Post-natal gestational age assessment using targeted metabolites of neonatal heel prick and umbilical cord blood: A GARBH-Ini cohort study from North India.

Background: Accurate assessment of gestational age (GA) and identification of preterm birth (PTB) at delivery is essential to guide appropriate post-natal clinical care. Undoubtedly, dating ultrasound sonography (USG) is the gold standard to ascertain GA, but is not accessible to the majority of pregnant women in low- and middle-income countries (LMICs), particularly in rural areas and small secondary care hospitals. Conventional methods of post-natal GA assessment are not reliable at delivery and are further compounded by a lack of trained personnel to conduct them. We aimed to develop a population-specific GA model using integrated clinical and biochemical variables measured at delivery. Methods: We acquired metabolic profiles on paired neonatal heel prick (nHP) and umbilical cord blood (uCB) dried blood spot (DBS) samples (n = 1278). The master data set consists of 31 predictors from nHP and 24 from uCB after feature selection. These selected predictors including biochemical analytes, birth weight, and placental weight were considered for the development of population-specific GA estimation and birth outcome classification models using eXtreme Gradient Boosting (XGBoost) algorithm. Results: The nHP and uCB full model revealed root mean square error (RMSE) of 1.14 (95% confidence interval (CI) = 0.82-1.18) and of 1.26 (95% CI = 0.88-1.32) to estimate the GA as compared to actual GA, respectively. In addition, these models correctly estimated 87.9 to 92.5% of the infants within ±2 weeks of the actual GA. The classification models also performed as the best fit to discriminate the PTB from term birth (TB) infants with an area under curve (AUC) of 0.89 (95% CI = 0.84-0.94) for nHP and an AUC of 0.89 (95% CI = 0.85-0.95) for uCB. Conclusion: The biochemical analytes along with clinical variables in the nHP and uCB data sets provide higher accuracy in predicting GA. These models also performed as the best fit to identify PTB infants at delivery.

Effect of extracorporeal shockwave therapy on the immunomodulatory and anti-inflammatory properties of cultured equine umbilical cord blood mesenchymal stromal cells.

There is a knowledge gap regarding the effect of extracorporeal shockwave treatment (ESWT) on the stress response and immunomodulatory and anti-inflammatory properties of equine umbilical cord blood mesenchymal stromal cells (CB-MSCs). The objective of this study was to investigate the presence of cellular oxidative stress, inflammatory response, and production of growth factors in CB-MSCs after treatment with ESWT. We hypothesized that CB-MSCs treated with ESWT will experience higher levels of cellular stress and increased production of anti-inflammatory cytokines and growth factors compared to untreated CB-MSCs.

Il existe un manque de connaissances concernant l'effet du traitement extracorporel par ondes de choc (ESWT) sur la réponse au stress et les propriétés immunomodulatrices et anti-inflammatoires des cellules stromales mésenchymateuses du sang de cordon ombilical équin (CB-MSCs). L'objectif de cette étude était d'étudier la présence de stress oxydatif cellulaire, de réponse inflammatoire et de production de facteurs de croissance dans les CB-MSCs après un traitement par ESWT. Nous avons émis l'hypothèse que les CB-MSCs traitées par ESWT connaîtront des niveaux plus élevés de stress cellulaire et une production accrue de cytokines anti-inflammatoires et de facteurs de croissance par rapport aux CB-MSCs non traitées.(Traduit par Docteur Serge Messier).

Poverty and neighborhood opportunity effects on neonate DNAm developmental age.

