-age and parity-matched women with uncomplicated pregnancies (controls), and their partners. We determined the partner-specific cytotoxic T-lymphocyte precursor frequency (CTLpf) and the CTLpf directed to unrelated partners with uncomplicated pregnancies. We measured the CTLpf in peripheral blood mononuclear cells (PBMCs) from cases and controls using limited-dilution assays. In addition, proliferation was tested in a mixed-lymphocyte culture (MLR). Results: The partner-specific CTLpf was significantly higher in cases compared with controls (median, 183 [15-338] vs 67 [9-232] per million PBMCs, P = .02). In contrast, in women with uncomplicated pregnancies, the partner-specific CTLpf was down-regulated compared with the CTLpf directed to an unrelated partner who fathered uncomplicated pregnancies (P = .02). No difference was found in partner-specific MLR response between cases and controls. Conclusion: These results suggest that women with preeclampsia have a higher cytotoxic T-cell response to paternal antigens compared with pregnant controls. This insufficiently suppressed immune response may eventually lead to the development of preeclampsia.

Amino-terminal pro-brain natriuretic peptide (NT-proBNP) is a biomarker of cardiac filling pressures in pre-eclampsia (Article)

2010-11-01T00:00:00Z

Objective: To evaluate if amino-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels reflect intracardiac filling pressures in pre-eclamptic patients. Study design: In a cross-sectional study we investigated 22 untreated critically ill pre-eclamptic women between 22 and 34 weeks gestation. All patients underwent intra-arterial blood pressure and central hemodynamic measurements and NT-proBNP was determined in stored plasma. Baseline characteristics, plasma NT-proBNP concentrations and relevant laboratory variables were investigated for correlations with hemodynamic values using Spearman's rank correlation test. Results: No significant correlations were demonstrated between NT-proBNP concentrations and variables associated with the severity of the pre-eclampsia. We found significant positive correlations between NT-proBNP and diastolic pulmonary pressure (r = 0.59; p = 0.005) and pulmonary capillary wedge pressure (PCWP) (r = 0.51; p = 0.015). Multiple linear regression analysis showed that the association between NT-proBNP and PCWP was not affected by creatinine level. Conclusion: NT-proBNP is a biomarker of left ventricular cardiac filling pressures in untreated pre-eclamptic patients.

Effect of postpartum lifestyle interventions on weight loss, smoking cessation, and prevention of smoking relapse: A systematic review (Article)

2010-10-01T00:00:00Z

Postpartum lifestyle interventions are recommended for women after pregnancies complicated by preeclampsia, intrauterine growth restriction, and/or gestational diabetes, since they are at increased cardiovascular risk. To identify potential intervention strategies to reduce this risk, a systematic review of the literature is presented on the effectiveness of postpartum lifestyle interventions aimed at weight loss, smoking cessation, and smoking relapse prevention. The main characteristics of these postpartum lifestyle interventions are briefly described. The PubMed, Embase, Web of Science, PsychInfo, and Cinahl databases were searched for studies on the effects of postpartum lifestyle interventions on weight loss, and smoking cessation or prevention of smoking relapse, initiated for up to 1 year postpartum. No studies on the effectiveness of postpartum lifestyle interventions after the aforementioned specific pregnancy complications were found. However, 21 studies are included that describe existing postpartum lifestyle interventions, which were applied to unselected (on the basis of pregnancy complications) postpartum women. Copyright

Rise in maternal mortality in the Netherlands (Article)

2010-03-01T00:00:00Z

Objective To assess causes, trends and substandard care factors in maternal mortality in the Netherlands. Design Confidential enquiry into the causes of maternal mortality. Setting Nationwide in the Netherlands. Population 2,557,208 live births. Methods Data analysis of all maternal deaths in the period 1993-2005. Main outcome measures Maternal mortality. Results The overall maternal mortality ratio was 12.1 per 100 000 live births, which was a statistically significant rise compared with the maternal mortality ratio of 9.7 in the period 1983-1992 (OR 1.2, 95% CI 1.0-1.5). The most frequent direct causes were (pre-)eclampsia, thromboembolism, sudden death in pregnancy, sepsis, obstetric haemorrhage and amniotic fluid embolism. The number of indirect deaths also increased, mainly caused by an increase in cardiovascular disorders (OR 2.5, 95% CI 1.4-4.6). Women younger than 20 years and older than 45 years, those with high parity or from nonwestern immigrant populations were at higher risk. Most substandard care was found in women with pre-eclampsia (91%) and in immigrant populations (62%). Conclusions Maternal mortality in the Netherlands has increased since 1983-1992. Pre-eclampsia remains the number one cause. Groups at higher risk for complications during pregnancy should be better identified early in pregnancy or before conception, in order to receive preconception advice and more frequent antenatal visits. There is an urgent need for the better education of women and professionals concerning the danger signs, and for the training of professionals in order to improve maternal health care.

