Adverse life events and allele-specific methylation of the serotonin transporter gene (SLC6A4) in adolescents: the TRAILS study.

OBJECTIVES: Adverse life events increase vulnerability to affective disorders later in life, possibly mediated by methylation of the serotonin transporter gene (SLC6A4). We investigated the relationship of SLC6A4 methylation with various types of adversity (perinatal adversity, traumatic youth experiences and stressful life events [SLEs]), as well as with the timing of SLEs (during childhood [0-11 years] or during adolescence [12-15 years]). In addition, we investigated whether different serotonin-transporter-linked polymorphic region genotypes were equally sensitive to SLE-related methylation. METHODS: In a population sample of 939 adolescents (mean age = 16.2 years), we assessed SLC6A4 methylation, SLC6A4 functionality (serotonin-transporter-linked polymorphic region "long" and "short" alleles, and rs25531), and adverse life events. RESULTS: Only a higher number of SLEs was positively associated with higher SLC6A4 methylation (B = 0.11, p = .011). Adolescent SLEs were associated with higher SLC6A4 methylation (B = 0.13, p = .004) independently of childhood SLEs (B = 0.02, p = .57). L-allele homozygotes showed a greater impact of SLEs on methylation (B = 0.37, p < .001) than did s-allele carriers (B = 0.04, p = .66), resulting in higher levels of SLC6A4 methylation for l-allele homozygotes among those experiencing high levels of SLEs. CONCLUSIONS: Our findings demonstrate a higher level of SLC6A4 methylation after SLEs in adolescents, with a more pronounced association for SLEs during adolescence than during childhood. Considering the allele-specific sensitivity of SLC6A4 methylation to SLEs, this study may help clarify the role of SLC6A4 in the development of affective disorders.

Validation of the SDQ in a multi-ethnic population of young children.

BACKGROUND: The Strengths and Difficulties Questionnaire (SDQ) is a valuable screening tool for identifying psychosocial problems. Its performance in a multi-ethnic society, common to many paediatric health care workers, has not been investigated. Because it is important that screening instruments are valid and reliable for all ethnic groups within one society, we examined differences in the SDQ's psychometric properties in a multi-ethnic society. METHODS: The SDQ parent (n = 8114) and teacher form (n = 9355) were completed as part of a preventive health check for children aged 5-6 years of Dutch and non-Dutch ethnic backgrounds. The Child Behaviour Checklist (CBCL)/Teacher Report Form (TRF) was administered to a subsample. RESULTS: Factor analysis of the parent-rated SDQ showed different rating patterns for two of the five subscales for non-Dutch children as compared with Dutch children. Cronbach's alpha for the total difficulties score varied by ethnic group (0.73-0.78 parent-rated SDQ, 0.80-0.83 teacher-rated SDQ), and coefficients were generally smaller for non-Dutch than for Dutch children (P < 0.05). Alpha coefficients for subscales varied between 0.31-0.85 for ethnic groups. Inter-rater correlations between parents and teachers for the total difficulties score varied between 0.20-0.41 between ethnic groups and were larger for Dutch than for non-Dutch children (P < 0.05). Concurrent validity was acceptable for most scales and most ethnic groups. CONCLUSION: The total difficulties score of the parent- and teacher-rated SDQ is valid and reliable for different ethnic groups within Dutch society. However, there are differences in reliability and validity of the subscales, which makes interpretation of the subscales difficult for certain ethnic groups.

Ethnicity, socioeconomic position and severity of problems as predictors of mental health care use in 5- to 8-year-old children with problem behaviour.

