High rates of placental inflammation among samples collected by the Multi-Omics for Mothers and Infants consortium.

BACKGROUND: The Multi-Omics for Mothers and Infants consortium aims to improve birth outcomes. Preterm birth is a major obstetrical complication globally and causes significant infant and childhood morbidity and mortality. OBJECTIVE: We analyzed placental samples (basal plate, placenta or chorionic villi, and the chorionic plate) collected by the 5 Multi-Omics for Mothers and Infants sites, namely The Alliance for Maternal and Newborn Health Improvement Bangladesh, The Alliance for Maternal and Newborn Health Improvement Pakistan, The Alliance for Maternal and Newborn Health Improvement Tanzania, The Global Alliance to Prevent Prematurity and Stillbirth Bangladesh, and The Global Alliance to Prevent Prematurity and Stillbirth Zambia. The goal was to analyze the morphology and gene expression of samples collected from preterm and uncomplicated term births. STUDY DESIGN: The teams provided biopsies from 166 singleton preterm (<37 weeks' gestation) and 175 term (≥37 weeks' gestation) deliveries. The samples were fixed in formalin and paraffin embedded. Tissue sections from these samples were stained with hematoxylin and eosin and subjected to morphologic analyses. Other placental biopsies (n=35 preterm, 21 term) were flash frozen, which enabled RNA purification for bulk transcriptomics. RESULTS: The morphologic analyses revealed a surprisingly high rate of inflammation that involved the basal plate, placenta or chorionic villi, and the chorionic plate. The rate of inflammation in chorionic villus samples, likely attributable to chronic villitis, ranged from 25% (Pakistan site) to 60% (Zambia site) of cases. Leukocyte infiltration in this location vs in the basal plate or chorionic plate correlated with preterm birth. Our transcriptomic analyses identified 267 genes that were differentially expressed between placentas from preterm vs those from term births (123 upregulated, 144 downregulated). Mapping the differentially expressed genes onto single-cell RNA sequencing data from human placentas suggested that all the component cell types, either singly or in subsets, contributed to the observed dysregulation. Consistent with the histopathologic findings, gene ontology analyses highlighted the presence of leukocyte infiltration or activation and inflammatory responses in both the fetal and maternal compartments. CONCLUSION: The relationship between placental inflammation and preterm birth is appreciated in developed countries. In this study, we showed that this link also exists in developing geographies. In addition, among the participating sites, we found geographic- and population-based differences in placental inflammation and preterm birth, suggesting the importance of local factors.

Organophosphate and Organohalogen Flame-Retardant Exposure and Thyroid Hormone Disruption in a Cross-Sectional Study of Female Firefighters and Office Workers from San Francisco.

Occupational exposures to flame retardants (FRs), a class of suspected endocrine-disrupting compounds, are of health concern for firefighters. We sought to characterize exposure to FR compounds and evaluate their association with thyroid hormone levels, a biomarker of early effect, in female firefighters and office workers in San Francisco. In a cross-sectional study, we measured replacement organophosphate and organohalogen FRs in spot urine samples from firefighters (N = 86) and office workers (N = 84), as well as total thyroxine (T4) and thyroid-stimulating hormone in plasma for 84 firefighters and 81 office workers. Median bis(1,3-dichloro-2-propyl)phosphate (BDCPP) levels were 5 times higher in firefighters than office workers. Among firefighters, a doubling of BDCPP was associated with a 2.88% decrease (95% confidence interval -5.28, -0.42) in T4. We did not observe significant associations between FRs and T4 among office workers. In the full group, intermediate body mass index and a college education were associated with higher FR levels. The inverse association observed between FRs and T4 coupled with the lack of studies on women workers and evidence of adverse health effects from FR exposure─including endocrine disruption and breast cancer risk─warrant further research on occupational exposures and identification of opportunities for exposure reduction.

Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco.

