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1.
Psychol Med ; : 1-13, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31439060

RESUMO

BACKGROUND: Maternal depression during pregnancy increases the risk for adverse developmental outcomes in children. However, the underpinning biological mechanisms remain unknown. We tested whether depression was associated with levels of and change in the inflammatory state during pregnancy, if early pregnancy overweight/obesity or diabetes/hypertensive pregnancy disorders accounted for/mediated these effects, and if depression added to the inflammation that typically accompanies these conditions. METHODS: We analyzed plasma high-sensitivity C-reactive protein (hsCRP) and glycoprotein acetyls at three consecutive stages during pregnancy, derived history of depression diagnoses before pregnancy from Care Register for Healthcare (HILMO) (N = 375) and self-reports (N = 347) and depressive symptoms during pregnancy using the Center for Epidemiological Studies Depression Scale completed concurrently to blood samplings (N = 295). Data on early pregnancy body mass index (BMI) and diabetes/hypertensive pregnancy disorders came from medical records. RESULTS: Higher overall hsCRP levels, but not change, during pregnancy were predicted by history of depression diagnosis before pregnancy [HILMO: mean difference (MD) = 0.69 standard deviation (s.d.) units; 95% confidence interval (CI) 0.26-1.11, self-report: MD = 0.56 s.d.; 95% CI 0.17-0.94] and higher depressive symptoms during pregnancy (0.06 s.d. per s.d. increase; 95% CI 0.00-0.13). History of depression diagnosis before pregnancy also predicted higher overall glycoprotein acetyls (HILMO: MD = 0.52 s.d.; 95% CI 0.12-0.93). These associations were not explained by diabetes/hypertensive disorders, but were accounted for and mediated by early pregnancy BMI. Furthermore, in obese women, overall hsCRP levels increased as depressive symptoms during pregnancy increased (p = 0.006 for interaction). CONCLUSIONS: Depression is associated with a proinflammatory state during pregnancy. These associations are mediated by early pregnancy BMI, and depressive symptoms during pregnancy aggravate the inflammation related to obesity.

2.
Nat Commun ; 10(1): 2548, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186427

RESUMO

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.


Assuntos
Metilação de DNA/genética , DNA/sangue , Interação Gene-Ambiente , Estudos de Coortes , Epigênese Genética , Feminino , Sangue Fetal , Genótipo , Humanos , Recém-Nascido , Masculino , Gravidez , Fatores de Risco
3.
Sleep Med ; 56: 201-210, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30819657

RESUMO

OBJECTIVE: Maternal depressive symptoms during pregnancy have been associated with poor offspring sleep. Yet, it remains unknown whether depressive symptoms throughout pregnancy are more harmful to the child than depressive symptoms only during certain time periods in pregnancy, whether associations are specific to pregnancy stage, whether maternal symptomatology after pregnancy mediates or adds to the prenatal effects, and whether any effects are specific to some child sleep characteristics. METHODS: A total of 2321 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Center for Epidemiological Studies Depression Scale biweekly between gestational weeks + days 12 + 0/13 + 6 and 38 + 0/39 + 6. At child's mean age of 3.5 (standard deviation = 0.7) years, mothers completed the Beck Depression Inventory-II and answered questions on child sleep quantity and quality using the Brief Infant Sleep Questionnaire (BISQ) and sleep disorders using the Sleep Disturbance Scale for Children. RESULTS: Maternal depressive symptoms showed high stability throughout pregnancy. Children of mothers with clinically significant symptomatology throughout pregnancy had shorter mother-rated sleep duration, longer sleep latency, higher odds for waking up two or more times during the night and for total and several specific sleep disorders. These associations were robust to covariates. However, maternal depressive symptoms at the child follow-up fully mediated the associations with sleep duration and awakenings, partially mediated those with sleep latency and disorders, and added to the effects on sleep disorders. CONCLUSION: Maternal depressive symptoms throughout pregnancy are associated with mother-rated child sleep quantity, quality, and disorders. Maternal depressive symptoms at child follow-up mediate and add to the prenatal adverse effects on child sleep characteristics.