BACKGROUND: Empirical research on mental health care use and its determinants in young school-aged children is still scarce. In this study, we investigated the role of ethnicity, socioeconomic position (SEP) and perceived severity by both parents and teachers on mental health care use in 5- to 8-year old children with emotional and/or behavioural problems. METHODS: Data from 1,269 children with a high score([P90) on the Strengths and Difficulties Questionnaire (SDQ) in the school year 2008­2009 were linked to psychiatric case register data over the years 2010­2011. Cox proportional hazards models were used to predict mental health care use from ethnicity, SEP and perceived severity of the child's problems. RESULTS: During the follow-up period, 117 children with high SDQ scores (9.2 %) had used mental health care for the first time. Ethnic minority children were less likely to receive care than Dutch children (HR Moroccan/Turkish:0.26; 95 % CI 0.13-0.54, HR other ethnicity: 0.26; 95 %CI 0.12-0.58). No socioeconomic differences were found.After correction for previous care use, ethnicity and parental perceived severity, impact score as reported by teachers was significantly associated with mental healthcare use (HR 1.58; 95 % CI 1.01­2.46). CONCLUSIONS: Ethnicity is an important predictor of mental health care use in young children. Already in the youngest school-aged children, ethnic differences in the use of mental health care are present.A distinct predictor of care use in this age group is severity of emotional and behavioural problems as perceived by teachers. Therefore, teachers may be especially helpful in the process of identifying young children who need specialist mental health care.

Ethnic differences in problem perception and perceived need as determinants of referral in young children with problem behaviour.

An underrepresentation of ethnic minority children in mental health care settings is consistently reported. Parents of ethnic minority children are, however, less likely to perceive problem behaviour in their children. Our hypothesis was that, as a result of ethnic differences in problem perception, referral to care by a child health professional (CHP) would be lower for 5- to 6-year-old (high-risk) children from ethnic minority backgrounds than for their peers from the ethnic majority (Dutch origin). For 10,951 children in grade two of elementary school, parents and/or teachers completed the Strengths and Difficulties Questionnaire (SDQ) as well as questions on problem perception (PP) and perceived need for professional care (PN). Referral information was obtained from the Electronic Child Records (ECR) for 1,034 of these children. These children had a high (>90th percentile) SDQ score, and were not receiving mental health care. CHP's referred 144 children (14 %) during the routine health assessments. A lower problem perception was reported by parents of ethnic minority children (40-72 %) than by parents of the ethnic majority group (80 %; p < 0.001), but there were no ethnic differences in referral (OR range 0.9-1.9-p > 0.05). No ethnic differences were found for parental PN, nor for teacher's PP or PN. Despite a lower problem perception in ethnic minority parents when compared to ethnic majority parents, no ethnic differences were found in referral of children with problem behaviour in a preventive health care setting.

Ethnic differences in problem perception and perceived need for care for young children with problem behaviour.

BACKGROUND: Problem perception and perceived need for professional care are important determinants that can contribute to ethnic differences in the use of mental health care. Therefore, we studied ethnic differences in problem perception and perceived need for professional care in the parents and teachers of 5- to 6-year-old children from the general population who were selected for having emotional and behavioural problems. METHODS: A cross-sectional study with data of 10,951 children from grade two of the elementary schools in the Rotterdam-Rijnmond area, The Netherlands. Parents and teachers completed the strengths and difficulties questionnaire (SDQ) as well as questions on problem perception and perceived need for care. The SDQ was used to identify children with emotional and behavioural problems. We included Dutch, Surinamese, Antillean, Moroccan and Turkish children in our sample with high (>P90) SDQ scores (N = 1,215), who were not currently receiving professional care for their problems. RESULTS: Amongst children with high SDQ scores, problem perception was lower in non-Dutch parents than in Dutch parents (49% vs. 81%, p < 0.01). These lower rates of problem perception could not be explained by differences in socioeconomic position or severity of the problems. No ethnic differences were found in parental perceived need and in problem perception and perceived need reported by teachers. Higher levels of problem perception and perceived need were reported by teachers than by parents in all ethnic groups (PP: 87% vs. 63% and PN: 48% vs. 23%). CONCLUSIONS: Child health professionals should be aware of ethnic variations in problem perception as low problem perception in parents of non-Dutch children may lead to miscommunication and unmet need for professional care for the child.

Cross-national comparison of the link between socioeconomic status and emotional and behavioral problems in youths.

