Placental Cultures Research Articles

Periconceptional exposure to lopinavir, but not darunavir, impairs decidualization: a potential mechanism leading to poor birth outcomes in HIV-positive pregnancies.

Periconceptional exposure to lopinavir, but not darunavir, impairs decidualization: a potential mechanism leading to poor birth outcomes in HIV-positive pregnancies.

Can vitamin C and interleukin 6 levels predict preterm premature rupture of membranes: evaluating possibilities in North Indian population.

ObjectiveWe aimed to evaluate the relation between plasma ascorbic acid levels and the occurrence of preterm premature rupture of membranes (PPROM) and whether patients with ascorbic acid deficiency have predisposition to microbial invasion, as revealed by serum interleukin-6 (IL-6) levels and confirmed by placental culture sensitivity evaluation.MethodsThis controlled study involved 50 women with PPROM at gestational age between 28 and 36.6 weeks. Fifty patients with uncomplicated pregnancy and intact membranes were observed as control group. Serum ascorbic acid and IL-6 levels were evaluated for PPROM group subjects and controls, matched by their gestational age and body mass index. Repeat samples for IL-6 were taken after 48 hours of admission in PROM group subjects and at the onset of labor in controls. Placental membranes were sent for culture sensitivity evaluation after delivery.ResultsThe mean plasma level of ascorbic acid was 0.60±0.35 mg/dL and 1.18±0.43 mg/dL in the PPROM and control groups, respectively, showing significant difference. Plasma IL-6 level rose from 18.18±5.94 pg/mL to 34.32±7.31 pg/mL after 48 hours of admission in the PPROM group (P=0.000). Plasma IL-6 level in controls rose from 5.59±4.36 pg/mL at admission to 7.36±3.67 pg/mL at the onset of labor. Membrane culture test results were positive in a total of 40 samples, of which 37 samples were from the PPROM group subjects.ConclusionVitamin C deficiency, when complemented with elevated serum IL-6 level, can predict susceptibility to PPROM in the third trimester; the risk increases in women with prior history of similar pathology.

Schinus terebenthifolius Raddi extracts: From sunscreen activity toward protection of the placenta to Zika virus infection, new uses for a well-known medicinal plant

Schinus terebinthifolius Raddi is a well-known medicinal plant native of South America. This species has demonstrated important biological activities such as antihypertensive and vasodilator, antimicrobial, anti-inflammatory and antioxidant. However, no studies have been, so far, reported with the fruits of S. terebinthifolius as a protector of the placenta against Zika virus infection and as sunscreen agents. The present study aimed to investigate new uses for the ethanolic fruit extracts of S. terebinthifolius, from fruits’peel (STPE) and from the whole fruits (STWFE). Zika virus (ZIKV) has been linked to several fetal malformations, such as microcephaly and other central nervous system abnormalities. Thus, the potential of these natural extracts against ZIKV infection was evaluated, using an in vitro method. The photoprotective potential, determined by spectrometry, along with phenolic content, antioxidant capacity, and chemical composition of both extracts were also evaluated. The chemical composition of the extracts was evaluated by HPLC-UV / vis. The cytotoxicity of peel and whole fruit extracts in vero E6 cell lines, in placental cell lines and placental explant cultures were evaluated by the MTT assay. The infectivity of placental cells and explants was evaluated by qRT-PCR and the effects of extracts on ZIKV infection were investigated using HTR-8/SVneo cells, pre-treated with 100 μg mL−1 of STWFE for 1 h, and infected with MR766 (AD) or PE243 (EH) ZIKV strains. STFE and STWFE were well-tolerated by both placental-derived trophoblast cell line HTR-8/SVneo as well as by term placental chorionic villi explants, which indicate absence of cytotoxicity in all analysed concentrations. Two strains of ZIKV were tested to access if pre-treatment of trophoblast cells with the STWFE would protect them against infection. Flow cytometry analysis revealed that STWFE extract greatly reduced ZIKV infection. The extracts were also photoprotective with SPF values equivalent to the standard, benzophenone-3. The formulations prepared in different concentrations of the extracts (5–10 %) had shown maximum SPF values of 32.21. STWFE represents a potential natural mixture to be used in pregnancy in order to restrain placental infection by ZIKV and might potentially protect fetus against ZIKV-related malformations. The extracts exhibited photoprotective activity and some of the phenolic compounds, mainly resveratrol, catechin and epicatechin, are active ingredients in all assayed activities. The development of biotechnological/medical products, giving extra value to products from family farming, is expected, with strong prospects for success.

