Associations between prenatal and early life stress and physical and mental health outcomes in prospective pregnancy and birth cohorts of children, adolescents and older adults : the role of epigenetics and genetics

Maternal depression and anxiety during pregnancy may present risks for the developing fetus and offspring lifelong physical and mental health. Exposure to postnatal early life stress (ELS) has also been extensively associated with health problems decades later. According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, environmental factors during pregnancy and early childhood may compromise the development of tissue, organs and systems, such as hypothalamic-pituitary-adrenal (HPA) axis. While the underlying biological mechanisms are not fully understood, epigenetic alterations and genetic vulnerability are the promising biomarkers, which have been suggested to mediate the association of antenatal and early adversity with physical and mental health later in life. The aim of this work was to examine whether exposure to maternal antenatal depression and anxiety was associated with polyepigenetic modifications in their children reflected by the polyepigenetic biomarkers of child’s epigenetic gestational age (GA) and glucocorticoid (GC) exposure score. Additionally, it explored whether these modifications were associated with and mediated the effects of antenatal exposures on child mental health outcomes and whether the associations were moderated by child’s sex. As epigenetic processes undergo age-related changes, the next aim was to study whether epigenetic modifications reflected by the polyepigenetic biomarker of epigenetic clock were associated with physical growth, neuroendocrine functioning, cognition and mental health in adolescents. Finally, this thesis also examined whether genetic variants in FKBP5, the gene that plays a role in the HPA-axis regulation, interacted with exposure to ELS in prediction of type 2 diabetes (T2D), cardiovascular disease (CVD), and quantitative glycemic traits in older adults. The participants for the studies come from three prospective cohorts. Studies I and II capitalize on the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) birth cohort. We had full information on genome-wide methylation and genotype from 817 fetal umbilical cord blood samples. In Study I, 694 mothers provided information on their history of depression diagnosed before pregnancy, 581 completed the Center for Epidemiological Studies Depression Scale (CES-D) throughout pregnancy, and 407 completed the Child Behavior Checklist (CBCL) at child’s mean age 3.7 years. DNA methylation (DNAm) GA of fetal cord blood DNA was based on the methylation profile of 148 selected CpG sites. Polyepigenetic biomarker of child’s epigenetic GA was calculated as the arithmetic difference between DNAm GA and chronological GA and adjusted for chronological GA. In Study II, we had information on child diagnoses of mental and behavioral disorders and the number of days the child had been receiving in- or outpatient treatment for these disorders as the primary diagnosis from birth to age 7.1-10.7 years (n=814). Mothers (n=583) reported depressive and anxiety symptoms during pregnancy, using CES-D and State Anxiety Inventory (STAI), respectively. A weighted cross-tissue polyepigenetic GC exposure score was calculated based on the methylation profile of 24 CpGs. Study III was based on the Glycyrrhizin in Licorice (Glaku) cohort. We had information available on DNA samples, physical growth and pubertal development, cognitive abilities, psychiatric problems assessed by mothers with CBCL questionnaire, and saliva samples to estimate cortisol levels for a subsample adolescents at the mean age of 12.3 (n=239). DNAm age was estimated using the Horvath age estimation algorithm. The polyepigenetic biomarker of epigenetic clock was calculated as the unstandardized residual from a linear regression of DNAm age on chronological age and six cell count types. For Study IV, a total of 1,728 Helsinki Birth Cohort Study (HBCS) participants born from 1934 to 1944 were genotyped for FKBP5 SNPs (rs1360780, rs9394309, rs9470080) and were administered a 2-hour (75 g) oral glucose tolerance test (OGTT) and a questionnaire on physician-diagnosed and medication use for chronic diseases at a mean