INTRODUCTION: In previous longitudinal studies in the US, lower socioeconomic status (SES) was associated with more emotional and behavioral problems. It remains unclear whether these findings can be generalized outside the US, as different countries vary in their health care systems and prevention of psychopathology in youth. Therefore, we studied the same associations in a comparable sample in The Netherlands and directly tested for differences between the US and The Netherlands. METHODS: The US (N=833) and Dutch (N=708) population samples were followed-up for 9 years. Age at baseline ranged from 8 to 16 years. Parents filled out behavior checklists. RESULTS: Analyses revealed very few differences between the two countries. In both countries, SES predicted syndrome scores and cumulative prevalence rates for internalizing and externalizing problems (withdrawn and aggressive behavior) and for thought and attention Problems. The SES gradient in syndrome scores was stable over time. Only for withdrawn behavior, the gradient was larger in young adulthood. CONCLUSION: Although the health care systems differ between the US and The Netherlands, the socioeconomic disparities in emotional and behavioral problems were similar.

Trajectories of CBCL attention problems in childhood.

The first aim of this study was to identify developmental trajectories of Attention Problems in twins followed from age 6 to 12 years. Second, we investigated whether singletons follow similar trajectories. Maternal longitudinal ratings on the Attention Problems (AP) subscale of the Child Behavior Checklist were obtained for a sample of 12,486 twins from the Netherlands Twin Register and for a general population sample of 1,346 singletons. Trajectories were analyzed by growth mixture modeling in twins, and compared with singletons. Teacher ratings on the AP subscale of the Teachers' Report Form were available for 7,179 twins and 1,211 singletons, and were used for cross-sectional mean comparisons at each age. All analyses were conducted for boys and girls separately. We identified three linear trajectories in both boys and girls, i.e., stable low (62-71%), low-increasing (15-18%), and high-decreasing (14-21%). Singletons followed three identical trajectories, with similar class proportions. Teacher ratings yielded no differences in mean levels of Attention Problems between twins and singletons. The development of Attention Problems from age 6 to 12 years can be characterized by stable low, low-increasing, and high-decreasing developmental trajectories. Twins and singletons are comparable with respect to the development of Attention Problems in childhood.

Anxiety and depression are risk factors rather than consequences of functional somatic symptoms in a general population of adolescents: the TRAILS study.

BACKGROUND: It is well known that functional somatic symptoms (FSS) are associated with anxiety and depression. However, evidence is lacking about how they are related to FSS. The aim of this study was to clarify these relationships and examine whether anxiety and depression are distinctly related to FSS. We hypothesized that anxiety contributes to the development of FSS and that depression is a consequence of FSS. METHODS: FSS, anxiety, and depression were measured in adolescents (N = 2230, 51% women) by subscales of the Youth Self-Report during three assessment waves (adolescents successively aged: 10-12, 12-14, and 14-17) and by corresponding subscales of the Child Behavior Checklist. Using structural equation models, we combined trait and state models of FSS with those of anxiety and depression, respectively. We identified which relationships (contemporaneous and two-year lagged) significantly connected the states of FSS with the states of anxiety and depression. RESULTS: Trait variables were all highly interrelated (r = .54-.63). Contrary to our hypothesis, both state anxiety (beta = .35) and state depression (beta = .45) had a strong contemporaneous effect on state FSS. In turn, state FSS had a weak two-year lagged effect on state anxiety (beta = .11) and an even weaker effect on state depression (beta = .06). CONCLUSIONS: While the effect of anxiety and depression on FSS is strong and immediate, FSS exert a weaker and delayed influence on anxiety and depression. Further research should be done to detect the exact ways in which anxiety and depression lead to FSS, and FSS lead to anxiety and depression.

A twin-singleton comparison of developmental trajectories of externalizing and internalizing problems in 6- to 12-year-old children.

