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Introduction: Prenatal exposure to stress has been associated with poor pregnancy outcomes, yet evidence linking stress and placental size is limited. Asthma is associated with worse pregnancy outcomes and women with asthma may be more susceptible to stress. Using the asthma-enriched B-WELL-Mom cohort, we examined the association between perceived stress and placental size., Methods: Placental measures of weight, length, width, and thickness were available for 345 women (262 with asthma) via placental pathology report. Perceived Stress Scale (PSS) scores were obtained in each trimester of pregnancy and categorized into quartiles (low quartile as reference). For associations between PSS and placental size, generalized estimating equations adjusted for maternal and infant factors were used to estimate regression coefficients (β) and 95% confidence intervals (95% CI). Full models and models stratified by asthma status were run., Results: Compared to Quartile 1, high levels of stress (Quartile 4) were associated with smaller placental weight (-20.63 95% CI: -37.01,-4.26) and length (-0.55 95% CI: -0.96,-0.15), but not width or thickness. Results by asthma status show a stronger association between perceived stress and shorter placental length in those with asthma and a stronger association between perceived stress and smaller placental thickness in those without asthma. Findings were robust to sensitivity analyses DISCUSSION: Higher levels of perceived stress were associated with smaller placental size. Additional research is warranted to understand the relationship between stress and placental size., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To determine frequency of hospital-acquired viral respiratory infections (HA-VRI) and associated outcomes in a NICU., Study Design: Prospective cohort study conducted from 4 October 2016 to 21 March 2017. Infants hospitalized from birth in the NICU had a weekly nasal swab collected for testing using a multiplex PCR assay capable of detecting 16 different respiratory viruses., Results: Seventy-four infants enrolled, with 5 (6.8%) testing positive for a virus (incidence rate of 1.3/1000 patient days). VRI positive infants had a younger gestational age (median 27 w vs. 32 w, p = 0.048); were hospitalized longer (97 d vs 43 d, p = 0.013); required more antibiotics (8 d vs. 4 d, p = 0.037) and were more likely to be diagnosed with bronchopulmonary dysplasia (p = 0.008) compared to VRI negative infants., Conclusion: Respiratory viruses are a frequent cause of HAI in the NICU and are associated with negative outcomes.

Rarely, liver tissue can be seen in the umbilical cord, where it is thought to result from ectopic localization during embryogenesis. The placental parenchyma is also a rare site for this occurrence. The exact pathophysiology of ectopic liver in the placenta is unknown. It has been considered that aberrant migration or displacement of cells from the developing hepatic buds leads to ectopic liver formation, including groups of liver cells that become entrapped in the foregut as the diaphragm closes. Additional hypotheses put forward have included monodermal teratoma and hepatocellular adenoma. While the lesions may not actually be adenomas, this term has been most utilized in the literature. Hepatocellular adenomas of the placenta are extremely rare; only 9 cases have been reported thus far. We report an additional occurrence of ectopic liver in the placenta, which is the only one reported in a stillborn, and review the literature.

Massive perivillous fibrinoid deposition (MFD) and maternal floor infarction (MFI) are lesions of unknown etiology associated with poor perinatal outcomes, including fetal intrauterine growth restriction and neurodevelopmental injury, high risks of pregnancy loss, and recurrence in subsequent gestations. MFI comprises massive intervillous fibrinoid deposition concentrated at the maternal floor. MFD is a similar lesion but is diffuse within the parenchyma. MFD/MFI lesions represent a spectrum of severity of cloak-like perivillous fibrinoid deposition, and there is mounting evidence that, often, they represent sequelae of immune-mediated phenomena and/or an imbalance in factors that normally maintain the fluidity of blood in the maternal space. There are only a handful of reported instances of discordant MFD/MFI occurrence in twin placentas. We present a fourth such occurrence in a fused, dichorionic diamniotic twin placenta and submit that our dizygotic twin gestation case provides additional supportive evidence that immune-mediated mechanisms are involved in the formation of pathological accumulations of fibrinoid, at least in some cases.

