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1.
Clin Epigenetics ; 16(1): 74, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38840168

RESUMO

BACKGROUND: Epigenetic modifications, particularly DNA methylation (DNAm) in cord blood, are an important biological marker of how external exposures during gestation can influence the in-utero environment and subsequent offspring development. Despite the recognized importance of DNAm during gestation, comparative studies to determine the consistency of these epigenetic signals across different ethnic groups are largely absent. To address this gap, we first performed epigenome-wide association studies (EWAS) of gestational age (GA) using newborn cord blood DNAm comparatively in a white European (n = 342) and a South Asian (n = 490) birth cohort living in Canada. Then, we capitalized on established cord blood epigenetic GA clocks to examine the associations between maternal exposures, offspring characteristics and epigenetic GA, as well as GA acceleration, defined as the residual difference between epigenetic and chronological GA at birth. RESULTS: Individual EWASs confirmed 1,211 and 1,543 differentially methylated CpGs previously reported to be associated with GA, in white European and South Asian cohorts, respectively, with a similar distribution of effects. We confirmed that Bohlin's cord blood GA clock was robustly correlated with GA in white Europeans (r = 0.71; p = 6.0 × 10-54) and South Asians (r = 0.66; p = 6.9 × 10-64). In both cohorts, Bohlin's clock was positively associated with newborn weight and length and negatively associated with parity, newborn female sex, and gestational diabetes. Exclusive to South Asians, the GA clock was positively associated with the newborn ponderal index, while pre-pregnancy weight and gestational weight gain were strongly predictive of increased epigenetic GA in white Europeans. Important predictors of GA acceleration included gestational diabetes mellitus, newborn sex, and parity in both cohorts. CONCLUSIONS: These results demonstrate the consistent DNAm signatures of GA and the utility of Bohlin's GA clock across the two populations. Although the overall pattern of DNAm is similar, its connections with the mother's environment and the baby's anthropometrics can differ between the two groups. Further research is needed to understand these unique relationships.


Assuntos
Povo Asiático , Metilação de DNA , Epigênese Genética , Sangue Fetal , Idade Gestacional , População Branca , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Povo Asiático/genética , Canadá , Estudos de Coortes , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética/genética , Sangue Fetal/química , Estudo de Associação Genômica Ampla/métodos , População Branca/genética
2.
Elife ; 122024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38829685

RESUMO

Precision gene editing in primary hematopoietic stem and progenitor cells (HSPCs) would facilitate both curative treatments for monogenic disorders as well as disease modelling. Precise efficiencies even with the CRISPR/Cas system, however, remain limited. Through an optimization of guide RNA delivery, donor design, and additives, we have now obtained mean precise editing efficiencies >90% on primary cord blood HSCPs with minimal toxicity and without observed off-target editing. The main protocol modifications needed to achieve such high efficiencies were the addition of the DNA-PK inhibitor AZD7648, and the inclusion of spacer-breaking silent mutations in the donor in addition to mutations disrupting the PAM sequence. Critically, editing was even across the progenitor hierarchy, did not substantially distort the hierarchy or affect lineage outputs in colony-forming cell assays or the frequency of high self-renewal potential long-term culture initiating cells. As modelling of many diseases requires heterozygosity, we also demonstrated that the overall editing and zygosity can be tuned by adding in defined mixtures of mutant and wild-type donors. With these optimizations, editing at near-perfect efficiency can now be accomplished directly in human HSPCs. This will open new avenues in both therapeutic strategies and disease modelling.


Assuntos
Edição de Genes , Células-Tronco Hematopoéticas , Humanos , Edição de Genes/métodos , Sistemas CRISPR-Cas , RNA Guia de Sistemas CRISPR-Cas/genética , Sangue Fetal/citologia , Células Cultivadas
3.
Wei Sheng Yan Jiu ; 53(3): 382-388, 2024 May.
Artigo em Chinês | MEDLINE | ID: mdl-38839580

RESUMO

OBJECTIVE: To investigate the situation of women's dietary quality during pregnancy and explore the correlations between maternal dietary index and fetal immune function. METHODS: From September 2010 to February 2011, pregnant women who had routine physical examination in Yuexiu District and Baiyun District Maternal and Child Health Hospital of Guangzhou were recruited as study objects to use 3-day 24-hour dietary review to investigate diet during pregnancy, and general demographic information of pregnant women was collected through questionnaire, and the neonatal umbilical cord blood was collected during delivery. Laboratory detection of immunological indicators included IgG, IgA, IgM, IFN-γ and IL-6. The quality of diet during pregnancy was evaluated by diet quality index for pregnancy(DQI-P), dietary balance index for pregnancy(DBI-P) and alternate Medierranean diet score(aMED). Spearman correlation analysis and multiple linear regression analysis were used to explore the correlations between dietary quality during pregnancy and fetal immune function. RESULTS: The mean score of total DQI-P score of the study subjects was 55.8±10.0, and the mean score of overall food diversity and protein food source diversity was as high as 12.0±2.4 and 4.8±0.7. The mean score of nutrient energy ratio and fatty acid energy ratio was only 0.3±1.0 and 0.4±1.0, indicating that the population had good dietary diversity during pregnancy, but the dietary adequacy, suitability and balance were poor. The total score of DBI-P score was-19.2±9.4. The positive end score was 4.6±2.9, only 7.2% of the subjects had a high degree of dietary intake during pregnancy. The negative end score was 23.9±7.9, indicating the status of moderate dietary intake. Dietary quality was 28.5±7.1. Only 0.6% of the study population had a balanced dietary situation, and more than 67.9% of pregnant women had high intake imbalance. The mean total score of aMED score was 4.9±1.3, and the proportion of the food intake of beans and nuts was less than the median population was 62.5% and 79.1%, respectively, indicating that the food intake of beans and nuts was insufficient in this population. After adjusting for confounding factors such as maternal age, parity, parity, prepregnancy BMI, weight gain during pregnancy, and mode of delivery, multiple linear regression analysis showed DQI-P during pregnancy and negatively with IL-6(ß=0.143, ß=-0.155, P<0.05). DBI-P was negatively associated with IL-6(ß=-0.177, P<0.01) and aMED and IFN-γ(ß=-0.161, P<0.01). CONCLUSION: The dietary quality of women in late pregnancy in Guangzhou is low, the dietary structure is unbalanced. Higher dietary quality during pregnancy can promote the development of fetal immune system and improve fetal immune function.