Research on twin-singleton differences in externalizing and internalizing problems in childhood is largely cross-sectional and yields contrasting results. The goal of this study was to compare developmental trajectories of externalizing and internalizing problems in 6- to 12-year-old twins and singletons. Child Behavior Checklist (CBCL) maternal reports of externalizing and internalizing problems were obtained for a sample of 9651 twins from the Netherlands Twin Register and for a representative general population sample of 1351 singletons. Latent growth modeling was applied to estimate growth curves for twins and singletons. Twin-singleton differences in the intercepts and slopes of the growth curves were examined. The developmental trajectories of externalizing problems showed a linear decrease over time, and were not significantly different for twins and singletons. Internalizing problems seem to develop similarly for twins and singletons up to age 9. After this age twins' internalizing symptoms start to decrease in comparison to those of singletons, resulting in less internalizing problems than singletons by the age of 12 years. Our findings confirm the generalizability of twin studies to singleton populations with regard to externalizing problems in middle and late childhood. The generalizability of studies on internalizing problems in early adolescence in twin samples should be addressed with care. Twinship may be a protective factor in the development of internalizing problems during early adolescence.

Prospective community study of family stress and anxiety in (pre)adolescents: the TRAILS study.

For prevention of anxiety in children and adolescents, it is important to know whether family stress is a predictor of anxiety. We studied this in 1,875 adolescents from the Tracking Adolescents' Individual Lives Survey (TRAILS) who were followed up for 2 years, from age 10-12 to 12-14 years. Adolescents reported anxiety and depression symptoms at both assessments, and parents reported family stress (family dysfunction and parenting stress) at the first assessment. Family dysfunction was not associated with future anxiety, whereas high parenting stress was. Furthermore, family dysfunction was more strongly associated with anxiety than with depression, whereas parenting stress was more strongly associated with depression. Level of parental psychopathology explained part of the association of family stress with anxiety. The associations were modest and the understanding of the origins of adolescents' anxiety will require identifying other factors than family stress that account for more of the variance.

Gender and body size affect the response of erythrocyte folate to folic acid treatment.

The recommended dietary allowance (RDA) differs between men and women for some vitamins, but not for folate. The RDA for folate is derived mainly from metabolic studies in women. We assessed if men differ from women in their response of erythrocyte folate to folic acid supplementation. We used data from 2 randomized placebo-controlled trials with folic acid: a 3-y trial in which subjects ingested 800 mug/d of folic acid (294 men and 112 women) and a 12-wk trial in which 187 men and 129 women ingested 0, 50, 100, 200, 400, 600, or 800 microg/d of folic acid in a parallel design (n = 38-42 per treatment group). In the 3-y trial, the erythrocyte folate concentration increased 10% (143 nmol/L, [95%CI 46, 241]) less in men than in women. In the 12-wk trial, regression analysis showed that the response of erythrocyte folate upon folic acid intake for men was 47 nmol/L lower than for women (P for beta(gender) = 0.022); for an intake of 800 microg/d folic acid, this resulted in a 5% lower response in men than in women. Differences in lean body size explained 56% of the difference in response of erythrocyte folate between men and women in the 3-y trial and 70% in the 12-wk trial. Men need more folic acid than women to achieve the same erythrocyte folate concentration, mainly because men have a larger lean body mass. This could be an indication that the RDA for folate should be higher for men than for women, or that the RDA should be expressed per kilogram of lean body mass.

Ethnic disparities in mental health and educational attainment: comparing migrant and native children.

UNLABELLED: STUDY BACKGROUND AND AIMS: Ethnic disparities in mental health in adolescence may play a role in the development of ethnic disparities in educational attainment. The aim of this study was to assess the contribution of ethnic disparities in mental health problems in adolescence to ethnic disparities in educational attainment in adulthood. METHODS: We followed two community samples of respectively 486 Dutch native and 168 Turkish migrant adolescents (11-15 years old) into adulthood (21-25 years old). Mental health was measured in adolescence, and educational attainment was assessed in adulthood. The contribution of mental health disparities to educational disparities was estimated by the degree of attenuation of the odds ratio (OR) for low education after adjustment for mental health problems. RESULTS: Adult Turkish men more often had attained lower education than Dutch men (OR 1.81 (1.01-3.25)). Additional adjustment for mental health problems during adolescence did not change the OR. In Turkish women, however, the OR was 1.94 (1.04-3.62), and adjustment for mental health problems lowered it by 96% to 1.04 (0.51-2.14). The contribution was mostly due to ethnic disparities in internalizing problems. CONCLUSION: In women, but not in men, ethnic disparities in mental health, especially internalizing problems, were a strong predictor for the development of ethnic disparities in educational attainment. Prevention or treatment of internalizing problems among Turkish girls will probably contribute to the prevention of educational disparities.

