Fetal Supraventricular Tachycardia: Histologic Evidence of Accessory Pathways Due to Incomplete Annulus Fibrosus Formation.

BACKGROUND: Atrioventricular (AV) reentrant tachycardia is a common type of supraventricular tachycardia (SVT) that occurs in the fetus and neonate. Although many tachycardias resolve within several weeks of birth or respond to medical management, disruptions in the cardiac annulus fibrosus and development of additional accessory pathways may lead to refractory dysrhythmia resulting in fetal hydrops and ultimately, fetal death. OBJECTIVES: While accessory pathways have been well documented anatomically in adult and childhood tachyarrhythmias, there are no reports of the histology of these pathways in human fetuses with SVT. RESEARCH DESIGN, SUBJECTS, MEASURES: This is a small case series of 2 fetuses with a history of SVT that resulted in fetal hydrops. RESULTS: In both cases, examination of the cardiac conduction system was unremarkable and examination of the atrioventricular junction revealed a focally thinned and/or discontinuous annulus fibrosus with documented direct continuity between the atrial and ventricular myocardium in 1 case. CONCLUSIONS: This case series demonstrates that thinning or absence of the annulus fibrosus is a feature seen in fetal SVT, and the development of subsequent aberrant AV connections due to defective formation of the annulus fibrosus suggests a possible cause for these arrhythmias.

Zika Virus Infection of Pregnant Ifnar1-/- Mice Triggers Strain-Specific Differences in Fetal Outcomes.

Zika virus (ZIKV) is a flavivirus that causes a constellation of adverse fetal outcomes collectively termed congenital Zika syndrome (CZS). However, not all pregnancies exposed to ZIKV result in an infant with apparent defects. During the 2015 to 2016 American outbreak of ZIKV, CZS rates varied by geographic location. The underlying mechanisms responsible for this heterogeneity in outcomes have not been well defined. Therefore, we sought to characterize and compare the pathogenic potential of multiple Asian-/American-lineage ZIKV strains in an established Ifnar1-/- pregnant mouse model. Here, we show significant differences in the rate of fetal demise following maternal inoculation with ZIKV strains from Puerto Rico, Panama, Mexico, Brazil, and Cambodia. Rates of fetal demise broadly correlated with maternal viremia but were independent of fetus and placenta virus titer, indicating that additional underlying factors contribute to fetal outcome. Our results, in concert with those from other studies, suggest that subtle differences in ZIKV strains may have important phenotypic impacts. With ZIKV now endemic in the Americas, greater emphasis needs to be placed on elucidating and understanding the underlying mechanisms that contribute to fetal outcome. IMPORTANCE Zika virus (ZIKV) transmission has been reported in 87 countries and territories around the globe. ZIKV infection during pregnancy is associated with adverse fetal outcomes, including birth defects, microcephaly, neurological complications, and even spontaneous abortion. Rates of adverse fetal outcomes vary between regions, and not every pregnancy exposed to ZIKV results in birth defects. Not much is known about how or if the infecting ZIKV strain is linked to fetal outcomes. Our research provides evidence of phenotypic heterogeneity between Asian-/American-lineage ZIKV strains and provides insight into the underlying causes of adverse fetal outcomes. Understanding ZIKV strain-dependent pathogenic potential during pregnancy and elucidating underlying causes of diverse clinical sequelae observed during human infections is critical to understanding ZIKV on a global scale.

African-Lineage Zika Virus Replication Dynamics and Maternal-Fetal Interface Infection in Pregnant Rhesus Macaques.

