Fetal Blood Research Articles

Comparative analysis of thiol-disulfide homeostasis dynamics between elective cesarean section and uncomplicated vaginal delivery: insights into perinatal oxidative balance.

Thiols are organic compounds containing sulfhydryl groups that exert antioxidant effects via dynamic thiol-disulfide homeostasis. The shift towards disulfide indicates the presence of an oxidative environment. Different modes of delivery can affect thiol-disulfide homeostasis. Accordingly, we planned this research to evaluate the effects of the mode of delivery on thiol-disulfide homeostasis in both maternal serum and fetal cord blood samples. We conducted a prospective case-control study involving two groups: vaginal delivery (n=50) and elective cesarean section (CS) (n=45). The vaginal delivery group exclusively comprised uncomplicated term deliveries, while the CS group included pregnant individuals with scheduled cesarean deliveries due to the absence of spontaneous labor onset. Maternal serum and fetal cord blood samples were collected, and thiol-disulfide exchanges were analyzed using an automated method capable of measuring both aspects of the thiol-disulfide balance. The levels of native thiol (-SH) and total thiol in both maternal serum and fetal cord blood samples were significantly higher in the vaginal delivery group than those in the CS group. An important discovery of our study was that fetal cord disulfide (-SS) level, which may reflect oxidative stress, was higher in newborns born via vaginal delivery when examined alone. However, in both maternal and fetal cord blood, the combined ratios, SS/SH ratio (%), SS/Total thiol ratio (%), and SH/Total thiol ratio (%) were observed to be similar between the groups in both maternal and fetal cord blood. It was observed that as the mother's weight gained during pregnancy increased, SS/SH and SS/total thiol increased (positive correlation), while SH/total thiol decreased (negative correlation). Our results showed that the dynamic thiol-disulfide homeostasis was greatly influenced by the way of delivery and supported the idea that vaginally-delivered infants may have more oxidative stress.

Ex vivo culture resting time impacts transplantation outcomes of genome-edited human hematopoietic stem and progenitor cells in xenograft mouse models

Ex vivo resting culture is a standard procedure following genome editing in hematopoietic stem and progenitor cells (HSPCs). However, prolonged culture may critically affect cell viability and stem cell function. We investigated whether varying durations of culture resting times impact the engraftment efficiency of human CD34+ HSPCs edited at the BCL11A enhancer, a key regulator in the expression of fetal hemoglobin. We employed electroporation to introduce CRISPR-Cas9 components for BCL11A enhancer editing and compared outcomes with nonelectroporated (NEP) and electroporated-only (EP) control groups. Post-electroporation, we monitored cell viability, death rates, and the frequency of enriched hematopoietic stem cell (HSC) fractions (CD34+CD90+CD45RA- cells) over a 48-hour period. Our findings reveal that while the NEP group showed an increase in cell numbers 24 hours post-electroporation, both EP and BCL11A-edited groups experienced significant cell loss. Although CD34+ cell frequency remained high in all groups for up to 48 hours post-electroporation, the frequency of the HSC-enriched fraction was significantly lower in the EP and edited groups compared to the NEP group. In NBSGW xenograft mouse models, both conditioned with busulfan and nonconditioned, we found that immediate transplantation post-electroporation led to enhanced engraftment without compromising editing efficiency. Human glycophorin A+ (GPA+) red blood cells (RBCs) sorted from bone marrow of all BCL11A edited mice exhibited similar levels of γ-globin expression, regardless of infusion time. Our findings underscore the critical importance of optimizing the culture duration between genome editing and transplantation. Minimizing this interval may significantly enhance engraftment success and minimize cell loss without compromising editing efficiency. These insights offer a pathway to improve the success rates of genome editing in HSPCs, particularly for conditions like sickle cell disease.