DNA methylation, a major epigenetic mechanism, may regulate coordinated expression of multiple genes at specific time points during alveolar septation in lung development. The objective of this study was to identify genes regulated by methylation during normal septation in mice and during disordered septation in bronchopulmonary dysplasia. In mice, newborn lungs (preseptation) and adult lungs (postseptation) were evaluated by microarray analysis of gene expression and immunoprecipitation of methylated DNA followed by sequencing (MeDIP-Seq). In humans, microarray gene expression data were integrated with genome-wide DNA methylation data from bronchopulmonary dysplasia versus preterm and term lung. Genes with reciprocal changes in expression and methylation, suggesting regulation by DNA methylation, were identified. In mice, 95 genes with inverse correlation between expression and methylation during normal septation were identified. In addition to genes known to be important in lung development (Wnt signaling, Angpt2, Sox9, etc.) and its extracellular matrix (Tnc, Eln, etc.), genes involved with immune and antioxidant defense (Stat4, Sod3, Prdx6, etc.) were also observed. In humans, 23 genes were differentially methylated with reciprocal changes in expression in bronchopulmonary dysplasia compared with preterm or term lung. Genes of interest included those involved with detoxifying enzymes (Gstm3) and transforming growth factor-β signaling (bone morphogenetic protein 7 [Bmp7]). In terms of overlap, 20 genes and three pathways methylated during mouse lung development also demonstrated changes in methylation between preterm and term human lung. Changes in methylation correspond to altered expression of a number of genes associated with lung development, suggesting that DNA methylation of these genes may regulate normal and abnormal alveolar septation.

Background: Otocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this developmental defect is largely unknown in humans., Methods and Results: This study reports a large family in which two cousins with micro/anophthalmia each gave birth to at least one child with otocephaly, suggesting a genetic relationship between anophthalmia and otocephaly. OTX2, a known microphthalmia locus, was screened in this family and a frameshifting mutation was found. The study subsequently identified in one unrelated otocephalic patient a sporadic OTX2 mutation. Because OTX2 mutations may not be sufficient to cause otocephaly, the study assayed the potential of otx2 to modify craniofacial phenotypes in the context of known otocephaly gene suppression in vivo. It was found that otx2 can interact genetically with pgap1, prrx1, and msx1 to exacerbate mandibular and midline defects during zebrafish development. However, sequencing of these loci in the OTX2-positive families did not unearth likely pathogenic lesions, suggesting further genetic heterogeneity and complexity., Conclusion: Identification of OTX2 involvement in otocephaly/dysgnathia in humans, even if loss of function mutations at this locus does not sufficiently explain the complex anatomical defects of these patients, suggests the requirement for a second genetic hit. Consistent with this notion, trans suppression of otx2 and other developmentally related genes recapitulate aspects of the otocephaly phenotype in zebrafish. This study highlights the combined utility of genetics and functional approaches to dissect both the regulatory pathways that govern craniofacial development and the genetics of this disease group.

Steroid sulfonation in the human brain has not been well characterized. The major sulfotransferase (SULT) isoforms that conjugate steroids in humans are SULT1E1, SULT2A1, and SULT2B1b. SULT2B1b catalyzes the sulfonation of 3β-hydroxysteroids, including neurosteroids dehydroepiandrosterone and pregnenolone, as well as cholesterol and several hydroxycholesterols. SULT2B1b mRNA and protein expression were detected in adult and fetal human brain sections, whereas neither mRNA, nor protein expression were identified for SULT1E1 or SULT2A1. Using immunohistochemical analysis, SULT2B1b expression was detected in neurons and oligodendrocytes in adult brain and in epithelial tissues in 28-week-old fetal brain. Sulfonation of cholesterol, oxysterols, and neurosteroids in the brain is apparently catalyzed by SULT2B1b since expression of neither SULT2A1 nor SULT1E1 was detected in human brain sections. SULT2B1b mRNA and protein were also detected in human U373-MG glioblastoma cells. Both mRNA and protein expression of liver X receptor (LXR)-β, but not LXR-α, were detected in U373-MG cells, and LXR-β activation resulted in a decrease in SULT2B1b protein expression. Since hydroxycholesterols are important physiological LXR activators, this suggests a role for regulation of sterol metabolism by LXR and SULT2B1b. Therefore, elucidating key enzymes in the metabolism of cholesterol and neurosteroids could help define the properties of steroid conjugation in the human brain.