Assuntos
Dieta , Humanos , Feminino , Gravidez , China , Adulto , Feto/imunologia , Inquéritos e Questionários , Sangue Fetal/imunologia , Sangue Fetal/química , Fenômenos Fisiológicos da Nutrição Materna , Inquéritos sobre Dietas , Interleucina-6/sangue
4.
Dan Med J ; 71(6)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38847410

RESUMO

INTRODUCTION: We aimed to investigate the prevalence of SARS-CoV-2 infection and SARS-CoV-2 antibodies in parturient women and their newborns during the first Danish COVID-19 wave and to identify associations with maternal background characteristics, self-reported symptoms, and pregnancy outcomes. METHODS: In a single-centre, prospective cohort study from Denmark, we invited 1,883 women with singleton pregnancies giving live birth from 25 May 2020 to 2 November 2020. Hereof, 953 (50.6%) women were included. Nasopharyngeal swabs, maternal and umbilical cord blood samples, and questionnaires were collected. Medical records were available for participants and non-participants. RESULTS: SARS-CoV-2 antibodies were found in 1.3% of the women. All newborns of seropositive women had SARS-CoV-2 antibodies in cord blood. No association was found between SARS-CoV-2 antibodies and pregnancy outcomes. Self-reported loss of smell correlated with seropositivity (p less-than 0.001). No women were hospitalised due to COVID-19 during pregnancy or had a positive nasopharyngeal swab intrapartum. CONCLUSIONS: The prevalence of COVID-19 in pregnancy was low during the first wave. Maternal SARS-CoV-2 antibodies were associated with antibodies in cord blood, loss of smell and positive SARS-CoV-2 swab during pregnancy, but not with any adverse pregnancy outcomes. FUNDING: Ferring Pharmaceuticals funded part of the study. TRIAL REGISTRATION: The study was approved by the Regional Committee on Health Research Ethics (H-20028002) and the Danish Data Protection Agency (P-2020-264).


Assuntos
Anticorpos Antivirais , COVID-19 , Complicações Infecciosas na Gravidez , Resultado da Gravidez , SARS-CoV-2 , Humanos , Gravidez , Feminino , COVID-19/epidemiologia , COVID-19/imunologia , Dinamarca/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Adulto , Estudos Prospectivos , Anticorpos Antivirais/sangue , SARS-CoV-2/imunologia , Recém-Nascido , Sangue Fetal/imunologia , Prevalência
5.
Front Endocrinol (Lausanne) ; 15: 1333755, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38800487

RESUMO

Background: Gestational Diabetes Mellitus (GDM) is frequently associated with chronic, low-grade inflammation. Whether this environment affects offspring anthropometry during early childhood remains to be elucidated. The aim of this study was to investigate the associations between maternal and fetal (cord blood-umbilical artery) inflammatory biomarkers and offspring weight and BMI up to 1 year in pregnancies with GDM. Methods: In this prospective secondary analysis of the MySweetheart study, we included 193 women with GDM and their offspring. Maternal and fetal (N=39) predictors included serum levels of inflammatory biomarkers including CRP, IL-6, and TNF-α at 24-32 weeks of gestational age (GA) and in the cord blood. Offspring outcomes were small and large for gestational age (SGA, LGA), sex- and age-adjusted weight, and BMI at birth and at 1 year. Univariate and multivariate regression models were performed. Associations were adjusted for maternal pre-pregnancy BMI, age, and ethnicity. Results: Mean maternal age was 33.6 ± 4.8 years, and pre-pregnancy BMI 25.9 ± 5.6 kg/m2. Their mean gestational age at the 1st GDM visit was 29 ± 2.4 weeks. Gestational age at delivery was 39.7 ± 1.1 weeks, with a mean birthweight of 3.4 ± 0.46 kg; 11.8% of offspring were LGA and 10.8% were SGA. At 1 year of age, mean offspring weight was 9.8 ± 1.2 kg and BMI z-score 0.23 ± 1.1 kg/m2. In the models including only maternal predictors, TNF-α at 24-32 weeks of GA was positively associated with SGA and inversely with offspring weight and BMI at birth and at 1 year (p ≤0.034). In the models including only fetal predictors and the combined model, CRP was inversely associated with BMI at 1 year (p ≤0.020). Conclusions: In women with GDM, maternal and fetal inflammatory biomarkers distinctively influenced offspring anthropometry during the first year of life, independent of maternal age, prepregnancy BMI and ethnicity. These results suggest that low-grade inflammation during pregnancy may affect the developing offspring by leading to a decrease in weight and BMI and may have implications for future personalized follow-up of women with GDM and their offspring.


