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The placenta is one of the most exciting organs. It is dynamic; its morphology and function continuously develop and adjust over its brief life span. It mediates the physiology of two distinct yet highly interconnected individuals. The pathology that develops in the placenta, and the adaptations the placenta undergoes to mitigate this pathology, may influence the later life health of the mother and baby (Circ Res, 116, 2015, 715; Hum Reprod Update, 17, 2011, 397; Nutr Rev 71, 2013, S88; Placenta, 36, 2015, S20). Pathological placenta examination may reveal macroscopic and microscopic patterns that provide valuable information to the obstetricians, neonatologists, and pediatricians caring for the family. The placenta often plays a key role in understanding adverse fetal outcomes such as hypoxic brain injury, cerebral palsy, fetal growth restriction, stillbirth, and neonatal death (Placenta, 35, 2014, 552; Placenta, 52, 2017, 58; Placenta, 30, 2009, 700; Obstet Gynecol, 114, 2009, 809; Clin Perinatol, 33, 2006, 503; Pediatr Dev Pathol, 11, 2008, 456; Arch Pathol Lab Med, 124, 2000, 1785). Moreover, it may help to understand the pathophysiology of pregnancy, improve management of subsequent pregnancies, and assist in medicolegal assessment. Placental pathologic examination may even provide evidence of susceptibility to adult-onset diseases such as diabetes (Pediatr Dev Pathol, 6, 2003, 54; Diabetes Metab, 36, 2010, 682; BJOG, 113, 2006, 1126; Int J Gynaecol Obstet, 104, 2009, S25; Zentralbl Gynakol, 97, 1975, 875). Pathologic examination of the placenta may thus be of tremendous value, particularly for those women experiencing an adverse pregnancy outcome. However, this potential utility may be entirely wasted, if the findings are not communicated in an effective manner to the appropriate clinicians. An optimized, readily understandable report of pathological findings is essential for clinical utility. [ABSTRACT FROM AUTHOR]

Objective Design Setting Population Methods Main outcome measures Results Conclusions To identify which components of maternal vascular malperfusion (MVM) pathology are associated with adverse pregnancy outcomes and to investigate the morphological phenotypes of MVM placental pathology and their relationship with distinct clinical presentations of pre‐eclampsia and/or fetal growth restriction (FGR).Retrospective cohort study.Tertiary care hospital in Toronto, Canada.Pregnant individuals with low circulating maternal placental growth factor (PlGF) levels (<100 pg/mL) and placental pathology analysis between March 2017 and December 2019.Association between each pathological finding and the outcomes of interest were calculated using the chi‐square test. Cluster analysis and logistic regression was used to identify phenotypic clusters, and their association with adverse pregnancy outcomes. Cluster analysis was performed using the K‐modes unsupervised clustering algorithm.Preterm delivery <34+0 weeks of gestation, early onset pre‐eclampsia with delivery <34+0 weeks of gestation, birthweight <10th percentile (small for gestational age, SGA) and stillbirth.The diagnostic features of MVM most strongly associated with delivery <34+0 weeks of gestation were: infarction, accelerated villous maturation, distal villous hypoplasia and decidual vasculopathy. Two dominant phenotypic clusters of MVM pathology were identified. The largest cluster (n = 104) was characterised by both reduced placental mass and hypoxic ischaemic injury (infarction and accelerated villous maturation), and was associated with combined pre‐eclampsia and SGA. The second dominant cluster (n = 59) was characterised by infarction and accelerated villous maturation alone, and was associated with pre‐eclampsia and average birthweight for gestational age.Patients with placental MVM disease are at high risk of pre‐eclampsia and FGR, and distinct pathological findings correlate with different clinical phenotypes, suggestive of distinct subtypes of MVM disease. [ABSTRACT FROM AUTHOR]