Using linear dichroism to measure the participation of fetal hemoglobin in sickle hemoglobin polymerization

Using linear dichroism to measure the participation of fetal hemoglobin in sickle hemoglobin polymerization

AsCas12a Gene Editing of HBG1/2 Promoters with Edit-301 Results in Early and Sustained Normalization of Hemoglobin and Increased Fetal Hemoglobin in Patients with Severe Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia

AsCas12a Gene Editing of HBG1/2 Promoters with Edit-301 Results in Early and Sustained Normalization of Hemoglobin and Increased Fetal Hemoglobin in Patients with Severe Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia

Development of a new staining protocol for the Kleihauer–Betke test to facilitate the reading of difficult cases

BackgroundThe Kleihauer–Betke (KB) test allows the detection of fetal red blood cells (containing fetal hemoglobin, HbF) in the maternal blood to identify and quantify potential fetal-maternal hemorrhages. In certain cases, detecting fetal red blood cells with conventional staining is difficult. False-positive results or overestimation of the quantity of fetal red blood cells may occur in cases of maternal hemoglobinopathy. In this study, we developed a new staining protocol to facilitate the reading of difficult smears and improve the precision of the quantification of fetal red blood cells; we also analyzed the performance of this new method. This study assessed blood samples with and without hemoglobin abnormalities, which present difficulties when interpreting the KB test.MethodsThe new staining formula is based on an improved elution technique and the use of a different stain instead of hematoxylin. To test this staining method, 16 samples from patients with abnormal hemoglobin electrophoresis and 14 samples from patients with normal hemoglobin electrophoresis were analyzed using the KB test with the classical staining method and the new staining method. In addition, a second series was prepared using the same samples spiked with fetal red blood cells from newborn blood, to compare the accuracy of the two methods in identifying fetal red blood cells.ResultsIn the 60 slides analyzed with both staining methods, we found that the new technique improved the accuracy from 78 to 85%; lowered the coefficient of variation between the operators, which decreased from 20.7% to 12.7%; increased the specificity in our population from 56 to 70%; and decreased the number of false-positive cases by 30%.ConclusionsWe successfully developed a new staining technique that facilitates the reading of difficult slides and improves the specificity of the detection of fetal red blood cells. This technique is recommended as a secondary method to use before sending the sample for additional exploration.

Noninvasive fetal blood group antigen genotyping.

Noninvasive fetal blood group antigen genotyping serves as a diagnostic tool to predict the risk of hemolytic disease of the fetus and newborn in pregnancies of immunized women. In addition, fetal RHD genotyping is used as an antenatal screening to guide targeted use of immunoglobulin prophylaxis in non-immunized RhD negative, pregnant women. Based on testing of cell-free DNA extracted from maternal plasma, these noninvasive assays demonstrate high performance accuracies. Consequently, noninvasive fetal blood group antigen genotyping has become standard care in transfusion medicine.

Massive fetomaternal hemorrhage: A case report.

We present a case with an incidental finding of abnormal cardiotocography (CTG) pattern as well as elevated middle cerebral artery peak systolic velocity (MCA-PSV) in an otherwise inconspicuous pregnancy. Massive fetomaternal hemorrhage (FMH) was detected as the cause by flow cytometry (FC), resulting in multiple cycles of fetal blood sampling (FBS) showing severe anemia, intrauterine transfusions (IUTs), a preterm delivery, and a healthy infant in follow-up examinations.

Sex-Dependent Variations in Hypothalamic Fatty Acid Profile and Neuropeptides in Offspring Exposed to Maternal Obesity and High-Fat Diet.

Maternal obesity and/or high-fat diet (HF) consumption can disrupt appetite regulation in their offspring, contributing to transgenerational obesity and metabolic diseases. As fatty acids (FAs) play a role in appetite regulation, we investigated the maternal and fetal levels of FAs as potential contributors to programmed hyperphagia observed in the offspring of obese dams. Female mice were fed either a control diet (CT) or HF prior to mating, and fetal and maternal blood and tissues were collected at 19 days of gestation. Elevated levels of linoleic acid were observed in the serum of HF dams as well as in the serum of their fetuses. An increased concentration of eicosadienoic acid was also detected in the hypothalamus of female HF-O fetuses. HF-O male fetuses showed increased hypothalamic neuropeptide Y (Npy) gene expression, while HF-O female fetuses showed decreased hypothalamic pro-opiomelanocortin (POMC) protein content. Both male and female fetuses exhibited reduced hypothalamic neurogenin 3 (NGN-3) gene expression. In vitro experiments confirmed that LA contributed to the decreased gene expression of Pomc and Ngn-3 in neuronal cells. During lactation, HF female offspring consumed more milk and had a higher body weight compared to CT. In summary, this study demonstrated that exposure to HF prior to and during gestation alters the FA composition in maternal serum and fetal serum and hypothalamus, particularly increasing n-6, which may play a role in the switch from POMC to NPY neurons, leading to increased weight gain in the offspring during lactation.

Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals.

Whole blood transcriptome analysis is a valuable approachin medical research, primarily due to the ease of sample collection and the richness of the information obtained. Since the expression profile of individual genes in the analysis is influenced by medical traits and demographic attributes such as age and gender, there has been a growing demand for a comprehensive database for blood transcriptome analysis. Here, we performed whole blood RNA sequencing (RNA-seq) analysis on 576 participants stratified by age (20-30s and 60-70s) and gender from cohorts of the Tohoku Medical Megabank (TMM). A part of female segment included pregnant women. We did not exclude the globin gene family in our RNA-seq study, which enabled us to identify instances of hereditary persistence of fetal hemoglobin based on the HBG1 and HBG2 expression information. Comparing stratified populations allowed us to identify groups of genes associated with age-related changes and gender differences. We also found that the immune response status, particularly measured by neutrophil-to-lymphocyte ratio (NLR), strongly influences the diversity of individual gene expression profiles in whole blood transcriptome analysis. This stratification has resulted in a data set that will be highly beneficial for future whole blood transcriptome analysis in the Japanese population.

Exagamglogene Autotemcel: First Approval.

Exagamglogene autotemcel (Casgevy™) is a genetically modified autologous CD34+ cell enriched population. It contains human haematopoietic stem and progenitor cells edited ex vivo by CRISPR/Cas9 (a DNA double strand break-inducing nuclease system) to differentiate into erythroid cells that produce high levels of foetal hemoglobin. Developed by Vertex Pharmaceuticals and CRISPR Therapeutics, exagamglogene autotemcel received its first approval on 16 November 2023 in the UK for the treatment of transfusion-dependent β-thalassemia (TDT) in patients aged ≥ 12years for whom haematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen matched related HSC donor is not available. On the same day, it was also approved in the UK for the treatment of sickle cell disease (SCD) in patients aged ≥ 12years with recurrent vasoocclusive crises (VOCs) who have the βS/βS, βS/β+ or βS/β0 genotype for whom HSC transplantation is appropriate and a human leukocyte antigen matched related HSC donor is not available. Subsequently, exagamglogene autotemcel was approved in the USA on 8 December 2023 for the treatment of SCD in patients aged ≥ 12years with recurrent VOCs and received a positive opinion in the EU on 14 December 2023 for the treatment of TDT and SCD. A regulatory assessment of exagamglogene autotemcel is currently underway for the treatment of TDT in the USA. This article summarizes the milestones in the development of exagamglogene autotemcel leading to these first approvals.

Quantitative Model-Based Assessment of Multiple Sickle Cell Disease Therapeutic Approaches Alone and in Combination.

Three sickle cell disease (SCD) treatment strategies, stabilizing oxygenated hemoglobin (oxyHb), lowering 2,3-BPG, and inducing fetal hemoglobin (HbF) expression aim to prevent red blood cell (RBC) sickling by reducing tense-state sickle hemoglobin that contributes to polymer formation. Induction of 30% HbF is seen as the gold standard because 30% endogenous expression is associated with a lack of symptoms. However, the level of intervention required to achieve equivalent polymerization protection by the other strategies is uncertain, and there is little understanding of how these approaches could work in combination. We sought to develop an oxygen saturation model that could assess polymerization protection of all three approaches alone or in combination by extending the Monod-Wymann-Changeux model to include additional mechanisms. Applying the model to monotherapies suggests 51% sickle hemoglobin (HbS) occupancy with an oxyHb stabilizer or lowering RBC 2,3 BPG concentrations to 1.8 mM would produce comparable polymerization protection as 30% HbF. The model predictions are consistent with observed clinical response to the oxyHb stabilizer voxelotor and the 2,3-BPG reducer etavopivat. The model also suggests combination therapy will have added benefit in the case of dose limitations, as is the case for voxelotor, which the model predicts could be combined with 20% HbF or 2,3-BPG reduction to 3.75 mM to reach equivalent protection as 30% HbF. The proposed model represents a unified framework that is useful in supporting decisions in preclinical and early clinical development and capable of evolving with clinical experience to gain new and increasingly confident insights into treatment strategies for SCD.