4.
J Mol Endocrinol ; 62(4): R255-R267, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30917337

RESUMO

Recent development of gas chromatography and liquid chromatography-tandem mass spectrometry (GC-MS/MS, LC-MS/MS) has provided novel tools to define sex steroid concentrations. These new methods overcome several of the problems associated with immunoassays for sex steroids. With the novel MS-based applications we are now able to measure small concentrations of the steroid hormones reliably and with high accuracy in both body fluids and tissue homogenates. The sensitivity of the tandem mass spectrometry assays allows us also for the first time to reliably measure picomolar or even femtomolar concentrations of estrogens and androgens. Furthermore, due to a high sensitivity and specificity of MS technology, we are also able to measure low concentrations of steroid hormones of interest in the presence of pharmacological concentration of other steroids and structurally closely related compounds. Both of these features are essential for multiple preclinical models for prostate cancer. The MS assays are also valuable for the simultaneous measurement of multiple steroids and their metabolites in small sample volumes in serum and tissue biopsies of prostate cancer patients before and after drug interventions. As a result, novel information about steroid hormone synthesis and metabolic pathways in prostate cancer has been obtained. In our recent studies, we have extensively applied a GC-MS/MS method to study androgen biosynthesis and metabolism in VCaP prostate cancer xenografts in mice. In the present review, we shortly summarize some of the benefits of the GC-MS/MS and novel LC-MS/MS assays, and provide examples of their use in defining novel mechanisms of androgen action in prostate cancer.

5.
Lancet Child Adolesc Health ; 3(2): 109-120, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30612946

RESUMO

BACKGROUND: The treatment of constitutional delay of growth and puberty (CDGP) is an underinvestigated area in adolescent medicine. We tested the hypothesis that peroral aromatase inhibition with letrozole is more efficacious than intramuscular injection of low-dose testosterone in inducing puberty in boys with CDGP. METHODS: We did a randomised, controlled, open-label trial at four paediatric centres in Finland. Boys aged at least 14 years with CDGP who wanted medical intervention and exhibited the first signs of puberty were randomly assigned in blocks of ten to receive either six intramuscular injections of low-dose testosterone (about 1 mg/kg bodyweight) every 4 weeks for 6 months or peroral letrozole 2·5 mg once daily for 6 months. All boys were followed up for 6 months after the end of treatment. The primary outcomes were changes in testicular volume and hormonal markers of puberty at 6 months after treatment initiation, which were assessed in all participants who received the assigned treatment. All patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01797718. FINDINGS: Between Aug 1, 2013, and Jan 30, 2017, 30 boys were randomly assigned to receive testosterone (n=15) or letrozole (n=15). One boy in the testosterone group was excluded from the primary analyses because of a protocol deviation. During treatment, boys in the letrozole group had higher serum concentrations of luteinising hormone, follicle-stimulating hormone, testosterone, and inhibin B than did boys in the testosterone group. Testicular growth from baseline to 6 months was greater in the letrozole group than in the testosterone group (7·2 mL [95% CI 5·2-9·3] vs 2·2 mL [1·4-2·9]; between-group difference per month 0·9 mL [95% CI 0·6-1·2], p<0·0001). Most adverse events were mild. One boy in the testosterone group had aggressive behaviour for 1 week after each injection, and one boy in the letrozole group had increased irritability at 6 months. INTERPRETATION: Letrozole might be a feasible alternative treatment to low-dose testosterone for boys with CDGP who opt for medical intervention. However, the risks and benefits of manipulating the reproductive axis during early puberty should be weighed carefully. FUNDING: Helsinki University Hospital, Academy of Finland, and Finnish Foundation for Pediatric Research.