Resolution of hypertension and proteinuria after preeclampsia (Article)

2009-12-01T00:00:00Z

OBJECTIVE: To estimate the time required for hypertension and proteinuria to resolve after preeclampsia, and to estimate how this time to resolution correlates with the levels of blood pressure and proteinuria during preeclampsia and prolonging pregnancy after the development of preeclampsia. METHODS: This is a historic prospective cohort study of 205 preeclamptic women who were admitted between 1990 and 1992 at the Erasmus MC Medical Centre, Rotterdam, The Netherlands. Data were collected at 1.5, 3, 6, 12, 18, and 24 months after delivery. Hypertension was defined as a blood pressure 140/90 mm Hg or higher or use of antihypertensive drugs. Proteinuria was defined as 0.3 g/d or more. Resolution of hypertension and proteinuria were analyzed with the Turnbull extension to the Kaplan-Meier procedure. Correlations were calculated with an accelerated failure time model. RESULTS: At 3 months postpartum, 39% of women still had hypertension, which decreased to 18% at 2 years postpartum. Resolution time increased by 60% (P<.001) for every 10-mm Hg increase in maximal systolic blood pressure, 40% (P=.044) for every 10-mm Hg increase in maximal diastolic blood pressure, and 3.6% (P=.001) for every 1-day increase in the diagnosis-to-delivery interval. At 3 months postpartum, 14% still had proteinuria, which decreased to 2% at 2 years postpartum. Resolution time increased by 16% (P=.001) for every 1-g/d increase in maximal proteinuria. Gestational age at onset of preeclampsia was not correlated with resolution time of hypertension and proteinuria. CONCLUSION: The severity of preeclampsia and the time interval between diagnosis and delivery are associated with postpartum time to resolution of hypertension and proteinuria. After preeclampsia, it can take up to 2 years for hypertension and proteinuria to resolve. Therefore, the authors suggest that further invasive diagnostic tests for underlying renal disease may be postponed until 2 years postpartum.

The effect of maternal ketanserin treatment on foetal 5-HT receptor function in umbilical cord artery of pre-eclamptic patients (Article)

2007-11-01T00:00:00Z

Background: Maternal treatment with the 5-HT2Areceptor antagonist ketanserin (KT) in pre-eclamptic patients is associated with a high placental transmission of KT, resulting in pharmacologically active levels of KT in the umbilical cord artery (UCA) and the neonate. Prolonged exposure to a 5-HT receptor antagonist may influence the functionality of foetal 5-HT receptors and compromise foetal development. Objective: To study whether exposure to KT influences the characteristics of foetal 5-HT receptors, functional studies were performed on 5-HT2Aand 5-HT1B/1Dreceptors in UCA from pre-eclamptic patients treated with KT. Methods: UCAs were obtained, immediately after delivery, from pre-eclamptic patients (n = 7), treated antenatally with intravenous KT. Pre-eclamptic patients (n = 13), not treated with KT (non-KT), were included as a control group. Segments of UCA were prepared and mounted in tissue baths and isometric force changes were determined. Cumulative concentration response curves to 5-HT and to the 5-HT1B/1Dreceptor agonist sumatriptan were constructed in the absence or presence of the 5-HT2Areceptor antagonist KT or the 5-HT1B/1Dreceptor antagonist GR125743, respectively. Results: All UCA segments showed contractile responses to both 5-HT and sumatriptan, and the concentration response curves showed a rightward shift with increasing concentrations of KT and GR125743, respectively, indicating the presence of functional 5-HT2Aand 5-HT1B/1Dreceptors in the foetal tissue. No significant differences were found in maximum response (Emax)(expressed in percent of response on 100 mM KCl) or potency (pEC50) of 5-HT in both groups (Emax= 141 ± 7.7%, pEC50= 7.67 ± 0.26 in KT-treated group and Emax= 162 ± 12.6%, pEC50= 7.69 ± 0.14 in non-KT treated group, respectively). No significant differences were found in the potency of the antagonist KT in both study groups (pKb= 7.65 ± 0.31 in KT group and 7.46 ± 0.17 in non-KT group, respectively). Similarly, with sumatriptan, no significant differences were found between KT-treated patients and non-KT treated patients (Emax= 142 ± 16.2 and 140 ± 14.7%, respectively, pEC50= 6.17 ± 0.37 and 6.41 ± 0.28 respectively, pKbof GR125743 = 7.83 ± 0.48 and 8.43 ± 0.29, respectively). Conclusion: Foetal exposure to KT in pre-eclamptic patients does not seem to influence the functional characteristics of 5-HT2Aand 5-HT1B/1Dreceptors in the UCA. Copyright