Enzyme-free sensitive SERS biosensor for the detection of thalassemia-associated microRNA-210 using a cascade dual-signal amplification strategy

Backgroundβ-thalassemia is a blood disorder caused by autosomal mutations. Gene modulation therapy to activate the γ-globin gene to induce fetal hemoglobin (HbF) synthesis has become a new option for the treatment of β-thalassemia. MicroRNA-210 (miR-210) contributes to studying the mechanism regulating γ-globin gene expression and is a potential biomarker for rapid β-thalassemia screening. Traditional miRNA detection methods perform well but necessitate complex and time-consuming miRNA sample processing. Therefore, the development of a sensitive, accurate, and simple miRNA level monitoring method is essential. ResultsWe have developed a non-enzymatic surface-enhanced Raman scattering (SERS) biosensor utilizing a signal cascade amplification of catalytic hairpin assembly reaction (CHA) and proximity hybridization-induced hybridization chain reaction (HCR). Au@Ag NPs were used as the SERS substrate, and methylene blue (MB)- modified DNA hairpins were used as the SERS tags. The SERS assay involved two stages: implementing the CHA-HCR cascade signal amplification strategy and conducting SERS measurements on the resulting product. The HCR was started by the products of target-triggered CHA, which formed lengthy nicked double-stranded DNA (dsDNA) on the Au@Ag NPs surface to which numerous SERS tags were attached, leading to a significant increase in the SERS signal intensity. High specificity and sensitivity for miR-210 detection was achieved by monitoring MB SERS intensity changes. The suggested SERS biosensor has a low detection limit of 5.13 fM and is capable of detecting miR-210 at concentration between 10 fM and 1.0 nM. SignificanceThe biosensor can detect miR-210 levels in the erythrocytes of β-thalassemia patients, enabling rapid screening for β-thalassemia and suggesting a novel approach for investigating the regulation mechanism of miR-210 on γ-globin gene expression. In the meantime, this innovative technique has the potential to detect additional miRNAs and to become an important tool for the early diagnosis of diseases and for biomedical research.

Association of free maternal and fetal ropivacaine after epidural analgesia for intrapartum caesarean delivery: a prospective observational trial

BackgroundRopivacaine is present in plasma in both protein-bound and free forms. The free form is responsible for the occurrence of toxic side effects. During obstetric epidural analgesia, free ropivacaine enters the fetal circulation depending on various factors. The aim of this study was to analyse a potential association between ropivacaine concentrations in maternal and fetal plasma and hence the extent of fetal exposure to ropivacaine. MethodsIn this prospective monocentre study, parturients who met the following criteria were included in the study: 1. epidural administration as part of obstetric anaesthesia, and 2. subsequent intrapartum caesarean delivery, which 3. was performed after an epidural bolus administration of ropivacaine within the existing epidural analgesia. Total and free ropivacaine concentrations were analysed in maternal blood at baseline, prior to epidural bolus administration for caesarean delivery, and in maternal and fetal (umbilical venous, oxygenated) blood at delivery. The results are presented as mean ± SD or median (25/75th percentile). ResultsWe screened 128 parturients who went into labour at term and requested epidural analgesia, of whom 39 were ultimately included in the study. An intrapartum caesarean delivery was performed after the epidural application of 207 (166/276) mg ropivacaine during an epidural treatment period of 577 (360/1010) min. Total and free ropivacaine concentrations were 1402 ± 357 ng/ml and 53 ± 46 ng/ml, respectively, in maternal venous blood and 457 ± 243 ng/ml and 43 ± 27 ng/ml, respectively, in fetal blood. The maternal total and free ropivacaine concentrations were significantly correlated (r = 0.873; P < 0.0001). ConclusionThe results of the present study suggest that determining the concentration of free ropivacaine in maternal blood may be a feasible option for estimating neonatal exposure to ropivacaine.

