Chronic Inflammatory Placental Disorders Associated With Recurrent Adverse Pregnancy Outcome

Chronic inflammatory placental disorders are a group of rare but devastating gestational syndromes associated with adverse pregnancy outcome. This review focuses on three related conditions: villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). The hallmark of these disorders is infiltration of the placental architecture by maternal immune cells and disruption of the intervillous space, where gas exchange between the mother and fetus occurs. Currently, they can only be detected through histopathological examination of the placenta after a pregnancy has ended. All three are associated with a significant risk of recurrence in subsequent pregnancies. Villitis of unknown etiology is characterised by a destructive infiltrate of maternal CD8+ T lymphocytes invading into the chorionic villi, combined with activation of fetal villous macrophages. The diagnosis can only be made when an infectious aetiology has been excluded. VUE becomes more common as pregnancy progresses and is frequently seen with normal pregnancy outcome. However, severe early-onset villitis is usually associated with fetal growth restriction and recurrent pregnancy loss. Chronic histiocytic intervillositis is characterised by excessive accumulation of maternal CD68+ histiocytes in the intervillous space. It is associated with a wide spectrum of adverse pregnancy outcomes including high rates of first-trimester miscarriage, severe fetal growth restriction and late intrauterine fetal death. Intervillous histiocytes can also accumulate due to infection, including SARS-CoV-2, although this infection-induced intervillositis does not appear to recur. As with VUE, the diagnosis of CHI requires exclusion of an infectious cause. Women with recurrent CHI and their families are predisposed to autoimmune diseases, suggesting CHI may have an alloimmune pathology. This observation has driven attempts to prevent CHI with a wide range of maternal immunosuppression. Massive perivillous fibrin deposition is diagnosed when >25% of the intervillous space is occupied by fibrin, and is associated with fetal growth restriction and late intrauterine fetal death. Although not an inflammatory disorder per se, MPFD is frequently seen in association with both VUE and CHI. This review summarises current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology and potential prophylaxis against recurrence in these three chronic inflammatory placental syndromes

Identification of a unique intervillous cellular signature in chronic histiocytic intervillositis

Introduction: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta characterized by an infiltrate of CD68+ cells in the intervillous space. CHI is associated with adverse pregnancy outcomes such as miscarriage, fetal growth restriction, and (late) intrauterine fetal death. The adverse pregnancy outcomes and a variable recurrence rate of 25–100% underline its clinical relevance. The pathophysiologic mechanism of CHI is unclear, but it appears to be immunologically driven. The aim of this study was to obtain a better understanding of the phenotype of the cellular infiltrate in CHI. Method: We used imaging mass cytometry to achieve in-depth visualization of the intervillous maternal immune cells and investigated their spatial orientation in situ in relation to the fetal syncytiotrophoblast. Results: We found three phenotypically distinct CD68+HLA-DR+CD38+ cell clusters that were unique for CHI. Additionally, syncytiotrophoblast cells in the vicinity of these CD68+HLA-DR+CD38+ cells showed decreased expression of the immunosuppressive enzyme CD39. Discussion: The current results provide novel insight into the phenotype of CD68+ cells in CHI. The identification of unique CD68+ cell clusters will allow more detailed analysis of their function and could result in novel therapeutic targets for CHI

Identification of a unique intervillous cellular signature in chronic histiocytic intervillositis

Introduction: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta characterized by an infiltrate of CD68+ cells in the intervillous space. CHI is associated with adverse pregnancy outcomes such as miscarriage, fetal growth restriction, and (late) intrauterine fetal death. The adverse pregnancy outcomes and a variable recurrence rate of 25-100% underline its clinical relevance. The pathophysiologic mechanism of CHI is unclear, but it appears to be immunologically driven. The aim of this study was to obtain a better understanding of the phenotype of the cellular infiltrate in CHI.Method: We used imaging mass cytometry to achieve in-depth visualization of the intervillous maternal immune cells and investigated their spatial orientation in situ in relation to the fetal syncytiotrophoblast.Results: We found three phenotypically distinct CD68+HLA-DR+CD38+ cell clusters that were unique for CHI. Additionally, syncytiotrophoblast cells in the vicinity of these CD68+HLA-DR+CD38+ cells showed decreased expression of the immunosuppressive enzyme CD39.Discussion: The current results provide novel insight into the phenotype of CD68+ cells in CHI. The identification of unique CD68+ cell clusters will allow more detailed analysis of their function and could result in novel therapeutic targets for CHI.Research into fetal development and medicin

Route knowledge and configural knowledge in typical and atypical development: a comparison of sparse and rich environments

Background: Individuals with Down syndrome (DS) and individuals with Williams syndrome (WS) have poor navigation skills, which impact their potential to become independent. Two aspects of navigation were investigated in these groups, using virtual environments (VE): route knowledge (the ability to learn the way from A to B by following a fixed sequence of turns) and configural knowledge (knowledge of the spatial relationships between places within an environment). Methods: Typically developing (TD) children aged 5 to 11 years (N = 93), individuals with DS (N = 29) and individuals with WS (N = 20) were presented with a sparse and a rich VE grid maze. Within each maze, participants were asked to learn a route from A to B and a route from A to C before being asked to find a novel shortcut from B to C. Results: Performance was broadly similar across sparse and rich mazes. The majority of participants were able to learn novel routes, with poorest performance in the DS group, but the ability to find a shortcut, our measure of configural knowledge, was limited for all three groups. That is, 59 % TD participants successfully found a shortcut, compared to 10 % participants with DS and 35 % participants with WS. Differences in the underlying mechanisms associated with route knowledge and configural knowledge and in the developmental trajectories of performance across groups were observed. Only the TD participants walked a shorter distance in the last shortcut trial compared to the first, indicative of increased configural knowledge across trials. The DS group often used an alternative strategy to get from B to C, summing the two taught routes together. Conclusions: Our findings demonstrate impaired configural knowledge in DS and in WS, with the strongest deficit in DS. This suggests that these groups rely on a rigid route knowledge based method for navigating and as a result are likely to get lost easily. Route knowledge was also impaired in both DS and WS groups and was related to different underlying processes across all three groups. These are discussed with reference to limitations in attention and/or visuo-spatial processing in the atypical groups