Following the Zika virus (ZIKV) outbreak in the Americas, ZIKV was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital Zika syndrome (CZS). The viruses responsible for this outbreak belonged to the Asian lineage of ZIKV. However, in vitro and in vivo studies assessing the pathogenesis of African-lineage ZIKV demonstrated that African-lineage isolates often replicated to high titers and caused more-severe pathology than Asian-lineage isolates. To date, the pathogenesis of African-lineage ZIKV in a translational model, particularly during pregnancy, has not been rigorously characterized. Here, we infected four pregnant rhesus macaques with a low-passage-number strain of African-lineage ZIKV and compared its pathogenesis to those for a cohort of four pregnant rhesus macaques infected with an Asian-lineage isolate and a cohort of mock-inoculated controls. The viral replication kinetics for the two experimental groups were not significantly different, and both groups developed robust neutralizing antibody titers above levels considered to be protective. There was no evidence of significant fetal head growth restriction or gross fetal harm at delivery (1 to 1.5 weeks prior to full term) in either group. However, a significantly higher burden of ZIKV viral RNA (vRNA) was found in the maternal-fetal interface tissues of the macaques exposed to an African-lineage isolate. Our findings suggest that ZIKV of any genetic lineage poses a threat to pregnant individuals and their infants. IMPORTANCE ZIKV was first identified in 1947 in Africa, but most of our knowledge of ZIKV is based on studies of the distinct Asian genetic lineage, which caused the outbreak in the Americas in 2015 to 2016. In its most recent update, the WHO stated that improved understanding of African-lineage ZIKV pathogenesis during pregnancy must be a priority. The recent detection of African-lineage isolates in Brazil underscores the need to understand the impact of these viruses. Here, we provide the first comprehensive assessment of African-lineage ZIKV infection during pregnancy in a translational nonhuman primate model. We show that African-lineage isolates replicate with kinetics similar to those of Asian-lineage isolates and can infect the placenta. However, there was no evidence of more-severe outcomes with African-lineage isolates. Our results highlight both the threat that African-lineage ZIKV poses to pregnant individuals and their infants and the need for epidemiological and translational in vivo studies with African-lineage ZIKV.

Dissecting the Cardiac Conduction System: Is It Worthwhile?

BACKGROUND: Pathologic examination of conduction system (CS) is not routinely performed, and histologic changes are mostly reported in forensic practice. METHODS: We studied the value of dissecting the CS in a cohort of pediatric patients with unexplained sudden death or severe, inexplicable arrhythmias. Histopathologic changes present in CS components were recorded and correlated with findings noted in other cardiac structures. RESULTS: Twenty-one subjects (11 unexplained sudden deaths and 10 life-threatening arrhythmias) were identified; 18 (86%) had CS pathologic abnormalities. In 13 patients (62%), the CS findings mirrored those found in other cardiac sections (inflammation, allograft vasculopathy, vascular fibromuscular dysplasia, cardiomyopathy-related changes, and tumor/tumor-like conditions). Five cases (24%) had abnormalities restricted to CS (bundle of His [BH] with fibrotic scar and patch material following ventricular septal defect repair, inflammation, BH with fibrosis and calcifications, and intimal fibroplasia of sinoatrial node artery). CONCLUSIONS: Pathologic changes within the CS are present in a high number of pediatric patients presenting with unexplained sudden death or life-threatening arrhythmias. Frequently, the findings mirror those observed in other cardiac structures. However, in a significant number of cases (24%), the changes are restricted to CS and likely explain the patients' symptoms or cause of death, suggesting that systematic dissection of CS unveils valuable information.

Presence of Germ Cells in Disorders of Sex Development: Implications for Fertility Potential and Preservation.

PURPOSE: We sought to determine the presence of germ cells in the gonads of patients with disorders of sex development to establish whether preservation of germ cells for future fertility potential is possible. We hypothesized that germ cells are present but vary by age and diagnosis. MATERIALS AND METHODS: We reviewed histology from patients with disorders of sex development who underwent gonadectomy/biopsy from 2002 to 2014 at a single institution for pathological classification of the gonad, composition of gonadal stroma and germ cell presence. RESULTS: A total of 44 patients were identified and germ cells were present in 68%. The presence and average number of germ cells per mm2 were analyzed by gonad type and diagnosis. By gonad type all ovotestes, most testes, ovaries and dysgenetic testes, and 15% of streak gonads had germ cells present. By diagnosis germ cells were present in all patients with complete androgen insensitivity syndrome, Denys-Drash syndrome, SRY mutation, mixed gonadal dysgenesis, ovotesticular conditions and StAR (steroid acute regulatory protein) deficiency, in some patients with persistent müllerian duct syndrome, XO/XY Turner syndrome and disorders of sex development not otherwise specified, and in none with complete or partial gonadal dysgenesis. Germ cells were present in the gonads of 88% of patients 0 to 3 years old, 50% of those 4 to 11 years old and 43% of those older than 12 years. CONCLUSIONS: Germ cells were present in the majority of our cohort and the presence decreased with age. This novel, fertility driven evaluation of germ cell quantity in a variety of disorders of sex development suggests that fertility potential may be greater than previously thought. Further studies must be done to evaluate a larger population and examine germ cell quality to determine the viability of these germ cells.

Ferumoxytol-enhanced magnetic resonance imaging with volume rendering: A new approach for the depiction of internal placental structure in vivo.

