Distinct sex-specific gene expression changes in the placenta in association with childhood allergy

BACKGROUND: The prevalence of allergic disease has risen significantly during recent years. A major component of the susceptibility to allergic disease is determined in prenatal life, when the placenta plays a central role in fetal growth and development. In this study, we aimed to identify the patterns of gene expression in the placenta that may program early immune function to increase susceptibility to allergy. METHODS: A set of immune genes known to be associated with asthma, allergy and inflammation were selected for analysis by quantitative real-time polymerase chain reaction (qRT-PCR) on placental tissue from infants who did or did not develop an allergy by 2 years of age. Analysis was performed on males and females separately for each allergy type including eczema, rhinitis or asthma. RESULTS: Of 11 candidate allergy-associated genes tested by qRT-PCR, 4 were found to be associated with the development of specific childhood allergy types (P < 0.05). These included MMP9 for both males and females that developed eczema, TLR7 for females that developed eczema, KITL1 for males that developed rhinitis and ORMDL3 for females that developed asthma. CONCLUSIONS: This study has identified altered expression of placental genes involved in inflammation in association with the development of specific allergies in childhood. The current data provide supporting evidence implicating the placenta in programming the fetal immune system in early life.Astrud R Tuck, Luke E Grzeskowiak, Annette Osei-Kumah, Zarqa Saif, Suzanne M Edwards, Andrew Tai, Susan L Prescott, MeriTulic, Richard Saffery, and Vicki L Clifto

The effects of maternal anxiety during pregnancy on IGF2/H19 methylation in cord blood

Compelling evidence suggests that maternal mental health in pregnancy can influence fetal development. The imprinted genes, insulin-like growth factor 2 (IGF2) and H19, are involved in fetal growth and each is regulated by DNA methylation. This study aimed to determine the association between maternal mental well-being during pregnancy and differentially methylated regions (DMRs) of IGF2 (DMR0) and the IGF2/H19 imprinting control region (ICR) in newborn offspring. Maternal depression, anxiety and perceived stress were assessed at 28 weeks of pregnancy in the Barwon Infant Study (n = 576). DNA methylation was measured in purified cord blood mononuclear cells using the Sequenom MassArray Platform. Maternal anxiety was associated with a decrease in average ICR methylation (Delta = -2.23%;95% CI = -3.68 to -0.77%), and across all six of the individual CpG units in anxious compared with non-anxious groups. Birth weight and sex modified the association between prenatal anxiety and infant methylation. When stratified into lower ( 3530 g) birth weight groups using the median birth weight, there was a stronger association between anxiety and ICR methylation in the lower birth weight group (Delta = -3.89%;95% CI = -6.06 to -1.72%), with no association in the higher birth weight group. When stratified by infant sex, there was a stronger association in female infants (Delta = -3.70%;95% CI = -5.90 to -1.51%) and no association in males. All the linear regression models were adjusted for maternal age, smoking and folate intake. These findings show that maternal anxiety in pregnancy is associated with decreased IGF2/H19 ICR DNA methylation in progeny at birth, particularly in female, low birth weight neonates. ICR methylation may help link poor maternal mental health and adverse birth outcomes, but further investigation is needed

Effect of an antenatal diet and lifestyle intervention and maternal BMI on cord blood DNA methylation in infants of overweight and obese women: The LIMIT Randomised Controlled Trial

Background: To investigate the effect of an antenatal diet and lifestyle intervention, and maternal prepregnancy overweight or obesity, on infant cord blood DNA methylation. Methods: We measured DNA methylation in 645 cord blood samples from participants in the LIMIT study (an antenatal diet and lifestyle intervention for women with early pregnancy BMI 25.0 kg/m2) using the Illumina 450K BeadChip array, and tested for any differential methylation related to the intervention, and to maternal early pregnancy BMI. We also analysed differential methylation in relation to selected candidate genes. Results: No CpG sites were significantly differentially methylated in relation to either the diet and lifestyle intervention, or with maternal early pregnancy BMI. There was no significant differential methylation in any of the selected genes related to the intervention, or to maternal BMI. Conclusion: We found no evidence of an effect of either antenatal diet and lifestyle, or of maternal early pregnancy BMI, on cord blood DNA methylation.Jennie Louise, Andrea R. Deussen, Berthold Koletzko, Julie Owens, Richard Saffery, Jodie M. Dod

Heterochromatin and RNAi Are Required to Establish CENP-A Chromatin at Centromeres