6.
Psychol Med ; : 1-11, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30688183

RESUMO

BACKGROUND: Synthetic glucocorticoids, to enhance fetal maturation, are a standard treatment when preterm birth before 34 gestational weeks is imminent. While morbidity- and mortality-related benefits may outweigh potential neurodevelopmental harms in children born preterm (<37 gestational weeks), this may not hold true when pregnancy continues to term (⩾37 gestational weeks). We studied the association of antenatal betamethasone exposure on child mental health in preterm and term children. METHODS: We included 4708 women and their children, born 2006-2010, from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction Study with information on both antenatal betamethasone treatment and child mental and behavioral disorders from the Finnish Hospital Discharge Register from the child's birth to 31 December 2016. Additional follow-up data on mother-reported psychiatric problems and developmental milestones were available for 2640 children at 3.5 (s.d. = 0.07) years-of-age. RESULTS: Of the children, 187 were born preterm (61 betamethasone-exposed) and 4521 at term (56 betamethasone-exposed). The prevalence of any mental and behavioral, psychological development, emotional and behavioral, and comorbid disorders was higher in the betamethasone-exposed, compared to non-exposed children [odds ratio 2.76 (95% confidence interval 1.76-4.32), 3.61 (2.19-5.95), 3.29 (1.86-5.82), and 6.04 (3.25-11.27), respectively]. Levels of psychiatric problems and prevalence of failure to meet the age-appropriate development in personal-social skills were also higher in mother-reports of betamethasone-exposed children. These associations did not vary significantly between preterm and term children. CONCLUSIONS: Antenatal betamethasone exposure may be associated with mental health problems in children born preterm and in those who end up being born at term.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30392118

RESUMO

Whether infant regulatory behavior problems already in the first month of life indicate an increased risk of childhood neurobehavioral problems, and whether maternal depression in the postpartum and early childhood underpins these associations remain unclear. Altogether, 2049-2364 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Neonatal Perception Inventory on regulatory behavior problems at the infant's age of 15.6 days (SD 3.2, range 1-30), the Infant Behavior Questionnaire-Revised on temperament at 6.5 months (SD 0.9, range 4.2-12.4), and the Ages and Stages Questionnaire-3 on developmental milestones and the Child Behavior Checklist on behavioral problems at 3.5 years (SD 0.7, range 1.9-6.0). Maternal depressive symptoms were measured by the Center for Epidemiological Studies Depression Scale (infancy follow-ups) and Beck Depression Inventory-II (childhood follow-up). Father-rated infant temperament and paternal depressive symptoms were also available (n = 1474). Higher levels of infant regulatory behavior problems predicted higher levels of mother- and father-rated negative affectivity temperament (0.13 SD units per SD unit, 95% confidence interval 0.09-0.17; and 0.09, 0.04-0.14, respectively), lower levels of mother-rated orienting/regulation temperament (- 0.09, - 0.13 to - 0.05) and problem-solving skills (- 0.12, - 0.21 to - 0.04), and higher levels of Externalizing (0.07, 0.03-0.11) and Total behavioral problems (0.07, 0.03-0.11). Regulatory behaviors partially mediated the effect of maternal depressive symptoms. Regulatory behavior problems already during the first month of life predict neurobehavioral outcomes, and partially mediate the effect of maternal depressive symptoms. Our study may inform design of interventions aimed at timely prevention in children at risk.

8.
Pediatr Res ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305694

RESUMO

INTRODUCTION: Maternal overweight/obesity and comorbid hypertensive disorders and gestational diabetes associate with neurodevelopmental delay in the offspring in childhood. We hypothesize that these maternal conditions associate also with the offspring regulatory behavior problems and impact on neurodevelopment via the offspring regulatory behavior. METHODS: A number of 3117 women of the PREDO Study filled in a questionnaire on regulatory behavior problems at the child's mean age of 16.9 days and 2116 of them a questionnaire on developmental milestones at the child's mean age of 42.2 months. Data on maternal BMI and comorbid disorders come from the Finnish Medical Birth Register. RESULTS: Offspring of overweight/obese mothers in comparison to normal weight mothers had higher levels of regulatory behavior problems and 22% (95% confidence interval 5-42%) higher odds of having problems on multiple domains of behavioral regulation at the mean age of 16.9 days. Offspring regulatory behavior problems partially mediated the association between maternal overweight/obesity and developmental milestones comprising communication, gross motor, fine motor, problem solving, and personal/social domains of development. Comorbid disorders did not associate with offspring regulatory behavior problems. CONCLUSION: Regulatory behavior problems of the offspring have prenatal origins and partially mediate the effects of maternal overweight/obesity on offspring neurodevelopment.