Background: Evidence of placental maternal vascular malperfusion is associated with significant perinatal outcomes such as preeclampsia, intrauterine growth restriction and preterm birth. Elevations in pre-pregnancy blood pressure increase the risk for poor perinatal outcomes; however, the evidence linking pre-pregnancy blood pressure and placental malperfusion is sparse.Materials and Methods: We conducted a retrospective case-control study of women with singleton gestations with placental evaluations who delivered at Magee-Womens Hospital in 2012. Charts from 100 deliveries with placental malperfusion lesions (vasculopathy, advanced villous maturation, infarct, or fibrin deposition) and 102 deliveries without placental malperfusion were randomly selected for screening. Blood pressure, demographic, and clinical data were abstracted from pre-pregnancy electronic medical records and compared between women with and without subsequent placental malperfusion lesions.Results: Overall, 48% of women had pre-pregnancy records, and these were similarly available for women with and without placental malperfusion. Women with placental malperfusion demonstrated a reduction in their pre- to early pregnancy decrease in diastolic blood pressure (DBP). Adjusted for race, pre-pregnancy BMI, age, pre-conception interval, and gestational age at the first prenatal visit, the difference in pre- to early pregnancy DBP was significantly less in women with placental malperfusion compared to those without this pathologic finding (- 1.35 mmHg drop vs - 5.6mmg, p < 0.05).Conclusion: A blunted early gestation drop in DBP may be a risk factor for placental malperfusion, perhaps related to early pregnancy vascular maladaptation. The ability of the electronic medical record to provide pre-pregnancy data serves as an underutilized approach to study pre-pregnancy health. [ABSTRACT FROM AUTHOR]

Background: Placental dysfunction, a root cause of common syndromes affecting human pregnancy, such as preeclampsia (PE), fetal growth restriction (FGR), and spontaneous preterm delivery (sPTD), remains poorly defined. These common, yet clinically disparate obstetrical syndromes share similar placental histopathologic patterns, while individuals within each syndrome present distinct molecular changes, challenging our understanding and hindering our ability to prevent and treat these syndromes. Methods: Using our extensive biobank, we identified women with severe PE (n = 75), FGR (n = 40), FGR with a hypertensive disorder (FGR + HDP; n = 33), sPTD (n = 72), and two uncomplicated control groups, term (n = 113), and preterm without PE, FGR, or sPTD (n = 16). We used placental biopsies for transcriptomics, proteomics, metabolomics data, and histological evaluation. After conventional pairwise comparison, we deployed an unbiased, AI-based similarity network fusion (SNF) to integrate the datatypes and identify omics-defined placental clusters. We used Bayesian model selection to compare the association between the histopathological features and disease conditions vs SNF clusters. Results: Pairwise, disease-based comparisons exhibited relatively few differences, likely reflecting the heterogeneity of the clinical syndromes. Therefore, we deployed the unbiased, omics-based SNF method. Our analysis resulted in four distinct clusters, which were mostly dominated by a specific syndrome. Notably, the cluster dominated by early-onset PE exhibited strong placental dysfunction patterns, with weaker injury patterns in the cluster dominated by sPTD. The SNF-defined clusters exhibited better correlation with the histopathology than the predefined disease groups. Conclusions: Our results demonstrate that integrated omics-based SNF distinctively reclassifies placental dysfunction patterns underlying the common obstetrical syndromes, improves our understanding of the pathological processes, and could promote a search for more personalized interventions. [ABSTRACT FROM AUTHOR]

Placental histopathology is a resource for investigating obesity-associated pregnancy conditions. However, studies oversample adverse pregnancies, biasing findings. We examine the association between prepregnancy obesity (risk factor for inflammation) and histologic placental inflammation (correlated with impaired infant neurodevelopment) and how selection bias may influence the association. Singleton term deliveries between 2008 and 2012 from the Magee Obstetric Maternal and Infant database were analyzed. Prepregnancy body mass index (BMI) was categorized as underweight, lean (referent), overweight, and obese. Outcomes were diagnoses of acute (acute chorioamnionitis and fetal inflammation) and chronic placental inflammation (chronic villitis). Risk ratios for associations between BMI and placental inflammation were estimated using selection bias approaches: complete case, exclusion of pregnancy complications, multiple imputation, and inverse probability weighting. E-values approximated how susceptible estimates were to residual selection bias. Across methods, obesity was associated with an 8–15% lower risk of acute chorioamnionitis, a 7%–14% lower risk of acute fetal inflammation, and a 12%–30% higher risk of chronic villitis relative to lean women. E-values indicated modest residual selection bias could explain away associations, though few measured indications of placental evaluations met this threshold. Obesity may contribute to placental inflammation, and we highlight robust methods to analyze clinical data susceptible to selection bias. [ABSTRACT FROM AUTHOR]