The effect of meconium-stained amniotic fluid on perinatal outcome in pregnancies complicated by preterm premature rupture of membranes.

To determine whether meconium-stained amniotic fluid (MSAF) encountered in pregnancies complicated by preterm premature rupture of membranes (PPROM) is associated with adverse maternal and perinatal outcome. A retrospective cohort study of all singleton pregnancies with PPROM and MSAF who delivered in a tertiary hospital at 24 + 0-36 + 6weeks of gestation between 2007 and 2017. Women with PPROM-MSAF (study group) were compared to women with PPROM and clear amniotic fluid (control group). Controls were matched to cases according to age, gravidity, parity and gestational age at delivery in a 3:1 ratio. Primary outcome was defined as neonatal intensive care unit admission. Secondary outcomes were neonatal adverse outcomes, chorioamnionitis and placental abruption diagnosed clinically or by placental cultures and histology. Seventy-five women comprised the study group and were matched to 225 women representing the control group. A significantly higher rate of neonatal intensive care unit admissions was noted in the study group compared to controls (61.3% vs. 45.7%, p = 0.03). Multivariate analysis demonstrated that MSAF is an independent risk factor for neonatal intensive care unit admission (adjusted OR = 2.82, 95% CI 1.39-5.75, p = 0.004). MSAF was found to be associated to higher rates of cesarean and operative vaginal deliveries (30.7% vs. 24.4% and 5.3% vs. 2.7%, p = 0.057, respectively) as well as to chorioamnionitis and placental abruption (33.3% vs. 19.3%, p = 0.034 and 16.0% vs. 7.7%, p = 0.021, respectively). MSAF is associated with higher frequencies of adverse perinatal outcome when compared to clear amniotic fluid in pregnancies complicated by PPROM.

Upregulation of pannexin-1 hemichannels explains the apparent death of the syncytiotrophoblast during human placental explant culture

BackgroundIt has been reported that during the culture of human placental explants, the syncytiotrophoblast dies between 3 and 24 h and is then replaced within 48 h by a new syncytiotrophoblast layer formed by the fusion of underlying cytotrophoblasts. Most frequently the death of the syncytiotrophoblast is indicated by the uptake of nuclear stains such as propidium iodide (PI). This process is reportedly similar in both early and late gestation placental explants. MethodsWe cultured first trimester placental explants for up to 48 h and tested membrane intactness by exposure to PI. Connexin and pannexin mRNAs were quantified by RT-PCR and protein levels determined by immunofluorescence. The syncytiotrophoblast membrane leak was determined by culturing explants in the presence of hemichannel blockers. Extrusion of extracellular vesicles from the syncytiotrophoblast was quantified. ResultsNuclei of the syncytiotrophoblast were stained with PI following approximately 4 h of culture and this was prevented by culturing the explants with pannexin-1 blockers. Expression of pannexin-1 hemichannels increased during explant culture (p = 0.0027). Extracellular vesicles were most abundantly extruded from the explants during the first 3 h of culture and the temporal pattern of extrusion was unaltered by blocking hemichannels. DiscussionWe show the mechanism of uptake of nuclear non-viability stains into the syncytiotrophoblast during explant culture is via upregulation of pannexin 1 hemichannels. Contrary to suggestions by some, the production of extracellular vesicles from cultured placental explants is not an in vitro artefact resulting from the apparent death of the syncytiotrophoblast in explant cultures.

Endoplasmic reticulum stress occurs in association with the extrusion of toxic extracellular vesicles from human placentae treated with antiphospholipid antibodies.