Determinants of daily smoking in Turkish young adults in the Netherlands.

BACKGROUND: As little is known about the determinants of smoking in large ethnic minorities in the Netherlands and other Western European countries, we studied the determinants of smoking young adult offspring of Turkish migrants to the Netherlands. METHODS: Cross-sectional survey of 439 Turkish adults (18-28 y) in 2003. Smokers were compared with never smokers for five groups of determinants: demographic and socioeconomic factors, behavioral and emotional problems, psychosocial factors, and cultural factors. Associations were measured by prevalence rate ratios. RESULTS: Prevalences for men were 51% for daily smoking, 12% for former smoking, and 38% for never smoking. For women they were 44%, 11%, and 47%, respectively. Without adjustment for other determinants, higher prevalence was associated with: emotional problems, boredom, life events, and being male; and, specifically among women, with low self-esteem and having children. The strongest determinants of daily smoking In multivariate models were alcohol use and demographic and socio-economic factors. Of the cultural factors only strong Muslim identification was associated with lower smoking prevalence. CONCLUSION: The high prevalence of smoking warrants action. Many of the well-known determinants of smoking in Western countries were also important among young adults from ethnic minorities. Women with children and people of a low educational level deserve special attention.

Material, psychosocial, and behavioural factors in the explanation of educational inequalities in mortality in The Netherlands.

STUDY OBJECTIVES: To assess the direct and indirect contributions of material, behavioural, and psychosocial factors to the explanation of educational inequalities in mortality simultaneously. DESIGN: Prospective observational study (1991-1998). SETTING: General population from south east Netherlands. PARTICIPANTS: 3979 men and women aged 15-74 years without severe chronic disease at baseline (1991). MAIN RESULTS: Material factors (type of health insurance, financial problems, and housing tenure), psychosocial factors (life events and external locus of control), and behavioural factors (smoking habits and physical activity) together reduced the relative risk of mortality of the lowest educated group from 2.57 (95%CI 1.43 to 4.64) to 1.01 (95%CI 0.50 to 2.03). Of these three groups of factors, material factors contributed most to the educational inequalities. Part of the contribution of material factors was via psychosocial factors and part via behavioural factors. Psychosocial factors contributed to educational inequalities, partly via behavioural factors. Behavioural and psychosocial factors contributed only marginally to the explanation independent of material factors. CONCLUSION: Educational inequalities in mortality were explained by material, psychosocial, and behavioural factors. Material factors contributed most to the explanation, partly via psychosocial and behavioural factors. Improving the material situation of lower educated people may substantially reduce educational inequalities in mortality, partly via the psychosocial and behavioural consequences of improved material circumstances.

Emotion recognition specialization and context-dependent risk of anxiety and depression in adolescents.

BACKGROUND: Some adolescents function poorly in apparently benign environments, while others thrive despite hassles and difficulties. The aim of this study was to examine if adolescents with specialized skills in the recognition of either positive or negative emotions have a context-dependent risk of developing an anxiety or depressive disorder during adolescence, depending on exposure to positive or harsh parenting. METHODS: Data came from a large prospective Dutch population study (N = 1539). At age 11, perceived parental rejection and emotional warmth were measured by questionnaire, and emotion recognition skills by means of a reaction-time task. Lifetime diagnoses of anxiety and depressive disorders were assessed at about age 19, using a standardized diagnostic interview. RESULTS: Adolescents who were specialized in the recognition of positive emotions had a relatively high probability to develop an anxiety disorder when exposed to parental rejection (Bspecialization*rejection = 0.23, P < 0.01) and a relatively low probability in response to parental emotional warmth (Bspecialization*warmth = -0.24, P = 0.01), while the opposite pattern was found for specialists in negative emotions. The effect of parental emotional warmth on depression onset was likewise modified by emotion recognition specialization (B = -0.13, P = 0.03), but the effect of parental rejection was not (B = 0.02, P = 0.72). In general, the relative advantage of specialists in negative emotions was restricted to fairly uncommon negative conditions. CONCLUSIONS: Our results suggest that there is no unequivocal relation between parenting behaviors and the probability to develop an anxiety or depressive disorder in adolescence, and that emotion recognition specialization may be a promising way to distinguish between various types of context-dependent reaction patterns.