Identification of a unique intervillous cellular signature in chronic histiocytic intervillositis

Introduction: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta characterized by an infiltrate of CD68+ cells in the intervillous space. CHI is associated with adverse pregnancy outcomes such as miscarriage, fetal growth restriction, and (late) intrauterine fetal death. The adverse pregnancy outcomes and a variable recurrence rate of 25–100% underline its clinical relevance. The pathophysiologic mechanism of CHI is unclear, but it appears to be immunologically driven. The aim of this study was to obtain a better understanding of the phenotype of the cellular infiltrate in CHI. Method: We used imaging mass cytometry to achieve in-depth visualization of the intervillous maternal immune cells and investigated their spatial orientation in situ in relation to the fetal syncytiotrophoblast. Results: We found three phenotypically distinct CD68+HLA-DR+CD38+ cell clusters that were unique for CHI. Additionally, syncytiotrophoblast cells in the vicinity of these CD68+HLA-DR+CD38+ cells showed decreased expression of the immunosuppressive enzyme CD39. Discussion: The current results provide novel insight into the phenotype of CD68+ cells in CHI. The identification of unique CD68+ cell clusters will allow more detailed analysis of their function and could result in novel therapeutic targets for CHI

The RAdio Galaxy Environment Reference Survey (RAGERS) : Evidence of an anisotropic distribution of submillimeter galaxies in the 4C 23.56 protocluster at z=2.48

High-redshift radio(-loud) galaxies (H$z$RGs) are massive galaxies with powerful radio-loud active galactic nuclei (AGNs) and serve as beacons for protocluster identification. However, the interplay between H$z$RGs and the large-scale environment remains unclear. To understand the connection between H$z$RGs and the surrounding obscured star formation, we investigated the overdensity and spatial distribution of submillimeter-bright galaxies (SMGs) in the field of 4C\,23.56, a well-known H$z$RG at $z=2.48$. We used SCUBA-2 data ($\sigma\,{\sim}\,0.6$\,mJy) to estimate the $850\,{\rm \mu m}$ source number counts and examine the radial and azimuthal overdensities of the $850\,{\rm \mu m}$ sources in the vicinity of the H$z$RG. The angular distribution of SMGs is inhomogeneous around the H$z$RG 4C\,23.56, with fewer sources oriented along the radio jet. We also find a significant overdensity of bright SMGs (${\rm S}_{850\rm\,\mu m}\geq5\,$mJy). Faint and bright SMGs exhibit different spatial distributions. The former are concentrated in the core region, while the latter prefer the outskirts of the H$z$RG field. High-resolution observations show that the seven brightest SMGs in our sample are intrinsically bright, suggesting that the overdensity of bright SMGs is less likely due to the source multiplicity

The effect of antenatal corticosteroid use on offspring cardiovascular function: A systematic review.

Funder: UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012621BACKGROUND: Antenatal corticosteroids (ACS) are recommended in threatened preterm labour to improve short-term neonatal outcome. Preclinical animal studies suggest detrimental effects of ACS exposure on offspring cardiac development; their effects in humans are unknown. OBJECTIVES: To systematically review the human clinical literature to determine the effects of ACS on offspring cardiovascular function. SEARCH STRATEGY: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines in MEDLINE, EMBASE and Cochrane databases. SELECTION CRITERIA: Offspring who had been exposed to ACS during fetal life, in comparison with those not receiving steroids, those receiving a placebo or population data, were included. Studies not performed in humans or that did not assess cardiovascular function were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently screened the studies, extracted the data and assessed the quality of the studies. Results were combined descriptively and analysed using a standardised Excel form. MAIN RESULTS: Twenty-six studies including 1921 patients were included, most of which were cohort studies of mixed quality. The type of ACS exposure, gestational age at exposure, dose and number of administrations varied widely. Offspring cardiovascular outcomes were assessed from 1 day to 36 years postnatally. The most commonly assessed parameter was arterial blood pressure (18 studies), followed by echocardiography (eight studies), heart rate (five studies), electrocardiogram (ECG, three studies) and cardiac magnetic resonance imaging (MRI, one study). There were no clinically significant effects of ACS exposure on offspring blood pressure. However, there were insufficient studies assessing cardiac structure and function using echocardiography or cardiac MRI to be able to determine an effect. CONCLUSIONS: The administration of ACS is not associated with long-term effects on blood pressure in exposed human offspring. The effects on cardiac structure and other measures of cardiac function were unclear because of the small number, heterogeneity and mixed quality of the studies. Given the preclinical and human evidence of potential harm following ACS exposure, there is a need for further research to assess central cardiac function in human offspring exposed to ACS