Background: Congenital mediastinal teratomas are rare and may present with nonimmune hydrops. The lesion may be misinterpreted on ultrasound., Cases: A 21-year-old woman, gravida 2, para 0111, was evaluated at 19 4/7 weeks of gestation for suspected fetal death. An ultrasonogram confirmed the death and revealed a posterior encephalocele and possible herniated liver in the chest. At autopsy a 5.2 x 7.5 x 1.0-cm mediastinal teratoma completely compressed the chest organs. No encephalocele was present. A 15-year-old woman, gravida 1, para 0, underwent an ultrasonogram at 27 weeks when fetal heart rate decelerations were detected. The ultrasound revealed hydrops and suggested a calcified left cardiac ventricular wall and diaphragmatic hernia. Autopsy of the stillborn female showed an 8.0 x 6.0 x 4.0-cm teratoma in the mediastinum, with small heart and lungs. A 23 2/7 weeks stillborn female was delivered to a 32-year-old woman, gravida 5, para 2, and noted to be hydropic. Ultrasound had suggested multiple anomalies and hydrops. Autopsy revealed a 23 g, 4.5 x 3.0 x 3.0-cm teratoma that filled the anterior mediastinum., Conclusion: Congenital mediastinal teratoma may be associated with fetal death. It is within the differential diagnosis of nonimmune hydrops, particularly if a thoracic mass is detected on ultrasonography.

Objective: The purpose of this study was to determine the association between in utero exposure to acute inflammation and long-term major neurodevelopmental disability at age 6 years among children born prior to 32 weeks' gestation., Study Design: This was a follow-up investigation of a cohort of maternal-infant dyads delivered between 23 and < 32 weeks' gestation. Surviving infants (and their mothers or caregivers) underwent a battery of psychological and neurodevelopmental tests between 5 and 8 years of age. Pregnancy and neonatal data were analyzed among children with versus those without major neurodevelopmental disability (including IQ < 70 [n = 41], cerebral palsy [CP, n = 11], and a composite major disability [n = 52])., Results: A total of 261 (70%) of the 375 maternal-infant dyads with surviving children were successfully recruited and evaluated at 6.8 +/- 0.7 years. Mean delivery gestational age (GA) and birthweight were 28.8 +/- 2.2 weeks and 1163 +/- 382 g, respectively. Neither surrogate indicators for nor direct markers of in utero exposure to acute inflammation were significantly associated with severe adverse outcomes. Delivery GA was significantly associated with outcome. Logistic regression indicated that each increasing gestational week was associated with a significantly decreased risk of an IQ < 70 (OR 0.75, 95% CI 0.6-0.9). An average 1.9 point increase in IQ at 6 years of age was observed per gestational week gained (23 to 32 weeks). Periventricular leukomalacia was associated with a 9.6 point mean deficit in IQ. The perceptive vocabulary scores (IQ proxy) of primary caregivers were significantly lower among children with an IQ < 70 vs > or = 70 (87.5 +/- 11.5 vs 92.1 +/- 11.2, P = .016)., Conclusion: Among children born between 23 and 32 weeks' gestation, neonatal complications, GA at delivery, and caregiver IQ, but not in utero exposure to acute inflammation, were associated with increased risk of severe adverse neurodevelopmental outcomes at age 6 years.

Objective: This study was undertaken to evaluate the frequency of umbilical cord blood infections with Ureaplasma urealyticum and Mycoplasma hominis in preterm 23- to 32-week births and to determine their association with various obstetric conditions, markers of placental inflammation, and newborn outcomes., Study Design: 351 mother/infant dyads with deliveries between 23 and 32 weeks' gestational age who had cord blood cultures for U. urealyticum and M. hominis had their medical records abstracted, other placental cultures performed, cord interleukin-6 levels determined, placentas evaluated histologically, and infant outcomes determined., Results: U. urealyticum and/or M. hominis were present in 23% of cord blood cultures. Positive cultures were more common in infants of nonwhite women (27.9% vs 16.8%; P = .016), in women less than 20 years of age, in those undergoing a spontaneous compared to an indicated preterm delivery (34.7% vs 3.2%; P = .0001), and in those delivering at earlier gestational ages. Intrauterine infection and inflammation were more common among infants with a positive U. urealyticum and M. hominis culture as evidenced by placental cultures for these and other bacteria, elevated cord blood interleukin-6 levels, and placental histology. Infants with positive cord blood U. urealyticum and M. hominis cultures were more likely to have neonatal systemic inflammatory response syndrome (41.3% vs 25.7%; P = .007; adjusted odds ratio, 1.86; 1.08-3.21) and probably bronchopulmonary dysplasia (26.8% vs 10.1%; P = .0001; adjusted odds ratio 1.99; 0.91-4.37), but were not significantly different for other neonatal outcomes, including respiratory distress syndrome, intraventricular hemorrhage, or death., Conclusion: U. urealyticum and M. hominis cord blood infections are far more common in spontaneous vs indicated preterm deliveries and are strongly associated with markers of acute placental inflammation. Positive cultures are associated with neonatal systemic inflammatory response syndrome and probably bronchopulmonary dysplasia.