Assuntos
Biomarcadores , Peso ao Nascer , Índice de Massa Corporal , Diabetes Gestacional , Inflamação , Humanos , Feminino , Gravidez , Diabetes Gestacional/sangue , Adulto , Biomarcadores/sangue , Estudos Prospectivos , Recém-Nascido , Inflamação/sangue , Lactente , Masculino , Sangue Fetal/metabolismo , Idade Gestacional , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Peso Corporal
6.
Ecotoxicol Environ Saf ; 278: 116427, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38733803

RESUMO

BACKGROUND: Neighborhood walkability may influence maternal-fetal exposure to environmental hazards and maternal-fetal health (e.g., fetal growth restriction, reproductive toxicity). However, few studies have explored the association between neighborhood walkability and hormones in pregnant women. METHODS: We included 533 pregnant women from the Hangzhou Birth Cohort Study II (HBCS-II) with testosterone (TTE) and estradiol (E2) measured for analysis. Neighborhood walkability was evaluated by calculating a walkability index based on geo-coded addresses. Placental metals were measured using inductively coupled plasma mass spectrometry (ICP-MS). TTE and E2 levels in umbilical cord blood were measured using chemiluminescence microparticle immunoassay (CMIA). Linear regression model was used to estimate the relationship between the walkability index, placental metals, and sex steroid hormones. Effect modification was also assessed to estimate the effect of placental metals on the associations of neighborhood walkability with TTE and E2. RESULTS: Neighborhood walkability was significantly linked to increased E2 levels (P trend=0.023). Compared with participants at the first quintile (Q1) of walkability index, those at the third quintiles (Q3) had lower chromium (Cr) levels (ß = -0.212, 95% CI = -0.421 to -0.003). Arsenic (As), cobalt (Co), manganese (Mn), molybdenum (Mo), nickel (Ni), lead (Pb), antimony (Sb), selenium (Se), tin (Sn), and vanadium (V) were linked to decreased TTE levels, and cadmium (Cd) was linked to increased TTE levels. No metal was significantly associated with E2 levels in trend analysis. In the analysis of effect modification, the associations of neighborhood walkability with TTE and E2 were significantly modified by Mn (P = 0.005) and Cu (P = 0.049) respectively. CONCLUSION: Neighborhood walkability could be a favorable factor for E2 production during pregnancy, which may be inhibited by maternal exposure to heavy metals.


Assuntos
Características de Residência , Caminhada , Humanos , Feminino , Gravidez , Adulto , China , Estudos de Coortes , Estradiol/sangue , Estradiol/análise , Testosterona/sangue , Sangue Fetal/química , Exposição Materna/estatística & dados numéricos , Poluentes Ambientais/análise , Poluentes Ambientais/sangue , Metais/análise , Metais/sangue , Hormônios Esteroides Gonadais/sangue , Hormônios Esteroides Gonadais/análise , Placenta/química , Placenta/efeitos dos fármacos , Metais Pesados/análise , Adulto Jovem
7.
Int J Mol Sci ; 25(10)2024 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-38791576

RESUMO

Obstructive sleep apnea (OSA) is quite prevalent during pregnancy and is associated with adverse perinatal outcomes, but its potential influence on fetal development remains unclear. This study investigated maternal OSA impact on the fetus by analyzing gene expression profiles in whole cord blood (WCB). Ten women in the third trimester of pregnancy were included, five OSA and five non-OSA cases. WCB RNA expression was analyzed by microarray technology to identify differentially expressed genes (DEGs) under OSA conditions. After data normalization, 3238 genes showed significant differential expression under OSA conditions, with 2690 upregulated genes and 548 downregulated genes. Functional enrichment was conducted using gene set enrichment analysis (GSEA) applied to Gene Ontology annotations. Key biological processes involved in OSA were identified, including response to oxidative stress and hypoxia, apoptosis, insulin response and secretion, and placental development. Moreover, DEGs were confirmed through qPCR analyses in additional WCB samples (7 with OSA and 13 without OSA). This highlighted differential expression of several genes in OSA (EGR1, PFN1 and PRKAR1A), with distinct gene expression profiles observed during rapid eye movement (REM)-OSA in pregnancy (PFN1, UBA52, EGR1, STX4, MYC, JUNB, and MAPKAP). These findings suggest that OSA, particularly during REM sleep, may negatively impact various biological processes during fetal development.


Assuntos
Sangue Fetal , Desenvolvimento Fetal , Apneia Obstrutiva do Sono , Humanos , Feminino , Gravidez , Sangue Fetal/metabolismo , Adulto , Apneia Obstrutiva do Sono/genética , Desenvolvimento Fetal/genética , Transcriptoma , Perfilação da Expressão Gênica , Complicações na Gravidez/genética
8.
JAMA Netw Open ; 7(5): e2411246, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38743419

