Search Results (409)

Background: This study presents an innovative approach to cardiovascular disease (CVD) risk prediction based on a comprehensive analysis of clinical, immunological and biochemical markers using mathematical modelling and machine learning methods. Baseline data include indices of humoral and cellular immunity (CD59, CD16, IL-10, CD14, CD19, CD8, CD4, etc.), cytokines and markers of cardiovascular disease, inflammatory markers (TNF, GM-CSF, CRP), growth and angiogenesis factors (VEGF, PGF), proteins involved in apoptosis and cytotoxicity (perforin, CD95), as well as indices of liver function, kidney function, oxidative stress and heart failure (albumin, cystatin C, N-terminal pro B-type natriuretic peptide (NT-proBNP), superoxide dismutase (SOD), C-reactive protein (CRP), cholinesterase (ChE), cholesterol, and glomerular filtration rate (GFR)). Clinical and behavioural risk factors were also considered: arterial hypertension (AH), previous myocardial infarction (PICS), aortocoronary bypass surgery (CABG) and/or stenting, coronary heart disease (CHD), atrial fibrillation (AF), atrioventricular block (AB block), and diabetes mellitus (DM), as well as lifestyle (smoking, alcohol consumption, physical activity level), education, and body mass index (BMI). Methods: The study included 52 patients aged 65 years and older. Based on the clinical, biochemical and immunological data obtained, a model for predicting the risk of premature cardiovascular aging was developed using mathematical modelling and machine learning methods. The aim of the study was to develop a predictive model allowing for the early detection of predisposition to the development of CVDs and their complications. Numerical methods of mathematical modelling, including Runge–Kutta, Adams–Bashforth and backward-directed Euler methods, were used to solve the prediction problem, which made it possible to describe the dynamics of changes in biomarkers and patients’ condition over time with high accuracy. Results: HLA-DR (50%), CD14 (41%) and CD16 (38%) showed the highest association with aging processes. BMI was correlated with placental growth factor (37%). The glomerular filtration rate was positively associated with physical activity (47%), whereas SOD activity was negatively correlated with it (48%), reflecting a decline in antioxidant defence. Conclusions: The obtained results allow for improving the accuracy of cardiovascular risk prediction, and form personalised recommendations for the prevention and correction of its development. Full article

Background: The reproducibility of research findings continues to be a challenge in many fields, including neurosciences. It is now required that biological variables such as sex and age be considered in preclinical and clinical research. Rodents are frequently used to model clinical conditions; however, litter information is rarely presented. Some studies utilize entire litters with each animal treated as an independent sample, while others equally assign animals from each litter to different groups/treatments, and others use averaged data. These methods can yield different results. Methods: This study used different analysis methods to evaluate embryo and placenta weights from E17.5 acid-sensing ion channel 2a (ASIC2a) mice with or without seizure exposure. Results: When each embryo was treated as an individual sample, fetal and placental weight significantly differed following seizures in the ASIC2a heterozygous (+/−) and homozygous (−/−) groups. Differences in fetal weight were driven by females in the ASIC2a+/− group and both sexes in the ASIC2a−/− group. These differences were lost when an average per sex/genotype/litter was used. There was no difference in placental weight when treated individually; however, female ASIC2a−/− placentas weighed less following seizures. This difference was lost with averaged data. ASIC2a−/− fetuses from −/− dams had reduced weights post-seizure exposure. Position on the uterine horn influenced embryo and placental weight. Conclusions: Our results indicate that using full litters analyzed as individual data points should be avoided, as it can lead to Type I errors. Furthermore, studies should account for litter effects and be transparent in their methods and results. Full article