Objective: Laminar necrosis, a band-like distribution of coagulative necrosis, has been reported at the choriodecidual interface of the free membranes of placentas of women with various adverse neonatal outcomes. Our goal in this study was to evaluate the frequency of an equivalent feature in the decidua basalis, diffuse decidual leukocytoclastic necrosis (DDLN), a diffuse coagulative necrosis admixed with karyorrhectic debris, in preterm births <32 weeks, and to determine its association with various obstetric conditions, markers of placental inflammation, and newborn outcome., Study Design: Four hundred and forty-six mother/infant dyads who delivered between 23 and 32 weeks gestational age (GA) had their medical records abstracted, a variety of placental and cord blood cultures performed, cord interleukin-6 (IL-6) levels determined, and the placentas evaluated histologically by a single pathologist (OFP)., Results: Women with DDLN (27%) were significantly more likely than other women to have preeclampsia (57.6 vs. 24.8%, p < 0.0001), an indicated preterm birth in this pregnancy (61.9 vs. 26.4%, p < 0.0001), and a prior indicated preterm birth (12.7 vs. 4.1%, p = 0.001), but were not more likely to have an abruption, diabetes, to smoke or be Black. Among DDLN-positive vs. DDLN-negative women, birth weight was significantly lower (1,069 +/- 373 vs. 1,171 +/- 389 g, p = 0.014), despite the GAs being similar (28.6 +/- 2.2 vs. 28.6 +/- 2.3 weeks, p = NS). Women with DDLN were less likely to have a positive placental culture for any organism (50.0 vs. 61.3%p = 0.03), Ureaplasma urealyticum and Mycoplasma hominis in either the placenta or cord blood (29.7 vs. 42.1%, p = 0.02), or an elevated cord blood IL-6 (21.5 vs. 32.9%, p = 0.059). They also were less likely to have acute inflammation of the membranes (27.4 vs. 56.4%, p < 0.0001), chorionic plate (17.0 vs. 48.6%, p < 0.0001) or cord (15.7 vs. 36.6%, p < 0.0001). Decidual necrosis in the free membranes also occurred more frequently in the presence vs. absence of DDLN (25.2 vs. 9.2%, p < 0.0001). Infants whose placentas had DDLN were significantly less likely to have neonatal systemic inflammatory response syndrome (20.7 vs. 35.2%, p = 0.004), but were not significantly different for other neonatal outcomes including respiratory distress syndrome, intraventricular hemorrhage or death., Conclusion: DDLN of the decidua basalis is relatively common in placentas of 23-32 week newborns, and, when present, is inversely associated with inflammatory maternal and newborn conditions and positively associated with preeclampsia, indicated preterm birth, and lower birth weight. The positive correlation of DDLN with obstetrical and neonatal conditions associated with underperfusion of the placental bed, suggests that DDLN may be a marker of vascular compromise.

Objective: The purpose of this study was to better understand the relationship between placental polymorphonuclear and mononuclear cell infiltrations with bacterial cultures, markers of inflammation, and preterm outcomes., Study Design: This was a prospective study in 446 women who were delivered of a singleton infant at <32 weeks of gestational age. Five placental sites were categorized as having polymorphonuclear or mononuclear infiltrations. Results were compared with placental and cord cultures, umbilical cord interleukin-6 levels, and neonatal outcomes., Results: Polymorphonuclear, but not mononuclear, cell infiltrations were more common at the earliest gestational ages and in black women (56.0% vs 39.3%; P < .01). Polymorphonuclear infiltration was associated with spontaneous preterm birth (73.9% vs 8.0%; P < .0001), but not with preeclampsia (9.9% vs 34%; P < .0001). Women with positive cultures, high interleukin-6 levels, and clinical chorioamnionitis all had significantly more polymorphonuclear infiltrations than did women without those conditions (all probability values, <.0001). In all sites, polymorphonuclear infiltration was associated with neonatal systemic inflammatory response syndrome (P < .0001) and in the cord with necrotizing enterocolitis (22.4% vs 13.5%; P = .02). Intraventricular hemorrhage and neonatal death were not associated with polymorphonuclear infiltration. Polymorphonuclear infiltration at all sites was associated with less respiratory distress syndrome (P < .01). Mononuclear cell infiltration, when present in the decidua basalis, was associated with an increase in neonatal intraventricular hemorrhage (23.8% vs 7.4%; P < .0004). Plasmacytic infiltrates were associated with increased intraventricular hemorrhage (29.4% vs 8.3%; P = .01) and neonatal death (27.8% vs 9.2%; P = .02)., Conclusion: Polymorphonuclear infiltrations of the free membranes, chorionic plate, and umbilical cord were associated with positive intrauterine cultures and elevated cord blood interleukin-6. There was also an association with systemic inflammatory response syndrome and necrotizing enterocolitis, but not with intraventricular hemorrhage or death, and with decreased respiratory distress syndrome. Decidual mononuclear cell infiltration was associated with an increased risk of intraventricular hemorrhage and decidual plasma cell infiltration with increased intraventricular hemorrhage and neonatal death.