We present the prenatal case of a 12.5-Mb duplication involving 6q25-qter and a 12.2-Mb deletion encompassing 10q26-qter diagnosed by aCGH, while conventional karyotype showed normal results. The genotype-phenotype correlation between individual microarray and clinical findings adds to the emerging atlas of chromosomal abnormalities associated with specific prenatal ultrasound abnormalities. [ABSTRACT FROM AUTHOR]

Context-Liver metastases usually present as radio- graphically detectable mass lesions that do not significantly compromise liver function. Rarely, metastatic carcinoma can diffusely infiltrate hepatic sinusoids, a pattern of metastasis that may be missed on imaging studies, and can result in liver failure. Objective-To describe the clinicopathologic features of 3 cases of diffuse intrasinusoidal hepatic metastases from primary breast carcinomas identified at autopsy. Design.-Clinical histories and radiographic, macroscopic, and microscopic appearances of the livers were compared. Sampled liver tissue was stained with antibodies to E-cadherin, smooth muscle actin, and CD44. Results.-Two of 3 cases had a history of infiltrating ductal carcinoma of the breast and presented with new-onset liver failure, but no hepatic metastases were identified on radiotogic imaging. An additional case had no history of carcinoma, presented with a severe thrombocytopenic thrombotic purpura-like syndrome, and metastatic carcinoma of the breast was diagnosed only at autopsy. The livers in all 3 cases at autopsy were homogeneous, firm, and tan-yellow, and contained no large metastatic lesions. Microscopically, poorly differentiated carcinoma diffusely infiltrated hepatic sinusoids. Antibodies to smooth muscle actin stained activated hepatic stellate cells lining involved sinusoids. Cell surface adhesion molecules, E-cadherin or CD44, were not detected in any hepatic metastases. Conclusion.-Diffuse intrasinusoidal hepatic metastases of breast carcinoma can occupy a large percentage of the hepatic volume, yet remain occult both radiographicalty and macroscopically. This type of metastatic spread can present as cryptogenic liver failure. The 3 cases we studied were associated with an absence of E-cadherin and CD44 expression. [ABSTRACT FROM AUTHOR]

Expression of endogenous transforming growth factor-β1 is reduced in many animal models of impaired wound healing, and addition of exogenous transforming growth factor-β has been shown to improve healing. To test the hypothesis that endogenous transforming growth factor-β1 is essential for normal wound repair, we have studied wound healing in mice in which the transforming growth factor-β1 gene has been deleted by homologous recombination. No perceptible differences were observed in wounds made in 3–10-day-old neonatal transforming growth factor-β1 null mice compared to wild-type littermates. To preclude interference from maternally transferred transforming growth factor-β1, cutaneous wounds were also made on the backs of 30-day-old transforming growth factor-β1 null and littermate control mice treated with rapamycin, which extends their lifetime and suppresses the inflammatory response characteristic of the transforming growth factor-β1 null mice. Again, no impairment in healing was seen in transforming growth factor-β1 null mice. Instead these wounds showed an overall reduction in the amount of granulation tissue and an increased rate of epithelialization compared to littermate controls. Our data suggest that release of transforming growth factor-β1 from degranulating platelets or secretion by infiltrating macrophages and fibroblasts is not critical to initiation or progression of tissue repair and that endogenous transforming growth factor-β1 may actually function to increase inflammation and retard wound closure. [ABSTRACT FROM AUTHOR]