BACKGROUND: Children from families with low socioeconomic status (SES), as determined by income, experience several negative outcomes, such as higher rates of newborn mortality and behavioral issues. Moreover, associations between DNA methylation and low income or poverty status are evident beginning at birth, suggesting prenatal influences on offspring development. Recent evidence suggests neighborhood opportunities may protect against some of the health consequences of living in low income households. The goal of this study was to assess whether neighborhood opportunities moderate associations between household income (HI) and neonate developmental maturity as measured with DNA methylation. METHODS: Umbilical cord blood DNA methylation data was available in 198 mother-neonate pairs from the larger CANDLE cohort. Gestational age acceleration was calculated using an epigenetic clock designed for neonates. Prenatal HI and neighborhood opportunities measured with the Childhood Opportunity Index (COI) were regressed on gestational age acceleration controlling for sex, race, and cellular composition. RESULTS: Higher HI was associated with higher gestational age acceleration (B = .145, t = 4.969, p = 1.56x10-6, 95% CI [.087, .202]). Contrary to expectation, an interaction emerged showing higher neighborhood educational opportunity was associated with lower gestational age acceleration at birth for neonates with mothers living in moderate to high HI (B = -.048, t = -2.08, p = .03, 95% CI [-.092, -.002]). Female neonates showed higher gestational age acceleration at birth compared to males. However, within males, being born into neighborhoods with higher social and economic opportunity was associated with higher gestational age acceleration. CONCLUSION: Prenatal HI and neighborhood qualities may affect gestational age acceleration at birth. Therefore, policy makers should consider neighborhood qualities as one opportunity to mitigate prenatal developmental effects of HI.

Association of Perinatal Cardiovascular Features with Angiotensin System Expressions in Maternal Preeclampsia.

We hypothesized and investigated whether prenatal exposure to preeclampsia (PE) would simultaneously affect perinatal cardiovascular features and angiotensin system expressions. This prospective study was composed of mother-neonate dyads with (n = 49) and without maternal preeclampsia (n = 48) in a single tertiary medical center. The neonates exposed to PE had significantly larger relative sizes for the left and right coronary arteries and a higher cord plasma level of aminopeptidase-N, which positively correlated with the maternal diastolic blood pressures and determined the relative sizes of the left and right coronary arteries, whereas the encoding aminopeptidase-N (ANPEP) mRNA level in the PE cord blood leukocytes was significantly decreased, positively correlated with the neonatal systolic blood pressures (SBPs), and negatively correlated with the cord plasma-induced endothelial vascular cell adhesion molecule-1 mRNA levels. The PE cord plasma significantly induced higher endothelial mRNA levels of angiotensin II type 1 receptor (AT1R) and AT4R, whereas in the umbilical arteries, the protein expressions of AT2R and AT4R were significantly decreased in the PE group. The endothelial AT1R mRNA level positively determined the maternal SBPs, and the AT4R mRNA level positively determined the neonatal chamber size and cardiac output. In conclusion, PE may influence perinatal angiotensin system and cardiovascular manifestations of neonates across placentae. Intriguing correlations between these two warrant further mechanistic investigation.

Human umbilical cord mesenchymal stem cell-based gene therapy for hemophilia B using scAAV-DJ/8-LP1-hFIXco transduction.

BACKGROUND: Hemophilia B is an X-linked bleeding disorder caused by a mutation in the gene responsible for encoding coagulation factor IX (FIX). Gene therapy offers promising potential for curing this disease. However, the current method of relatively high dosage of virus injection carries inherent risks. The purpose of this study was to introduce a novel scAAV-DJ/8-LP1-hFIXco vector transduced human umbilical cord blood derived mesenchymal stem cells (HUCMSCs) as an alternative cell-based gene therapy to conventional gene therapy for Hemophilia B. METHODS: The LP1-hFIXco gene structure was designed by us through searching the literature from NCBI and the scAAV-DJ/8-LP1-hFIXco vector was constructed by a commercial company. The HUCMSCs were cultivated in routine approach and transduced with scAAV-DJ/8-LP1-hFIXco vector. The human FIX activation system was employed for detection of hFIXco activity. The RNA and protein expression levels of the hFIXco were evaluated using PCR and western blot techniques. In animal studies, both NSG and F9-KO mice were used for the experiment, in which clotting time was utilized as a parameter for bleeding assessment. The immunohistochemical analysis was used to assess the distribution of HUCMSCs in mouse tissue sections. The safety for tumorigenicity of this cell-based gene therapy was evaluated by pathological observation after hematoxylin-eosin staining. RESULTS: The transduction of HUCMSCs with the scAAV-DJ/8-LP1-hFIXco vector results in consistent and sustainable secretion of human FIXco during 5 months period both in vitro and in mouse model. The secretion level (hFIXco activity: 97.1 ± 2.3% at day 7 to 48.8 ± 4.5% at 5 months) was comparable to that observed following intravenous injection with a high dose of the viral vector (hFIXco activity: 95.2 ± 2.2% to 40.8 ± 4.3%). After a 5-month observation period, no clonal expansions of the transduced cells in tissues were observed in any of the mice studied. CONCLUSIONS: We have discovered a novel and safer HUCMSCs mediated approach potentially effective for gene therapy in hemophilia B.