Objective: For unknown reasons, a previous preterm birth (PTB) is a major risk factor for PTB in the current pregnancy. Our goal is to evaluate placental histology for clues related to the recurrent nature of PTB., Study Design: Four hundred fifty-seven mother/infant dyads delivering between 23 and 32 weeks were first classified as having a spontaneous (S) or indicated (I) PTB, and then sorted into the following mutually exclusive categories by pregnancy history: 1) nulliparous; 2) having no previous PTB; 3) having any previous IPTB; or 4) having a previous SPTB. The placentas were evaluated for acute inflammation in the free membranes, umbilical cord, and chorionic plate, chronic inflammation in the membranes and decidua basalis, thrombosis in the chorionic plate and umbilical cord, and diffuse decidual leukocytoclastic necrosis (DDLN), a lesion associated with decreased placental perfusion., Results: Women who had a SPTB were far more likely (85.5 vs 14.4 P < .0001) to have a SPTB in the previous pregnancy, while women with an IPTB were significantly more likely to have had a previous IPTB (89.7 vs 10.3 P < .0001). Nulliparas and women with previous term births each had about 64% SPTB and 36% IPTB. Acute inflammation at any site was present in 73.9% of SPTB versus 8.0% of IPTB (P < .0001). Chorionic plate thrombosis was also more common in SPTB than IPTB (16.2 vs 7.6, P = .01). Chronic inflammation at any site was more common in IPTB than SPTB (21.0 vs 12.7%, P = .02), as was DDLN (46.5 vs 16.1, P < .0001). When classified by SPTB and IPTB in the current pregnancy, the histologic results were not further influenced by the previous pregnancy history., Conclusion: SPTB and IPTB are strongly repetitive. Women with SPTB are significantly more likely to have acute inflammation in the free membranes, chorionic plate, and cord, and chorionic plate thrombosis, while women with an IPTB are significantly more likely to have chronic inflammation and especially DDLN. Past obstetric history does not further influence the placental histology.

Otocephaly, characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia, is an extremely rare anomalad, identified in less than 1 in 70,000 births. The malformation spectrum is essentially lethal, because of ventilatory problems, and represents a developmental field defect of blastogenesis primarily affecting thefirst branchial arch derivatives. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. Polyhydramnios may be the presenting feature, but prenatal diagnosis has been uncommon. We present five new cases of otocephaly, the largest published series to date, with comprehensive review of the literature and an update of research in the etiopathogenesis of this malformation complex. One of our cases had situs inversus, and two presented with unexplained polyhydramnios. Otocephaly, while quite rare, should be considered in the differential diagnosis of this gestational complication.

Intrathoracic ectopic lobe of the liver in the presence of a normal intact diaphragm is extremely rare. We report a case of a 13-month-old male initially diagnosed with pneumonia and pulmonary sequestration who was found to have an intrathoracic liver lobe and intact diaphragm. The presence of this condition suggests an event preceding closure of the diaphragm and illustrates the unique potential of pediatric pathology to shed light on human embryology.