* Context.--The number of neonates with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is increasing, and in a few there are reports of intrauterine infection. Objective.--To characterize the placental pathology findings in a preselected cohort of neonates infected by transplacental transmission arising from maternal infection with SARS-CoV-2, and to identify pathology risk factors for placental and fetal infection. Design.--Case-based retrospective analysis by a multinational group of 19 perinatal specialists of the placental pathology findings from 2 cohorts of infants delivered to mothers testing positive for SARS-CoV-2: live-born neonates infected via transplacental transmission who tested positive for SARS-CoV-2 after delivery and had SARS-CoV-2 identified in cells of the placental fetal compartment by molecular pathology, and stillborn infants with syncytiotrophoblast positive for SARS-CoV-2. Results.--In placentas from all 6 live-born neonates acquiring SARS-CoV-2 via transplacental transmission, the syncytiotrophoblast was positive for coronavirus using immunohistochemistry, RNA in situ hybridization, or both. All 6 placentas had chronic histiocytic intervillositis and necrosis of the syncytiotrophoblast. The 5 stillborn/terminated infants had placental pathology findings that were similar, including SARS-CoV-2 infection of the syncytiotrophoblast, chronic histiocytic intervillositis, and syncytiotrophoblast necrosis. Conclusions.--Chronic histiocytic intervillositis together with syncytiotrophoblast necrosis accompanies SARS-CoV-2 infection of syncytiotrophoblast in live-born and stillborn infants. The coexistence of these 2 findings in all placentas from live-born infants acquiring their infection prior to delivery indicates that they constitute a pathology risk factor for transplacental fetal infection. Potential mechanisms of infection of the placenta and fetus with SARSCoV-2, and potential future studies, are discussed. [ABSTRACT FROM AUTHOR]

Background: Fetal sex is known to affect pregnancy outcomes. In current clinical practice, monitoring of fetal well-being is based on Doppler ultrasound measurements of major placental and fetal vessels. The objective of this study was to investigate the effect of fetal sex on Doppler parameters throughout gestation in healthy pregnancy. Methods: A prospective study was conducted in 240 pregnant women with ultrasound examinations at a 4-weekly interval between 12 and 38 weeks of gestation. Pulsed Doppler spectra were collected for the umbilical arteries (UAs), middle cerebral artery (MCA), descending abdominal aorta (DAo), and ductus venosus (DV). Linear mixed effects models were used to determine if the pulsatility indices (PIs) of these vessels depended on gestational age and fetal sex. Results: While there were no differences in the MCA PI and DV PIV over gestation between female and male fetuses, the trajectory of the UA and DAo PIs differed by fetal sex (p = 0.02 and p = 0.01, respectively). Conclusions: Doppler ultrasound parameters were found to be dependent on fetal sex for some vessels and not for others in healthy pregnancies. Further investigations are needed to understand the physiological mechanisms for these sex differences and the relevance for disease processes in pregnancy. [ABSTRACT FROM AUTHOR]