age of 61.5 years. Of them, 273 were exposed to ELS defined as separation from biological parents at a mean age of 4.7 years due to evacuations during World War II. In Study I we found that lower child’s epigenetic GA at birth was significantly associated with maternal history of depression diagnosed before pregnancy and higher antenatal depressive symptoms. It also prospectively predicted child’s total and internalizing problems in early childhood, partially mediating the association of maternal antenatal depression with child internalizing problems, although only in boys. It may signal about their developmental vulnerability to maternal depression during pregnancy (Study I). In Study II we show that while polyepigenetic GC exposure score at birth was not predictive of higher risk for any mental and behavioral disorder in childhood, lower score was associated with more days spent in in- or outpatient treatment for any mental and behavioral disorder as the primary diagnosis. This finding may contribute to better understanding and identification of children at risk for more severe mental and behavioral disorders already at birth (Study II). Next, we demonstrate that adolescents with epigenetic clock age acceleration (AA) displayed more advanced physical growth and development, had higher salivary cortisol upon awakening and higher odds for displaying borderline clinically significant internalizing problems, which may index risk of earlier aging and age-related diseases (Study III). Finally, Study IV revealed that three selected FKBP5 polymorphisms moderated the association of ELS on insulin and glucose values at fasting state and/or during an OGTT in late adulthood, supporting the role of gene-environment interaction and HPA axis dysregulation in the development of metabolic disorders. These study findings provide valuable insights on how the polyepigenetic biomarkers of antenatal adverse exposures and aging and biomarkers of genetic vulnerability in combination with the information about ELS might contribute to early identification of individuals at risk for complex mental and physical disorders enabling timely targeted preventive and therapeutic interventions.Developmental Origins of Health and Disease (DOHaD)-hypoteesin mukaan raskaudenaikaiset ja varhaislapsuuden ympäristötekijät voivat vaikuttaa kudosten, elinten ja elimistön säätelyjärjestelmien, kuten hypotalamus-aivolisäke-lisämunuainen -akseli (HPAA) toimintaan pitkälläkin aikajänteellä. Esimerkiksi raskaudenaikainen masennus ja ahdistus voivat haitata sikiön kehittymistä ja lisätä terveysongelmien riskiä syntymän jälkeen. Myös varhaislapsuuden stressi voi lisätä terveysongelmien riskiä. Epigeneettiset muutokset ja geneettinen vaihtelu ovat lupaavia biomarkkereita, joiden on ehdotettu välittävän ja muokkaavan sikiöaikaisten ja varhaislapsuuden ympäristövaikutusten yhteyksiä fyysiseen ja henkiseen terveyteen myöhemmässä elämässä. Tämän työn tarkoituksena oli tutkia, liittyykö altistuminen raskaudenaikaiselle masennukselle ja ahdistukselle kahteen lapsen epigeneettiseen biomarkkeriin: epigeneettiseen gestaatioikään ja glukokortikoidialtistuksesta kertovaan epigeneettiseen indikaattoriin. Lisäksi työssä selvitettiin, välittyikö raskaudenaikaisten altisteiden vaikutus lasten mielenterveyteen näiden biomarkkereiden kautta. Seuraavana tavoitteena oli tutkia kolmannen epigeneettisen biomarkkerin, epigeneettisen kellon, yhteyksiä fyysiseen kasvuun, neuroendokriinisiin vasteisiin, kognitiivisiin kykyihin ja mielenterveyteen murrosikäisillä. Lopuksi tässä opinnäytetyössä tutkittiin myös HPAA säätelyssä olennaisen FKBP5 geenin varianttien ja varhaisen stressin yhteisvaikutusta insuliini- ja glukoositasoihin sekä tyypin 2 diabetekseen ja sydän- ja verisuonitauteihin myöhäisessä aikuisuudessa. Tutkimuksiin osallistujat tulevat kolmesta prospektiivisesta kohortista. Osatutkimukset I ja II hyödynsivät PREDO syntymäkohortin aineistoa. Tähän kuuluu genominlaajuinen metylaatio- ja genomiaineisto 817:sta napaverinäytteestä. Osatutkimuksessa I, 694:ltä äidiltä oli lisäksi tieto masennusdiagnoosista ennen raskautta, 581 täytti CES-D masennusoirekyselyn raskauden aikana ja 407 täytti CBCL-kyselyn lapsen käyttäytymis- ja tunneongelmista kun lapset olivat keskimäärin 3.7 -vuotiaita. Epigeneettinen gestaatioikä eli määriteltiin 148 