Syphilis, which is caused by Treponema pallidum, remains one of the most common congenital infection worldwide and has tremendous consequences for the mother and her developing foetus if left untreated. The complexity of the exposure to this pathogen extends beyond the well-established clinical manifestations, as it can profoundly affect placental histomorphology. This study aimed to compare T. pallidum-exposed placental villi structures with healthy placentae at term to evaluate the histomorphological differences using stereology. In this case-control study conducted at term (38 weeks ± 2 weeks), 78 placentae were collected from the hospital delivery suites, comprising 39 cases (T. pallidum-exposed) and 39 controls (non-exposed), who were gestational age-matched with other potential confounders excluded. Blood samples from the umbilical vein and placental basal plate were tested for syphilis, using rapid diagnostic test (RDT) kits for T. pallidum (TP) antibodies (IgG and IgM) to classify placentae as exposed to T. pallidum (cases) and non-exposed (controls). Tissue sections were prepared and stained with haematoxylin and eosin, and the mean volume densities of syncytial knots, foetal capillaries, syncytial denuded areas, and intervillous spaces were estimated using stereological methods. Statistical analysis was performed to compare the mean values between the case and control groups. Stereological assessment revealed significant differences between the T. pallidum-exposed and non-exposed groups with regard to syncytial knots (p < 0.0001), syncytial denudation (p < 0.0001), and foetal capillaries (p < 0.0001), but no significant difference in the intervillous space was found (p = 0.1592). Therefore, our study shows, for the first time, that the histomorphology of human placental villi appears to be altered by exposure to T. pallidum. It will, therefore, be interesting to determine whether these changes in the placental villi translate into long-term effects on the baby. Full article

Adequate birth weight is essential for animal survival and subsequent growth. However, the mechanism by which placental DNA methylation influences fetal growth remains incompletely understood. This study employed whole-genome bi-sulfite sequencing (WGBS) and RNA sequencing to analyze placental tissues from two weak piglets and two normal piglets born to the same sow. Transcriptome analysis identified 1989 differentially expressed genes (DEGs) enriched in blood/immune processes. Additionally, differentially methylated regions linked to DEG repression were enriched in extracellular matrix (ECM) receptors and angiogenesis pathways. To investigate the role of DNA methylation in gene regulation, porcine trophoblast cells (PTr2) were treated with either DMSO (control) or the DNA methylation inhibitor 5-Aza-2′-deoxycytidine (5-Aza). Real-time quantitative PCR (RT-qPCR) analysis demonstrated significant upregulation of PACC1, SLC7A1, and PKP1 gene expression in the 5-Aza-treated group compared to controls (p < 0.05). Furthermore, methylation-specific PCR (MS-PCR) assays confirmed that the transcriptional activity of these genes is directly modulated by DNA methylation. These findings suggest that the dynamic regulation of DNA methylation in gene promoters may influence variations in placental morphology and birth weight in piglets, offering new insights into epigenetic regulation of fetal development, though larger studies are needed for validation. Full article

Epigenetic regulation, particularly DNA methylation, plays a crucial role in embryonic development by controlling gene expression patterns. The disruption of this regulation by environmental factors can have long-lasting consequences. Opioid drugs, such as morphine, are known to cross the placental barrier and affect the developing central nervous system, yet their precise epigenetic effects during early development remain unclear. This study aimed to elucidate the impact of chronic morphine exposure on the DNA methylation landscape and gene expression in mouse embryonic stem cells (mESCs). mESCs were chronically exposed to morphine (10 μM for 24 h). Genome-wide bisulfite sequencing was performed to identify DNA methylation changes, while RNA sequencing (RNA-Seq) assessed corresponding gene expression alterations. Global levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were quantified using mass spectrometry. Morphine exposure induced global DNA hypomethylation and identified 16,808 differentially methylated genes (DMGs) related to development, cell signalling, metabolism, and transcriptional regulation. Integrative transcriptomic analysis with RNA-Seq data revealed 651 overlapping genes, including alterations in key epigenetic regulators involved on DNA methylation machinery. Specifically, Tet1 was upregulated with promoter hypomethylation, while Dnmt1 was downregulated, without changes in promoter methylation after morphine exposiure. Mass spectrometry results confirmed a global decrease in 5mC levels alongside increased 5hmC, indicating the involvement of both passive and active demethylation pathways. These findings demonstrate for the first time that morphine disrupts the epigenetic homeostasis of mESCs by promoting global and gene-specific DNA demethylation, which might be key to the phenotypic changes that occur in adulthood. This work provides novel mechanistic insights into how opioid exposure during early development may lead to persistent epigenetic alterations, with potential long-term implications for neurodevelopment and disease susceptibility. Full article