BACKGROUND: Environmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential biomarker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA. METHODS: We measured serum concentrations of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters (N = 84) and office workers (N = 79) who participated in the 2014-15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length. RESULTS: Regression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA (ß (95%CI) = 0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis (1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis (2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (- 0.14(- 0.28, - 0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and concentrations of exposure between the two groups and/or potential unmeasured confounding. CONCLUSION: Our findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes.

Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.

In preeclampsia (PE), cytotrophoblast (CTB) invasion of the uterus and spiral arteries is often shallow. Thus, the placenta's role has been a focus. In this study, we tested the hypothesis that decidual defects are an important determinant of the placental phenotype. We isolated human endometrial stromal cells from nonpregnant donors with a previous pregnancy that was complicated by severe PE (sPE). Compared with control cells, they failed to decidualize in vitro as demonstrated by morphological criteria and the analysis of stage-specific antigens (i.e., IGFBP1, PRL). These results were bolstered by global transcriptional profiling data that showed they were transcriptionally inert. Additionally, we used laser microdissection to isolate the decidua from tissue sections of the maternal-fetal interface in sPE. Global transcriptional profiling revealed defects in gene expression. Also, decidual cells from patients with sPE, which dedifferentiated in vitro, failed to redecidualize in culture. Conditioned medium from these cells failed to support CTB invasion. To mimic aspects of the uterine environment in normal pregnancy, we added PRL and IGFBP1, which enhanced invasion. These data suggested that failed decidualization is an important contributor to down-regulated CTB invasion in sPE. Future studies will be aimed at determining whether this discovery has translational potential with regard to assessing a woman's risk of developing this pregnancy complication.

Human stem cells from single blastomeres reveal pathways of embryonic or trophoblast fate specification.

Mechanisms of initial cell fate decisions differ among species. To gain insights into lineage allocation in humans, we derived ten human embryonic stem cell lines (designated UCSFB1-10) from single blastomeres of four 8-cell embryos and one 12-cell embryo from a single couple. Compared with numerous conventional lines from blastocysts, they had unique gene expression and DNA methylation patterns that were, in part, indicative of trophoblast competence. At a transcriptional level, UCSFB lines from different embryos were often more closely related than those from the same embryo. As predicted by the transcriptomic data, immunolocalization of EOMES, T brachyury, GDF15 and active ß-catenin revealed differential expression among blastomeres of 8- to 10-cell human embryos. The UCSFB lines formed derivatives of the three germ layers and CDX2-positive progeny, from which we derived the first human trophoblast stem cell line. Our data suggest heterogeneity among early-stage blastomeres and that the UCSFB lines have unique properties, indicative of a more immature state than conventional lines.

Grown Ultrathin Bacterial Cellulose Mats for Optical Applications.

A facile and effective method is described for the biosynthesis of ultrathin bacterial cellulose (BC) mats, which are green, inexpensive, lightweight, and flexible. Physical properties studied include thickness, morphology, reflectance, transmittance, and crystallinity index. BC mat thickness was varied by controlling the depth of the culture broth so that films with predictable thickness, between 113 and 1114 nm, were produced. These BC films have similar fiber morphology to corresponding mm thick BC films prepared under static culture conditions. To increase BC film hydrophobicity, surface trihexylsilylated BC (THSBC) mats with DSavg 0.015 were prepared. Both native and THSBC mats were investigated as antireflection coatings for silicon substrates. The 328 ± 42 nm thick BC mat demonstrated broadband, interference type antireflection over a spectral range of 500-1800 nm. Different reflection properties obtained as a function of BC film orientation reveals that engineered density gradients can be used to manipulate BC optical properties. Thus, optical quality and environmental friendly ultrathin BC films are promising biomaterials for next-generation optoelectronic devices.

Placental transcriptomes in the common aneuploidies reveal critical regions on the trisomic chromosomes and genome-wide effects.