RESUMO

Importance: The cord blood proteome, a repository of proteins derived from both mother and fetus, might offer valuable insights into the physiological and pathological state of the fetus. However, its association with birth weight and growth trajectories early in life remains unexplored. Objective: To identify cord blood proteins associated with birth weight and the birth weight ratio (BWR) and to evaluate the associations of these cord blood proteins with early growth trajectories. Design, Setting, and Participants: This cohort study included 288 mother-child pairs from the ongoing prospective Environmental Influence on Early Aging birth cohort study. Newborns were recruited from East-Limburg Hospital in Genk, Belgium, between February 2010 and November 2017 and followed up until ages 4 to 6 years. Data were analyzed from February 2022 to September 2023. Main Outcomes and Measures: The outcome of interest was the associations of 368 inflammatory-related cord blood proteins with birth weight or BWR and with early life growth trajectories (ie, rapid growth at age 12 months and weight, body mass index [BMI] z score, waist circumference, and overweight at age 4-6 years) using multiple linear regression models. The BWR was calculated by dividing the birth weight by the median birth weight of the population-specific reference growth curve, considering parity, sex, and gestational age. Results are presented as estimates or odds ratios (ORs) for each doubling in proteins. Results: The sample included 288 infants (125 [43.4%] male; mean [SD] gestation age, 277.2 [11.6] days). The mean (SD) age of the child at the follow-up examination was 4.6 (0.4) years old. After multiple testing correction, there were significant associations of birth weight and BWR with 7 proteins: 2 positive associations: afamin (birth weight: coefficient, 341.16 [95% CI, 192.76 to 489.50]) and secreted frizzled-related protein 4 (SFRP4; birth weight: coefficient, 242.60 [95% CI, 142.77 to 342.43]; BWR: coefficient, 0.07 [95% CI, 0.04 to 0.10]) and 5 negative associations: cadherin EGF LAG 7-pass G-type receptor 2 (CELSR2; birth weight: coefficient, -237.52 [95% CI, -343.15 to -131.89]), ephrin type-A receptor 4 (EPHA4; birth weight: coefficient, -342.78 [95% CI, -463.10 to -222.47]; BWR: coefficient, -0.11 [95% CI, -0.14 to -0.07]), SLIT and NTRK-like protein 1 (SLITRK1; birth weight: coefficient, -366.32 [95% CI, -476.66 to -255.97]; BWR: coefficient, -0.11 [95% CI, -0.15 to -0.08]), transcobalamin-1 (TCN1; birth weight: coefficient, -208.75 [95% CI, -305.23 to -112.26]), and unc-5 netrin receptor D (UNC5D; birth weight: coefficient, -209.27 [95% CI, -295.14 to -123.40]; BWR: coefficient, -0.07 [95% CI, -0.09 to -0.04]). Further evaluation showed that 2 proteins were still associated with rapid growth at age 12 months (afamin: OR, 0.32 [95% CI, 0.11-0.88]; TCN1: OR, 2.44 [95% CI, 1.26-4.80]). At age 4 to 6 years, CELSR2, EPHA4, SLITRK1, and UNC5D were negatively associated with weight (coefficients, -1.33 to -0.68 kg) and body mass index z score (coefficients, -0.41 to -0.23), and EPHA4, SLITRK1, and UNC5D were negatively associated with waist circumference (coefficients, -1.98 to -0.87 cm). At ages 4 to 6 years, afamin (OR, 0.19 [95% CI, 0.05-0.70]) and SLITRK1 (OR, 0.32 [95% CI, 0.10-0.99]) were associated with lower odds for overweight. Conclusions and Relevance: This cohort study found 7 cord blood proteins associated with birth weight and growth trajectories early in life. Overall, these findings suggest that stressors that could affect the cord blood proteome during pregnancy might have long-lasting associations with weight and body anthropometrics.


Assuntos
Peso ao Nascer , Sangue Fetal , Humanos , Sangue Fetal/química , Sangue Fetal/metabolismo , Feminino , Peso ao Nascer/fisiologia , Masculino , Recém-Nascido , Pré-Escolar , Proteômica/métodos , Criança , Bélgica , Lactente , Estudos Prospectivos , Proteoma/análise , Proteoma/metabolismo , Adulto , Desenvolvimento Infantil/fisiologia , Estudos de Coortes
9.
Environ Int ; 187: 108720, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38718676

RESUMO

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFASs) influences neurodevelopment. Thyroid homeostasis disruption is thought to be a possible underlying mechanism. However, current epidemiological evidence remains inconclusive. OBJECTIVES: This study aimed to explore the effects of prenatal PFAS exposure on the intelligence quotient (IQ) of school-aged children and assess the potential mediating role of fetal thyroid function. METHODS: The study included 327 7-year-old children from the Sheyang Mini Birth Cohort Study (SMBCS). Cord serum samples were analyzed for 12 PFAS concentrations and 5 thyroid hormone (TH) levels. IQ was assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models (GLM) and Bayesian Kernel Machine Regression (BKMR) were used to evaluate the individual and combined effects of prenatal PFAS exposure on IQ. Additionally, the impact on fetal thyroid function was examined using a GLM, and a mediation analysis was conducted to explore the potential mediating roles of this function. RESULTS: The molar sum concentration of perfluorinated carboxylic acids (ΣPFCA) in cord serum was significantly negatively associated with the performance IQ (PIQ) of 7-year-old children (ß = -6.21, 95 % confidence interval [CI]: -12.21, -0.21), with more pronounced associations observed among girls (ß = -9.57, 95 % CI: -18.33, -0.81) than in boys. Negative, albeit non-significant, cumulative effects were noted when considering PFAS mixture exposure. Prenatal exposure to perfluorooctanoic acid, perfluorononanoic acid, and perfluorooctanesulfonic acid was positively associated with the total thyroxine/triiodothyronine ratio. However, no evidence supported the mediating role of thyroid function in the link between PFAS exposure and IQ. CONCLUSIONS: Increased prenatal exposure to PFASs negatively affected the IQ of school-aged children, whereas fetal thyroid function did not serve as a mediator in this relationship.


Assuntos
Poluentes Ambientais , Fluorocarbonos , Inteligência , Efeitos Tardios da Exposição Pré-Natal , Glândula Tireoide , Humanos , Feminino , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Criança , Gravidez , Fluorocarbonos/toxicidade , Fluorocarbonos/sangue , Masculino , Inteligência/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Poluentes Ambientais/sangue , Poluentes Ambientais/toxicidade , Coorte de Nascimento , Estudos de Coortes , Hormônios Tireóideos/sangue , Testes de Inteligência , China , Exposição Materna/efeitos adversos , Sangue Fetal/química , Ácidos Alcanossulfônicos/sangue , Ácidos Alcanossulfônicos/toxicidade
10.
Sci Rep ; 14(1): 10980, 2024 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-38744864