Expression of placental CD146 is dysregulated by prenatal alcohol exposure and contributes in cortical vasculature development and positioning of vessel-associated oligodendrocytes.

Recent data showed that prenatal alcohol exposure (PAE) impairs the "placenta-brain" axis controlling fetal brain angiogenesis in human and preclinical models. Placental growth factor (PlGF) has been identified as a proangiogenic messenger between these two organs. CD146, a partner of the VEGFR-1/2 signalosome, is involved in placental angiogenesis and exists as a soluble circulating form. The aim of the present study was to investigate whether placental CD146 may contribute to brain vascular defects described in fetal alcohol spectrum disorder. At a physiological level, quantitative reverse transcription polymerase chain reaction experiments performed in human placenta showed that CD146 is expressed in developing villi and that membrane and soluble forms of CD146 are differentially expressed from the first trimester to term. In the mouse placenta, a similar expression pattern of CD146 was found. CD146 immunoreactivity was detected in the labyrinth zone and colocalized with CD31-positive endothelial cells. Significant amounts of soluble CD146 were quantified by ELISA in fetal blood, and the levels decreased after birth. In the fetal brain, the membrane form of CD146 was the majority and colocalized with microvessels. At a pathophysiological level, PAE induced marked dysregulation of CD146 expression. The soluble form of CD146 decreased in both placenta and fetal blood, whereas it increased in the fetal brain. Similarly, the expression of several members of the CD146 signalosome, such as VEGFR2 and PSEN, was differentially impaired between the two organs by PAE. At a functional level, targeted repression of placental CD146 by in utero electroporation (IUE) of CRISPR/Cas9 lentiviral plasmids resulted in (i) a decrease in cortical vessel density, (ii) a loss of radial vascular organization, and (iii) a reduced density of oligodendrocytes. Statistical analysis showed that the more the vasculature was impaired, the more the cortical oligodendrocyte density was reduced. Altogether, these data support that placental CD146 contributes to the proangiogenic "placenta-brain" axis and that placental CD146 dysfunction contributes to the cortical oligo-vascular development. Soluble CD146 would represent a promising placental biomarker candidate representative of alcohol-induced neurovascular defects in neonates, as recently suggested by PlGF (patents WO2016207253 and WO2018100143).

Neurological abnormalities among pediatric patients with sickle cell disease in Saudi Arabia: a single-center retrospective study.

Sickle cell disease (SCD) is a common inherited blood disorder characterized by the production of abnormal sickle-shaped red blood cells. SCD can lead to various complications including neurological issues. Early detection and treatment are crucial for preventing these complications. This study aimed to describe the neurological manifestations, radiological findings, and neurological diagnosis related to SCD in Saudi children with the aim of contributing to the formulation of population-based guidelines for screening and treating SCD-related neurological complications. This descriptive retrospective study included pediatric patients aged < 14 years diagnosed with SCD who were regularly followed up at the hematology clinic in KAMC, Jeddah, Saudi Arabia, from January 2008 to January 2022. Demographic and clinical data were collected from the clinical charts of 101 participants. This study included 101 patients with SCD with a mean age of 23 months at diagnosis. Among these, 59% had SCD and high fetal hemoglobin (HbF) levels. Neurological sequelae, including seizures, stroke, and other abnormalities, were observed in 26.7% of patients. There were no significant differences in the onset of neurological issues between the patients with SCD-high HbF and those with other SCD phenotypes. This study highlights the increased risk of brain injury and neurocognitive deficits in children with SCD. The occurrence of neurological sequelae in many patients emphasizes the need for early detection and intervention. Some patients experience neurological complications despite having high HbF levels, suggesting that further interventions are needed. This study has some limitations, including its small sample size and retrospective nature. Early detection and intervention are crucial for neurological complications in patients with SCD. This study emphasizes the need for further research and effective treatment strategies considering the presence of neurological complications despite the presence of high HbF levels. Large-scale studies and population-specific guidelines are warranted for better understanding and management of SCD-related neurological complications in the Saudi population.