Antiphospholipid autoantibodies (aPLs), a major maternal risk factor for preeclampsia, are taken into the syncytiotrophoblast where they bind intracellular vesicles and mitochondria. Subsequently, large quantities of extracellular vesicles (EVs) extruded from syncytiotrophoblast into the maternal circulation are altered such that they cause maternal endothelial cell activation. However, the mechanism driving this change is unknown. First trimester placental explants were treated with aPL for 18 h. The EVs were then collected by different centrifugation. The levels of HSP 70, misfolded proteins, caspase 8 activity, and Mixed Lineage Kinase domain-Like (MLKL) were measured in placental explants and EVs. In addition, the levels of TNF-α and CD95 in conditioned medium were also measured. Treating placental explants with aPL caused an increase in levels of HSP 70, misfolded proteins and MLKL in placental explants and EVs. Increased activity of caspase 8 was also seen in placental explants. Higher levels of TNF-α were seen conditioned medium from aPL-treated placental explant cultures. aPLs appear to induce endoplasmic reticulum stress in the syncytiotrophoblast in a manner that involved caspase 8 and TNF-α. To avoid accumulation of the associated misfolded proteins and MLKL, the syncytiotrophoblast exports these potentially dangerous proteins in EVs. It is likely that the dangerous proteins that are loaded into placental EVs in preeclampsia contribute to dysfunction of the maternal cells.

Palmitic acid activates NLRP3 inflammasome and induces placental inflammation during pregnancy in mice.

Maternal obesity is one of the major risk factors for pregnancy complications and is associated with low-grade chronic systemic inflammation due to higher levels of pro-inflammatory cytokines such as interleukin (IL)-1β. Pregnant women with obesity have abnormal lipid profiles, characterized by higher levels of free fatty acids, especially palmitic acid (PA). Previously, we reported that PA stimulated IL-1β secretion via activation of NLRP3 inflammasome in human placental cells. These observations led us to hypothesize that higher levels of PA induce NLRP3 inflammasome activation and placental inflammation, resulting in pregnancy complications. However, the effects of PA on NLRP3 inflammasome during pregnancy in vivo remain unclear. Therefore, PA solutions were administered intravenously into pregnant mice on day 12 of gestation. Maternal body weight was significantly decreased and absorption rates were significantly higher in PA-injected mice. The administration of PA significantly increased IL-1β protein and the mRNA expression of NLRP3 inflammasome components (NLRP3,ASC, and caspase-1) within the placenta. In murine placental cell culture, PA significantly stimulated IL-1β secretion, and this secretion was suppressed by a specific NLRP3 inhibitor (MCC950). Simultaneously, the number of macrophages/monocytes and neutrophils, together with the mRNA expression of these chemokines increased significantly in the placentas of PA-treated mice. Treatment with PA induced ASC assembling and IL-1β secretion in macrophages, and this PA-induced IL-1β secretion was significantly suppressed in NLRP3-knockdown macrophages. These results indicate that transient higher levels of PA exposure in pregnant mice activates NLRP3 inflammasome and induces placental inflammation, resulting in the incidence of absorption.

Localization of Indoleamine 2,3-Dioxygenase-1 and Indoleamine 2,3-Dioxygenase-2 at the Human Maternal-Fetal Interface

Immunohistochemical localization of indoleamine 2,3-dioxygenase-1 and indoleamine 2,3-dioxygenase-2, the first and rate-limiting enzyme in tryptophan metabolism along the kynurenine pathway, has been studied in order to better understand the physiological significance of these enzymes at the maternal-fetal interface of human pregnancy with a gestational age of 7 weeks (n = 1) and term placentas (37-40 weeks of gestation, n = 5). Indoleamine 2,3-dioxygenase-1 protein immunoreactivity was found in glandular epithelium of the decidua and the endothelium of the fetal blood vessels in the villous stroma with some additional positive cells in the villous core and in the decidua. The syncytiotrophoblast stained strongly for indoleamine 2,3-dioxygenase-2. Immunoreactivity of kynurenine, the immediate downstream product of indoleamine 2,3-dioxygenase-mediated tryptophan metabolism, showed the same localization as that of indoleamine 2,3-dioxygenase-1 and indoleamine 2,3-dioxygenase-2, suggesting these are functional enzymes. Interferon-γ added to placental villous explant culture markedly stimulated expression level of both mRNA and immunoreactivity of indoleamine 2,3-dioxygenase-1. The different cellular expression and interferon-γ sensitivity of these enzymes at the maternal-fetal interface suggests distinct physiological roles for each enzyme in normal human viviparity.