RESUMO

During pregnancy, multiple immune regulatory mechanisms establish an immune-tolerant environment for the allogeneic fetus, including cellular signals called cytokines that modify immune responses. However, the impact of maternal HIV infection on these responses is incompletely characterized. We analyzed paired maternal and umbilical cord plasma collected during labor from 147 people with HIV taking antiretroviral therapy and 142 HIV-uninfected comparators. Though cytokine concentrations were overall similar between groups, using Partial Least Squares Discriminant Analysis we identified distinct cytokine profiles in each group, driven by higher IL-5 and lower IL-8 and MIP-1α levels in pregnant people with HIV and higher RANTES and E-selectin in HIV-unexposed umbilical cord plasma (P-value < 0.01). Furthermore, maternal RANTES, SDF-α, gro α -KC, IL-6, and IP-10 levels differed significantly by HIV serostatus (P < 0.01). Although global maternal and umbilical cord cytokine profiles differed significantly (P < 0.01), umbilical cord plasma profiles were similar by maternal HIV serostatus. We demonstrate that HIV infection is associated with a distinct maternal plasma cytokine profile which is not transferred across the placenta, indicating a placental role in coordinating local inflammatory response. Furthermore, maternal cytokine profiles in people with HIV suggest an incomplete shift from Th2 to Th1 immune phenotype at the end of pregnancy.


Assuntos
Citocinas , Infecções por HIV , Complicações Infecciosas na Gravidez , Humanos , Gravidez , Feminino , Infecções por HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , Citocinas/sangue , Adulto , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Uganda , Sangue Fetal/metabolismo , Adulto Jovem
11.
Mediators Inflamm ; 2024: 9986187, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38716374

RESUMO

Objective: Fetal growth restriction (FGR) is a significant contributor to negative pregnancy and postnatal developmental outcomes. Currently, the exact pathological mechanism of FGR remains unknown. This study aims to utilize multiomics sequencing technology to investigate potential relationships among mRNA, gut microbiota, and metabolism in order to establish a theoretical foundation for diagnosing and understanding the molecular mechanisms underlying FGR. Methods: In this study, 11 healthy pregnant women and nine pregnant women with FGR were divided into Control group and FGR group based on the health status. Umbilical cord blood, maternal serum, feces, and placental tissue samples were collected during delivery. RNA sequencing, 16S rRNA sequencing, and metabolomics methods were applied to analyze changes in umbilical cord blood circulating mRNA, fecal microbiota, and metabolites. RT-qPCR, ELISA, or western blot were used to detect the expression of top 5 differential circulating mRNA in neonatal cord blood, maternal serum, or placental tissue samples. Correlation between differential circulating mRNA, microbiota, and metabolites was analyzed by the Spearman coefficient. Results: The top 5 mRNA genes in FGR were altered with the downregulation of TRIM34, DEFA3, DEFA1B, DEFA1, and QPC, and the upregulation of CHPT1, SMOX, FAM83A, GDF15, and NAPG in newborn umbilical cord blood, maternal serum, and placental tissue. The abundance of Bacteroides, Akkermansia, Eubacterium_coprostanoligenes_group, Phascolarctobacterium, Parasutterella, Odoribacter, Lachnospiraceae_UCG_010, and Dielma were significantly enriched in the FGR group. Metabolites such as aspartic acid, methionine, alanine, L-tryptophan, 3-methyl-2-oxovalerate, and ketoleucine showed notable functional alterations. Spearman correlation analysis indicated that metabolites like methionine and alanine, microbiota (Tyzzerella), and circulating mRNA (TRIM34, SMOX, FAM83A, NAPG) might play a role as mediators in the communication between the gut and circulatory system interaction in FGR. Conclusion: Metabolites (METHIONINE, alanine) as well as microbiota (Tyzzerella) and circulating mRNA (TRIM34, SMOX, FAM83A, NAPG) were possible mediators that communicated the interaction between the gut and circulatory systems in FGR.


Assuntos
Retardo do Crescimento Fetal , Microbioma Gastrointestinal , RNA Mensageiro , Humanos , Feminino , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/microbiologia , Gravidez , RNA Mensageiro/metabolismo , Adulto , Sangue Fetal/metabolismo , RNA Ribossômico 16S/genética , Placenta/metabolismo , Placenta/microbiologia , Fezes/microbiologia , Recém-Nascido , Multiômica
12.
Pediatrics ; 153(6)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38721668

RESUMO

Molecular autopsy has recently been gaining attention as a means of postmortem diagnosis; however, it is usually performed using the victim's blood sample at the time of death. Here, we report the first case of a deceased infant with Brugada syndrome whose diagnosis was made with banked cord blood. A seemingly healthy 1-year-old male infant collapsed while having a fever; this collapse was witnessed by his mother. Despite cardiopulmonary resuscitation, he died of ventricular fibrillation. No abnormalities of cardiac structure were identified on autopsy. Genomic samples were not stored at the time because of a lack of suspicion for familial arrhythmia. Five years later, his sister showed Brugada electrocardiogram pattern while febrile from Kawasaki disease. Their father showed a spontaneous type 1 Brugada electrocardiogram pattern. A heterozygous SCN5A p.R893C variant was found by genetic testing in the proband's father and sister. Furthermore, the proband's genetic testing was performed using his banked cord blood, which identified the same variant. Family history of Brugada syndrome with an SCN5A-R893C variant and clinical evidence led to a postmortem diagnosis of Brugada syndrome in the proband. Identification of this variant in this case later contributed to verifying SCN5A-R893C as a pathogenic variant through data accumulation. Banked cord blood may prove useful for conducting molecular autopsies in previously undiagnosed cases of sudden death in which genomic samples were not stored.