Methylation of NR3C1 and SLC6A4 and internalizing problems. The TRAILS study.

BACKGROUND: The relationship between early adverse life events and later internalizing problems could be mediated by DNA methylation. Adversity has been associated with higher methylation levels in the glucocorticoid receptor gene (NR3C1) and the serotonin transporter gene (SLC6A4) in adolescents. We investigated cross-sectional and prospective associations of NR3C1 and SLC6A4 methylation with adolescents׳ clinical diagnoses of internalizing disorders and internalizing symptom scores. METHODS: In a population sample (mean age=16.2) we measured DNA methylation in three regions of NR3C1 (NR3C1_1, N=454; NR3C1_2, N=904; NR3C1_3, N=412) and one region of SLC6A4 (N=939) at baseline. Internalizing problems were operationalized as clinical DSM-IV diagnoses, assessed at 3 year follow-up with a diagnostic interview, and internalizing symptom scores, assessed with Self-Report questionnaires at baseline and follow-up. RESULTS: Only NR3C1_1 methylation was positively associated with risk of lifetime internalizing disorders, and with symptom scores at follow-up. However, after accounting for baseline symptom scores there was only a tendency for association with internalizing symptom scores at follow-up. There was no association between SLC6A4 methylation and risk of lifetime internalizing disorders. SLC6A4 methylation and internalizing symptom scores showed a tendency for association, also after accounting for baseline symptom scores. LIMITATIONS: There was no repeated measure of DNA methylation to study causality between methylation and internalizing problems. Gene expression data were not available. CONCLUSIONS: Although the role of gene methylation in the development of internalizing problems remains unclear, our findings suggest that gene methylation, particularly of NR3C1, may be involved in the development of internalizing problems in adolescence.

Glucocorticoid receptor gene methylation and HPA-axis regulation in adolescents. The TRAILS study.

Early life adversity and psychopathology are thought to be linked through HPA-axis deregulation. Changes in methylation levels of stress reactivity genes such as the glucocorticoid receptor gene (NR3C1) can be induced by adversity. Higher NR3C1 methylation levels have been associated with a reduced NR3C1 expression, possibly leading to impaired negative feedback regulation of the HPA-axis. In this study we tested whether methylation levels of NR3C1 were associated with HPA-axis regulation, operationalized as cortisol responses. In 361 adolescents (mean age 16.1, SD=0.6), salivary cortisol samples were collected before, during, and after a social stress task, from which response measures (cortisol activation and recovery) were calculated. Higher NR3C1 methylation levels were associated with a flattened cortisol recovery slope, indicating a delayed recovery time. Cortisol response activation was not associated with NR3C1 methylation. These results suggest that methylation of NR3C1 may impair negative feedback of the HPA-axis in adolescents.

Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose-response study.