Background: Hypertensive disorders of pregnancy (HDP) are associated with short-term cardiac structure and function abnormalities, but later life changes are not well studied.Objectives: This study aimed to determine if HDP history is associated with echocardiographic differences 8 to 10 years after delivery, and if subgroups with placental maternal vascular malperfusion (MVM) lesions or current hypertension may be particularly affected.Methods: Women with pregnancies delivered from 2008 to 2009 were selected from a clinical cohort with abstracted pregnancy and placental pathology data to undergo transthoracic echocardiography (2017 to 2020). Medical history, blood pressure, and weight were measured at the study visit.Results: The authors enrolled 132 women (10 ± 1 years post-delivery, age 38 ± 6 years): 102 with normotensive pregnancies and 30 with HDP: pre-eclampsia (n = 21) or gestational hypertension (n = 9). Compared with women with normotensive pregnancies, those with HDP history were more likely to have current hypertension (63% vs. 26%; p < 0.001). After adjusting for age, race, MVM lesions, body mass index, current hypertension, and hemoglobin A1c, women with HDP history had higher interventricular septal thickness (β = 0.08; p = 0.04) and relative wall thickness (β = 0.04; p = 0.04). In subgroup analyses, those with both HDP history and current hypertension had a higher proportion of left ventricular remodeling (79.0%) compared with all other groups (only HDP [36.4%; p = 0.01], only current hypertension [46.2%; p = 0.02], and neither HDP nor hypertension [38.2%; p < 0.001]), and lower mitral inflow E/A and annular e'. Accounting for placental MVM lesions did not impact results.Conclusions: Women with both HDP history and current hypertension have pronounced differences in left ventricular structure and function a decade after pregnancy, warranting continued surveillance and targeted therapies for cardiovascular disease prevention. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence of sex differences in placental vascular development. The objective of this study was to investigate the effect of fetal sex on uterine artery pulsatility index (PI) throughout gestation in a cohort of normal and complicated pregnancies. Methods: A prospective longitudinal study was conducted in 240 pregnant women. Pulsed wave Doppler ultrasound of the proximal uterine arteries was performed at a 4-weekly interval between 14 and 40 weeks of gestation. The patients were classified retrospectively as normal or complicated (one or more of maternal preeclampsia, preterm birth, or small for gestational age). To assess if the change in uterine artery PI during gestation differed between normal and complicated pregnancies and between fetal sexes, the uterine artery PI was modeled using a linear function of gestational age and the rate of change was estimated from the slope. Results: While the uterine artery PI did not differ over gestation between females and males for normal pregnancies, the trajectory of this index differed by fetal sex for pregnancies complicated by either preeclampsia, preterm birth, or fetal growth restriction (p < 0.0001). The male fetuses in the complicated pregnancy group had an elevated slope compared to the other groups (p < 0.0001), suggesting a more progressive deterioration in uteroplacental perfusion over gestation. Conclusions: The uterine artery PI is widely used to assess uteroplacental function in clinical settings. The observation that this metric changes more rapidly in complicated pregnancies where the fetus was male highlights the importance of sex when interpreting hemodynamic markers of placental maturation. [ABSTRACT FROM AUTHOR]

The recently identified ferroptotic cell death is characterized by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidylethanolamine (Hp-PE). The seleniumdependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to nontoxic lipid alcohols in a tissue-specificmanner. While placental oxidative stress and lipotoxicity are hallmarks of placental dysfunction, the possible role of ferroptosis in placental dysfunction is largely unknown. We found that spontaneous preterm birth is associated with ferroptosis and that inhibition of GPX4 causes ferroptotic injury in primary human trophoblasts and during mouse pregnancy. Importantly, we uncovered a role for the phospholipase PLA2G6 (PNPLA9, iPLA2beta), known to metabolize Hp-PE to lyso-PE and oxidized fatty acid, in mitigating ferroptosis induced by GPX4 inhibition in vitro or by hypoxia/ reoxygenation injury in vivo. Together, we identified ferroptosis signaling in the human and mouse placenta, established a role for PLA2G6 in attenuating trophoblastic ferroptosis, and provided mechanistic insights into the ill-defined placental lipotoxicity that may inspire PLA2G6-targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Neonates born to women with confirmed or suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection should have testing of the nasopharynx, placenta and cord blood as soon as possible after birth, after thorough cleaning of the neonate. All 3 of the neonate's nasopharyngeal swabs were positive for SARS-CoV-2 gene targets via RT-PCR testing; neonatal plasma tested positive on day 4, and stool was positive on day 7. Debate regarding transmission via blood or during the birth process is common.[5] Thorough immediate testing is needed to understand the route of transmission of SARS-CoV-2 infection. [Extracted from the article]