Assuntos
Autopsia , Síndrome de Brugada , Sangue Fetal , Canal de Sódio Disparado por Voltagem NAV1.5 , Humanos , Síndrome de Brugada/genética , Síndrome de Brugada/diagnóstico , Masculino , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Lactente , Eletrocardiografia , Morte Súbita/etiologia
13.
Acta Pharm ; 74(2): 343-354, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38815198

RESUMO

Remifentanil is an ultra-short-acting synthetic opioid-class analgesic which might be increasingly used "off-label" as pain management during labour. Side effects in parturients during labour, and in the infant at birth are of particular concern, especially respiratory depression which is concentration-dependent, and can occur at levels as low as 3-5 ng mL-1. The safety of such use, particularly in newborns due to remifentanil placental transfer, has not been fully demonstrated yet, partly due to the lack of a suitable non-invasive analytical method. The aim of our work was to develop a sensitive method to monitor the levels of remifentanil in neonates by a non-invasive sampling of umbi lical cord blood to support efficacy and safety trials. The presented LC-MS method is sensitive enough to reliably quantify remifentanil in just 20 µL of blood at only 0.3 ng mL-1. The dried blood spot sample preparation included solvent extraction with subsequent solid-phase extraction. The method was validated in terms of accuracy, precision, recovery, matrix effect, and stability, and was successfully applied to a small pilot study. The estimated arterial blood concentrations at the time of delivery ranged from 0.2 to 0.3, and up to 0.9 ng mL-1 in neonatal, and maternal samples, respectively.


Assuntos
Analgésicos Opioides , Teste em Amostras de Sangue Seco , Sangue Fetal , Remifentanil , Espectrometria de Massas em Tandem , Remifentanil/sangue , Humanos , Espectrometria de Massas em Tandem/métodos , Recém-Nascido , Teste em Amostras de Sangue Seco/métodos , Analgésicos Opioides/sangue , Feminino , Sangue Fetal/química , Cromatografia Líquida/métodos , Gravidez , Piperidinas/sangue , Projetos Piloto , Reprodutibilidade dos Testes , Extração em Fase Sólida/métodos
15.
JAMA Netw Open ; 7(5): e2413399, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38805224

RESUMO

Importance: Disturbances in maternal, placental, and fetal metabolism are associated with developmental outcomes. Associations of maternal, placental, and fetal metabolism with subsequent neurodevelopmental outcomes in the child are understudied. Objective: To investigate the metabolic associations within the maternal-placental-fetal unit and subsequent neurodevelopmental outcomes in younger siblings of children with autism spectrum disorder (ASD). Design, Setting, and Participants: This cohort study was conducted within a subset of the Markers of Autism Risk in Babies, Learning Early Signs (MARBLES) cohort. MARBLES is a prospective birth cohort of younger siblings of children with ASD assessed for neurodevelopmental outcomes at approximately age 36 months. Participants in MARBLES were recruited through the UC Davis MIND Institute. This subset of the MARBLES cohort included younger siblings born between 2009 and 2015. Maternal third trimester serum, placental tissue, and umbilical cord serum samples were collected from participants. Only pregnancies with at least 2 of these sample types were included in this analysis. Data analysis was conducted from March 1, 2023, to March 15, 2024. Exposures: Quantitative metabolomics analysis was conducted on maternal third trimester serum, as well as placental tissue and umbilical cord serum collected at delivery. Main Outcomes and Measures: Using the Autism Diagnostic Observation Schedule and Mullen Scales of Early Learning, outcomes were classified as ASD, other nontypical development (non-TD), and typical development (TD). Results: This analysis included 100 maternal serum samples, 141 placental samples, and 124 umbilical cord serum samples from 152 pregnancies (median [IQR] maternal age, 34.6 [30.8-38.3] years; median [IQR] gestational age, 39.0 [38.6-39.7] weeks; 87 [57.2%] male infants). There was no evidence that the maternal third trimester serum metabolome was significantly associated with the other metabolomes. The placental and cord serum metabolomes were highly correlated (first latent variate pair: R2 = 0.75; P < .001) and the variate scores for each tissue were significantly associated with reduced risk of non-TD (placenta: relative risk [RR], 0.13; 95% CI, 0.02-0.71; cord: RR, 0.13; 95% CI, 0.03-0.70) but not ASD (placenta: RR, 1.09; 95% CI, 0.42-2.81; cord: RR, 0.63; 95% CI, 0.23-1.73) compared with the TD reference group. Conclusions and Relevance: In this cohort study of children with high familial risk of ASD, placental and cord serum metabolism at delivery were highly correlated. Furthermore, placental and cord serum metabolic profiles were associated with risk of non-TD.


Assuntos
Transtorno do Espectro Autista , Placenta , Humanos , Feminino , Gravidez , Placenta/metabolismo , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/metabolismo , Masculino , Estudos Prospectivos , Pré-Escolar , Adulto , Sangue Fetal/metabolismo , Sangue Fetal/química , Metabolômica/métodos , Desenvolvimento Infantil/fisiologia , Lactente , Estudos de Coortes , Irmãos , Terceiro Trimestre da Gravidez
16.
Early Hum Dev ; 193: 106036, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38733833

RESUMO

BACKGROUND: Inter-alpha inhibitor proteins (IAIPs) are structurally related proteins found in the systemic circulation with immunomodulatory anti-inflammatory properties. Reduced levels are found in inflammatory related conditions including sepsis and necrotizing enterocolitis, and in neonatal rodents after exposure to hypoxia ischemia. In the current study, cord blood IAIP levels were measured in neonates with and without exposure to hypoxic-ischemic encephalopathy (HIE). METHODS: This is a prospective cohort study including infants born ≥36 weeks over a one-year period. Term pregnancies were divided into two groups: a "reference control" (uncomplicated term deliveries), and "moderate to severe HIE" (qualifying for therapeutic hypothermia). IAIPs were quantified using a sensitive ELISA on the cord blood samples. RESULTS: The study included 57 newborns: Reference control group (n = 13) and moderate/severe HIE group (n = 44). Measurement of IAIP cord blood concentrations in moderate to severe HIE group [278.2 (138.0, 366.0) µg/ml] revealed significantly lower IAIP concentrations compared with the control group [418.6 (384.5, 445.0) µg/ml] (p = 0.002). CONCLUSIONS: These findings suggest a potential role for IAIPs as indicators of neonates at risk for HIE. IAIP levels could have diagnostic implications in the management of HIE. Future research is required to explore the relationship between HIE and IAIPs as biomarkers for disease severity. CATEGORY OF STUDY: Translational.