9.
Int J Obes (Lond) ; 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254363

RESUMO

BACKGROUND: While several studies have demonstrated that obesity increases the risk of pre-eclampsia (PE), the mechanisms have yet to be elucidated. We assessed the association between maternal/paternal obesity and PE and hypothesized that maternal body mass index (BMI) would be associated with an adverse inflammatory and angiogenic profile. High-sensitivity C-reactive protein (hs-CRP) and following serum angiogenic markers were determined: soluble endoglin (sEng), soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). METHODS: Data on BMI were available from 1450 pregnant women with PE and 1065 without PE. Serum concentrations of hs-CRP and angiogenic markers were available from a subset at first and third trimesters. RESULTS: Prepregnancy BMI was higher in the PE group than in controls (mean ± SD) 25.3 ± 5.2 vs. 24.1 ± 4,4, p < 0.001, adjusted for parity, mother's age, and smoking status before pregnancy. Increased hs-CRP concentrations were observed in both PE and non-PE women similarly according to BMI category. In women with PE, a higher BMI was associated with lower sFlt-1 and sEng concentrations throughout the pregnancy (p = 0.004, p = 0.008, respectively). There were no differences in PlGF in PE women according to BMI. CONCLUSIONS: We confirmed increased pre-pregnancy BMI in women with PE. Enhanced inflammatory state was confirmed in all women with overweight/obesity. Partly paradoxically we observed that PE women with obesity had less disturbed levels of angiogenic markers than normal weight women with PE. This should be taken into account when angiogenic markers are used in PE prediction.

10.
Steroids ; 140: 24-31, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30149073

RESUMO

OBJECTIVE: Obesity may alter serum steroid concentrations and metabolism. We investigated this in healthy young women with increased body fat and their leaner co-twin sisters. DESIGN: Age and genetic background both strongly influence serum steroid levels and body composition. This is a cross-sectional study of 13 female monozygotic twin pairs (age, 23-36 years), ten of which were discordant for body mass index (median difference in body weight between the co-twins, 19 kg). METHODS: We determined body composition by dual energy X-ray absorptiometry and magnetic resonance imaging, serum androgens by liquid chromatography-tandem mass spectrometry, and mRNA expression of genes in subcutaneous adipose tissue and adipocytes. RESULTS: The heavier women had lower serum dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) (P < 0.05 for all) compared to their leaner co-twins with no differences in serum testosterone or androstenedione levels. Serum DHEA correlated inversely with %body fat (r = -0.905, P = 0.002), and DHT positively with SHBG (r = 0.842, P = 0.002). In adipose tissue or adipocytes, expressions of STS (steroid sulfatase) and androgen-related genes were significantly higher in the heavier compared to the leaner co-twin, and within pairs, correlated positively with adiposity but were not related to serum androgen levels. None of the serum androgen or SHBG levels correlated with indices of insulin resistance. CONCLUSIONS: Serum DHEA levels were best predicted by %body fat, and serum DHT by SHBG. These or other serum androgen concentrations did not reflect differences in androgen-related genes in adipose tissue. General or intra-abdominal adiposity were not associated with increased androgenicity in young women.

11.
Maturitas ; 115: 37-44, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30049345

RESUMO

OBJECTIVES: Chronic stress, also associated with climacteric-related symptoms, may influence cortisol secretion. We studied cortisol metabolism in peri- and postmenopausal women with diverse climacteric-related symptoms. STUDY DESIGN AND MAIN OUTCOME MEASURES: The study population was 35 women, aged 45-70 years. Plasma cortisol levels were measured from blood samples collected every 20 min over 24 h. Urinary cortisol was analysed from 24-hour urine collections. Climacteric-related symptoms (vasomotor, sleep, depressive, anxiety, cognitive, sexual, menstrual, and somatic) were evaluated with the Women's Health Questionnaire (WHQ). Associations between cortisol variables (24-hour, night, day, maximum, minimum, morning baseline, cortisol awakening response (CAR), area under the curve, slope, and 24-hour urinary cortisol) and the symptoms were first examined with a correlation analysis. Then, the women were divided into two groups according to their climacteric symptomatology, and differences in cortisol variables between the groups were investigated. Diurnal cortisol curves by symptomatology were also analyzed visually. RESULTS: In the correlation analysis, more frequent vasomotor symptoms were associated with a higher CAR (rs = 0.37, p = 0.039) and lower 24-hour urinary cortisol excretion (rs= -0.45, p = 0.012), and more frequent depressive symptoms were associated with a higher minimum cortisol level (rs = 0.33, p = 0.0498). When the women were divided into two groups, women with more frequent vasomotor (p = 0.012) or somatic symptoms (p = 0.021) had a lower 24-hour urinary cortisol excretion than less symptomatic women. CONCLUSIONS: Although previous studies have reported associations between climacteric-related symptoms and cortisol secretion, these two factors were not substantially interrelated in our study.