Fluoride-related changes in the fetal cord blood proteome; a pilot study.

BACKGROUND: Fluoride exposure during pregnancy has been associated with various effects on offspring, including changes in behavior and IQ. To provide clues to possible mechanisms by which fluoride may affect human fetal development, we completed proteomic analyses of cord blood serum collected from second-trimester pregnant women residing in northern California, USA. OBJECTIVE: To identify changes in cord blood proteins associated with maternal serum fluoride concentration in pregnant women. METHODS: The proteomes of 19 archived second-trimester cord blood samples from women living in northern California, USA, and having varied serum fluoride concentrations, were analyzed by quantitative mass spectrometry. The 327 proteins that were quantified were characterized by their abundance relative to maternal serum fluoride concentration, and subjected to pathway analyses using PANTHER and Ingenuity Pathway Analysis processes. RESULTS: Pathway analyses showed significant increases in process related to reactive oxygen species and cellular oxidant detoxification, associated with increasing maternal serum fluoride concentrations. Pathways showing significant decreases included complement cascade, suggesting alterations in alterations in process associated with inflammation. CONCLUSION: Maternal fluoride exposure, as measured by serum fluoride concentrations in a small, but representative sample of women from northern California, USA, showed significant changes in the second trimester cord blood proteome relative to maternal serum fluoride concentration.

Moderate Prenatal Alcohol Exposure Increases Toll-like Receptor Activity in Umbilical Cord Blood at Birth: A Pilot Study.

The prevalence of prenatal alcohol exposure (PAE) is increasing, with evidence suggesting that PAE is linked to an increased risk of infections. PAE is hypothesized to affect the innate immune system, which identifies pathogens through pattern recognition receptors, of which toll-like receptors (TLRs) are key components. We hypothesized that light-to-moderate PAE would impair immune responses, as measured by a heightened response in cytokine levels following TLR stimulation. Umbilical cord samples (10 controls and 8 PAE) from a subset of the Ethanol, Neurodevelopment, Infant and Child Health Study-2 cohort were included. Peripheral blood mononuclear cells (PMBCs) were stimulated with one agonist (TLR2, TLR3, TLR4, or TLR9). TLR2 agonist stimulation significantly increased pro-inflammatory interleukin-1-beta in the PAE group after 24 h. Pro- and anti-inflammatory cytokines were increased following stimulation with the TLR2 agonists. Stimulation with TLR3 or TLR9 agonists displayed minimal impact overall, but there were significant increases in the percent change of the control compared to PAE after 24 h. The results of this pilot investigation support further work into the impact on TLR2 and TLR4 response following PAE to delineate if alterations in levels of pro- and anti-inflammatory cytokines have clinical significance that could be used in patient management and/or attention to follow-up.

Exploring the potential of predicted miRNAs on the genes involved in the expansion of hematopoietic stem cells.

A major challenge in therapeutic approaches applying hematopoietic stem cells (HSCs) is the cell quantity. The primary objective of this study was to predict the miRNAs and anti-miRNAs using bioinformatics tools and investigate their effects on the expression levels of key genes predicted in the improvement of proliferation, and the inhibition of differentiation in HSCs isolated from Human umbilical cord blood (HUCB). A network including genes related to the differentiation and proliferation stages of HSCs was constructed by enriching data of text (PubMed) and StemChecker server with KEGG signaling pathways, and was improved using GEO datasets. Bioinformatics tools predicted a profile from miRNAs containing miR-20a-5p, miR-423-5p, and chimeric anti-miRNA constructed from 5'-miR-340/3'-miR-524 for the high-score genes (RB1, SMAD4, STAT1, CALML4, GNG13, and CDKN1A/CDKN1B genes) in the network. The miRNAs and anti-miRNA were transferred into HSCs using polyethylenimine (PEI). The gene expression levels were estimated using the RT-qPCR technique in the PEI + (miRNA/anti-miRNA)-contained cell groups (n = 6). Furthermore, CD markers (90, 16, and 45) were evaluated using flow cytometry. Strong relationships were found between the high-score genes, miRNAs, and chimeric anti-miRNA. The RB1, SMAD4, and STAT1 gene expression levels were decreased by miR-20a-5p (P < 0.05). Additionally, the anti-miRNA increased the gene expression level of GNG13 (P < 0.05), whereas the miR-423-5p decreased the CDKN1A gene expression level (P < 0.01). The cellular count also increased significantly (P < 0.05) but the CD45 differentiation marker did not change in the cell groups. The study revealed the predicted miRNA/anti-miRNA profile expands HSCs isolated from HUCB. While miR-20a-5p suppressed the RB1, SMAD4, and STAT1 genes involved in cellular differentiation, the anti-miRNA promoted the GNG13 gene related to the proliferation process. Notably, the mixed miRNA/anti-miRNA group exhibited the highest cellular expansion. This approach could hold promise for enhancing the cell quantity in HSC therapy.