Biomimetic Micropatterned Adhesive Surfaces To Mechanobiologically Regulate Placental Trophoblast Fusion.

The placental syncytiotrophoblast is a giant multinucleated cell that forms a tree-like structure and regulates transport between mother and baby during development. It is maintained throughout pregnancy by continuous fusion of trophoblast cells, and disruptions in fusion are associated with considerable adverse health effects including diseases such as preeclampsia. Developing predictive control over cell fusion in culture models is hence of critical importance in placental drug discovery and transport studies, but this can currently be only partially achieved with biochemical factors. Here, we investigate whether biophysical signals associated with budding morphogenesis during development of the placental villous tree can synergistically direct and enhancetrophoblast fusion. We use micropatterning techniques to manipulate physical stresses in engineered microtissues and demonstrate that biomimetic geometries simulating budding robustly enhance fusion and alter spatial patterns of synthesis of pregnancy-related hormones. These findings indicate that biophysical signals play a previously unrecognized and significant role in regulating placental fusion and function, in synergy with established soluble signals. More broadly, our studies demonstrate that biomimetic strategies focusing on tissue mechanics can be important approaches to design, build, and test placental tissue cultures for future studies of pregnancy-related drug safety, efficacy, and discovery.

Patterns of placental antimicrobial resistance in preterm birth before 30 completed weeks gestation complicated by preterm prelabour rupture of membranes.

While many guidelines recommend a 10-day course of oral erythromycin following preterm prelabour rupture of membranes (PPROM) as derived from the ORACLE I trial, evidence is emerging that this may encourage a state of antenatal genital tract dysbiosis. In addition, erythromycin's lack of efficacy toward Gram-negative microorganisms may promote colonisation and infection, conveying more significant unrecognised risk for very and extremely preterm newborns. To define patterns of placental infection or colonisation in newborns born before 30 completed weeks gestation following PPROM. Retrospective cohort study of mother-infant dyads who delivered at<30 completed weeks gestation following PPROM in a South Australian tertiary perinatal centre between January 2012 and December 2015. Main outcome measures included placental and neonatal culture and sensitivities within 72h of delivery and histologic chorioamnionitis. Categorical characteristics were analysed using two-sided Fisher's exact test and numerical characteristics via analysis of variance. During the four years studied, 126 infant-mother dyads were identified. Where a placental swab was taken, 23.9% cultured Gram-negative organisms and the majority (58.8%) were antimicrobial-resistant. Those that received erythromycin had increased incidence of antimicrobial-resistant Gram-negative organisms on placental swab (P=0.02). All cases of neonatal early-onset sepsis (EOS), including two cases of multi-resistant Gram-negative EOS, occurred in those who received erythromycin. The current antibiotic recommendations for PPROM may promote selection of unhindered antimicrobial-resistant Gram-negative organisms and may increase risk of Gram-negative EOS in very and extremely preterm newborns. Further wide-scale examination of antibiotic recommendations in PPROM is necessary.