INTRODUCTION: Placental function is vitally important, but placental assessment is limited by current imaging methods in vivo. The goal of this study is to determine if ferumoxytol-enhanced MR studies might be used to depict placental structure during pregnancy. METHODS: Ten pregnant women were referred for MRI evaluation of abnormal placentation. The study group was composed five of these patients whose placentas were normal at pathology. MR studies consisted of pre-contrast SSFSE (single-shot fast spin-echo), SSFP (steady-state free procession), diffusion, and ferumoxytol-enhanced acquisitions. The post-contrast sequences were compared to pre-contrast SSFSE, SSFP, and diffusion acquisitions for features of correspondence. MR images were also compared to histopathology for anatomic landmarks including the three-ring pattern of the functional vascular exchange unit (the placentone) created by this central cavity surrounded by a ring of clustered villi, and an outer ring of dispersed villi corresponding to the maternal venous outflow channel. The measured sizes of these features on MR were compared to reported sizes. RESULTS: Post-ferumoxytol images showed enhancement of the maternal blood within the placenta, notably the intervillous space and the myometrial vessels. The unenhanced fetal vessels were most visible on the MinIP (minimum intensity projection) images; the enhanced maternal vessels were most visible on the MIP (maximum intensity projection) images. Composite MIP/MinIP images show the relation of maternal and fetal circulations. The signal intensities replicate the relative contributions from enhanced maternal blood and unenhanced chorionic villi. DISCUSSION: Ferumoxytol-enhanced MR imaging can depict the internal anatomy of the placenta in vivo of clarity and detail. This could represent a new diagnostic approach to placental disorders.

Normal placental structural anatomy: ultrasound and doppler features elucidated with US-MR image fusion and ferumoxytol-enhanced MRI.

PURPOSE: To elucidate ultrasound features of normal placental anatomy through correlation of gray-scale and ultrasound Doppler with ferumoxytol-enhanced MRI features using US-MR image fusion. METHODS: All patients referred to MR for ultrasound findings worrisome for PAS (placenta accreta spectrum) were included in this retrospective study. MR studies included a ferumoxytol-enhanced T1-weighted MRI. Ultrasound imaging included gray-scale, color Doppler, power Doppler, and spectral Doppler techniques. After the MR, US-MRI fusion was performed by co-registering a MR acquisition to real-time US, which allowed precise, point-to-point correlation of placental features. RESULTS: Fourteen patients at risk for PAS were studied using the US-MR image fusion. At delivery, there were six cases without PAS (gestational age range: 24 weeks 3 days to 34 weeks 0 days), and these composed the study cohort. Placental features that were on high signal intensity on post-ferumoxytol acquisitions represent spaces with maternal blood flow and corresponded to hypoechoic areas on ultrasound created by a paucity of reflective interfaces (villi). Color and spectral Doppler allowed the separation of maternal and fetal circulations in individual perfusional domains and demonstrated spiral artery inflow, circulation around the villous tree, and return of blood flow to the basal plate. Recognizable histopathologic features by ultrasound included the central cavity, villous tree, and venous return channels. CONCLUSION: Internal placental architecture can be discerned on ultrasound. This anatomy can be correlated and confirmed with ferumoxytol-MR through US-MR fusion. Understanding this structural anatomy on ultrasound could serve as a basis to identify normal and abnormal placental features.

Ferumoxytol-enhanced MR demonstration of changes to internal placental structure in placenta accreta spectrum: Preliminary findings.

INTRODUCTION: The goal of this pilot study is to determine if ferumoxytol-enhanced MR might provide a new approach to the diagnosis of placenta accreta spectrum (PAS), and if so, to identify signs of PAS. METHODS: Ten pregnant women were referred for MRI evaluation for PAS. MR studies consisted of pre-contrast SSFSE, SSFP, DWI, and ferumoxytol-enhanced sequences. Post-contrast images were rendered as MIP and MinIP images to separately display the maternal and fetal circulations respectively. Two readers examined the images for architectural changes to placentone (fetal cotyledon) that might distinguish PAS cases from normal. Attention was given to the size and morphology of the placentone, villous tree, and vascularity. In addition, the images were examined for evidence of fibrin/fibrinoid, intervillous thrombus, basal and chorionic plate bulges. Interobserver agreement was characterized with kappa coefficients and levels of confidence for feature identification was recorded on a 10-point scale. RESULTS: At delivery, there were five normal placentas and five with PAS (one accreta, two increta, two percreta). The ten changes of placental architecture in PAS included: focal/regional expansion of placentone(s); lateral displacement and compression of the villous tree; disruption of a regular pattern of normal placentones; bulging of the basal plate; bulging of the chorionic plate; transplacental stem villi; linear/nodular bands at basal plate; non-tapering villous branches; intervillous hemorrhage; and dilated subplacental vessels. All these changes were more common in PAS; the first five achieved statistical significance in this small sample. The interobserver agreement and confidence for the identification of these features was good to excellent except for dilated subplacental vessels. DISCUSSION: Ferumoxytol-enhanced MR imaging appears to depict derangements of the internal architecture of placentas with PAS, thereby suggesting a promising new strategy to diagnose PAS.