Heterochromatin is defined by distinct posttranslational modifications on histones, such as methylation of histone H3 at lysine 9 (H3K9), which allows heterochromatin protein 1 (HP1)–related chromodomain proteins to bind. Heterochromatin is frequently found near CENP-A chromatin, which is the key determinant of kinetochore assembly. We have discovered that the RNA interference (RNAi)–directed heterochromatin flanking the central kinetochore domain at fission yeast centromeres is required to promote CENP-A(Cnp1) and kinetochore assembly over the central domain. The H3K9methyltransferase Clr4 (Suv39); the ribonuclease Dicer, which cleaves heterochromatic double-stranded RNA to small interfering RNA (siRNA); Chp1, a component of the RNAi effector complex (RNA-induced initiation of transcriptional gene silencing; RITS); and Swi6 (HP1) are required to establish CENP-A(Cnp1) chromatin on naïve templates. Once assembled, CENP-A(Cnp1) chromatin is propagated by epigenetic means in the absence of heterochromatin. Thus, another, potentially conserved, role for centromeric RNAi-directed heterochromatin has been identified

Многоцентровое исследование эффективности неоадъювантной терапии САРОХ/бевацизумаб у неоперабельных больных с метастазами колоректального рака в печени

Проанализированы результаты многоцентрового исследования II фазы, в котором показана эффективность и безопасность комбинации режима CAPOX с бевацизумабом при неоадъювантной терапии не подлежащих хирургическому лечению пациентов с метастазами колоректального рака в печени: резектабельность последних была достигнута в 44% случаев, 12-месячная выживаемость: общая – 96%, безрецидивная – 50%. Ключевые слова: колоректальный рак, метастазы в печени, бевацизумаб, капецитабин, оксалиплатин.The results of multicentre study of II phase are analyzed. The efficacy and safety of combined regimen CAPOX + bevacizumab in adjuvant therapy of patients not selected for upfront resection and with colorectal cancer metastasis in liver is demonstrated. The respectability was achieved in 44% of cases, 12-month survival, overall, survival 96%, without relapse 50%. Key Words: bevacizumab, capecitabine, colorectal cancer, liver metastases, oxaliplati

Cognitive Behavioral Therapy for Antenatal Depression in a Pilot Randomized Controlled Trial and Effects on Neurobiological, Behavioral and Cognitive Outcomes in Offspring 3-7 Years Postpartum:A Perspective Article on Study Findings, Limitations and Future Aims

Purpose of Article: In a previous pilot randomized controlled trial including 54 pregnant women with depression, maternal mood improved after Cognitive Behavioural Therapy (CBT) compared to treatment as usual (TAU), showing medium to large effect sizes. The effect persisted up to 9 months postpartum, with infant outcomes also showing medium to large effects favoring CBT in various child domains. This perspective article summarizes the results of a follow-up that was performed approximately 5 years later in the same cohort, assessing the effects of antenatal Cognitive Behavioural Therapy for depression and anxiety on child buccal cell DNA-methylation, brain morphology, behavior and cognition. Findings: Children from the CBT group had overall lower DNA-methylation compared to children from the TAU group. Mean DNA-methylation of all NR3C1 promoter-associated probes did not differ significantly between the CBT and TAU groups. Children from the CBT group had a thicker right lateral occipital cortex and lingual gyrus. In the CBT group, Voxel-Based-Morphometry analysis identified one cluster showing increased gray matter concentration in the right medial temporal lobe, and fixel-based analysis revealed reduced fiber-bundle-cross-section in the Fornix, the Optical Tract, and the Stria Terminalis. No differences were observed in full-scale IQ or Total Problems Score. When the total of hypotheses tests in this study was considered, differences in DNA-methylation and brain measurements were no longer significant. Summary: Our explorative findings suggest that antenatal depression treatment decreases overall child DNA-methylation, increases cortical thickness, and decreases white matter fiber-bundle cross-section in regions involved in cognitive function and the stress response. Nevertheless, larger studies are warranted to confirm our preliminary conclusion that CBT in pregnancy alters neurobiological outcomes in children. Clinical relevance remains unclear as we found no effects of antenatal CBT on child behavior or cognition (yet)

Neighbourhood socioeconomic circumstances, adiposity and cardiometabolic risk measures in children with severe obesity