Assuntos
Hidrocortisona/metabolismo , Menopausa/fisiologia , Idoso , Ansiedade/sangue , Ansiedade/urina , Ritmo Circadiano , Cognição , Depressão/sangue , Depressão/urina , Feminino , Humanos , Hidrocortisona/sangue , Hidrocortisona/urina , Menopausa/sangue , Menopausa/urina , Pessoa de Meia-Idade , Comportamento Sexual , Sono/fisiologia , Inquéritos e Questionários , Saúde da Mulher
12.
BMC Pregnancy Childbirth ; 18(1): 279, 2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-29970026

RESUMO

BACKGROUND: The proportion of hyperglycosylated human chorionic gonadotropin (hCG-h) to total human chorionic gonadotropin (%hCG-h) during the first trimester is a promising biomarker for prediction of early-onset pre-eclampsia. We wanted to evaluate the performance of clinical risk factors, mean arterial pressure (MAP), %hCG-h, hCGß, pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF) and mean pulsatility index of the uterine artery (Uta-PI) in the first trimester in predicting pre-eclampsia (PE) and its subtypes early-onset, late-onset, severe and non-severe PE in a high-risk cohort. METHODS: We studied a subcohort of 257 high-risk women in the prospectively collected Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) cohort. Multivariate logistic regression was used to construct the prediction models. The first model included background variables and MAP. Additionally, biomarkers were included in the second model and mean Uta-PI was included in the third model. All variables that improved the model fit were included at each step. The area under the curve (AUC) was determined for all models. RESULTS: We found that lower levels of serum PlGF concentration were associated with early-onset PE, whereas lower %hCG-h was associated with the late-onset PE. Serum PlGF was lower and hCGß higher in severe PE, while %hCG-h and serum PAPP-A were lower in non-severe PE. By using multivariate regression analyses the best prediction for all PE was achieved with the third model: AUC was 0.66, and sensitivity 36% at 90% specificity. Third model also gave the highest prediction accuracy for late-onset, severe and non-severe PE: AUC 0.66 with 32% sensitivity, AUC 0.65, 24% sensitivity and AUC 0.60, 22% sensitivity at 90% specificity, respectively. The best prediction for early-onset PE was achieved using the second model: AUC 0.68 and 20% sensitivity at 90% specificity. CONCLUSIONS: Although the multivariate models did not meet the requirements to be clinically useful screening tools, our results indicate that the biomarker profile in women with risk factors for PE is different according to the subtype of PE. The heterogeneous nature of PE results in difficulty to find new, clinically useful biomarkers for prediction of PE in early pregnancy in high-risk cohorts. TRIAL REGISTRATION: International Standard Randomised Controlled Trial number ISRCTN14030412 , Date of registration 6/09/2007, retrospectively registered.

13.
Pregnancy Hypertens ; 2018 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-29803331

RESUMO

OBJECTIVES: To study first and second/third trimester levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) in FINNPEC case-control cohort. The participants were further divided into subgroups based on parity and onset of the disease. Recommended cut-off values in aid of pre-eclampsia (PE) prediction and diagnosis were also tested. METHODS: First trimester serum samples were available from 221 women who later developed PE and 239 women who did not develop PE. Second/third trimester serum samples were available from 175 PE and 55 non-PE women. sFlt-1 and PlGF were measured electro-chemiluminescence immunoassays and sEng by ELISA. RESULTS: In all timepoints PlGF, endoglin and the sFlt-1/PlGF ratio were increased in the PE group compared to the non-PE group. The serum concentrations of sFlt-1 were increased only at second/third trimester in PE women. Higher concentrations of s-Flt1, endoglin and higher sFlt/PlGF ratio were found at the third trimester in primiparous women compared to multiparous women. Primiparous PE women also had lower concentrations of PlGF at the third trimester. The proportion of women exceeding all cut-offs of the sFlt-1/PlGF ratio (≥33, ≥38, ≥85 and ≥110) was greater in the PE group, but there were also pre-eclamptic women who met rule-out cut-off or did not meet rule-in cut-off. CONCLUSIONS: Primiparous pregnancies have more anti-angiogenic profile during second/third trimester compared with multiparous pregnancies. Our findings also suggest that certain maternal characteristics, e.g. BMI, smoking and pre-existing diseases, should be taken into account when different sFlt-1/PlGF ratio cut-offs are utilized.