BACKGROUND: Elevated homocysteine concentrations, a likely risk factor for cardiovascular disease, can be lowered effectively with folic acid. The minimum dose of folic acid required for maximal reduction of homocysteine concentrations is not yet known reliably. OBJECTIVE: We aimed to determine the lowest folic acid dose that decreases plasma homocysteine concentrations adequately in healthy older adults. DESIGN: A dose-response trial with a randomized, double-blind, parallel-group, placebo-controlled design was carried out among 316 Dutch men and women aged 50-75 y. Subjects received daily for 12 wk either a placebo or 1 of the 6 following folic acid doses: 50, 100, 200, 400, 600, or 800 micro g. The relative changes in plasma homocysteine concentration in response to increasing doses of folic acid were used to calculate the dose-response curve. An adequate dose of folic acid was defined as the dose that induced >or= 90% of the maximal reduction in homocysteine concentration. RESULTS: The relative decrease in plasma homocysteine concentration was associated exponentially with increasing doses of folic acid. From the dose-response curve, the adequate daily dose of folic acid was estimated to be 392 micro g, which decreased plasma homocysteine concentrations 22%. CONCLUSION: In older adults, daily supplementation with folic acid effectively lowers plasma homocysteine concentrations, and a daily dose of approximately 400 micro g is the minimum dose required for adequate homocysteine reduction.

Association of postmenopausal hormone replacement therapy with carotid atherosclerosis and soluble thrombomodulin: the vascular aging (EVA) study. Etude du Vieillissement Artériel.

Hormone replacement therapy (HRT) may reduce atherosclerosis among postmenopausal women, partly by reducing vascular endothelium damage. We have tested this hypothesis by evaluating the association of HRT with firstly, carotid intima media thickness (IMT) and plaques, and secondly, with endothelial cell damage, indicated by soluble thrombomodulin (sTM). Then, we tested the association between the two markers of atherosclerosis and the levels of sTM. Among 747 postmenopausal women included into the EVA study, we compared 154 HRT users (including 80% transdermal treatment) with 593 never users. Carotid IMT and plaques were measured with B-mode ultrasonography and sTM with ELISA. At least one plaque was detected among 13.6% of HRT users and 27.3% of never users. After adjustment for confounding factors, the odds ratio for the presence of plaque was 0.45 (95% confidence interval, 0.25-0.78, P=0.005) in HRT users in comparison with nonusers. HRT users had a slightly lower crude mean IMT than nonusers, but the difference was not significant. sTM was positively associated with mean IMT (P for trend=0.001) but not with plaques. Finally, estrogen users had a lower sTM level than nonusers (difference 0.14 ng/ml, P=0.03). As HRT was associated with sTM and plaques, but not with IMT, while sTM was only associated with IMT, our hypothesis was not confirmed. This suggests that the possible beneficial effects of HRT on atherosclerosis may not go through the endothelial cell damage assessed by plasma thrombomodulin.

Corticotropin (ACTH)-reactive immunoglobulins in adolescents in relation to antisocial behavior and stress-induced cortisol response. The TRAILS study.

Elevated levels of corticotropin (ACTH)-reactive immunoglobulins (ACTH IgG) were found in males with conduct disorder, suggesting their involvement in the biology of antisocial behavior. We first aimed to confirm these findings in a large general population sample of adolescents. Secondly, we studied the association between ACTH IgG levels and hypothalamic-pituitary-adrenal (HPA) axis response to stress. Free and total ACTH IgG levels were measured in sera of 1230 adolescents (15-18 years). HPA axis activity was determined by measuring salivary cortisol before, during, and after a social stress test. Antisocial behavior was assessed using the Antisocial Behavior Questionnaire. ACTH peptide and IgG affinity kinetics for ACTH were assayed in a subsample of 90 adolescents selected for high or low ACTH IgG levels. In boys, higher total ACTH IgG levels were associated with higher antisocial behavior scores (ß=1.05, p=0.04), especially at high levels of free ACTH IgG. In girls, antisocial behavior was associated with low free ACTH IgG levels (ß=-0.20, p=0.04). Stress-induced cortisol release was associated with free ACTH IgG in boys (ßareaunderthecurve=-0.67, p<0.01), and with total ACTH IgG in girls (ßrecovery=0.84, p=0.05). The affinity kinetics assay showed that ACTH IgG association rates were lower in both boys and girls with high ACTH IgG levels. These data show that ACTH IgG levels are related to antisocial behavior and HPA axis response to stress in adolescents. The mechanisms behind these associations, including different ACTH binding properties of IgG in subjects with antisocial behavior, deserve further attention.