Clinically responsive placental examination seeks to provide useful information regarding the etiology, prognosis, and recurrence risk of pregnancy disorders. The purpose of this study was to assemble and validate a complete set of the placental reaction patterns seen with amniotic fluid infection in the hope that this might provide a standardized diagnostic framework useful for practicing pathologists. Study cases (14 with amniotic fluid infection, 6 controls) were reviewed blindly by six pathologists after agreement on a standard set of diagnostic criteria. After analysis of initial results, criteria were refined and a second, overlapping set of cases were reviewed. Majority vote served as the gold standard. Grading and staging of maternal and fetal inflammatory responses was found to be more reproducible using a two- versus three-tiered grading system than a three- versus five-tiered staging system (overall agreement 81% vs. 71%). Sensitivity, specificity, and efficiency for individual observations ranged from 67-100% (24/30 > 90%). Reproducibility was measured by unweighted kappa values and interpreted as follows: < 0.2, poor; 0.2-0.6, fair/moderate; > 0.6, substantial. Kappa values for the 12 lesions evaluated in 20 cases by the six pathologists were: acute chorioamnionitis/maternal inflammatory response (any, 0.93; severe 0.76; advanced stage, 0.49); chronic (subacute) chorioamnionitis (0.25); acute chorioamnionitis/fetal inflammatory response (any, 0.90; severe, 0.55; advanced stage, 0.52); chorionic vessel thrombi (0.37); peripheral funisitis (0.84); acute villitis (0.90); acute intervillositis/intervillous abscesses (0.65), and decidual plasma cells (0.30). Adoption of this clearly defined, clinically relevant, and pathologically reproducible terminology could enhance clinicopathologic correlation and provide a framework for future clinical research.

Expression of the surrogate light (psi L) chain genes encoding the VpreB and lambda 5/14.1 proteins is restricted to B-lineage cells. Pro-B and pre-B cells produce psi L chains, but whether both employ these as cell surface receptor components remains enigmatic. Recombinant human VpreB protein was used to generate a large panel of monoclonal anti-VpreB Abs to examine this issue. Native psi L chain proteins within pro-B cells as well as those serving as receptor components on pre-B cells were precipitated by 16 of the 26 anti-VpreB Abs. Surrogate light chains were easily detected on pre-B cell lines, whereas these anti-VpreB Abs reacted with pro-B cell lines only after plasma membrane permeabilization. The subpopulation of normal bone marrow cells bearing pre-B receptors included large and small pre-B cells exclusively, although pro-B cells also contained intracellular VpreB. VpreB proteins were not detected on or within B cells in bone marrow or the circulation, but a subpopulation of B cells in germinal centers was found to express the VpreB proteins intracellularly. Surrogate L chains are thus intermittently produced during human B-lineage differentiation, while their role as receptor components appears limited to the pre-B cell stage.

The placental pathology in two second trimester fetal losses associated with mild maternal disseminated intravascular coagulation are reported. Case one had a dental abscess, a leukocytosis of 36300 white blood cells/m, and evidence of mild consumptive coagulopathy at 20 weeks. Case two had septic findings including disseminated intravascular thrombosis associated with pyelonephritis. The placentae had extensive intervillous thrombosis at the periphery of spiral arterial flow. It is hypothesized that in mild disseminated intravascular coagulation, the trophoblast inhibits fibrinolysis, favouring thrombosis perhaps due to production of plasminogen activator inhibitor.

The ligand specificity of the integrin cell adhesion receptors probably determines the ability of specific integrins to promote tumor cell proliferation and metastasis. Therefore, we compared the expression of integrin alphaVbeta3, a promiscuous receptor that binds with high affinity to numerous cell matrix proteins, with the expression of integrin alphaVbeta5 and the integrin beta 1 subunit (which pairs with multiple alpha subunits) in neuroblastic tumors at various stages of differentiation. Undifferentiated neuroblastoma tumors rapidly invade and metastasize, whereas ganglioneuroblastomas rarely metastasize. Differentiating neuroblastomas are associated with an intermediate prognosis. Paraffin sections of neuroblastic tumors at various stages of differentiation obtained at biopsy from 17 patients were hybridized with antisense integrin subunit-specific alphaV, beta3, beta1, and beta5 riboprobes. All neuroblastic tumors and seven adrenal glands obtained at autopsy were analyzed immunohistochemically with antibodies directed toward the alphaV, beta3, beta1, and beta5 subunits. The alphaV subunit was expressed in neuroblastic tumors independent of the stage of differentiation, although mRNA and protein expression were generally weak in ganglioneuroblastomas, and was also detected in adrenal gland medullae. The beta1 subunit was detected in most neuroblastic tumors independent of the stage of differentiation as well as in adrenal gland medullae. In contrast, the beta3 subunit, which was not expressed in adrenal gland medullae, was expressed at the protein and mRNA levels in undifferentiated neuroblastomas (six of seven and seven of seven, respectively) but was not expressed in neuroblasts or ganglion cells in ganglioneuroblastomas (one case weakly positive out of five). The beta 5 subunit was expressed at the protein (five of five) and mRNA (four of five) levels in the ganglion cells of ganglioneuroblastomas and, although mRNA for this subunit was detectable in undifferentiated tumors, the protein was not detectable. The expression of integrin alphaVbeta3 in undifferentiated neuroblastomas may contribute to the rapid growth of these tumors and their tendency to metastasize.