The suppressive regulator of cell fusion, suppressyn, is specifically expressed in the human placenta and is thought to play a crucial role in trophoblast fusion or syncytialization. Previous studies have suggested that alterations in its expression are associated with aberrant placental development, such as the immature placental morphology observed in Down syndrome, and may contribute to the pathogenesis of fetal growth restriction. While syncytialization in trophoblasts is an essential process for normal placental development, the precise molecular causes of its dysregulation remain poorly understood. In the present study, we aimed to elucidate the potential contribution of genomic variation to the loss of suppressyn function, extending previous analyses of expression abnormalities in perinatal disorders. Through sequence analysis, (1) we identified six polymorphisms within the coding region of the suppressyn gene, and (2) discovered that certain deletions and specific amino acid substitutions result in a complete loss of suppressyn-mediated inhibition of cell fusion. Although these mutations have not yet been reported in disease-associated genomic databases, our findings suggest that comprehensive genomic studies of perinatal and other disorders may reveal pathogenic variants of suppressyn, thereby uncovering novel genetic contributions to placental dysfunction. It is also anticipated that these findings might direct the development of therapeutic strategies targeting loss-of-function mutations. Full article

Background: Prematurely born newborns with low birth weight constitute a group of patients who require special care from the first days of life. Prematurity and low birth weight affect about 13.4 million infants. Risk factors include placental disorders but also factors related to the mother, such as smoking, alcohol drinking, drug use, malnutrition, or certain diseases. It is imperative to educate women of reproductive age (15–49) about the basic factors influencing embryonic development, such as oral health, diet, medicine intake, and harmful habits. Even though most women are aware of the negative impact of harmful habits on the fetus, still too little attention is paid to oral health in pregnant women. Poor oral health may influence the well-being of the future mother, as well as of the child. Therefore, women of reproductive age and those who are pregnant must have adequate knowledge on this subject. The aim of this study was to assess the knowledge of Polish women of reproductive age (15–49) regarding oral health during pregnancy, including the impact of dental treatment, oral hygiene, and maternal oral conditions on pregnancy outcomes and the health of the newborn. Materials and Methods: This was a cross-sectional study of 508 women, in the reproductive age, whose age ranged from 18 to 49 years old. The surveys were conducted from April 2020 to November 2020. The questionnaire was originally developed based on the available literature and consisted of seven sections: basic information, general health and habits, pregnancy status and dental care, knowledge of treatment options during pregnancy, oral health status and its association with the risk of preterm birth, prematurity and the child’s oral health, and breastfeeding and oral development. Results: After excluding incomplete questionnaires, a total of 499 questionnaires were included in the analysis. Women participating in the study had a fairly good understanding of the impact of oral health on the fetus and the role of breastfeeding in the development of the stomatognathic system (from 50% to 70% correct answers). However, even though most respondents had completed higher education (344/68.94%), their knowledge of oral health, preterm birth, and low birth weight was very limited (including the impact of inflammation on the intrauterine development of the child or bacteria and transfer across the placenta). In these sections, the percentage of correct answers ranged from less than 20% to 50%. When analyzing knowledge by age, education, number of births, and place of residence, the highest levels of knowledge were observed among respondents with higher education, particularly those aged 27–32. Conclusions: Respondents had a fairly good understanding of the general impact of oral health during pregnancy and recognition of the importance of breastfeeding for infants. However, their knowledge about the impact of bacteria and inflammation in the mother’s oral cavity on prematurity and low birth weight was limited. Therefore, educating women of reproductive age and pregnant women on this topic is essential, as it may help reduce the adverse consequences of prematurity. Full article

Background/Objectives: The application of shear wave elastography (SWE) for the assessment of placental disease is still unproven and there is limited data correlating placental biomechanical properties with aberrations in fetal growth. This study investigated changes in placental shear wave velocity (SWV) in early and late fetal growth restriction (FGR). Methods: We analyzed three study cohorts: Pregnancies with appropriate growth for gestational age (AGA) and those with early (<32 weeks’) and late (>32 weeks’) FGR. Mean SWV at two time points was compared in the following cohorts: all FGR vs. AGA, early FGR vs. late FGR, early FGR vs. AGA, and late FGR vs. AGA. Results: The study comprised 222 women—79 (35.6%) FGR and 143 (64.4%) AGA. Of the FGR pregnancies, 37 (46.8%) were early and 42 (53.2%) were late. On multivariate analysis mean, SWV was not increased in FGR compared to AGA placentae (β 0.21, 95% CI −0.17–0.60, p 0.28). It was also not increased in early FGR compared to late FGR or AGA placentae (β 0.36, 95% CI −0.06–0.77, p 0.09). We observed an effect measure modification by pre-eclampsia, increasing mean SWV to a greater extent in AGA compared to FGR cases. Conclusions: Although previous studies have shown an association between placental SWV and FGR, our study showed no difference between cases and controls. The interaction of pre-eclampsia indicated that SWE may have a greater role in pre-eclampsia than in FGR alone. Further investigation of the influence of increased maternal vascular pressure on placental stiffness would be beneficial. Full article

Background/Objective: Preeclampsia (PE) remains a leading cause of maternal and fetal morbidity and mortality. Early prediction is crucial for timely intervention and management. The ophthalmic artery (OA) Doppler assessment in the first trimester has emerged as a potential tool for predicting PE, particularly early PE, with delivery <37 weeks of gestation. This study aimed to evaluate and compare the relationship of ophthalmic artery Doppler parameters at 11–13 weeks of gestation with the subsequent development of early and late PE. Methods: A prospective observational analysis was conducted on 4054 pregnant women, including 114 who developed PE. OA Doppler assessment of the pulsatility index (PI) and peak systolic velocity (PSV) ratio, mean arterial pressure (MAP), uterine artery PI (UtA-PI), and serum placental growth factor (PlGF) were compared between women who later developed early PE and late PE with those who did not develop PE. Results: In the PE groups, particularly those with early PE, compared to the no PE group, the OA PSV ratio and UtA-PI were higher and PlGF was lower. Conclusion: A first-trimester OA Doppler assessment shows promise as a non-invasive method for the prediction of PE. Further prospective, multicenter studies are needed to validate these findings. Full article

Background: Salmonella infections impose a substantial global health burden, with an estimated 95.1 million cases occurring annually. Pregnant women exhibit a heightened vulnerability due to pregnancy-specific immune adaptations and dietary habits that increase their risk of Salmonella exposure, facilitating possible damage to the placental barrier. Despite this significant burden, Salmonella-associated placental pathology remains poorly understood, particularly its impact on foetal development through microstructural alterations. Aim: This study utilised stereology to assess histomorphological and functional alterations in term placentae of Salmonella Typhi-exposed placentae, compared to unexposed controls. Methods: A hospital-based case-control study was conducted in Ghana. Of 237 screened women, 62 placentae were selected for analysis, comprising 31 Salmonella-exposed cases (IgG/IgM-positive in placental and cord blood) and 31 gestational age-matched controls (IgG/IgM-negative). Placental tissues were processed for histology and stereology. Neonatal birthweights were also compared. Results: Stereological assessment revealed significantly higher mean volume densities of syncytial knots in the study group (0.4755 ± 0.04) compared to the controls (0.3342 ± 0.04, p = 0.0219). Syncytial denudation was increased in the study group (0.8113 ± 0.09) relative to the controls (0.1975 ± 0.08, p < 0.0001). Foetal capillary volume density was also significantly elevated in the study group (5.1010 ± 0.32) compared to the controls (3.562 ± 0.47, p < 0.0001). In contrast, intervillous space volume was significantly reduced in the study group (9.5810 ± 0.05) compared to the controls (11.593 ± 0.26, p = 0.0053). Neonates of exposed mothers showed a non-significant reduction in birthweight. Conclusion: Salmonella Typhi exposure in pregnancy induces subtle, yet significant alterations in placental architecture, compromising villous integrity and vascular organisation. Although birthweight may appear unaffected, the observed changes point to reduced placental efficiency and merit further research into their developmental consequences and long-term effects on babies. Full article