14.
Gynecol Endocrinol ; : 1-5, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29790386

RESUMO

Circulating estrogens fluctuate during the menstrual cycle but it is not known whether this fluctuation is related to local hormone levels in adipose tissue. We analyzed estrogen concentrations and gene expression of estrogen-regulating enzymes in breast subcutaneous adipose tissue in premenopausal women with (n = 11) and without (n = 17) estrogen receptor-positive breast cancer. Estrone (E1) was the predominant estrogen in premenopausal breast adipose tissue, and E1 and mRNA expression of CYP19A1 in adipose tissue correlated positively with BMI. Adipose tissue estradiol (E2) concentrations fluctuated during the menstrual cycle, similarly to the serum concentrations. In women with breast cancer median adipose tissue E1 (1519 vs. 3244, p < .05) and E2 (404 vs. 889 pmol/kg, p < .05) levels were lower in the follicular than in the luteal phase whereas in control women no significant differences were observed. In the follicular phase, mRNA expressions of HSD17B1 (median 0.06; interquartile range 0.05-0.07 vs. 0.17; 0.03-0.2, p = .010) and CYP19A1 (0.08; 0.07-0.14 vs. 0.22; 0.09-0.54, p = .025) were lower in women with breast cancer than in controls. In conclusion, the changes in adipose tissue E1 and E2 concentrations and the estrogen-regulating CYP19A1 and HSD17B1 during the menstrual cycle may be related to dysfunctional local estrogen metabolism in women with breast cancer.

15.
J Am Acad Child Adolesc Psychiatry ; 57(5): 321-328.e2, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29706161

RESUMO

OBJECTIVE: Maternal antenatal depression may compromise the fetal developmental milieu and contribute to individual differences in aging and disease trajectories in later life. We evaluated the association between maternal antenatal depression and a novel biomarker of aging at birth, namely epigenetic gestational age (GA) based on fetal cord blood methylation data. We also examined whether this biomarker prospectively predicts and mediates maternal effects on early childhood psychiatric problems. METHOD: A total of 694 mothers from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) Study provided information on history of depression diagnosed before pregnancy; 581 completed the Center for Epidemiological Studies Depression Scale throughout pregnancy, and 407 completed the Child Behavior Checklist at child's age 3.7 years (SD = 0.75 year). DNA methylation (DNAm) GA of fetal cord blood DNA was based on the methylation profile of 148 selected cytosine linked to guanine by phosphate (CpG) sites. Epigenetic GA was calculated as the arithmetic difference between DNAm GA and chronological GA and adjusted for chronological GA. RESULTS: Maternal history of depression diagnosed before pregnancy (mean difference = -0.25 SD units, 95% CI = -0.46 to -0.03) and greater antenatal depressive symptoms (-0.08 SD unit per 1-SD unit increase, 95% CI = -0.16 to -0.004) were associated with child's lower epigenetic GA. Child's lower epigenetic GA, in turn, prospectively predicted total and internalizing problems and partially mediated the effects of maternal antenatal depression on internalizing problems in boys. CONCLUSION: Maternal antenatal depression is associated with lower epigenetic GA in offspring. This lower epigenetic GA seems to be associated with a developmental disadvantage for boys, who, in early childhood, show greater psychiatric problems.