Background: It has recently been shown that neighbourhood socioeconomic disadvantage in childhood is associated with obesity, hypertension, fatty liver, and type 2 diabetes in adulthood. However, it is largely unknown whether neighbourhood socioeconomic circumstances are important predictors of adiposity and associated measures in children, especially in those with severe obesity. Therefore, we evaluated the associations between neighbourhood socioeconomic factors with the severity of obesity, and related cardiometabolic risk factors in a cohort of obese children.Methods: The Childhood Overweight BioRepository of Australia (COBRA) cohort study comprises 444 children (mean age 11.1 years, mean BMI z-score 2.5). Neighbourhood socioeconomic advantage/disadvantage was evaluated based on postcode information by the national Australian Socio-Economic Indexes for Areas (SEIFA) scores. Participants/parents also completed self-administered questionnaires on neighbourhood related facilities, family education and family income.Results: In analyses adjusted for age, sex and pubertal status, SEIFA indicating neighbourhood education/occupation was negatively associated with BMI, waist circumference and body fat%. Higher family education was associated with lower BMI. Neighbourhood walkability was related to lower waist circumference. Good shopping facilities in the neighbourhood were associated with increased risk of dyslipidemia and fatty liver, and the existence of parks and playgrounds nearby was related to dyslipidemia.Conclusions: The present data suggest that neighbourhood-related issues are associated with less severe adiposity among children with established obesity. Concerning cardiometabolic risk factors, shopping facilities were related to dyslipidemia and fatty liver. These findings suggest that increased awareness and efforts are needed to diminish socioeconomic inequalities between neighbourhoods.</p

DNA content of a functioning chicken kinetochore

© The Author(s) 2014. In order to understand the three-dimensional structure of the functional kinetochore in vertebrates, we require a complete list and stoichiometry for the protein components of the kinetochore, which can be provided by genetic and proteomic experiments. We also need to know how the chromatin-containing CENP-A, which makes up the structural foundation for the kinetochore, is folded, and how much of that DNA is involved in assembling the kinetochore. In this MS, we demonstrate that functioning metaphase kinetochores in chicken DT40 cells contain roughly 50 kb of DNA, an amount that corresponds extremely closely to the length of chromosomal DNA associated with CENP-A in ChIP-seq experiments. Thus, during kinetochore assembly, CENP-A chromatin is compacted into the inner kinetochore plate without including significant amounts of flanking pericentromeric heterochromatin. © 2014 The Author(s).Wellcome Trust [grant number 073915]; Wellcome Trust Centre for Cell Biology (core grant numbers 077707 and 092076); Darwin Trust of Edinburg

Telomere length and vascular phenotypes in a population-based cohort of children and midlife adults

Background: Telomere length has been inversely associated with cardiovascular disease in adulthood, but its relationship to preclinical cardiovascular phenotypes across the life course remains unclear. We investigated associations of telomere length with vascular structure and function in children and midlife adults.Methods and Results: Population-based cross-sectional CheckPoint (Child Health CheckPoint) study of 11- to 12-year-old children and their parents, nested within the LSAC (Longitudinal Study of Australian Children). Telomere length (telomeric genomic DNA [T]/β-globin single-copy gene [S] [T/S ratio]) was measured by quantitative polymerase chain reaction from blood-derived genomic DNA. Vascular structure was assessed by carotid intima-media thickness, and vascular function was assessed by carotid-femoral pulse-wave velocity and carotid elasticity. Mean (SD) T/S ratio was 1.09 (0.55) in children (n=1206; 51% girls) and 0.81 (0.38) in adults (n=1343; 87% women). Linear regression models, adjusted for potential confounders, revealed no evidence of an association between T/S ratio and carotid intima-media thickness, carotid-femoral pulse-wave velocity, or carotid elasticity in children. In adults, longer telomeres were associated with greater carotid elasticity (0.14% per 10-mm Hg higher per unit of T/S ratio; 95% CI, 0.04%-0.2%; P=0.007), but not carotid intima-media thickness (-0.9 μm; 95% CI, -14 to 13 μm; P=0.9) or carotid-femoral pulse-wave velocity (-0.10 m/s; 95% CI, -0.3 to 0.07 m/s; P=0.2). In logistic regression analysis, telomere length did not predict poorer vascular measures at either age.Conclusions: In midlife adults, but not children, there was some evidence that telomere length was associated with vascular elasticity but not thickness. Associations between telomere length and cardiovascular phenotypes may become more evident in later life, with advancing pathological changes