The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to major obstetric pathologies, including placenta accreta spectrum, early onset preeclampsia, and fetal growth restriction. Characterization of the normal differentiation processes is, thus, essential for the analysis of these pathologies. Our gene expression analysis, employing purified human CTB and EVT cells, demonstrates a mechanism similar to the epithelial–mesenchymal transition (EMT), which underlies CTB–EVT differentiation. In parallel, DNA methylation profiling shows that CTB cells, already hypomethylated relative to non-trophoblast cell lineages, show further genome-wide hypomethylation in the transition to EVT. A small subgroup of genes undergoes gains of methylation (GOM), associated with differential gene expression (DE). Prominent in this GOM-DE group are genes involved in epithelial–mesenchymal plasticity (EMP). An exemplar is the transcription factor RUNX1, for which we demonstrate a functional role in regulating the migratory and invasive capacities of trophoblast cells. This analysis highlights epigenetically regulated genes acting to underpin the epithelial–mesenchymal plasticity characteristic of human trophoblast differentiation. Identification of these elements provides important information for the obstetric disorders in which these processes are dysregulated. Full article

Background/Objective: Small-for-gestational-age (SGA) status constitutes a significant risk factor for adverse neonatal outcomes and predisposes individuals to long-term health complications. Detecting pregnancies at risk early in gestation could significantly improve perinatal outcomes. Recent evidence suggests that ophthalmic artery Doppler assessment in the first trimester may contribute to the prediction of impaired placentation reflected in increased risk for preeclampsia. This study aimed to investigate the association between first-trimester ophthalmic artery Doppler parameters and the subsequent birth of small-for-gestational-age (SGA) neonates. Methods: In this prospective observational analysis, 4054 pregnant women underwent ophthalmic artery Doppler evaluation at 11–13 weeks gestation. Maternal demographics, biophysical and biochemical markers, and ophthalmic artery Doppler measurements of pulsatility index (PI) and peak systolic velocity (PSV) ratio were obtained. Outcomes were classified based on birthweight into the ≤3rd percentile and >3rd percentile and ≤10th percentile and >10th percentile groups. To determine the predictive value of Doppler indices, statistical methods included comparative analyses and the receiver operating characteristic (ROC) curves. Results: The analysis indicated that increased PSV ratio at 11–13 weeks gestation correlated with an increased risk of SGA. The PI was not found to be a significant discriminator between pregnancies complicated by SGA and non-SGA pregnancies. Conclusions: First-trimester ophthalmic artery Doppler assessment offers promise as a non-invasive technique for the early identification of pregnancies at risk for SGA neonates. Further validation through large, multicenter studies is needed to confirm its utility and to standardize its use in clinical protocols. Full article

Background: The World Health Organization (WHO) defines stillbirth as the loss of a fetus after 28 weeks of gestation. Annually, approximately 2 million stillbirths occur worldwide. Projections indicate that by 2030, this figure could rise to nearly 15.9 million, with half of these stillbirths expected to take place in Sub-Saharan Africa. In the global literature, causes include placental complications, birth defects, and maternal health issues, though often the cause is unknown. Stillbirths have significant emotional and financial impacts on families. Methods: The process involves using chi-square tests to identify candidate covariates for model building. The relative risk (RR) measures the association between variables using the sample data of 1435 mothers collected retrospectively. Since these tests are independent, covariates might be interrelated. The unadjusted RR from the bivariate analysis is then refined using stepwise logistic regression, guided by the Akaike Information Criterion (AIC), to select the best subset of covariates among the candidate variables. The logistic model’s regression coefficients provide the adjusted RR (aRR), indicating the strength of the association between a factor and stillbirth. Results: The model fit results reveal that heavy bleeding in the second or third trimester increases stillbirth risk by 4.69 times. Other factors, such as water breaking early in the third trimester (aRR = 3.22), severe back pain (aRR = 2.61), and conditions like anemia (aRR = 2.45) and malaria (aRR = 2.74), also heightened the risk. Further, mothers with a history of hypertension faced a 3.89-times-greater risk, while multifetal pregnancies increased risk by over 6 times. Conversely, proper mental and physical relaxation could reduce stillbirth risk by over 60%. Additionally, mothers aged 20 to 35 had a 40% lower risk than younger or older mothers. Conclusions: This research study identifies the significant predictors for forecasting stillbirth in pregnant women, and the results could help in the development of health monitoring strategies during pregnancy to reduce stillbirth risks. The research findings further support the importance of targeted interventions for high-risk groups. Full article

The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin, as well as the placental transfer of enrofloxacin and ciprofloxacin, have not been studied. The aims of this study were (1) to evaluate the pharmacokinetics of enrofloxacin and ciprofloxacin by intravenous and intramuscular administration of 7.5 mg/kg in pregnant goats; (2) to determine the placental transfer of enrofloxacin and ciprofloxacin; (3) to conduct a PK/PD analysis to calculate the PK/PD cutoff of different dose regimens; and (4) to evaluate the tentative epidemiological cutoff values for coagulase-negative staphylococci wild-type isolates from goats. Plasmatic concentrations of enrofloxacin and ciprofloxacin in pregnant goats were well described by the parent–metabolite model. Simultaneous modeling of enrofloxacin and ciprofloxacin in each individual allowed for a PK/PD analysis that considered both drugs with antimicrobial activity. Our results show that both enrofloxacin and ciprofloxacin crossed the placenta in goats: fetal/maternal concentration ratio were 0.58 ± 0.05 and 0.03 ± 0.01 for enrofloxacin and ciprofloxacin. MIC values of coagulase-negative staphylococci isolates (n = 90) were obtained, and tentative epidemiological cutoffs were calculated at 0.25 and 0.5 mg/L for enrofloxacin and ciprofloxacin. According to PK/PDco values, an intravenous dose regimen of 10 mg/kg/day was considered the most appropriate, but based on the PK/PDco, culture, and AST data, an effective dosing regimen with the lowest possible dose could be selected to minimize the potential risk of fetal exposure to enrofloxacin. Full article

Genomic imprinting is critical for mammalian development, but its regulation varies across species. The insulin-like growth factor 2 receptor (IGF2R), which is a maternally expressed imprinted gene critical for cell proliferation and differentiation, as well as embryonic and placental development, is classically regulated by differentially methylated regions (DMRs) and lncRNA-Airn in mice. However, studies on this in equus are scarce, especially in terms of mechanistic studies. In the present study, heart, liver, spleen, lung, kidney, brain, and muscle samples were obtained from horses, donkeys, and hybrids, and gene expression and imprinting state were tested to investigate the imprinting regulation of Igf2r in these animals. Bisulfite sequencing combined with an allele-specific expression analysis revealed a tissue-specific loss of imprinting in the mule liver and hybrid brain tissues. Strikingly, we found that the maternal-specific expression of equine Igf2r did not rely on the canonical DMRs or lncRNA-Airn. Surprisingly, DNA methylation of a specific region called CpG island 2 (CpGI2) in the Igf2r promoter showed cis-acting inheritance, meaning that the DNA methylation patterns of the parental alleles are retained in hybrid tissues. Notably, the DNA methylation of CpGI2 correlated negatively with Igf2r expression in the spleen (R² = 0.8797, p = 6.46 × 10⁻⁶), lung (R² = 0.8569, p = 1.57 × 10⁻⁵), and kidney (R² = 0.8650, p = 3.85 × 10⁻⁶). Our findings suggest that imprinting may work differently in other species. This study provides a framework for understanding imprinting diversity in hybrids and shows that equine hybrids can be used to study how epigenetic inheritance works. Full article