The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum.

Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3-54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages' CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for p < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR). Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations. The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses.

27-Hydroxycholesterol inhibits trophoblast fusion during placenta development by activating PI3K/AKT/mTOR signaling pathway.

Trophoblast cell syncytialization is essential for placental and fetal development. Abnormal trophoblast cell fusion leads to pregnancy pathologies, such as preeclampsia (PE), intrauterine growth restriction (IUGR), and miscarriage. 27-hydroxycholesterol (27-OHC) is the most abundant oxysterol in human peripheral blood synthesized by sterol 27-hydroxylase (CYP27A1) and is considered a critical mediator between hypercholesterolemia and a variety of related disorders. Gestational hypercholesterolemia was associated with spontaneous preterm delivery and low birth weight (LBW) in term infants, yet the mechanism is unclear. In this study, two trophoblast cell models and CD-1 mice were used to evaluate the effects of 27-OHC on trophoblast fusion during placenta development. Two different kinds of trophoblast cells received a dosage of 2.5, 5, or 10 uM 27-OHC. Three groups of pregnant mice were randomly assigned: control, full treatment (E0.5-E17.5), or late treatment (E13.5-E17.5). All mice received daily intraperitoneal injections of saline (control group) and 27-OHC (treatment group; 5.5mg/kg). In vitro experiments, we found that 27-OHC inhibited trophoblast cell fusion in primary human trophoblasts (PHT) and forskolin (FSK)-induced BeWo cells. 27-OHC up-regulated the expression of the PI3K/AKT/mTOR signaling pathway-related proteins. Moreover, the PI3K inhibitor LY294002 rescued the inhibitory effect of 27-OHC. Inhibition of trophoblast cell fusion by 27-OHC was also observed in CD-1 mice. Furthermore, fetal weight and placental efficiency decreased and fetal blood vessel development was inhibited in pregnant mice treated with 27-OHC. This study was the first to prove that 27-OHC inhibits trophoblast cell fusion by Activating PI3K/AKT/mTOR signaling pathway. This study reveals a novel mechanism by which dyslipidemia during pregnancy results in adverse pregnancy outcomes.

Characterization of a cohort of Angolan children with sickle cell anemia treated with hydroxyurea

BackgroundSickle Cell Anemia (SCA) is a monogenic disease, although its severity and response to treatment are very heterogeneous. ObjectivesThis study aims to characterize a cohort of Angolan children with SCA and evaluate their response to hydroxyurea (HU) treatment and the potential side effects and toxicity. MethodsThe study enrolled 215 patients between 3 and 12 years old before and after the administration of HU, at a fix dose of 20 mg/kg/day for 12 months. ResultsA total of 157 patients started HU medication and 141 of them completed the 12-month treatment. After initiating HU treatment, the frequency of clinical events decreased (transfusions 53.4 %, hospitalizations 47.1 %). The response to HU medication varied among patients, with some experiencing an increase in fetal hemoglobin (HbF) of <5 %. The mean increase in HbF was 11.9 %, ranging from 1.8 % to 31 %. Responders to HU treatment were 57 %, inadequate responders 38.7 % and non-adherent 4.2 %. No clinical side effects related to HU were reported. Hematological toxicities were transient and reversible. Children naïve to HU and with lower HbF reported higher number of hospitalizations caused by malaria infection. During HU treatment, the frequency of malaria episodes did not appear to be affected by HbF levels. Conclusionsthe present study provided a valuable contribution to the understanding of the clinical and laboratory profiles of Angolan children with SCA. These findings support the evidence that the implementation of prophylactic measures and treatment with HU is associated with increased survival in children with SCA.