1516. Early-Onset Neonatal Sepsis Due to Haemophilus influenzae

Background Haemophilus influenzae causes serious invasive disease across all ages, but has not been widely described in neonatal early-onset sepsis (EOS). EOS, likely caused by organisms acquired from the mother, can lead to significant morbidity and mortality, particularly for preterm infants. There are reports of increasing ampicillin resistance in H. influenzae. We describe a case series of EOS due to H. influenzae at our institution.MethodsNeonatal H. influenzae EOS was identified based on positive sterile site cultures at <72 hours of life in infants hospitalized at an Intermountain Healthcare (IHC) facility from 2007–2017. Demographics, clinical and microbiologic data were obtained through an IRB-approved electronic chart and microbiology review.ResultsTwelve neonates with H. influenzae EOS were identified over 11 years. Nine were preterm (<37 weeks); five were extremely preterm (<28 weeks). Eight had low birth weight (<2,500 g); five had very low birth weight (<1,500 g). Most (66%) mothers were primigravida; median maternal age was 24.5 years. Only four (33%) mothers had prolonged rupture of membranes (>24 hours). All infants had signs and symptoms of sepsis within 24 hours of birth. The majority (10/12) had a blood culture positive for H. influenzae from the time of delivery. Two infants had negative delivery blood cultures but a H. influenzae-positive placental culture. No infant had > 1 day of bacteremia. One H. influenzae isolate was serotype b, one serotype c and one non-typeable, but most isolates (9/12) were not serotyped. Only one isolate produced a β-lactamase. All infants were empirically started on ampicillin and gentamicin at delivery. Nine infants underwent lumbar puncture, two were suggestive of meningitis but cultures were negative. Five infants developed interventricular hemorrhage and six required vasoactive medications. No infant died.Conclusion H. influenzae is an infrequent but important cause of neonatal EOS. H. influenzae EOS occurred in infants with known risk factors, including prolonged rupture of membranes, prematurity, and low birth weight. Recognition of H. influenzae as a potential pathogen in EOS has implications for the use of empiric antibiotic therapy particularly ampicillin, in septic neonates.Disclosures All authors: No reported disclosures.

The Contribution of an Infectious Workup in Understanding Stillbirth.

This study was aimed to assess the utility of diagnostic tests of maternal and fetal infection in the evaluation of stillbirth. A single-center retrospective study from January 2011 to December 2016 of all women presenting to the hospital with intrauterine fetal death at or after 20 weeks of gestation. Standard evaluation included review of medical records, clinical and laboratory inflammatory workup, maternal serologies, fetal autopsy, placental pathology, and fetal and placental cultures. A suspected infectious etiology was defined as meeting at least two diagnostic criteria, and only after exclusion of any other identifiable stillbirth cause. During the 7-year study period, 228 cases of stillbirth were diagnosed at our center. An infectious etiology was the suspected cause of stillbirth in 35 cases (15.3%). The mean gestational age of infection-related stillbirth was 28 1/7 (range: 22-37) weeks, while for a noninfectious etiology, it was 34 0/7 (range: 25-38) weeks (p = 0.005). Placental histological findings diagnostic of overt chorioamnionitis and funisitis were observed in 31 (88.5%) cases. In 16 (45.7%) cases the placental and fetal cultures were positive for the same pathogen. Serology of acute infection was positive in three (8.5%) of the cases. Maternal and fetal infectious workup is valuable in the investigation of stillbirth, particularly before 30 weeks of gestation and should be considered a part of standard evaluation.

Non-typeable Haemophilus influenzae-associated early pregnancy loss: an emerging neonatal and maternal pathogen

ObjectivesThere is increasing evidence indicating an association between invasive non-typeable Haemophilus influenzae (NTHi) infection in pregnancy and early pregnancy loss. As the diagnosis relies on microbiological investigation of post-mortem placental and foetal samples, a significant proportion of NTHi-related pregnancy loss remains unrecognised. To better characterise NTHi in septic abortion, we report NTHi cases associated with early pregnancy loss.MethodsWe reviewed all post-mortems at <24 weeks gestation with histologically proven acute chorioamnionitis on placental histology and enrolled cases with at least one matched foetal and placental sample culture positive for NTHi. The study was approved by the NHS Lothian Caldicott Guardian.ResultsIn our cohort, invasive NTHi has accounted for 20% of infections associated with early pregnancy loss prior to 24 weeks gestation. All patients were young and healthy pregnant women at < 20 weeks' gestation who presented with abdominal pain, PV bleed /discharge and were septic at the time of presentation. One patient with previous history of miscarriage who presented with cervical incompetence had more severe pathology suggestive of early intrauterine pneumonia.ConclusionThe burden of invasive NTHi disease in early pregnancy loss is likely to be much larger than currently recognised. NTHi should be considered in pregnant women presenting with abdominal pain and PV bleed/discharge in whom clinical signs of sepsis are present. Active surveillance should be considered in this patient group including septic abortion to capture the true prevalence of this emerging pathogen to inform preventative and therapeutic approaches.