16.
Int J Obes (Lond) ; 42(5): 995-1007, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29686379

RESUMO

BACKGROUND/OBJECTIVES: Previous studies have linked maternal pre-pregnancy obesity (BMI ≥30 kg/m2) with suboptimal neurodevelopment in her offspring; however, the literature is not entirely consistent. Whether these effects are muddled by maternal self-reports of pre-pregnancy weight and height, or are driven or amplified by the well often comorbid hypertensive and diabetic pregnancy and pre-pregnancy disorders, remains unclear. We examined whether maternal early pregnancy obesity is associated with developmental delay in her offspring, and if the associations are driven or amplified by diabetic and hypertensive pregnancy and pre-pregnancy disorders. SUBJECTS/METHODS: A total of 2504 mother-child dyads participated in the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study. Data on maternal early pregnancy obesity, pre-pregnancy, and gestational hypertension, pre-eclampsia, type 1 and gestational diabetes were derived from the Finnish Medical Birth Register. At the child's mean age of 42.1 (SD = 8.2) months the mothers completed the Ages and Stages Questionnaire (ASQ) Third edition for developmental milestones. RESULTS: Children of obese mothers had 1.81-2.74 (p-values <0.02) higher odds of failing to meet the development that is typical for a child's age (developmental domain score ≤-2SD below the child's age) on the communication, fine and gross motor, problem solving and personal/social skills and children of overweight mothers had 2.14 (p = 0.002) higher odds of failing to meet the development that is typical for the child's age on communication skills. Odds of developmental delay were also higher for children of mothers with pre-eclampsia and gestational diabetes. The associations were robust to covariates and confounders, the effects of overweight/obesity and pre-eclampsia were not driven by the other disorders, and overweight/obesity and hypertensive and diabetic disorders did not show additive effects. CONCLUSIONS: Maternal early pregnancy overweight, obesity, and pre-eclampsia are independently associated with neurodevelopmental delay in her offspring. Further studies unraveling the underlying mechanisms are warranted.

17.
Depress Anxiety ; 35(8): 732-741, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29667739

RESUMO

BACKGROUND: Maternal depressive symptoms during and after pregnancy predict poorer child neurodevelopment. The effects of timing, symptom severity, and additive influences remain unclear. METHODS: A total of 2,231 mothers of the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Center for Epidemiological Studies Depression Scale biweekly up to 14 times during pregnancy and twice up to 12 months after pregnancy. At child's age 1.9-5.7 years, the mothers completed the Beck Depression Inventory-II on their concurrent depressive symptoms and Ages and Stages Questionnaire on child developmental milestones. RESULTS: Higher mean maternal depressive symptoms, each biweekly score, and consistently clinically relevant symptomatology during pregnancy predicted lower total developmental milestones, fine and gross motor, communication, problem solving, and personal/social skills scores in children. Although maternal depressive symptoms up to 12 months after pregnancy and in early childhood also predicted lower developmental milestones scores, developmental milestones scores were the lowest in children whose mothers' depressive symptoms were above the clinical cutoff either only during pregnancy, both during and up to 12 months after pregnancy, or at each three time-points. CONCLUSION: Maternal depressive symptoms during pregnancy, in the first year postpartum and in early childhood are associated with poorer child neurodevelopment. Our findings further suggest that antenatal and postpregnancy depression have additive effects on neurodevelopment. Children of mothers with the most chronic and severe depressive symptoms during pregnancy had the most neurodevelopmental disadvantages. Our findings emphasize the adverse effects of maternal depression during and after pregnancy and in early childhood on child neurodevelopment.


Assuntos
Desenvolvimento Infantil/fisiologia , Filho de Pais Incapacitados/psicologia , Transtorno Depressivo/psicologia , Mães/psicologia , Complicações na Gravidez/psicologia , Adulto , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Gravidez
18.
Clin Chim Acta ; 482: 78-83, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29596816

RESUMO

BACKGROUND: Serotonin (5-hydroxytyramine) is a mediator of gastrointestinal smooth muscle contraction, and is secreted by neuroendocrine neoplasms (NENs). We developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for serum serotonin to be used in NEN diagnostics and follow-up. METHODS: We used serum samples from healthy volunteers (n = 31) and patients suspected or monitored for NEN (n = 98). Serotonin-D4 internal standard was added to samples before solid phase extraction (SPE) and quantification by LC-MS/MS. The effects of sample handling and preparation on serotonin stability were studied. Finally, we established a provisional reference range for serum serotonin and compared our assay with serum 5-hydroxyindoleacetic acid (5-HIAA) for detection of NENs. RESULTS: Our assay is sensitive and has a wide linear range (10-10,000 nmol/l). Serum serotonin is stable for 7 days at room temperature and for 3 months at -20 °C. Sampling temperature is not critical. Normal range for serum serotonin was 270-1490 nmol/l. We found that serum serotonin and 5-HIAA performed equally well as diagnostic tests for NENs. CONCLUSIONS: Our LC-MS/MS assay for serum serotonin is well suited for clinical research and patient diagnostics. Our results confirm that it can complement 5-HIAA in diagnosis of NENs.