Thyroid hormone transport by monocarboxylate transporters (Article)

2007-06-01T00:00:00Z

Thyroid hormone (TH) is essential for the normal development and metabolism of different tissues. TH action and metabolism take place intracellularly, which requires cellular uptake via transporters. Several transporter families have been identified, of which the monocarboxylate transporter (MCT) family deserves special attention. So far, only MCT1, MCT2, MCT3, MCT4 and MCT6 have been demonstrated to transport monocarboxylates; MCT8 has been identified as a specific TH transporter. MCT8 mutations in humans are associated with severe psychomotor retardation and elevated 3,3′,5-triiodothyronine (T3) levels. Recently, MCT8 knockout mice have been shown to perfectly imitate the thyroid state in patients with MCT8 mutations; however, they lack the neurological defects. Although it was long hypothesized that a T-type amino acid transporter also transports iodothyronines, it only recently became clear that MCT10 is involved in the bidirectional transport of aromatic amino acids and iodothyronines. MCT10 preferentially transports T3even more effectively than does MCT8. However, its precise function in the human body is poorly understood.

Susceptibility to pre-eclampsia is associated with multiple genetic polymorphisms in maternal biotransformation enzymes (Article)

2007-05-01T00:00:00Z

Background/Aims: Probably no single gene is responsible for pre-eclampsia, but the disease merely is the result of polymorphisms in several genes in association with environmental factors. We therefore studied the simultaneous occurrence of several genetic polymorphisms in biotransformation enzymes in women who had developed pre- eclampsia, either with or without the HELLP syndrome, in comparison with healthy controls. Methods: The results of two previous studies on genetic polymorphisms in glutathione S-transferases P1, M1 and T1, epoxide hydrolase (EPHX) and cytochrome P4501A1 (CYP1A1) in 167 women with a history of pre-eclampsia and in 110 controls were combined. χ2analyses were used for statistical evaluation of the number of polymorphisms between cases and controls. Results: There was a significant association with the number of genetic polymorphisms in biotransformation enzymes, pointing at an increased toxification or decreased detoxification, in women with a history of pre-eclampsia, as compared to healthy controls (p < 0.001). Conclusion: Women withthe simultaneous occurrence of two or more genetic polymorphisms in the above-mentioned biotransformation enzymes, most probably resulting in a disturbed detoxification capacity, may be at increased risk for pre-eclampsia. Copyright

Hemolysis, elevated liver enzymes and low platelets during pregnancy due to Vitamin B12 and folate deficiencies (Article)

2007-04-01T00:00:00Z

Nicardipine in pre-eclamptic patients: Placental transfer and disposition in breast milk (Article)

2007-02-01T00:00:00Z

To assess the safety risks to the fetus and neonate caused by maternal use of nicardipine in pre-eclamptic patients, we evaluated the placental transfer and the transfer to breast milk after maternal intravenous administration of nicardipine. In ten pre-eclamptic subjects, nicardipine concentrations of maternal blood (P) and both arterial and venous umbilical cord blood samples (Uarterialand Uvenous) were assessed, and the U/P ratio was calculated as an indication of placental transfer. We found a median transfer of 0.15 (Uarterial/P, range 0.05-0.22) and 0.17 (Uvenous/P, range 0.023-0.22). The highest umbilical cord concentration found after maternal dosage of 4.5 mg/hour was 18 ng/ml, which can be considered as subtherapeutic. Therefore, adverse fetal reactions caused by a direct pharmacological effect of nicardipine are unlikely to occur. Nicardipine levels were determined in 34 breast milk samples of seven women, and were found to be undetectable in 82% of the samples. In six breast milk samples of four different women, nicardipine levels (ranging from 5.1 to 18.5 ng/ml) were detectable during maternal nicardipine dosages ranging from 1 to 6.5 mg/hour. The maximum possible exposure of a neonate to nicardipine was calculated to be less than 300 ng/day, which is an insignificant fraction of therapeutic dosages used in neonates. In conclusion, the exposure of a fetus and neonate to nicardipine through placental transfer and disposition in breast milk expression is low.

Hemodynamic studies in preeclampsia: implications for management (Doctoral Thesis)

1995-11-15T00:00:00Z

Preeclampsia is a condition unique to pregnancy, characterized by hypertension and proteinuria. Nulliparous pregnancies and those affected by preexisting hypertension, diabetes and renal disease are at increased risk. Preeclampsia may develop during pregnancy, labor or in the early puerperium, and it occurs in about 5 percent of all pregnancies. It is a complex clinical syndrome potentially involving all maternal organ systems, with hypertension representing but one manifestation. When generalized convulsions are present, the condition is referred to as eclampsia.