Assuntos
alfa-Globulinas , Sangue Fetal , Hipóxia-Isquemia Encefálica , Humanos , Recém-Nascido , Sangue Fetal/química , Sangue Fetal/metabolismo , Feminino , Hipóxia-Isquemia Encefálica/sangue , Masculino , Estudos de Casos e Controles , Estudos Prospectivos , Biomarcadores/sangue
17.
J Neuroinflammation ; 21(1): 121, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38720368

RESUMO

BACKGROUND: Umbilical cord blood (UCB) cells are a promising treatment for preterm brain injury. Access to allogeneic sources of UCB cells offer the potential for early administration to optimise their therapeutic capacities. As preterm infants often require ventilatory support, which can contribute to preterm brain injury, we investigated the efficacy of early UCB cell administration following ventilation to reduce white matter inflammation and injury. METHODS: Preterm fetal sheep (0.85 gestation) were randomly allocated to no ventilation (SHAM; n = 5) or 15 min ex utero high tidal volume ventilation. One hour following ventilation, fetuses were randomly allocated to i.v. administration of saline (VENT; n = 7) or allogeneic term-derived UCB cells (24.5 ± 5.0 million cells/kg; VENT + UCB; n = 7). Twenty-four hours after ventilation, lambs were delivered for magnetic resonance imaging and post-mortem brain tissue collected. Arterial plasma was collected throughout the experiment for cytokine analyses. To further investigate the results from the in vivo study, mononuclear cells (MNCs) isolated from human UCB were subjected to in vitro cytokine-spiked culture medium (TNFα and/or IFNγ; 10 ng/mL; n = 3/group) for 16 h then supernatant and cells collected for protein and mRNA assessments respectively. RESULTS: In VENT + UCB lambs, systemic IFNγ levels increased and by 24 h, there was white matter neuroglial activation, vascular damage, reduced oligodendrocytes, and increased average, radial and mean diffusivity compared to VENT and SHAM. No evidence of white matter inflammation or injury was present in VENT lambs, except for mRNA downregulation of OCLN and CLDN1 compared to SHAM. In vitro, MNCs subjected to TNFα and/or IFNγ displayed both pro- and anti-inflammatory characteristics indicated by changes in cytokine (IL-18 & IL-10) and growth factor (BDNF & VEGF) gene and protein expression compared to controls. CONCLUSIONS: UCB cells administered early after brief high tidal volume ventilation in preterm fetal sheep causes white matter injury, and the mechanisms underlying these changes are likely dysregulated responses of the UCB cells to the degree of injury/inflammation already present. If immunomodulatory therapies such as UCB cells are to become a therapeutic strategy for preterm brain injury, especially after ventilation, our study suggests that the inflammatory state of the preterm infant should be considered when timing UCB cells administration.


Assuntos
Volume de Ventilação Pulmonar , Animais , Ovinos , Feminino , Humanos , Volume de Ventilação Pulmonar/fisiologia , Sangue Fetal/citologia , Gravidez , Citocinas/metabolismo , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Respiração Artificial/métodos , Respiração Artificial/efeitos adversos , Animais Recém-Nascidos
18.
J Orthop Surg Res ; 19(1): 323, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38811966

RESUMO

BACKGROUND: To investigate the effect and underlying mechanism of umbilical cord blood-mononuclear cells (UCB-MNCs) in treating knee osteoarthritis (KOA) in rabbits. METHODS: A rabbit KOA model was prepared by anterior cruciate ligament transection (ACLT). Fifty New Zealand white rabbits were randomly divided into the control group, model group, sodium hyaluronate (SH) group, platelet-rich plasma (PRP) group and UCB-MNC group. Knee injections were performed once a week for five consecutive weeks. The gross view of the knee joint, morphology of knee cartilage and structural changes in the knee joint were observed on CT scans, and graded by the Lequesne MG behavioral score and the Mankin score. TNF-α and IL-1ß levels in the synovial fluid of the knee were measured by the enzyme-linked immunosorbent assay (ELISA). Expression levels of MMP-13 and COL-II in the knee cartilage were detected by Western blotting and qRT-PCR. RESULTS: The Lequesne MG behavioral score and the Mankin score were significantly higher in the model group than those in the control group (P < 0.05). Rabbits in the SH, PRP and UCB-MNC groups had sequentially lower scores than those in the model group. Imaging features of KOA were more pronounced in the model group than in the remaining groups. CB-MNC significantly relieved KOA, compared to SH and PRP. Significantly higher levels of TNF-α and IL-1ß in the synovial fluid of the knee, and up-regulated MMP-13 and down-regulated COL-II in the knee cartilage were detected in the model group than in the control group. These changes were significantly reversed by the treatment with SH, PRP and UCB-MNCs, especially UCB-MNCs. CONCLUSION: Injections of UCB-MNCs into knees protect the articular cartilage and hinder the progression of KOA in rabbits by improving the local microenvironment at knee joints.