Abstract The quality of the intrauterine environment, in which the placenta plays a critical role, affects birth outcomes and lifelong health. The effect of metal contaminants on the growth and functioning of the placenta have not been widely reported but may provide insights into how metal exposures lead to these outcomes. We examined relationships between placental concentrations of cadmium (Cd), arsenic (As), mercury (Hg) and lead (Pb) and measures of placental growth and functioning (placental weight, placental efficiency (the log ratio of placental weight and birth weight), chorionic disc area and disc eccentricity) as part of the New Hampshire Birth Cohort Study (N = 1159). We additionally examined whether these associations were modified by placental concentrations of essential elements zinc (Zn) and selenium (Se). Associations were evaluated using generalized linear models. Multivariable-adjusted differences in placental weight were − 7.81 g (95% CI: −15.42, −2.48) with every ng/g increase in the Cd concentration of placenta (p -Value = 0.0009). Greater decrements in placental weight and efficiency associated with placental Cd were observed for females. For placentae with below median Zn and Se concentrations, decrements in placental weight were − 8.81 g (95% CI: −16.85, −0.76) and − 13.20 g (95% CI: −20.70, −5.70) respectively. The Cd concentration of placenta was also associated with reductions in placental efficiency both overall, and in Zn- and Se-stratified models. No appreciable differences were observed with other elements (As, Hg or Pb) and with other placental measures (chorionic disc area and disc eccentricity). In structural equation models, placental weight was a mediator in the relation between placental Cd concentration and reduced birth weight. Our findings suggest a role of interacting essential and contaminant elements on birth weight that may be mediated by changes in the growth and function of the placenta. Highlights • Arsenic, cadmium, mercury and lead concentrations were measured in placenta. • Measured placental outcomes were weight, efficiency, area and eccentricity. • Placental cadmium was associated with reduced placental weight and efficiency. • Female placentas are more affected by cadmium than male. • Placental weight is a mediator between Cd in placenta and infant birth weight. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) infection during pregnancy in humans is associated with an increased incidence of congenital anomalies including microcephaly as well as fetal death and miscarriage and collectively has been referred to as Congenital Zika Syndrome (CZS). Animal models for ZIKV infection in pregnancy have been developed including mice and non-human primates (NHPs). In macaques, fetal CZS outcomes from maternal ZIKV infection range from none to significant. In the present study we develop the olive baboon (Papio anubis), as a model for vertical transfer of ZIKV during pregnancy. Four mid-gestation, timed-pregnant baboons were inoculated with the French Polynesian ZIKV isolate (104 ffu). This study specifically focused on the acute phase of vertical transfer. Dams were terminated at 7 days post infection (dpi; n = 1), 14 dpi (n = 2) and 21 dpi (n = 1). All dams exhibited mild to moderate rash and conjunctivitis. Viremia peaked at 5–7 dpi with only one of three dams remaining mildly viremic at 14 dpi. An anti-ZIKV IgM response was observed by 14 dpi in all three dams studied to this stage, and two dams developed a neutralizing IgG response by either 14 dpi or 21 dpi, the latter included transfer of the IgG to the fetus (cord blood). A systemic inflammatory response (increased IL2, IL6, IL7, IL15, IL16) was observed in three of four dams. Vertical transfer of ZIKV to the placenta was observed in three pregnancies (n = 2 at 14 dpi and n = 1 at 21 dpi) and ZIKV was detected in fetal tissues in two pregnancies: one associated with fetal death at ~14 dpi, and the other in a viable fetus at 21 dpi. ZIKV RNA was detected in the fetal cerebral cortex and other tissues of both of these fetuses. In the fetus studied at 21 dpi with vertical transfer of virus to the CNS, the frontal cerebral cortex exhibited notable defects in radial glia, radial glial fibers, disorganized migration of immature neurons to the cortical layers, and signs of pathology in immature oligodendrocytes. In addition, indices of pronounced neuroinflammation were observed including astrogliosis, increased microglia and IL6 expression. Of interest, in one fetus examined at 14 dpi without detection of ZIKV RNA in brain and other fetal tissues, increased neuroinflammation (IL6 and microglia) was observed in the cortex. Although the placenta of the 14 dpi dam with fetal death showed considerable pathology, only minor pathology was noted in the other three placentas. ZIKV was detected immunohistochemically in two placentas (14 dpi) and one placenta at 21 dpi but not at 7 dpi. This is the first study to examine the early events of vertical transfer of ZIKV in a NHP infected at mid-gestation. The baboon thus represents an additional NHP as a model for ZIKV induced brain pathologies to contrast and compare to humans as well as other NHPs. [ABSTRACT FROM AUTHOR]