Association of cord blood Ang-1 and sCD105 levels with bronchopulmonary dysplasia in preterm infants.

BACKGROUND: To investigate the relationship between cord blood levels of Angiopoietin-1 (Ang-1) and S-endoglin (sCD105) and bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: Sixty-one preterm infants admitted to the neonatal intensive care unit of the study hospital between July 2021 and September 2022 were included. Cord blood was collected after the birth of premature infants. Ang-1 and sCD105 levels were quantified using the vascular endothelial growth factor enzyme-linked immunosorbent assay. Preterm infants were divided into BPD and non-BPD groups, and differences in Ang-1 and sCD105 levels between the two groups were compared. A binary logistic model was used to assess the association between low and high levels Ang-1 and BPD in preterm infants. RESULTS: In the study, there were 20 preterm infants with BPD (32.8%) and 41 preterm infants with non-BPD (67.2%). Ang-1 concentration levels were lower in the BPD group than in the non-BPD group (7105.43 (5617.01-8523.00) pg/ml vs. 10488.03 (7946.19-15962.77) pg/ml, P = 0.027). However, the sCD105 concentration levels were not significantly different between the BPD and non-BPD groups (P = 0.246). A median Ang-1 concentration of 8800.40 pg/ml was calculated. Logistic regression analysis showed that after adjusting for gestational age, birth weight, and maternal prenatal steroid hormone application, the odds ratio (OR) was 8.577 for the risk of BPD in preterm infants with Ang-1 concentrations of ≤ 8800.40 pg/ml compared to those with Ang-1 concentrations of > 8800.40 pg/ml (OR: 8.577, 95% confidence interval: 1.265-58.155, P = 0.028). CONCLUSION: Our study indicated that Ang-1 levels in the cord blood of preterm infants may be associated the risk of BPD. In the future, we will continue to conduct study with large samples.

Molecular and biochemical evaluation of oxidative effects of cord blood CD34+ MPs on hematopoietic cells.

A graft source for allogeneic hematopoietic stem cell transplantation is umbilical cord blood, which contains umbilical cord blood mononuclear cells (MNCs and mesenchymal stem cells, both an excellent source of extracellular microparticles (MPs). MPs act as cell communication mediators, which are implicated in reactive oxygen species formation or detoxification depending on their origin. Oxidative stress plays a crucial role in both the development of cancer and its treatment by triggering apoptotic mechanisms, in which CD34+ cells are implicated. The aim of this work is to investigate the oxidative stress status and the apoptosis of HL-60 and mononuclear cells isolated from umbilical cord blood (UCB) following a 24- and 48-hour exposure to CD34 + microparticles (CD34 + MPs). The activity of superoxide dismutase, glutathione reductase, and glutathione S-transferase, as well as lipid peroxidation in the cells, were employed as oxidative stress markers. A 24- and 48-hour exposure of leukemic and mononuclear cells to CD34 + -MPs resulted in a statistically significant increase in the antioxidant activity and lipid peroxidation in both cells types. Moreover, CD34 + MPs affect the expression of BCL2 and FAS and related proteins and downregulate the hematopoietic differentiation program in both HL-60 and mononuclear cells. Our results indicate that MPs through activation of antioxidant enzymes in both homozygous and nonhomozygous cells might serve as a means for graft optimization and enhancement.

SARS-CoV-2 anti-RBD and anti-N protein responses are differentially regulated between mother-child pairs: insight from a national study cohort at the Faroe Islands.

Background: Knowledge about SARS-CoV-2 antibody dynamics in neonates and direct comparisons with maternal antibody responses are not well established. This study aimed to characterize and directly compare the maternal and infant antibody response in a national birth cohort from the Faroe Islands. Methods: The levels of immunoglobulins (Ig) targeting the receptor binding domain (RBD) of the spike protein and the nucleocapsid protein (N protein) of SARS-CoV-2 were investigated in maternal blood and umbilical cord blood from neonates. The study included 537 neonates and 565 mothers from the Faroe Islands, and follow-up samples were collected 12 months after birth. Multiple linear regression models were used to assess associations of maternal parameters with maternal and neonatal Ig levels and pregnancy outcomes. Results: The finding showed that neonates acquired varying levels of SARS-CoV-2 antibodies through transplacental transfer, and the levels were significantly influenced by the mother's vaccination and infection status. The study also found that maternal vaccination and the presence of SARS-CoV-2 antibodies targeting spike RBD were associated with gestational age and APGAR scores. Furthermore, the anti-RBD and -N protein-specific antibody response dynamics during 12 months after birth exhibited differences between mothers and children. RBD and N protein responses were maintained at follow-up in the mother's cohort, while only the N protein response was maintained at follow-up in the children's cohort. Conclusion: In conclusion, SARS-CoV-2-specific immune responses in newborns rely on maternal immunity, while the persistence of SARS-CoV-2-specific Igs appears to be differently regulated between mothers and children. The study provides new insights into the dynamics of SARS-CoV-2-specific immune responses in newborns and underscores the nuanced relationship between maternal factors and neonatal humoral responses.

Toxoplasma gondii suppress human cord blood cell differentiation to the NK cell population.

BACKGROUND: Toxoplasma gondii is an obligate intracellular protozoan parasite that can invade all mammalian cells. It is well established that natural killer (NK) cells have critical protective roles in innate immunity during infections by intracellular pathogens. In the current study, we conducted an in vitro experiment to evaluate NK cell differentiation and activation from human umbilical cord blood mononuclear cells (UCB-MNCs) after infection with T. gondii tachyzoites. METHODS: UCB-MNCs were infected by fresh tachyzoites of type I (RH) or type II (PTG) strains of T. gondii pre-expanded in mesenchymal stem cells for 2 weeks in a medium enriched with stem cell factor, Flt3, IL-2, and IL-15. Flow cytometry analysis and western blot analysis were performed to measure the CD57+, CD56+, and Granzyme A (GZMA). RESULTS: Data revealed that incubation of UCB-MNCs with NK cell differentiation medium increased the CD57+, CD56+, and GZMA. UCB-MNCs cocultured with PTG tachyzoites showed a significant reduction of CD56+ and GZMA, but nonsignificant changes, in the levels of CD56+ compared to the control UCB-MNCs (p > .05). Noteworthy, 2-week culture of UCB-MNCs with type I (RH) tachyzoites significantly suppressed CD57+, CD56+, and GZMA, showing reduction of NK cell differentiation from cord blood cells. CONCLUSION: Our findings suggest that virulent T. gondii tachyzoites with cytopathic effects inhibit NK cell activation and eliminate innate immune responses during infection, and consequently enable the parasite to continue its survival in the host body.

Comparison of Apgar scores and cord blood gas parameters in fetuses with isolated congenital heart disease and healthy controls.

OBJECTIVE: This retrospective study aimed to investigate how congenital heart disease (CHD) affects early neonatal outcomes by comparing Apgar scores and umbilical cord blood gas parameters between fetuses with structural cardiac anomalies and healthy controls. Additionally, within the CHD group, the study explored the relationship between these parameters and mortality within six months. METHODS: Data from 68 cases of prenatally diagnosed CHD were collected from electronic medical records, excluding cases with missing data or additional comorbidities. Only patients delivered by elective cesarean section, without any attempt at labor, were analyzed to avoid potential confounding factors. A control group of 147 healthy newborns was matched for delivery route, maternal age, and gestational week. Apgar scores at 1, 5, and 10 minutes, as well as umbilical cord blood pH, base deficit, and lactate levels, were recorded. RESULTS: Maternal age, gestational week at delivery, and birth weight were similar between the CHD and control groups. While Apgar score distribution was significantly lower at 1st, 5th, and 10th minutes in the CHD group, umbilical cord blood gas parameters did not show significant differences between groups. Within the CHD group, lower umbilical cord blood pH and larger base deficit were associated with mortality within six months. CONCLUSION: Newborns with CHD exhibit lower Apgar scores compared to healthy controls, suggesting potential early neonatal challenges. Furthermore, umbilical cord blood pH and base deficit may serve as predictors of mortality within six months in CHD cases. Prospective studies are warranted to validate these findings and integrate them into clinical practice, acknowledging the study's retrospective design and limitations.

Pregnancy induced hypertension and umbilical cord blood DNA methylation in newborns: an epigenome-wide DNA methylation study.

OBJECTIVIES: Pregnancy induced hypertension (PIH) syndrome is a disease that unique to pregnant women and is associated with elevated risk of offspring cardiovascular diseases (CVDs) and neurodevelopmental disorders in their kids. Previous research on cord blood utilizing the Human Methylation BeadChip or EPIC array revealed that PIH is associated with specific DNA methylation site. Here, we investigate the whole genome DNA methylation landscape of cord blood from newborns of PIH mother. METHODS: Whole-genome bisulfite sequencing (WGBS) was used to examine the changes in whole genome DNA methylation in the umbilical cord blood of three healthy (NC) and four PIH individuals. Using methylKit, we discovered Hypo- and hyper- differentially methylated probes (DMPs) or methylated regions (DMRs) in the PIH patients' cord blood DNA. Pathway enrichments were assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment assays. DMPs or DMRs relevant to the immunological, neurological, and circulatory systems were also employed for enrichment assay, Metascape analysis and PPI network analysis. RESULTS: 520 hyper- and 224 hypo-DMPs, and 374 hyper- and 186 hypo-DMRs between NC and PIH group, respectively. Both DMPs and DMRs have enhanced pathways for cardiovascular, neurological system, and immune system development. Further investigation of DMPs or DMRs related to immunological, neurological, and circulatory system development revealed that TBK1 served as a hub gene for all three developmental pathways. CONCLUSION: PIH-associated DMPs or DMRs in umbilical cord blood DNA may play a role in immunological, neurological, and circulatory system development. Abnormal DNA methylation in the immune system may also contribute to the development of CVDs and neurodevelopment disorders.

Longitudinal Analysis of One-Carbon Metabolism-Related Metabolites in Maternal and Cord Blood of Japanese Pregnant Women.

One-carbon metabolism (OCM) is a complex and interconnected network that undergoes drastic changes during pregnancy. In this study, we investigated the longitudinal distribution of OCM-related metabolites in maternal and cord blood and explored their relationships. Additionally, we conducted cross-sectional analyses to examine the interrelationships among these metabolites. This study included 146 healthy pregnant women who participated in the Chiba Study of Mother and Child Health. Maternal blood samples were collected during early pregnancy, late pregnancy, and delivery, along with cord blood samples. We analyzed 18 OCM-related metabolites in serum using stable isotope dilution liquid chromatography/tandem mass spectrometry. We found that serum S-adenosylmethionine (SAM) concentrations in maternal blood remained stable throughout pregnancy. Conversely, S-adenosylhomocysteine (SAH) concentrations increased, and the total homocysteine/total cysteine ratio significantly increased with advancing gestational age. The betaine/dimethylglycine ratio was negatively correlated with total homocysteine in maternal blood for all sampling periods, and this correlation strengthened with advances in gestational age. Most OCM-related metabolites measured in this study showed significant positive correlations between maternal blood at delivery and cord blood. These findings suggest that maternal OCM status may impact fetal development and indicate the need for comprehensive and longitudinal evaluations of OCM during pregnancy.

Associations between mycoestrogen exposure and sex steroid hormone concentrations in maternal serum and cord blood in the UPSIDE pregnancy cohort.

Zearalenone (ZEN) is a fungal-derived toxin found in global food supplies including cereal grains and processed foods, impacting populations worldwide through diet. Because the chemical structure of ZEN and metabolites closely resembles 17ß-estradiol (E2), they interact with estrogen receptors α/ß earning their designation as 'mycoestrogens'. In animal models, gestational exposure to mycoestrogens disrupts estrogen activity and impairs fetal growth. Here, our objective was to evaluate relationships between mycoestrogen exposure and sex steroid hormone concentrations in maternal circulation and cord blood for the first time in humans. In each trimester, pregnant participants in the UPSIDE study (n = 297) provided urine for mycoestrogen analysis and serum for hormone analysis. At birth, placental mycoestrogens and cord steroids were measured. We fitted longitudinal models examining log-transformed mycoestrogen concentrations in relation to log-transformed hormones, adjusting for covariates. Secondarily, multivariable linear models examined associations at each time point (1st, 2nd, 3rd trimesters, delivery). We additionally considered effect modification by fetal sex. ZEN and its metabolite, α-zearalenol (α-ZOL), were detected in >93% and >75% of urine samples; >80% of placentas had detectable mycoestrogens. Longitudinal models from the full cohort exhibited few significant associations. In sex-stratified analyses, in pregnancies with male fetuses, estrone (E1) and free testosterone (fT) were inversely associated with ZEN (E1 %Δ: -6.68 95%CI: -12.34, -0.65; fT %Δ: -3.22 95%CI: -5.68, -0.70); while α-ZOL was positively associated with E2 (%Δ: 5.61 95%CI: -1.54, 9.85) in pregnancies with female fetuses. In analysis with cord hormones, urinary mycoestrogens were inversely associated with androstenedione (%Δ: 9.15 95%CI: 14.64, -3.30) in both sexes, and placental mycoestrogens were positively associated with cord fT (%Δ: 37.13, 95%CI: 4.86, 79.34) amongst male offspring. Findings support the hypothesis that mycoestrogens act as endocrine disruptors in humans, as in animal models and livestock. Additional work is needed to understand impacts on maternal and child health.

Vitamin D Metabolites in Mother-Infant Dyads and Associated Clinical Outcomes in a Population of Nigerian Women.

Low levels of vitamin D in maternal and cord blood have been associated with neonatal sepsis. This study assessed the association of vitamin D metabolites (25(OH)D, 3-epi-25(OH)D3, and 24,25(OH)2D3) levels in maternal and cord blood with newborn sepsis evaluation in Nigerian mother-infant dyads. Maternal and cord blood from 534 mothers and 536 newborns were processed using liquid chromatography-tandem mass spectrometry. Spearman correlation was used to compare continuous variables, Mann-Whitney for dichotomous variables, and Kruskal-Wallis for two or more groups. High cord percent 3-epi-25(OH)D3 levels were positively associated with newborn evaluation for sepsis (p = 0.036), while maternal and cord 25(OH)D and 24,25(OH)2D3 levels were not. Being employed was positively associated with maternal and newborn 3-epi-25(OH)D3 concentrations (p = 0.007 and p = 0.005, respectively). The maternal 3-epi-25(OH)D3 and percent 3-epi-25(OH)D3 were positively associated with vaginal delivery (p = 0.013 and p = 0.012, respectively). Having a weight-for-age Z-score ≤ -2 was positively associated with newborn percent 3-epi-25(OH)D3 levels (p = 0.004), while a weight-for-length Z-score ≤ -3 was positively associated with maternal and newborn percent 3-epi-25(OH)D3 levels (p = 0.044 and p = 0.022, respectively). Our study highlights the need to further investigate the biological role of 3-epi-25(OH)D3 and its clinical significance in fetal growth and newborn outcome.

Off-the-Shelf Cord-Blood Mesenchymal Stromal Cells: Production, Quality Control, and Clinical Use.