Ultrasound microvascular flow imaging: evaluating fetal mesenteric blood flow and predicting postnatal surgery in meconium peritonitis

Objective This study explored the characteristics of fetal mesenteric blood flow perfusion across various gestational weeks and evaluated the efficacy of Microvascular Flow (MV-Flow) imaging technology in assessing intestinal wall blood flow in fetuses with meconium peritonitis (MP). Method In this retrospective study, we analyzed 35 fetuses with MP and 160 healthy fetuses. We examined the correlation between the Vascular Index (VI) of mesenteric perfusion and gestational age, conducted an analysis comparing MP operative and non-operative groups, and developed a predictive model for surgical intervention. Results The VI value demonstrated no significant change with increasing gestational age (correlation coefficient = 0.005, p = 0.946). For healthy fetuses, VI ranged approximately from 34.66% to 67.26% using the automatic ellipse method. The MP operative group exhibited significantly more cesarean deliveries (100% vs. 52.9%, p = 0.003), shorter gestational periods (34.76 ± 2.16 weeks vs. 37.48 ± 1.55 weeks, p < 0.001), lower birth weights (2762.14 ± 452.76 g vs. 3225.88 ± 339.98 g, p = 0.003), more persistent ascites (92.9% vs. 52.9%, p = 0.021), more frequent intestinal wall echo reductions (57.1% vs. 5.9%, p = 0.004), and lower VI (18.57 ± 5.51% vs. 39.41 ± 7.02%, p < 0.001). A predictive model was established: Logit (P)=8.86 - (0.37* VI) + (1.49* ascites), yielding an area under the curve of 0.857, with 78.6% sensitivity and 88.2% specificity. The VI value was significantly associated with the need for postnatal surgery (OR = 0.689, 95% confidence interval: 0.511 − 0.929, p = 0.015). A Receiver Operating Characteristic curve analysis for VI in predicting postnatal surgery showed an area under the curve of 0.971, with an optimal cutoff value of 35%, achieving 91% sensitivity and 94.4% specificity. Conclusion MV-Flow imaging effectively quantified fetal bowel wall blood flow perfusion. There was no significant change in VI across different gestational weeks. Significantly lower VI values in MP fetuses indicated an increased risk of intestinal wall necrosis and the potential need for postnatal surgical intervention.

Upregulation of hepatic nuclear receptors in extremely preterm ovine fetuses undergoing artificial placenta therapy

Objective Extremely preterm infants have low Nuclear Receptor (NR) expression in their developing hepatobiliary systems, as they rely on the placenta and maternal liver for compensation. NRs play a crucial role in detoxification and the elimination of both endogenous and xenobiotic substances by regulating key genes encoding specific proteins. In this study, we utilized an Artificial Placenta Therapy (APT) platform to examine the liver tissue expression of NRs of extremely preterm ovine fetuses. This fetal model, resembling a “knockout placenta,” lacks placental and maternal support, while maintaining a healthy extrauterine survival. Methods Six ovine fetuses at 95 ± 1 d gestational age (GA; term = ∼150 d)/∼600 g delivery weight were maintained on an APT platform for a period of 120 h (APT Group). Six age-matched, in utero control fetuses were delivered at 99–100 d GA (Control Group). Fetal liver tissue samples and blood samples were collected at delivery from both groups and assessed mRNA expression of NRs and target transporters involved in the hepatobiliary transport system using quantitative PCR. Data were tested for group differences with ANOVA (p < .05 deemed significant). Results mRNA expression of NRs was identified in both the placenta and the extremely preterm ovine fetal liver. The expression of HNF4α, LRH1, LXR, ESR1, PXR, CAR, and PPARα/γ were significantly elevated in the liver of the APT Group compared to the Control Group. Moreover, target transporters NTCP, OATP1B3, BSEP, and MRP4 were upregulated, whereas MRP2 and MRP3 were unchanged. Although there was no evidence of liver necrosis or apoptotic changes histologically, there was an impact in the fetal liver of the ATP group at the tissue level with a significant increase in TNFα mRNA, a cytokine involved in liver inflammation, and blood elevation of transaminases. Conclusion A number of NRs in the fetal liver were significantly upregulated after loss of placental-maternal support. However, the expression of target transporter genes appeared to be insufficient to compensate role of the placenta and maternal liver and avoid fetal liver damage, potentially due to insufficient excretion of organic anions.