Organ weight changes associated with body mass index determined from a medical autopsy population.

CONTEXT: Existing organ weight charts used by pathologists for patients undergoing medical autopsy do not illustrate the effect of obesity and age on organ weights among a general population of older individuals with multiple comorbidities. METHODS: We retrospectively reviewed 300 medical autopsy reports to extract data to analyze the effect of obesity and age on organ weights. RESULTS: In both men and women, there were statistically significant increases in organ weights with body mass index (BMI) but decreases with age for liver, spleen, and kidneys. In men, increased age was associated with increased left ventricular wall thickness, whereas increased BMI was associated with increased heart weight. In women, only BMI was associated with changes in all 3 anatomic cardiac parameters (heart weight and thickness of the right and left ventricular walls). Age effects were not observed for heart parameters in women. Thyroid weight increased with BMI in men but not in women. CONCLUSIONS: The findings demonstrate changes in organ weights/sizes with obesity and age in a population of patients with multiple comorbidities. The differential effects of age and BMI on the heart between men and women raise the possibility that increased BMI in women may have a greater impact on cardiovascular causes of death than that in men.

Human immune globulin treatment controls Zika viremia in pregnant rhesus macaques.

There are currently no approved drugs to treat Zika virus (ZIKV) infection during pregnancy. Hyperimmune globulin products such as VARIZIG and WinRho are FDA-approved to treat conditions during pregnancy such as Varicella Zoster virus infection and Rh-incompatibility. We administered ZIKV-specific human immune globulin as a treatment in pregnant rhesus macaques one day after subcutaneous ZIKV infection. All animals controlled ZIKV viremia following the treatment and generated robust levels of anti-Zika virus antibodies in their blood. No adverse fetal or infant outcomes were identified in the treated animals, yet the placebo control treated animals also did not have signs related to congenital Zika syndrome (CZS). Human immune globulin may be a viable prophylaxis and treatment option for ZIKV infection during pregnancy, however, more studies are required to fully assess the impact of this treatment to prevent CZS.

Previous exposure to dengue virus is associated with increased Zika virus burden at the maternal-fetal interface in rhesus macaques.

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that macaques with a prior DENV-2 exposure had a higher burden of ZIKV vRNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.

Predicting relapse in favorable histology Wilms tumor using gene expression analysis: a report from the Renal Tumor Committee of the Children's Oncology Group.

PURPOSE: The past two decades has seen significant improvement in the overall survival of patients with favorable histology Wilms tumor (FHWT); however, this progress has reached a plateau. Further improvements may rely on the ability to better stratify patients by risk of relapse. This study determines the feasibility and potential clinical utility of classifiers of relapse based on global gene expression analysis. EXPERIMENTAL DESIGN: Two hundred fifty FHWT of all stages enriched for relapses treated on National Wilms Tumor Study-5 passed quality variables and were suitable for analysis using oligonucleotide arrays. Relapse risk stratification used support vector machine; 2- and 10-fold cross-validations were applied. RESULTS: The number of genes associated with relapse was less than that predicted by chance alone for 106 patients (32 relapses) with stages I and II FHWT treated with chemotherapy, and no further analyses were done. This number was greater than expected by chance for 76 local stage III patients. Cross-validation including an additional 68 local stage III patients (total 144 patients, 53 relapses) showed that classifiers for relapse composed of 50 genes were associated with a median sensitivity of 47% and specificity of 70%. CONCLUSIONS: This study shows the feasibility and modest accuracy of stratifying local stage III FHWT using a classifier of <50 genes. Validation using an independent patient population is needed. Analysis of genes differentially expressed in relapse patients revealed apoptosis, Wnt signaling, insulin-like growth factor pathway, and epigenetic modification to be mechanisms important in relapse. Potential therapeutic targets include FRAP/MTOR and CD40.