napaveren DNA:n metylaatiokohdan (CpG) perusteella. Tutkimuksessa II aineistona oli lasten mielenterveys- ja käyttäytymishäiriöiden diagnoosit sekä niiden päivien lukumäärästä, jolloin lapsi oli ollut näiden sairauksien takia avo- tai sairaalahoidossa syntymästä 7.1 - 10.7 vuoden ikään saakka (n = 814). Äidit raportoivat myös raskaudenaikaisen masennusoireensa CES-D kyselyllä ahdistuksensa STAI kyselyllä (n = 583). Glukokortikoidialtistuksesta kertova epigeneettinen biomarkkeri laskettiin 24 CpG:n metylaatioprofiilin perusteella. Tutkimus III perustui Glaku -kohortin aineistoon. Aineistona oli DNA-näytteet, fyysinen kasvu ja murrosiän kehitys, kognitiiviset kyvyt, CBCL-kyselylomakkeella raportoidut käyttäytymis- ja tunneongelmat ja sylkinäytteistä määritetty kortisolipitoisuus keskimäärin 12.3 -vuoden iässä (n = 239). Epigeneettinen ikä arvioitiin Horvathin algoritmilla. Tutkimuksessa IV määritettiin FKBP5 geenin variantit (rs1360780, rs9394309, rs9470080) n=1728 HBCS -tutkimukseen osallistuneelta vuosina 1934–1944 syntyneeltä. Heille tehtiin myös 2-tunnin (75 g) sokerirasitustesti ja he raportoivat lääkärin diagnosoimista kroonisista sairauksista ja lääkkeidenkäytöstä keskimäärin 61.5 vuoden iässä. Tutkittavista 273 oli altistunut varhaiselle stressille, joka märiteltiin eroksi biologisista vanhemmista 2. maailmansodan aikana tapahtuneen evakuoinnin (sotalapsi) vuoksi keskimäärin 4.7 vuoden iässä. Tutkimuksessa I havaitsimme, että matalampi lapsen epigeneettinen gestaatioikä, suhteessa kronologiseen gestaatioikään syntymähetkellä liittyi ennen raskautta diagnosoituun äidin masennukseen ja raskausaikaisiin masennusoireisiin. Se ennusti myös lapsen käyttäytymis- ja tunneongelmia varhaislapsuudessa sekä välitti osittain äidin masennuksen yhteyttä lapsen tunneongelmiin, erityisesti pojilla. Tutkimuksessa II osoitimme, että glukokortikoidialtistuksesta kertovan epigeneettisen indikaattorin matalmpi taso liittyi lapsen mielenterveyden ja käyttäytymishäiriön vuoksi sairaalassa tai avohoidossa vietetyn hoitojakson pituuteen. Tutkimuksessa III osoitimme, että korkeampi epigeneettinen ikä suhteessa kronologiseen ikään, oli yhteydessä fyysiseen kasvuun ja kehitykseen, korkeampiin syljen kortisolitasoihin heräämisen jälkeen ja lievien internalisoivien ongelmien korkeampaan riskiin. Lopulta Tutkimuksessa IV osoitimme, että kolme FKBP5-varianttia muokkasi varhaislapsuuden stressikokemuksen yhteyttä korkeampiin paaston- ja/tai sokerirasituksen jälkeisiin insuliini- ja glukoosiarvoihin myöhäisessä aikuisiässä. Nämä tutkimustulokset antavat arvokasta tietoa siitä, kuinka raskauden- tai lapsuuden aikaisten altistusten tai ikääntymisen epigeneettiset biomarkkerit ja geneettiset biomarkkerit yhdessä varhaista stressiä kuvaavan tiedon kanssa voivat auttaa tunnistamaan ajoissa ne henkilöt, joilla on kohonnut riski mielenterveyden ongelmille tai fyysisille sairauksille. Tunnistaminen mahdollistaa ennaltaehkäisevien toimenpiteiden kohdentamisen oikea-aikaisesti jopa vuosikymmeniä ennen oireiden ilmaantumista

Measurement of differential cross sections for top quark pair production using the lepton plus jets final state in proton-proton collisions at 13 TeV

National Science Foundation (U.S.

Search for pair-produced resonances decaying to jet pairs in proton-proton collisions at √s=8 TeV

Results are reported of a general search for pair production of heavy resonances decaying to pairs of hadronic jets in events with at least four jets. The study is based on up to 19.4 fb(-1) of integrated luminosity from proton-proton collisions at a center-of-mass energy of 8 TeV, recorded with the CMS detector at the LHC. Limits are determined on the production of scalar top quarks (top squarks) in the framework of R-parity violating supersymmetry and on the production of color-octet vector bosons (colorons). First limits at the LHC are placed on top squark production for two scenarios. The first assumes decay to a bottom quark and a light-flavor quark and is excluded for masses between 200 and 385 GeV, and the second assumes decay to a pair of light-flavor quarks and is excluded for masses between 200 and 350 GeV at 95% confidence level. Previous limits on colorons decaying to light-flavor quarks are extended to exclude masses from 200 to 835 GeV

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia