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Journal of Neuroinflammation Jan 2024Preterm birth is often associated with chorioamnionitis and leads to increased risk of neurodevelopmental disorders, such as autism. Preterm birth can lead to cerebellar...
BACKGROUND
Preterm birth is often associated with chorioamnionitis and leads to increased risk of neurodevelopmental disorders, such as autism. Preterm birth can lead to cerebellar underdevelopment, but the mechanisms of disrupted cerebellar development in preterm infants are not well understood. The cerebellum is consistently affected in people with autism spectrum disorders, showing reduction of Purkinje cells, decreased cerebellar grey matter, and altered connectivity.
METHODS
Preterm rhesus macaque fetuses were exposed to intra-amniotic LPS (1 mg, E. coli O55:B5) at 127 days (80%) gestation and delivered by c-section 5 days after injections. Maternal and fetal plasma were sampled for cytokine measurements. Chorio-decidua was analyzed for immune cell populations by flow cytometry. Fetal cerebellum was sampled for histology and molecular analysis by single-nuclei RNA-sequencing (snRNA-seq) on a 10× chromium platform. snRNA-seq data were analyzed for differences in cell populations, cell-type specific gene expression, and inferred cellular communications.
RESULTS
We leveraged snRNA-seq of the cerebellum in a clinically relevant rhesus macaque model of chorioamnionitis and preterm birth, to show that chorioamnionitis leads to Purkinje cell loss and disrupted maturation of granule cells and oligodendrocytes in the fetal cerebellum at late gestation. Purkinje cell loss is accompanied by decreased sonic hedgehog signaling from Purkinje cells to granule cells, which show an accelerated maturation, and to oligodendrocytes, which show accelerated maturation from pre-oligodendrocytes into myelinating oligodendrocytes.
CONCLUSION
These findings suggest a role of chorioamnionitis on disrupted cerebellar maturation associated with preterm birth and on the pathogenesis of neurodevelopmental disorders among preterm infants.
Topics: Infant, Newborn; Female; Infant; Animals; Humans; Pregnancy; Hedgehog Proteins; Macaca mulatta; Chorioamnionitis; Premature Birth; Escherichia coli; Infant, Premature; Cerebellum; RNA, Small Nuclear
PubMed: 38200558
DOI: 10.1186/s12974-024-03012-y -
Frontiers in Immunology 2024Rupture of the gestational membranes often precedes major pregnancy complications, including preterm labor and preterm birth. One major cause of inflammation in the...
INTRODUCTION
Rupture of the gestational membranes often precedes major pregnancy complications, including preterm labor and preterm birth. One major cause of inflammation in the gestational membranes, chorioamnionitis (CAM) is often a result of bacterial infection. The commensal bacterium , or Group B (GBS) is a leading infectious cause of CAM. Obesity is on the rise worldwide and roughly 1 in 4 pregnancy complications is related to obesity, and individuals with obesity are also more likely to be colonized by GBS. The gestational membranes are comprised of several distinct cell layers which are, from outermost to innermost: maternally-derived decidual stromal cells (DSCs), fetal cytotrophoblasts (CTBs), fetal mesenchymal cells, and fetal amnion epithelial cells (AECs). In addition, the gestational membranes have several immune cell populations; macrophages are the most common phagocyte. Here we characterize the effects of palmitate, the most common long-chain saturated fatty acid, on the inflammatory response of each layer of the gestational membranes when infected with GBS, using human cell lines and primary human tissue.
RESULTS
Palmitate itself slightly but significantly augments GBS proliferation. Palmitate and GBS co-stimulation synergized to induce many inflammatory proteins and cytokines, particularly IL-1β and matrix metalloproteinase 9 from DSCs, CTBs, and macrophages, but not from AECs. Many of these findings are recapitulated when treating cells with palmitate and a TLR2 or TLR4 agonist, suggesting broad applicability of palmitate-pathogen synergy. Co-culture of macrophages with DSCs or CTBs, upon co-stimulation with GBS and palmitate, resulted in increased inflammatory responses, contrary to previous work in the absence of palmitate. In whole gestational membrane biopsies, the amnion layer appeared to dampen immune responses from the DSC and CTB layers (the choriodecidua) to GBS and palmitate co-stimulation. Addition of the monounsaturated fatty acid oleate, the most abundant monounsaturated fatty acid in circulation, dampened the proinflammatory effect of palmitate.
DISCUSSION
These studies reveal a complex interplay between the immunological response of the distinct layers of the gestational membrane to GBS infection and that such responses can be altered by exposure to long-chain saturated fatty acids. These data provide insight into how metabolic syndromes such as obesity might contribute to an increased risk for GBS disease during pregnancy.
Topics: Humans; Female; Streptococcus agalactiae; Pregnancy; Interleukin-1beta; Streptococcal Infections; Chorioamnionitis; Palmitates; Extraembryonic Membranes; Toll-Like Receptor 2
PubMed: 38855112
DOI: 10.3389/fimmu.2024.1409378 -
Archives of Gynecology and Obstetrics Jul 2024Spontaneous previable rupture of membranes complicates approximately 0.4-0.7% of pregnancies and is associated with severe maternal and neonatal morbidity and mortality.... (Review)
Review
Spontaneous previable rupture of membranes complicates approximately 0.4-0.7% of pregnancies and is associated with severe maternal and neonatal morbidity and mortality. Intra-amniotic inflammation is present in up to 94.4% of cases, most often caused by a bacterial infection. In comparison, the effectiveness of antibiotic therapy in its eradication reaches less than 17%. Inflammatory activity in the amniotic cavity disrupts the physiological development of the fetus with an increase in maternal, fetal, and neonatal inflammatory morbidity through the development of fetal inflammatory response syndrome, maternal chorioamnionitis, and neonatal sepsis. Amniopatch is an invasive therapeutic technique based on intra-amniotic administration of maternal hemoderivates in the form of thromboconcentrate and plasma cryoprecipitate to provide the temporary closure of the fetal membranes defect and secondary restitution of normohydramnios with correction of pressure-volume ratios. The supposed basis of this physical-mechanical action is the aggregation of coagulant components of amniopatch in the area of the defect with the formation of a valve cap. The background for the formulation of the hypothesis on the potential anti-infectious and anti-inflammatory action of non-coagulant components of amniopatch involved: i) clinical-academic and publishing outputs of the authors based on their many years' experience with amniopatch application in the treatment of spontaneous previable rupture of membranes (2008-2019), ii) the documented absence of clinically manifested chorioamnionitis in patients treated this way with a simultaneously reduced incidence of neonatal respiratory distress syndrome compared to expectant management (tocolysis, corticotherapy, antibiotic therapy). The non-coagulant components of plasma cryoprecipitate include mainly naturally occurring isohemagglutinins, albumin, and soluble plasma fibrinogen. Although these components of the amniopatch have not been attributed a significant therapeutic role, the authors assume that due to their opsonizing and aggregative properties, they can significantly participate in optimizing the intrauterine environment through the reduction in bacterial and cytokine charge in the amniotic fluid. The authors think these facts constitute a vital stimulus to future research-academic activity and, at the same time, an idea for reconsidering the therapeutic role of amniopatch as a tool for improving perinatal results of spontaneous previable ruptures of membranes.
Topics: Humans; Pregnancy; Female; Fetal Membranes, Premature Rupture; Fibrinogen; Chorioamnionitis; Anti-Inflammatory Agents; Infant, Newborn; Anti-Infective Agents; Factor VIII
PubMed: 38642127
DOI: 10.1007/s00404-024-07399-0 -
International Journal of Molecular... May 2024Danger-associated molecular patterns (DAMPs) are elevated within the amniotic cavity, and their increases correlate with advancing gestational age, chorioamnionitis, and...
Danger-associated molecular patterns (DAMPs) are elevated within the amniotic cavity, and their increases correlate with advancing gestational age, chorioamnionitis, and labor. Although the specific triggers for their release in utero remain unclear, it is thought that they may contribute to the initiation of parturition by influencing cellular stress mechanisms that make the fetal membranes (FMs) more susceptible to rupture. DAMPs induce inflammation in many different tissue types. Indeed, they precipitate the subsequent release of several proinflammatory cytokines that are known to be key for the weakening of FMs. Previously, we have shown that in vitro stretch of human amnion epithelial cells (hAECs) induces a cellular stress response that increases high-mobility group box-1 (HMGB1) secretion. We have also shown that cell-free fetal DNA (cffDNA) induces a cytokine response in FM explants that is fetal sex-specific. Therefore, the aim of this work was to further investigate the link between stretch and the DAMPs HMGB1 and cffDNA in the FM. These data show that stretch increases the level of cffDNA released from hAECs. It also confirms the importance of the sex of the fetus by demonstrating that female cffDNA induced more cellular stress than male fetuses. Our data treating hAECs and human amnion mesenchymal cells with HMGB1 show that it has a differential effect on the ability of the cells of the amnion to upregulate the proinflammatory cytokines and propagate a proinflammatory signal through the FM that may weaken it. Finally, our data show that sulforaphane (SFN), a potent activator of Nrf2, is able to mitigate the proinflammatory effects of stretch by decreasing the levels of HMGB1 release and ROS generation after stretch and modulating the increase of key cytokines after cell stress. HMGB1 and cffDNA are two of the few DAMPs that are known to induce cytokine release and matrix metalloproteinase (MMP) activation in the FMs; thus, these data support the general thesis that they can function as potential central players in the normal mechanisms of FM weakening during the normal distension of this tissue at the end of a normal pregnancy.
Topics: Humans; HMGB1 Protein; Female; Pregnancy; Inflammation; Extraembryonic Membranes; Cell-Free Nucleic Acids; Male; Amnion; Cytokines; Epithelial Cells; Cells, Cultured; Alarmins
PubMed: 38791199
DOI: 10.3390/ijms25105161 -
Early Human Development Nov 2023To compare the neonatal outcomes of early preterm births according to delivery indications and determine the obstetric risk factors associated with adverse outcomes.
OBJECTIVE
To compare the neonatal outcomes of early preterm births according to delivery indications and determine the obstetric risk factors associated with adverse outcomes.
METHODS
We retrospectively studied pregnancies delivered between 22 + 0 and 26 + 6 weeks at the tertiary center between April 2013 and April 2022. Stillbirths, elective termination of pregnancy, and multifetal pregnancies were excluded. Patients were classified into two groups according to delivery indications: spontaneous preterm birth (sPTB) due to premature rupture of membranes (PROM), preterm labor, or acute cervical insufficiency; and indicated preterm birth (iPTB). Obstetric and neonatal outcomes were compared between the groups.
RESULTS
Of the 121 neonates, 73 % (88/121) underwent sPTB. The overall survival rates were 73 % and 49 % in the sPTB and iPTB groups, respectively (p = 0.017). Multivariate logistic regression analysis was performed with adjustment for gestational age at delivery, fetal growth restriction, cesarean section, histological chorioamnionitis, and funisitis. Moreover, in the 1-year follow-up, the proportion of body mass below the third percentile was significantly higher in the iPTB-group than in the sPTB-group (53 % vs. 20 %, p = 0.019). Furthermore, diagnoses of developmental delay and cerebral palsy were slightly higher in the iPTB-group (33 % and 20 %, respectively) than in the sPTB-group (27 % and 9 %, respectively); however, this difference was not statistically significant.
CONCLUSIONS
In early preterm births, iPTB was associated with a higher neonatal mortality than sPTB.
Topics: Humans; Pregnancy; Infant, Newborn; Female; Premature Birth; Retrospective Studies; Cesarean Section; Obstetric Labor, Premature; Chorioamnionitis; Gestational Age
PubMed: 37844515
DOI: 10.1016/j.earlhumdev.2023.105873 -
Poultry Science Feb 2024The study aimed to analyze the biological value of eggs and extra-embryonic structures affecting pheasant hatchability depending on the eggshell's color. Eggs (1,415)...
The study aimed to analyze the biological value of eggs and extra-embryonic structures affecting pheasant hatchability depending on the eggshell's color. Eggs (1,415) from 62-wk-old pheasants were used. The quality of fresh blue (BL), brown (BR), and green (G) eggs were analyzed. Incubation lasted for 25 d. Thick albumen (d 0, 1, 7, 14), amniotic fluid (d 14, 18), and the yolk (d 0-14) were collected. The pH, viscosity, lysozyme activity, crude protein (CP) content in albumen and amnion, pH, vitelline membrane strength, and fatty acids (FA) content in the yolk were performed. The lowest hatchability was in the BL group, and the highest was in the G group. BL group showed lower eggshell thickness and strength and higher egg weight. In thick albumen and amniotic fluid, the pH decreased with the incubation. In the yolk, there was an increasing trend (P = 0.015), with a decrease on d 18 (P < 0.001). The vitelline membrane strength decreased after 1 d of incubation, excluding BR eggs (P < 0.001). Thick albumen viscosity was higher on d 14 in the G group than in other dates and groups, the lowest in amniotic fluid, and slightly higher in BL and BR eggs. On d 18, amniotic fluid viscosity increased (P < 0.001). The lowest viscosity was indicated in BL eggs (P < 0.001). The lysozyme activity in thick albumen on d 14 was the highest (uniquely in BR and G groups), and the lowest values were found in amniotic fluid on d 14; after four d, the activity increased (P < 0.001). The CP content was higher in the BL group on d 14. In amnion, on d 14, the CP content was the lowest (<1%) and increased on d 18 (P < 0.001). There was a higher FA content (especially UFA) in the G group and a decrease in FA content after d 14 (P < 0.001). It was found that eggs with green eggshells have the highest biological value, and blue eggs are the least useful for incubation.
Topics: Animals; Chickens; Egg Shell; Muramidase; Ovum; Meat; Albumins; Quail; Fatty Acids; Eggs; Egg Yolk
PubMed: 38134460
DOI: 10.1016/j.psj.2023.103338 -
Journal of Biomaterials Applications Jul 2024The reparative properties of amniotic membrane allografts are well-suited for a broad spectrum of specialties. Further enhancement of their utility can be achieved by...
The reparative properties of amniotic membrane allografts are well-suited for a broad spectrum of specialties. Further enhancement of their utility can be achieved by designing to the needs of each application through the development of novel processing techniques and tissue configurations. As such, this study evaluated the material characteristics and biological properties of two PURION processed amniotic membrane products, a lyophilized human amnion, intermediate layer, and chorion membrane (LHACM) and a dehydrated human amnion, chorion membrane (DHACM). LHACM is thicker; therefore, its handling properties are ideal for deep, soft tissue deficits; whereas DHACM is more similar to a film-like overlay and may be used for shallow defects or surgical on-lays. Characterization of the similarities and differences between LHACM and DHACM was conducted through a series of and studies relevant to the healing cascade Compositional analysis was performed through histological staining along with assessment of barrier membrane properties through equilibrium dialysis. cellular response was assessed in fibroblasts and endothelial cells using cell proliferation, migration, and metabolic assays. The cellular response was assessed in an athymic nude mouse subcutaneous implantation model. The results indicated the PURION process preserved the native membrane structure, nonviable cells and collagen distributed in the individual layers of both products. Although, LHACM is thicker than DHACM, a similar composition of growth factors, cytokines, chemokines and proteases is retained and consequently elicit comparable and cellular responses. In culture, both treatments behaved as potent mitogens, chemoattractants and stimulants, which translated to the promotion of cellular infiltration, neocollagen deposition and angiogenesis in a murine model. PURION processed LHACM and DHACM differ in physical properties but possess similar and activities highlighting the impact of processing method on the versatility of clinical use of amniotic membrane allografts.
Topics: Chorion; Amnion; Animals; Humans; Mice; Mice, Nude; Allografts; Wound Healing; Cell Proliferation; Biocompatible Materials; Female; Fibroblasts; Materials Testing; Cell Movement
PubMed: 38616137
DOI: 10.1177/08853282241246034 -
Fukushima Journal of Medical Science Nov 2023The incidence of Acinetobacter infections has increased in recent years. Acinetobacter infections are resistant to most antibiotics and can be found in hospitalized...
The incidence of Acinetobacter infections has increased in recent years. Acinetobacter infections are resistant to most antibiotics and can be found in hospitalized patients. Pregnancies complicated by severe sepsis or septic shock are associated with a higher rate of preterm labor and delivery, fetal infection, and operative delivery. This case report describes septic shock due to Acinetobacter lwoffii infection in the 31st week of gestation. A 47-year-old woman, with a gestation of 31 weeks and one day, presented with a fever, and signs of bacterial infection on laboratory tests. Although the patient was started on tazobactam/piperacillin, she went into septic shock, and was transferred to our hospital. Cesarean section was performed at a gestation of 31 weeks and 4 days because of severe maternal pneumonia and non-reassuring fetal status. A. lwoffii was detected in blood cultures collected at the previous hospital, and susceptibility to piperacillin and meropenem to A. lwoffii was confirmed. The pneumonia responded to antibiotic treatment and there were no findings of infection in the neonate. Maternal sepsis is an infrequent but important complication, causing significant maternal and fetal morbidity and fetal and neonatal mortality; therefore, early antibiotic therapy is required to improve the clinical outcome.
Topics: Infant, Newborn; Humans; Pregnancy; Female; Middle Aged; Shock, Septic; Acinetobacter Infections; Cesarean Section; Anti-Bacterial Agents; Piperacillin; Pneumonia
PubMed: 37766560
DOI: 10.5387/fms.2022-43 -
MBio Oct 2023Group B (GBS) colonizes the female reproductive tract (FRT) and causes adverse pregnancy outcomes and invasive disease following vertical transmission to the fetus or...