Background Recently, mesenchymal stromal cells (MSCs) have gained recognition for their clinical utility in transplantation to induce tolerance and to improve/replace pharmacological immunosuppression. Cord blood (CB)-derived MSCs are particularly attractive for their immunological naivety and peculiar anti-inflammatory and anti-apoptotic properties. OBJECTIVES: The objective of this study was to obtain an inventory of CB MSCs able to support large-scale advanced therapy medicinal product (ATMP)-based clinical trials. STUDY DESIGN: We isolated MSCs by plastic adherence in a GMP-compliant culture system. We established a well-characterized master cell bank and expanded a working cell bank to generate batches of finished MSC(CB) products certified for clinical use. The MSC(CB) produced by our facility was used in approved clinical trials or for therapeutic use, following single-patient authorization as an immune-suppressant agent. RESULTS: We show the feasibility of a well-defined MSC manufacturing process and describe the main indications for which the MSCs were employed. We delve into a regulatory framework governing advanced therapy medicinal products (ATMPs), emphasizing the need of stringent quality control and safety assessments. From March 2012 to June 2023, 263 of our Good Manufacturing Practice (GMP)-certified MSC(CB) preparations were administered as ATMPs in 40 subjects affected by Graft-vs.-Host Disease, nephrotic syndrome, or bronco-pulmonary dysplasia of the newborn. There was no infusion-related adverse event. No patient experienced any grade toxicity. Encouraging preliminary outcome results were reported. Clinical response was registered in the majority of patients treated under therapeutic use authorization. CONCLUSIONS: Our 10 years of experience with MSC(CB) described here provides valuable insights into the use of this innovative cell product in immune-mediated diseases.

Association between maternal age and sex-based neonatal free triiodothyronine levels.

BACKGROUND: Advanced maternal age may affect the intrauterine environment and increase the risk of neurodevelopmental disorders in offspring. Thyroid hormones are critical for fetal neurological development but whether maternal age influences fetal thyroid hormone levels in euthyroid mothers is unknown. OBJECTIVE: This study evaluated the association between cord blood thyroid hormones and maternal age, fetal sex, maternal thyroid function, and other perinatal factors. METHODS: The study population consisted of 203 healthy women with term singleton pregnancies who underwent elective cesarean section. Maternal levels of free T3 (fT3), free T4 (fT4) and TSH before delivery, and cord levels of fT3, fT4 and TSH were measured. Spearman's correlation coefficient and multiple linear regression analyses were performed to determine the correlation between cord thyroid hormone parameters and maternal characteristics. RESULTS: There were no significant differences in maternal serum or cord blood thyroid hormone levels between male and female births. In multivariate linear regression analysis, maternal age and maternal TSH values were negatively associated with the cord blood levels of fT3 in all births, after adjusting for confounding factors. Maternal age was more closely associated with the cord blood levels of fT3 in female than in male births. CONCLUSION: The inverse association between maternal age and cord blood levels of fT3 in euthyroid pregnant women suggested an impact of maternal aging on offspring thyroid function.

Plasma polyamines during pregnancy and their relationships with maternal allergies and the immune response of the neonates.

BACKGROUND: Some studies have reported that polyamine levels may influence immune system programming. The aim of this study was to evaluate the polyamine profile during gestation and its associations with maternal allergy and cytokine production in cord blood cells in response to different allergenic stimuli. METHODS: Polyamines were determined in plasma of pregnant women (24 weeks, N = 674) and in umbilical cord samples (N = 353 vein and N = 160 artery) from the Mediterranean NELA birth cohort. Immune cell populations were quantified, and the production of cytokines in response to different allergic and mitogenic stimuli was assessed in cord blood. RESULTS: Spermidine and spermine were the most prevalent polyamines in maternal, cord venous, and cord arterial plasma. Maternal allergies, especially allergic conjunctivitis, were associated with lower spermine in umbilical cord vein. Higher levels of polyamines were associated with higher lymphocyte number but lower Th2-related cells in cord venous blood. Those subjects with higher levels of circulating polyamines in cord showed lower production of inflammatory cytokines, especially IFN-α, and lower production of Th2-related cytokines, mainly IL-4 and IL-5. The effects of polyamines on Th1-related cytokines production were uncertain. CONCLUSIONS: Spermidine and spermine are the predominant polyamines in plasma of pregnant women at mid-pregnancy and also in umbilical cord. Maternal allergic diseases like allergic conjunctivitis are related to lower levels of polyamines in cord vein, which could influence the immune response of the newborn. Cord polyamine content is related to a decreased Th2 response and inflammatory cytokines production, which might be important to reduce an allergenic phenotype in the neonate.