Spondweni virus causes fetal harm in Ifnar1-/- mice and is transmitted by Aedes aegypti mosquitoes.

Spondweni virus (SPONV) is the most closely related known flavivirus to Zika virus (ZIKV). Its pathogenic potential and vector specificity have not been well defined. SPONV has been found predominantly in Africa, but was recently detected in a pool of Culex quinquefasciatus mosquitoes in Haiti. Here we show that SPONV can cause significant fetal harm, including demise, comparable to ZIKV, in a mouse model of vertical transmission. Following maternal inoculation, we detected infectious SPONV in placentas and fetuses, along with significant fetal and placental histopathology, together suggesting vertical transmission. To test vector competence, we exposed Aedes aegypti and Culex quinquefasciatus mosquitoes to SPONV-infected bloodmeals. Aedes aegypti could efficiently transmit SPONV, whereas Culex quinquefasciatus could not. Our results suggest that SPONV has the same features that made ZIKV a public health risk.

Chromatin context dominates estrogen regulation of pS2 gene expression.

Chromatin structure and transcription factor activity collaborate to set the transcription level of a gene. Our understanding of the relative contributions of each of these factors at a specific gene is limited. We studied the effects of an altered chromatin environment on the activity of the estrogen-responsive pS2 promoter. We created stable cell lines with the pS2 promoter situated in an alternative chromatin site in addition to it being in its native site. Both promoters were estrogen-responsive for estrogen receptor alpha (ERalpha) recruitment, but transcription was inducible only at the native site. At the recombinant site, transcription was high and constitutive. Higher histone H3 and H4 acetylation (acH3 and acH4), as well as trimethylated lysine 4 on histone H3 levels, was observed at the recombinant site compared to the native site in vehicle treated cells. Inhibition of histone deacetylases (HDACs) resulted in increased acH4, but only modest increases in acH3, ERalpha binding and basal transcription at the native pS2 site. Inhibiting HDACs had no effect on transcription from the recombinant site. These data suggest that highly active chromatin is not only permissive for transcription, but can override the requirement for the transcription factor at an inducible promoter.

High histone acetylation and decreased polycomb repressive complex 2 member levels regulate gene specific transcriptional changes during early embryonic stem cell differentiation induced by retinoic acid.

Histone modifications play a crucial role during embryonic stem (ES) cell differentiation. During differentiation, binding of polycomb repressive complex 2 (PRC2), which mediates trimethylation of lysine 27 on histone H3 (K27me3), is lost on developmental genes that are transcriptionally induced. We observed a global decrease in K27me3 in as little as 3 days after differentiation of mouse ES cells induced by retinoic acid (RA) treatment. The global levels of the histone K27 methyltransferase EZH2 also decreased with RA treatment. A loss of EZH2 binding and K27me3 was observed locally on PRC2 target genes induced after 3 days of RA, including Nestin. In contrast, direct RA-responsive genes that are rapidly induced, such as Hoxa1, showed a loss of EZH2 binding and K27me3 after only a few hours of RA treatment. Following differentiation induced by leukemia inhibitor factor (LIF) withdrawal without RA, Hoxa1 was not transcriptionally activated. Small interfering RNA-mediated knockdown of EZH2 resulted in loss of K27me3 during LIF withdrawal, but the Hoxa1 gene remained transcriptionally silent after loss of this repressive mark. Induction of histone hyperacetylation overrode the repressive K27me3 modification and resulted in Hoxa1 gene expression. Together, these data show that there are multiple temporal phases of derepression of PRC2 target genes during ES cell differentiation and that other epigenetic marks (specifically, increased acetylation of histones H3 and H4), in addition to derepression, are important for gene-specific transcriptional activation. This report demonstrates the temporal interplay of various epigenetic changes in regulating gene expression during early ES cell differentiation.

Embryonic stem cell biology.

ES cell research represents an exploding field of exploration. Initially predicted to provide rapid cures for numerous human diseases, the clinical usefulness of ES cell-derived cells remains untested in humans. However, ES cells have rapidly expanded our knowledge of human development and the molecular details of differentiation. Our ability to generate relatively pure populations of specifically differentiated cells for transplantation has markedly improved. It is hoped that soon researchers will overcome the biologic impediments to successful treatment of human disease with ES cell-derived cells.

The Placental Distal Villous Hypoplasia Pattern: Interobserver Agreement and Automated Fractal Dimension as an Objective Metric.