The Effect of Maternal Obesity on Placental Cell-Free DNA Release in a Mouse Model.

The fetal fraction of cell-free DNA (cfDNA) in maternal plasma is decreased in obese women. The underlying mechanism is not well understood. The amount of cfDNA released from the placenta has not been directly examined in maternal obesity. We sought to quantify release of cfDNA from the placenta and fetal membranes in maternal diet-induced obesity using explant cultures in an established mouse model. C57BL6/J females were fed either 60% high-fat diet or 10% fat-matched control diet for 14 weeks prepregnancy and throughout gestation. Placentas and fetal membranes were collected on e18 and randomly allocated to time 0-, 1-, or 6-hour culture times. The CfDNA was isolated from culture media, quantified, and normalized to tissue weight. Placentas from obese dams released significantly less cfDNA compared to those of lean dams at time 0 (45.8 ± 4.3 ng/mg vs 65.6 ± 7.9 ng/mg, P = .02). Absolute cfDNA levels increased with longer placental culture, with no significant differences between obese and lean dams at 1 and 6 hours. Membranes released significantly less cfDNA than did placentas at every time point. Maternal obesity is associated with decreased release of cfDNA from the placenta compared to lean controls immediately after tissue harvest. This may provide an alternative explanation for the lower fetal fraction of cfDNA noted in maternal obesity.

Deep microbial analysis of multiple placentas shows no evidence for a placental microbiome.

To resolve the controversy regarding the presence of a microbiota in the placenta. Classical and molecular microbiological study. All samples were collected during caesarean section. A total of 28 human placentas and six murine placentas. All 28 human placentas were checked for 16S rRNA gene amplification products. Three locations from four selected human placentas and three 'environmental controls' for each placenta were placed in seven culture media. The four selected human placentas were further analysed using Gram stain, immunohistochemistry for bacteria, electron microscopy, and TaqMan RT-qPCR. Six placentas from three SPF mice were cut into four pieces each, and further analysed for 16S rRNA gene amplification. Microbiological and molecular evidence of bacteria. None of the placental cultures used for the full analysis, or their environmental cultures, was positive for bacterial growth. None of the other methods showed any evidence of bacteria. Immunohistochemistry showed negligible bacterial counts. None of the murine placentas showed evidence of 16S rRNA gene amplification. Our results support that the fetal environment in the womb is sterile. Based on the immunohistochemistry and the limit of detection of the other methods used, if a placental microbiome exists, it is of extreme low biomass, and thus its effect on clinical phenotypes is probably minor, if it exists at all. Using several microbiological and molecular methods in parallel, we found no compelling evidence of bacteria in human and mouse placentas.

Tissue factor and thrombomodulin: Determination of mRNA levels in exosomes derived from human placental explant cultures.