During pregnancy, placental trophoblasts at the feto-maternal interface produce a broad repertoire of microRNA (miRNA) species. These species include miRNA from the primate-specific chromosome 19 miRNA cluster (C19MC), which is expressed nearly exclusively in the placenta. Trafficking of these miRNAs among the maternal, placental, and fetal compartments is unknown. To determine miRNA expression and trafficking patterns during pregnancy, we sequenced miRNAs in triads of human placenta and of maternal and fetal blood and found large subject-to-subject variability, with C19MC exhibiting compartment-specific expression. We therefore created humanized mice that transgenically express the entire 160-kb human C19MC locus or lentivirally express C19MC miRNA members selectively in the placenta. C19MC transgenic mice expressed a low level of C19MC miRNAs in diverse organs. When pregnant, female C19MC mice exhibited a strikingly elevated (>40-fold) expression of C19MC miRNA in the placenta, compared with other organs, that resembled C19MC miRNAs patterns in humans. Our mouse models showed that placental miRNA traffic primarily to the maternal circulation and that maternal miRNA can traffic to the placenta and even into the fetal compartment. These findings define an extraordinary means of nonhormonal, miRNA-based communication between the placenta and feto-maternal compartments. [ABSTRACT FROM AUTHOR]

Context.--The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories. Objective.--To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community. Data Sources.--Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible. Conclusions.--The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfu-sion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the association between maternal 25-hydroxyvitamin D (25(OH)D) and the risk of spontaneous preterm birth (sPTB) before 35 weeks’ gestation. A random subcohort from the US Collaborative Perinatal Project (1959–1965) was sampled (n = 2,629) and augmented with all remaining cases of sPTB before 35 weeks’ gestation for a total of 767 cases. Banked serum samples collected at 26 weeks’ gestation or earlier were assayed for 25(OH)D. Constructs for vascular histology and inflammatory histology were developed from placental pathology examinations. There was no relationship between 25(OH)D and sPTB among white women. Among nonwhite mothers, serum 25(OH)D levels of 30–<50, 50–<75, and ≥75 nmol/L were associated with reductions of 1.0–1.6 cases of sPTB per 100 live births and 20%–30% reductions in risk of sPTB compared with 25(OH)D levels less than 30 nmol/L after adjustment for prepregnancy body mass index (weight (kg)/height (m)2), season, and other confounders. This association was driven by inflammation-mediated cases of sPTB and sPTB cases without placental lesions. A sensitivity analysis for unmeasured confounding by exercise, fish intake, and skin color suggested some bias away from the null in the conventional results, but conclusions were generally supported. The vitamin D–sPTB relationship should be examined in modern cohorts with detailed data on skin pigmentation and other covariates. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) infection is one of the leading prenatal causes of congenital mental retardation and deformities world-wide. Access to cultured human neuronal lineages, necessary to understand the species specific pathogenic effects of HCMV, has been limited by difficulties in sustaining primary human neuronal cultures. Human induced pluripotent stem (iPS) cells now provide an opportunity for such research. We derived iPS cells from human adult fibroblasts and induced neural lineages to investigate their susceptibility to infection with HCMV strain Ad169. Analysis of iPS cells, iPS-derived neural stem cells (NSCs), neural progenitor cells (NPCs) and neurons suggests that (I) iPS cells are not permissive to HCMV infection, i.e., they do not permit a full viral replication cycle; (ii) Neural stem cells have impaired differentiation when infected by HCMV; (iii) NPCs are fully permissive for HCMV infection; altered expression of genes related to neural metabolism or neuronal differentiation is also observed; (iv) most iPS-derived neurons are not permissive to HCMV infection; and (v) infected neurons have impaired calcium influx in response to glutamate. [ABSTRACT FROM AUTHOR]