The distal villous hypoplasia (DVH) pattern is a placental correlate of fetal growth restriction. Because the pattern seems to involve less complexity than do appropriately developed placental villi, we postulated that it may be associated with lower fractal dimension-a mathematical measure of complexity. Our study objectives were to evaluate interobserver agreement related to the DVH pattern among expert pathologists and to determine whether pathologist classification of DVH correlates with fractal dimension. A study set of 30 images of placental parenchyma at ×4 magnification was created by a single pathologist from a digital slide archive. The images were graded for the DVH pattern according to pre-specified definitions and included 10 images graded as "no DVH" (grade  =  0), 10 with mild to moderate DVH (grade  =  1), and 10 with severe DVH (grade  =  2). The images were randomly sorted and shown to a panel of 4 international experts who similarly graded the images for DVH. Weighted kappas were calculated. For each image, fractal dimension was calculated by the Box Counting method. The correlation coefficient between (1) the averaged DVH scores obtained by the 5 pathologists and (2) fractal dimension was calculated. The mean weighted kappa score among the observers was 0.59 (range: 0.42-0.70). The correlation coefficient between fractal dimension and the averaged DVH score was -0.915 (P < 0.001). Expert pathologists achieve fair to substantial agreement in grading DVH, indicating consensus on the definition of DVH. Distal villous hypoplasia correlates extremely well with fractal dimension and represents an objective measure for DVH.

Osteochondroma With Contiguous Bronchogenic Cyst of the Scapula.

Osteochondroma is a benign bone tumor composed of a bony protrusion with an overlying cartilage cap. Osteochondromas arise in the scapula in 3% to 5% of cases, making them the most common benign bone tumor in this location. Scapular osteochondromas cause various pathologies of the shoulder girdle, including snapping scapula syndrome, chest wall deformity, shoulder impingement, and bursa formation. Bronchogenic cyst is an exceedingly rare finding in the periscapular area. It is a congenital cystic mass lined by tracheobronchial structures and respiratory epithelium. To our knowledge, there are no reports of a contiguous osteochondroma and bronchogenic cyst. A 12-month-old boy presented with an incidentally noted mass on the spine of the scapula, which drained scant, clear fluid through an adjacent pinprick-sized hole. Imaging revealed an exostosis with an adjacent cystic mass. The mass and cyst were excised en bloc, and histopathologic examination confirmed the diagnosis of osteochondroma with contiguous bronchogenic cyst. In this case, we present the report of a novel dual lesion.

Placental mesenchymal dysplasia without fetal development in a twin gestation: a case report and review of the spectrum of androgenetic biparental mosaicism.

We report a dichorionic twin gestation with diffuse placental mesenchymal dysplasia (PMD) and androgenetic biparental mosaicism (ABM) involving one twin's placenta with complete absence of fetal development for that twin. To our knowledge, this is the 1st reported case of PMD without fetal development. We discuss the gross, histologic, and genetic hallmarks of PMD and the spectrum of variability depending on degree and distribution of ABM.

Transcription factor accessibility and histone acetylation of the progesterone receptor gene differs between parental MCF-7 cells and a subline that has lost progesterone receptor expression.

The human progesterone receptor (PgR) gene has a complex promoter that produces alternate mRNAs encoding the PgRA (94 kDa) and PgRB (120 kDa) protein isoforms. Expression of PgR is induced by estradiol (E(2)) in the breast, reproductive tract and many cell lines despite the lack of a classical estrogen responsive element (ERE) in the promoter regions. We employed chromatin immunoprecipitation (ChIP) to analyze the sites of estrogen receptor alpha (ERalpha) and Sp1 occupancy of the PgR promoters in vivo. We also assessed the functional relevance of histone acetylation levels on the accessibility of transcription factors to the promoter and subsequent hormone-induced transcription. We utilized MCF-7 human breast cancer cells that express PgR in response to E(2) and the MCF-7 derived C4 cell strain that has lost PgR expression as a model system. We found that promoter-wide levels of histone acetylation were not decreased in C4 cells, but that access was partially blocked for Sp1 and completely blocked for ERalpha. The basal level of histone acetylation at six localized regions of the promoter did show some differences between cell lines, but it did not correlate with transcription factor binding. Furthermore, we found only a modest and highly localized change in histone acetylation levels in response to E(2) at only one of three sites of ERalpha binding in MCF-7 cells. This was at the B1 site at the distal 5' end of the promoter. This site also showed a significant decrease in basal histone acetylation in C4 compared to MCF-7 cells. We speculate that the histone acetylation level at this site may be a marker for chromatin structure that affects the access of transcription factors to the whole promoter.