Excoriation (skin picking) disorder is included in the DSM-5 in the obsessive compulsive and related disorders category. It is defined as the recurrent urge to touch, scratch, scrape, scrub, rub, squeeze, bite or dig in the skin, leading to skin lesions. It is a rare disorder (1.4–5.4% of the population) and occurs mainly in women.this article reports the case of a 31-year-old female patient, initially assessed by dermatology and orthopaedics for the presence of infected ulcerated lesions on her lower limbs, with other superficial lesions from scratching on her chest, arms, forearms, back and head. The patient also reported symptoms of anxiety, so was assessed by consultation-liaison psychiatry.skin picking, normal behaviour in mammals, becomes pathological from a psychiatric point of view when it is repetitive and persistent, as in the case of excoriation disorder. In view of the reported relationship with the obsessive-compulsive spectrum, use of selective serotonin reuptake inhibitors and cognitive behavioural therapy are recommended.El trastorno por excoriación está incluido en el DSM - 5 dentro de la categoría de trastorno obsesivo compulsivo y trastornos relacionados. Se define como la urgencia de tocar, rascar, frotar, restregar, friccionar, apretar, morder o excavar la piel de forma recurrente hasta producirse lesiones cutáneas. Es un trastorno poco frecuente (1.4 - 5.4% de la población) y se presenta principalmente en mujeres.Se presenta el caso de una mujer de 31 años quien fue valorada por dermatología y ortopedia por presencia de lesiones ulceradas e infectadas en miembros inferiores, junto con otras lesiones superficiales por rascado en tórax, brazos, antebrazos, espalda y cabeza; además reportando síntomas ansiosos, razón por la cual es valorada por el servicio de Psiquiatría de enlace.El rascado cutáneo, conducta normal en los mamíferos, cobra valor patológico desde el punto de vista psiquiátrico al ser un acto repetitivo y persistente, como la conducta que se presenta en el trastorno por excoriación. Dada la relación descrita con el espectro obsesivo - compulsivo, se recomienda el uso de inhibidores selectivos de la recaptación de serotonina y la terapia cognitivo conductual.

Evaluation of FasL and TRAIL in exosomes derived from placental explant cultures of women with early- and late-onset preeclampsia.

El proyecto DIADA, entendido como una experiencia de implementación de un modelo de atención en salud mental, en el contexto de un país de medianos ingresos como Colombia, incentiva la necesaria discusión acerca de su papel en el marco de la salud mental global. El siguiente artículo expone los puntos principales en los que ocurre esta relación, entendiendo cómo el proyecto contribuye a la salud mental global, y de forma paralela, cómo la salud mental global nutre el desarrollo de este proyecto. Se reflexiona sobre aspectos como el tamizaje sistemático de pacientes con trastornos mentales, el uso de tecnologías en salud, la adopción del modelo colaborativo, la investigación en implementación, el aprendizaje colaborativo y el sistema de salud colombiano, puntos claves al momento de interpretar este ciclo de retroalimentación entre lo individual y lo global. El análisis de estos componentes demuestra cómo el aprendizaje colaborativo es un eje central en el crecimiento de la salud mental global, desde la incorporación de metodologías, implementación de modelos, evaluación de desenlaces y, finalmente, la difusión de los resultados obtenidos entre actores locales, regionales e internacionales.The DIADA project, understood as a mental healthcare implementation experience in the context of a middle-income country like Colombia, promotes a necessary discussion about its role in the global mental health framework. The following article outlines the main points by which this relationship occurs, understanding how the project contributes to global mental health and, at the same time, how global mental health nurtures the development of this project. It reflects on aspects like the systematic screening of patients with mental illness, the use of technology in health, the adoption of a collaborative model, the investigation on implementation, a collaborative learning and the Colombian healthcare system. These are all key aspects when interpreting the feedback cycle between the individual and the global. The analysis of these components shows how collaborative learning is a central axis in the growth of global mental health: from the incorporation of methodologies, implementation of models, assessment of outcomes and, finally, the dissemination of results to local, regional and international stakeholders.

Olive Leaf Extract (OleaVita) Suppresses Inflammatory Cytokine Production and NLRP3 Inflammasomes in Human Placenta.