Prostaglandin E1 (PGE1) causes skeletal hypertrophy, a phenomenon noted when it is administered for several weeks to maintain ductus arteriosus patency in neonates with congenital heart disease. This effect, a dose-dependent and reversible hyperostosis, was described radiologically as bone within bone, but skeletal histopathology was not studied. We compared postmortem gross, radiological, and histological bone findings for untreated controls and term gestation infants after 4, 27, and 56 days of continuous 0.1-0.2 microgram/kg/min PGE1. Bone was not significantly different from controls after 4 days of PGE1. Radiographs were negative after 27 days, but femoral cortex showed early periosteal osteoblast proliferation. At 56 days of PGE1, there was severe, radiologically apparent neocortex formation in tubular, rib, and scapular bones. Corresponding sections of femoral shaft revealed distinctive histopathology with thickened periosteum and fibrocartilage-like tissue covering an exuberant neocortex of closely aligned, gracile, woven bone trabeculae. Paratrabecular stroma contained ectatic capillaries orthogonally oriented to the periosteum, suggesting that a vascular reaction to PGE1 is important in the observed effect. The native cortex was partially resorbed; because it is stress shielded by the neocortex and no inflammation was present, this was interpreted as a secondary effect. We conclude that PGE1-associated paracortical bone hypertrophy is distinct from inflammatory processes and that its early stages may not be apparent radiologically. Moreover, the time course of PGE1-induced osteoblast proliferation and mineralization suggests that experimental use for 4-8 weeks may benefit conditions such as ununited fractures.

A 43-year-old white man with a history of cigarette smoking, hypertension, nephrolithiasis, and cervical degenerative arthritis was hospitalized for sudden-onset severe, substernal, and pleuritic chest pain with epigastric radiation. Despite evaluation, the cause remained unclear and the patient expired on hospital day 5. Autopsy revealed acute Stanford type A aortic dissection, hemopericardium, and hemothorax. Grossly, the aorta and its branches, including uninvolved medium-sized arteries, displayed extreme mural fragility. Microscopic examination showed a primary lymphoplasmacytic aortitis-periaortitis without giant cells. Rents within the tunica media, medial-adventitial inflammation, and elastic fiber disruption were limited to sites of gross aortic dissection. Muscular arteries showed patchy, chronic arteritis-periarteritis without giant cell infiltrate or aneurysm formation. This case documents an unusual association of primary lymphoplasmacytic aortitis and aortic dissection.

The enzyme, 3 beta-hydroxysteroid dehydrogenase/delta 5-4 isomerase (3 beta-HSD) is an essential element in the biosynthetic pathway for potent adrenal steroid hormones that appear to regulate maturation of many tissues in utero and are critical for homeostasis after birth. The results of prior studies are suggestive that 3 beta-HSD activity in the human fetal adrenal (HFA) is very low and restricted to the outer zone of cortical cells, the neocortex (NC), during mid-gestation. Near the time of birth, however, there must be enhanced expression of this enzyme to allow for adaptation to extrauterine life. In the present study, we sought to characterize, by use of immunohistochemical methods, the cellular localization and developmental changes of 3 beta-HSD in the HFA during the interval of 11-41 wks gestation. Early in gestation, 11-15 wks, we noted considerable 3 beta-HSD in NC and in occasional fetal zone (FZ) cells as well. Thereafter until 24-25 wks, 3 beta-HSD was very low in NC cells and virtually absent from the FZ. Throughout the third trimester, the outer 1/2-2/3 of the NC was increasingly immunostained and clusters of immunoreactive cells also appeared near the central medullary vein of the adrenal. The NC cells and those located in the cortical cuff region that expressed 3 beta-HSD resembled zona glomerulosa cells. Among many other fetal tissues studied, only testicular Leydig cells (18,19 wks) and hilar cells of the ovary (26 wks) were found to contain 3 beta-HSD in quantities sufficient to be detected by immunohistochemistry. These results are suggestive of a heretofore undocumented stimulus to 3 beta-HSD in the HFA in early gestation followed by a suppression of the adrenal concentration of this enzyme during mid-gestation. High levels of 3 beta-HSD in early development may facilitate cortisol production, which is believed to play a role in differentiation of the medullary precursors during this developmental period. The control of adrenal 3 beta-HSD during human fetal development may be more complex than initially envisioned and requires further study.