Group B (GBS) colonizes the female reproductive tract (FRT) and causes adverse pregnancy outcomes and invasive disease following vertical transmission to the fetus or newborn. Despite this major public health burden, the mechanisms of GBS FRT colonization are understudied. A recent transposon sequencing screen identified GBS factors contributing to vaginal colonization and ascending spread, including a putative DNA-cytosine methyltransferase (Dcm). We constructed a Δ deletion strain and confirmed that contributes to murine FRT colonization. Investigation of the evolutionary origin of the gene reveals that it is widely distributed across GBS and is encoded as part of a prophage genome that displays evidence of horizontal transfer between GBS strains. We further show that Dcm contributes to 5mC methylation and global regulation of genes involved in carbohydrate metabolism, transcription regulation, and known adhesins and metabolic factors involved in GBS colonization. Interestingly, GBS genes that are induced in the presence of the highly glycosylated vaginal mucin MUC5B were significantly downregulated in the ∆ mutant. Furthermore, the ∆ mutant exhibited reduced binding to immobilized mucin and was attenuated in its ability to grow on numerous carbon sources including the carbohydrates found on mucins. While the ∆ mutant displayed enhanced clearance from the FRT in wild-type mice, there was no significant difference in mice, indicating that Dcm-mediated regulation requires MUC5B to promote GBS colonization. This is the first report to characterize the impact of a DNA methyltransferase on GBS gene regulation and FRT colonization. IMPORTANCE Group B (GBS) colonizes the female reproductive tract (FRT) in one-third of women, and carriage leads to numerous adverse pregnancy outcomes including the preterm premature rupture of membranes, chorioamnionitis, and stillbirth. The presence of GBS in the FRT during pregnancy is also the largest predisposing factor for the transmission of GBS and invasive neonatal diseases, including pneumonia, sepsis, and meningitis. The factors contributing to GBS colonization are still being elucidated. Here, we show for the first time that GBS transcription is regulated by an orphan DNA cytosine methyltransferase (Dcm). Many GBS factors are regulated by Dcm, especially those involved in carbohydrate transport and metabolism. We show that GBS persistence in the FRT is dependent on the catabolism of sugars found on the vaginal mucin MUC5B. Collectively, this work highlights the regulatory importance of a DNA methyltransferase and identifies both host and bacterial factors required for GBS colonization.
PubMed: 37905908
DOI: 10.1128/mbio.02306-23 -
The Journal of Maternal-fetal &... Dec 2024The present study investigated the relationship between bronchopulmonary dysplasia (BPD) and intra-amniotic infection with species.
OBJECTIVES
The present study investigated the relationship between bronchopulmonary dysplasia (BPD) and intra-amniotic infection with species.
METHODS
This was a single-center, retrospective cohort study. Patients with singleton pregnancies who underwent inpatient management at our department for preterm premature rupture of membranes (PPROM), preterm labor, cervical insufficiency, and asymptomatic cervical shortening at 22-33 gestational weeks were included. Amniocentesis was indicated for patients with PPROM or an elevated maternal C-reactive protein level (≥0.58 mg/dL). Patients with an amniotic fluid IL-6 concentration ≥3.0 ng/mL were diagnosed with intra-amniotic inflammation, while those with positive aerobic, anaerobic, , and spp. cultures were diagnosed with microbial invasion of the amniotic cavity (MIAC). Patients who tested positive for both intra-amniotic inflammation and MIAC were considered to have intra-amniotic infection. An umbilical vein blood IL-6 concentration >11.0 pg/mL indicated fetal inflammatory response syndrome (FIRS). The maternal inflammatory response (MIR) and fetal inflammatory response (FIR) were staged using the Amsterdam Placental Workshop Group Consensus Statement.
RESULTS
Intra-amniotic infection with spp. was diagnosed in 37 patients, intra-amniotic infection without spp. in 28, intra-amniotic inflammation without MIAC in 58, and preterm birth without MIR/FIR and FIRS in 86 as controls. Following an adjustment for gestational age at birth, the risk of BPD was increased in patients with intra-amniotic infection with spp. (adjusted odds ratio: 10.5; 95% confidence interval: 1.55-71.2), but not in those with intra-amniotic infection without spp. or intra-amniotic inflammation without MIAC.
CONCLUSION
BPD was only associated with intra-amniotic infection with species.
Topics: Pregnancy; Infant, Newborn; Humans; Female; Ureaplasma; Chorioamnionitis; Retrospective Studies; Bronchopulmonary Dysplasia; Prevalence; Interleukin-6; Prenatal Exposure Delayed Effects; Placenta; Premature Birth; Fetal Membranes, Premature Rupture; Amniotic Fluid; Inflammation
PubMed: 38418200
DOI: 10.1080/14767058.2024.2320670