Assuntos
Ácido Hidroxi-Indolacético/sangue , Tumores Neuroendócrinos/diagnóstico , Serotonina/sangue , Cromatografia Líquida/métodos , Humanos , Tumores Neuroendócrinos/induzido quimicamente , Tumores Neuroendócrinos/metabolismo , Projetos Piloto , Valores de Referência , Serotonina/efeitos adversos , Serotonina/metabolismo , Extração em Fase Sólida , Manejo de Espécimes , Espectrometria de Massas em Tandem/métodos
19.
Sci Rep ; 8(1): 791, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29335435

RESUMO

Maternal depressive symptoms during pregnancy predict increased psychiatric problems in children. The underlying biological mechanisms remain unclear. Hence, we examined whether alterations in the morphology of 88 term placentas were associated with maternal depressive symptoms during pregnancy and psychiatric problems in 1.9-3.1-years old (Mean = 2.1 years) toddlers. Maternal depressive symptoms were rated biweekly during pregnancy with the Center of Epidemiological Studies Depression Scale (n = 86). Toddler psychiatric problems were mother-rated with the Child Behavior Checklist (n = 60). We found that higher maternal depressive symptoms throughout pregnancy [B = -0.24 Standard Deviation (SD) units: 95% Confidence Interval (CI) = -0.46; -0.03: P = 0.03; Mean difference = -0.66 SDs; 95% CI = -0.08; -1.23: P = 0.03; between those with and without clinically relevant depressive symptoms] were associated with lower variability in the placental villous barrier thickness of γ-smooth muscle actin-negative villi. This placental morphological change predicted higher total (B = -0.34 SDs: 95% CI = -0.60; -0.07: P = 0.01) and internalizing (B = -0.32 SDs: 95% CI = -0.56; -0.08: P = 0.01) psychiatric problems in toddlers. To conclude, our findings suggest that both maternal depressive symptoms during pregnancy and toddler psychiatric problems may be associated with lower variability in the villous membrane thickness of peripheral villi in term placentas. This lower heterogeneity may compromise materno-fetal exchange, suggesting a possible role for altered placental morphology in the fetal programming of mental disorders.


Assuntos
Depressão/patologia , Transtornos Mentais/diagnóstico , Mães/psicologia , Placenta/patologia , Actinas/metabolismo , Adulto , Pré-Escolar , Vilosidades Coriônicas/metabolismo , Feminino , Humanos , Lactente , Masculino , Relações Mãe-Filho , Pré-Eclâmpsia/diagnóstico , Gravidez , Complicações na Gravidez , Escalas de Graduação Psiquiátrica
20.
Psychol Med ; 48(14): 2353-2363, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29338797

RESUMO

BACKGROUND: Previous studies have linked maternal obesity with depressive symptoms during and after pregnancy. It remains unknown whether obesity associates with consistently elevated depressive symptoms throughout pregnancy, predicts symptoms postpartum when accounting for antenatal symptoms, and if co-morbid hypertensive and diabetic disorders add to these associations. We addressed these questions in a sample of Finnish women whom we followed during and after pregnancy. METHODS: Early pregnancy body mass index, derived from the Finnish Medical Birth Register and hospital records in 3234 PREDO study participants, was categorized into underweight (<18.5 kg/m2), normal weight (18.5-24.99 kg/m2), overweight (25-29.99 kg/m2), and obese (⩾30 kg/m2) groups. The women completed the Center for Epidemiological Studies Depression Scale biweekly during pregnancy, and at 2.4 (s.d. = 1.2) and/or 28.2 (s.d. = 4.2) weeks after pregnancy. RESULTS: In comparison to normal weight women, overweight, and obese women reported higher levels of depressive symptoms and had higher odds of clinically significant depressive symptoms during (23% and 43%, respectively) and after pregnancy (22% and 36%, respectively). Underweight women had 68% higher odds of clinically significant depressive symptoms after pregnancy. Overweight and obesity also predicted higher depressive symptoms after pregnancy in women not reporting clinically relevant symptomatology during pregnancy. Hypertensive and diabetic disorders did not explain or add to these associations. CONCLUSIONS: Maternal early pregnancy overweight and obesity and depressive symptoms during and after pregnancy are associated. Mental health promotion should be included as an integral part of lifestyle interventions in early pregnancy obesity and extended to benefit also overweight and underweight women.

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