The transforming growth factorß(TGF-ß) signaling pathway, which is activated by the TGF-ßreceptor complex consisting of type I and type II TGF-ßreceptors (TGFBR1 and TGFBR2), regulates cell growth and death. TGF-ßand components of its signaling pathway, particularly TGFBR2, have been implicated as tumor suppressor genes and important antimitogenic factors in the gastrointestinal tract and liver. An in vivo approach to study these effects has been hindered by the embryonic lethality of Tgfbr2-/- mice and poor viability of the Tgfb1-/- mice. Consequently, we have developed a hepatocyte-specific Tgfbr2 knockout mouse, the Alb-cre Tgfbr2flx/flx mouse, to study the physiologically relevant effects of TGF-ßsignaling on epithelial cell proliferation in vivo. After 70%hepatectomy, we observed increased proliferation and an increased liver mass?:?body weight ratio in the Alb-cre Tgfbr2flx/flx mice compared to Tgfbr2flx/flx mice. We also observed decreased expression and increased phosphorylation of p130 in the livers from the Alb-cre Tgfbr2flx/flx mice as well as increased expression of cyclin E, which is transcriptionally regulated, in part, by p130:E2F4. Consistent with these results, in a hepatocyte cell line derived from the Tgfbr2flx/flx mice, we found that TGF-ßincreases the nuclear localization of E2F4, and presumably the transcriptional repression of the p130:E2F4 complex. Thus, we have demonstrated that TGF-ßsignaling in vivo regulates the mitogenic response in the regenerating liver, affecting the liver mass?:?body weight ratio after partial hepatectomy, and that these mitogenic responses are accompanied by alterations in p130 expression and phosphorylation, implicating p130 as one of the proteins regulated in vivo by TGF-ßduring liver regeneration.Oncogene (2005) 24, 3028-3041. doi:10.1038/sj.onc.1208475 Published online 7 February 2005 [ABSTRACT FROM AUTHOR]

Administration of transforming growth factor-β (TGF-β) has been found to be of therapeutic benefit in various mouse disease models and has potential clinical usefulness. However, the ability to track the distribution of exogenously administered, recombinant forms of these proteins has been restricted by cross-reactivity with endogenous TGF-β and related TGF-β isoforms. We describe novel FLAG- and hemagglutinin (HA)-tagged versions of mature TGF-β1 that retain full biological activity as demonstrated by their ability to inhibit the growth of Mv1Lu epithelial cells, and to induce phosphorylation of the TGF-β signaling intermediate, smad 2. Intracellular FLAG- and HA-TGF-β1 can be detected in transfected cells by confocal immunofluorescence microscopy. We also describe sandwich ELISAs designed to specifically detect epitope-tagged TGF-β and demonstrate the utility of these tagged ligands as probes for TGF-β receptor expression by flow cytometry. The design of these fully functional epitope-tagged TGF-β proteins should facilitate studies such as the evaluation of in vivo peptide pharmacodynamics and trafficking of TGF-β ligand–receptor complexes. [Copyright &y& Elsevier]

The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cancer, is a central mediator of TGF-β signaling. It was previously shown that mice homozygous for a null mutation of Smad4 (Smad4-/-) died prior to gastrulation displaying impaired extraembryonic membrane formation and endoderm differentiation. Here we show that Smad4+/- mice began to develop polyposis in the fundus and antrum when they were over 6–12 months old, and in the duodenum and cecum in older animals at a lower frequency. With increasing age, polyps in the antrum show sequential changes from hyperplasia, to dysplasia, in-situ carcinoma, and finally invasion. These alterations are initiated by a dramatic expansion of the gastric epithelium where Smad4 is expressed. However, loss of the remaining Smad4 wild-type allele was detected only in later stages of tumor progression, suggesting that haploinsufficiency of Smad4 is sufficient for tumor initiation. Our data also showed that overexpression of TGF-β1 and Cyclin D1 was associated with increased proliferation of gastric polyps and tumors. These studies demonstrate that Smad4 functions as a tumor suppressor in the gastrointestinal tract and also provide a valuable model for screening factors that promote or prevent gastric tumorigenesis. Oncogene (2000) 19, 1868–1874 [ABSTRACT FROM AUTHOR]