The placenta is essential for pregnancy and produces both pro-inflammatory and anti-inflammatory cytokines. Excessive production of inflammatory cytokines, involving interleukin-1β (IL-1β), IL-6, and IL-8, from placental tissues is associated with pregnancy complications. Olive leaf extract has several health benefits, including anti-inflammatory functions. OleaVita is a new commercial olive leaf extract; it is hypothesized to suppress placental inflammation. In human placental tissue culture, OleaVita treatment inhibited the secretion of inflammatory cytokines and NF-κB p65 protein expression. OleaVita also suppressed toll-like receptor ligands-induced IL-1β secretion in human placental tissues. IL-1β is regulated by the NLRP3 inflammasomes, a pivotal regulator of various diseases. OleaVita significantly decreased NLRP3 and pro-IL-1β protein expression, suggesting that it has an inhibitory effect on NLRP3 inflammasome activation. Thus, OleaVita is beneficial as an inhibitor of inflammation and NLRP3 inflammasome activation, and may be used as a supplement for the treatment and prevention of inflammatory diseases.

Pro- and anti-inflammatory effects of sulforaphane on placental cytokine production

Placental inflammation increases the risk of adverse pregnancy outcomes and possibly neurodevelopmental disorders in the offspring. Previous research suggests it may be possible to modulate the placental immune response to bacteria to favor an anti-inflammatory phenotype with dietary factors. Sulforaphane (SFN) is a dietary supplement with known anti-inflammatory activities, however, its effects on placental cytokine production are unclear. Therefore, we evaluated the effects of SFN on biomarkers of inflammation and neurodevelopment under basal conditions and a setting of mild infection. Placental explant cultures were established and treated with up to 10 μM SFN in the presence and absence of 107 CFU/ml heat-killed E. coli. Concentrations of IL-1β, TNF-α, IL-6, sgp130, HO-1 and BDNF in conditioned medium were quantified by immunoassay. SFN increased antioxidant HO-1 expression in the absence, but not the presence, of infection. SFN inhibited IL-1β and IL-10, but tended to promote, TNF-α production by bacteria-stimulated cultures. IL-6 and BDNF were inhibited by SFN irrespective of co-treatment with E.coli. A negative regulator of IL-6 signaling, sgp130, was increased by SFN under basal conditions, but not in E. coli-stimulated cultures. These results suggest that SFN has mixed effects on the placenta inhibiting both pro-inflammatory (IL-1β) and anti-inflammatory factors (IL-10) but promoting regulators of oxidative stress and inflammation (HO-1 and sgp130) in an infection-dependent manner.

239: The contribution of an infectious workup to understanding stillbirth

Stillbirth remains unexplained in a significant proportion of fetuses, even after a thorough evaluation. Despite the known contribution of infectious etiologies to this devastating pregnancy outcome, the yield such a workup is of unproven benefit. We aimed to assess the utility of diagnostic tests of maternal and fetal infection in the evaluation of stillbirth. A single center retrospective study from 1/2011-3/2017 of all women presenting to the hospital with intra-uterine fetal death at or after 20 weeks of gestation. Standard evaluation included a maternal interview, review of medical records, clinical and laboratory inflammatory workup, serology testing (for syphilis, Parvovirus B19, Rubella, CMV, Listeria, Toxoplasmosis, Hepatitis B and C) fetal autopsy, placental pathology and fetal and placental cultures. Additional standard stillbirth workup, including Kleinhauer-Betke, blood for group and screen and HbA1C, was obtained. An infectious etiology was considered the underlying cause of stillbirth if it was supported by at least two diagnostic tests (concordant pathogenic maternal and fetal cultures, histological chorioamnionitis, maternal symptoms of infection or positive serologies) and there was no other probable cause. During the 7-year study period, 228 cases of stillbirth occurred. Placental histological findings diagnostic of overt chorioamnionitis were observed in 69 (30.3%) cases. Serologies of acute infection were positive in 11 (4.8%) of the cases. In 39 cases the placental and abortus cultures were positive for the same pathogen. An infectious etiology was the probable cause of stillbirth, supported by at least two diagnostic tests, in 35 cases (15.3%). The mean gestational age of stillbirth caused by an infection was 29 weeks, while for a non-infectious etiology it was 32 weeks (p=0.005). Diagnostic tests of maternal and fetal infection are valuable in the investigation of stillbirth, particularly before 30 weeks of gestation and should be considered a part of standard evaluation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)