Hemangiomas are the most common tumor of the head and neck in children, including intracranial neoplasms. Capillary hemangioma in turn is the commonest type of hemangioma. Our case establishes that its anatomic distribution may include the intracranial compartment. We were unable to distinguish capillary hemangioma from meningioma based on imaging findings alone.

The case of a combined intra- and extraspinal neurenteric cyst in an infant is reported. This case is unique because an intraspinal cyst was not suspected clinically until large numbers of squamous epithelial cells were obtained at lumbar puncture performed as part of a workup for a septic entity. The cyst extended from an intradural location ventral to the conus medullaris at L-1 through a ventrolateral defect in the S-4 vertebral body to communicate with a large presacral component. The entire cystic cavity was lined by stratified squamous epithelium. The possible pathogenesis of this lesion is discussed.

A female infant born at term to phenotypically normal nonconsanguinous parents had hypertension, thrombocytopenia, hydrocephalus, callosal agenesis, and nonlethal rhizomelic osteochondrodysplasia. Her osteochondrodysplasia was characterized roentgenographically by shortening and metaphyseal broadening of long bones, without bowing, and by platyspondyly, with deficient ossification of dorsal and central portions of vertebral bodies. By light microscopy, the iliac crest growth plate showed expansion of the zone of chondrocyte hypertrophy and degeneration, with faulty columnar alignment, sparse vascular ingrowth, and irregular mineralization at the zone of chondroosseous transformation. These findings appear to define a novel osteochondrodysplasia, which in association with hypertension, thrombocytopenia, hydrocephalus, and callosal agenesis may constitute a new syndrome.

We describe an 18-year-old white male who developed lower extremity ischemia requiring amputation. He presented at 14 with pulmonary infiltrates, hepatosplenomegaly, fever, rash, adenopathy, uveitis, and arthralgias; clinical and laboratory findings were consistent with Mycoplasma pneumoniae infection. Despite adequate treatment with antibiotics, he developed chronic arthralgias and fevers, with rash and pericardial effusion. Criteria for the diagnosis of systemic lupus erythematosus were not met; juvenile rheumatoid arthritis was diagnosed presumptively. Over the subsequent 4 years he developed lymphadenopathy with biopsy-proven nonnecrotizing granulomas, chronic leg ulceration with granulomatous histology, and acute-onset impending gangrene of the left foot. A biopsy of the posterior tibial artery demonstrated giant cell arteritis. Although the histologic features were consistent with Takayasu's arteritis, complete aortic arteriography was normal. Examination of the amputated leg showed multifocal segmental giant cell arteritis. Clinicopathologic features suggested, but were not fully consistent with, juvenile systemic granulomatosis. His disease may represent a separate sarcoid-like entity in the broad spectrum of vasculitis.

Bony abnormalities caused by thanatophoric dysplasia affect the base of the skull and the vertebrae as well as the ribs and appendicular long bones. We present our findings in a full-term infant with thanatophoric dysplasia in whom the posterior fossa, the rostral vertebral column, and the neuraxis at and adjoining the craniovertebral junction were studied by dissection, roentgenography, and histologic examination. In this infant, malformations of the vertebral laminae, most prominent in the basiocciput and atlas vertebra, led to compression of the rostral cervical spinal cord, causing gliosis and focal necrosis. Stenosis of the foramen magnum and spinal canal may contribute to the ventilatory insufficiency that often causes death in patients with thanatophoric dysplasia. We suggest that the causes of death in patients with thanatophoric dysplasia and other severe forms of osteochondrodysplasia should be sought in neuraxial injury rather than attributed solely to pulmonary hypoplasia.

An unusual case of heterotopic brain tissue was confused as a lymphangioma in the neck. Although these lesions are rare, they should be included in the differential diagnosis of congenital head and neck masses. They can compress and deform surrounding structures and cause airway obstruction in the newborn. Excision is curative, but the possibility of encephalocele should be eliminated by prior computed tomography scan.