Assuntos
Osteoartrite do Joelho , Animais , Coelhos , Osteoartrite do Joelho/terapia , Osteoartrite do Joelho/patologia , Sangue Fetal , Modelos Animais de Doenças , Masculino , Leucócitos Mononucleares/transplante , Leucócitos Mononucleares/metabolismo , Interleucina-1beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Líquido Sinovial/metabolismo , Plasma Rico em Plaquetas , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Distribuição Aleatória
19.
Chemosphere ; 359: 142321, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38754495

RESUMO

Rare earth elements (REEs) are emerging contaminants that are increasingly used in high technology products. However, limited information is available regarding exposure to REEs and associated health effects in neonates. This study aimed to investigate the association between REE concentrations and thyroid hormone levels, as well as birth outcomes in 109 newborns in Beijing, China. We measured the concentrations of 16 REEs and thyroid hormones in umbilical cord serum. To assess the impact of exposure to individual REEs and REE mixtures on thyroid hormone levels and birth outcomes, we employed univariate linear regression, least absolute shrinkage and selection operator (LASSO), and weighted quantile sum (WQS) models. We detected 14 REEs at high rates (92.6%-100%), with yttrium exhibiting the highest median (interquartile range) concentration [43.94 (0.33-172.55) ng/mL], followed by scandium [3.64 (0.46-11.15) ng/mL]. Univariate analyses showed that per logarithmic (ln)-unit change of neodymium (Nd) and samarium (Sm) was associated with 0.039 [95% confidence interval (CI): 0.001, 0.007] and 0.031 (95% CI: 0.003, 0.060) increases in free thyroxine (FT4) levels, respectively. Moreover, 14 REEs exhibited significant associations with triiodothyronine (T3) levels, resulting in increases ranging from 0.066 to 0.307. Elevated concentrations of terbium (Tb) [per ln-unit change: -0.021 (95% CI: -0.041, -0.01)] and lutetium (Lu) [-0.023 (95% CI: -0.043, -0.002)] were inversely correlated with birth length in newborns. A further multiple exposure analysis employing the LASSO model identified Sm, Nd, Y, Sc, and Lu as critical factors influencing FT4 and T3 levels. Additionally, WQS analyses showed positive associations between exposure to a mixture of 14 REEs and FT4 (P = 0.046), T3 (P < 0.001), and birth length (P = 0.049). These findings suggest that in utero exposure to REEs might disrupt thyroid hormone homeostasis and impact intrauterine growth. Further studies are warranted to validate these findings and elucidate the underlying mechanisms.


Assuntos
Sangue Fetal , Metais Terras Raras , Hormônios Tireóideos , Humanos , Recém-Nascido , Feminino , Hormônios Tireóideos/sangue , Sangue Fetal/química , Metais Terras Raras/sangue , Gravidez , Poluentes Ambientais/sangue , Adulto , Masculino , China , Pequim , Tiroxina/sangue , Exposição Materna/estatística & dados numéricos , Exposição Materna/efeitos adversos
20.
Am J Physiol Heart Circ Physiol ; 326(6): H1538-H1543, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38758126

RESUMO

Elevated cardiac troponin I (cTnI), a myocardial damage biomarker, has been reported in cord blood of neonates delivered vaginally or by cesarean section. Although the neonatal peak likely reflects the physiological adjustment to extrauterine life, a better understanding of serial prepartum changes is required to determine physiological causes of fetal cTnI release. We longitudinally sampled eight healthy lambs (20 days before spontaneous birth to 5 days postnatal), and from three fetuses receiving intravenous IGF-1. Samples were collected into heparin, and the plasma was stored at -80°C for later determination of high-sensitivity (hs) cTnI levels (BeckmanCoulter UniCel DxI Access IA; log transformed detection limit = 0.30, quantification limit = 0.78, 99th percentile = 1.78). Positive and negative control samples were drawn from an adult ewe during a terminal experiment (myocardial ischemia) and similarly assessed. hs-cTnI data were log transformed from ng/L. Log(hs-cTnI) was 1.47 ± 0.30 (means ± SD) at 20 days before birth and declined to 1.02 ± 0.65 in fetuses 12 ± 4 h before birth (P < 0.0001, R2 = 0.7869). Birth stimulated a delayed, transient peak in hs-cTnI (P = 0.0058). Newborn (43 ± 19 min postnatal) levels were 1.39 ± 0.40 (P = 0.0650 vs. fetus on day of birth) and 2.14 ± 0.63 the day after birth (P = 0.0331 vs. newborn). The second day after birth, levels declined to 1.65 ± 0.48 (P = 0.0238 vs. day 1). IGF-1 infusion increased hs-cTnI levels 25-50% over baseline (P = 0.0252, R2 = 0.9938). Baseline adult ewe log(hs-cTnI) was below the limit of detection; 3 h following coronary artery ligation, levels were 3.21. In conclusion, we newly report that fetal hs-cTnI levels decline concomitantly with reduced proliferation of cardiomyocytes toward term.NEW & NOTEWORTHY Serial blood samples were collected from catheterized, normally developing fetal and newborn lambs and high-sensitivity cardiac troponin I (hs-cTnI) levels were assessed, providing unprecedented insight into the physiological processes leading to high levels in the perinatal period. Moderately high levels of hs-cTnI found in the normally developing fetus declined toward term. An elevation to high levels peaked the day after birth, after which hs-cTnI declined again. Stimulation of fetal cardiomyocyte proliferation with IGF-1 also elevated hs-cTnI.


Assuntos
Fator de Crescimento Insulin-Like I , Troponina I , Animais , Troponina I/sangue , Feminino , Fator de Crescimento Insulin-Like I/metabolismo , Gravidez , Ovinos , Animais Recém-Nascidos , Biomarcadores/sangue , Sangue Fetal/metabolismo , Parto , Feto/metabolismo
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