OBJECTIVE: Chromosomal aberrations are frequently associated with birth defects and pregnancy losses. Trisomy 13, Trisomy 18 and Trisomy 21 are the most common, clinically relevant fetal aneusomies. This study used a transcriptomics approach to identify the molecular signatures at the maternal-fetal interface in each aneuploidy. METHODS: We profiled placental gene expression (13-22 weeks) in T13 (n = 4), T18 (n = 4) and T21 (n = 8), and in euploid pregnancies (n = 4). RESULTS: We found differentially expressed transcripts (≥2-fold) in T21 (n = 160), T18 (n = 80) and T13 (n = 125). The majority were upregulated and most of the misexpressed genes were not located on the relevant trisomic chromosome, suggesting genome-wide dysregulation. A smaller number of the differentially expressed transcripts were encoded on the trisomic chromosome, suggesting gene dosage. In T21, <10% of the genes were transcribed from the Down syndrome critical region (21q21-22), which contributes to the clinical phenotype. In T13, 15% of the upregulated genes were on the affected chromosome (13q11-14), and in T18, the percentage increased to 24% (18q11-22 region). CONCLUSION: The trisomic placental (and possibly fetal) phenotypes are driven by the combined effects of genome-wide phenomena and increased gene dosage from the trisomic chromosome. © 2016 John Wiley & Sons, Ltd.

Maternal decidual macrophages inhibit NK cell killing of invasive cytotrophoblasts during human pregnancy.

Human pregnancy is an immunological paradox. Semiallogeneic (fetal) placental cells (extravillous cytotrophoblasts [CTBs]) invade the uterine lining (decidua), which contains a unique decidual natural killer (dNK) cell population, identified by the cell surface phenotype CD56(bright) CD16(-) CD3(-) and CD14(+) CD206(+) macrophages (dMac). Previous reports suggested that human dNK cells are not a threat to the fetoplacental unit because they are anergic. In contrast, here we showed that purified and exogenously stimulated dNK cells are capable killers of cellular targets, including semiallogeneic CTBs. However, dMacs in the decidual leukocyte (DL) population restrained dNK killing through a transforming growth factor beta1 (TGF-beta1)-dependent mechanism. Our findings support a new model whereby dNK cells, capable of killing CTBs, are prevented from doing so by neighboring macrophages, thus protecting the fetal cells from NK cell attack. We speculate that this mechanism would inhibit dNK cell-mediated killing, even under conditions where high levels of cytokines may stimulate dNK cells, which could pose a threat to the developing placenta.

Establishment of human trophoblast progenitor cell lines from the chorion.

Placental trophoblasts are key determinants of in utero development. Mouse trophoblast (TB) stem cells, which were first derived over a decade ago, are a powerful cell culture model for studying their self-renewal or differentiation. Our attempts to isolate an equivalent population from the trophectoderm of human blastocysts generated colonies that quickly differentiated in vitro. This finding suggested that the human placenta has another progenitor niche. Here, we show that the chorion is one such site. Initially, we immunolocalized pluripotency factors and TB fate determinants in the early gestation placenta, amnion, and chorion. Immunoreactive cells were numerous in the chorion. We isolated these cells and plated them in medium containing fibroblast growth factor which is required for human embryonic stem cell self-renewal, and an inhibitor of activin/nodal signaling. Colonies of polarized cells with a limited lifespan emerged. Trypsin dissociation yielded continuously self-replicating monolayers. Colonies and monolayers formed the two major human TB lineages-multinucleate syncytiotrophoblasts and invasive cytotrophoblasts (CTBs). Transcriptional profiling experiments revealed the factors associated with the self-renewal or differentiation of human chorionic TB progenitor cells (TBPCs). They included imprinted genes, NR2F1/2, HMGA2, and adhesion molecules that were required for TBPC differentiation. Together, the results of these experiments suggested that the chorion is one source of epithelial CTB progenitors. These findings explain why CTBs of fully formed chorionic villi have a modest mitotic index and identify the chorionic mesoderm as a niche for TBPCs that support placental growth.

GROα regulates human embryonic stem cell self-renewal or adoption of a neuronal fate.

Previously we reported that feeders formed from human placental fibroblasts (hPFs) support derivation and long-term self-renewal of human embryonic stem cells (hESCs) under serum-free conditions. Here, we show, using antibody array and ELISA platforms, that hPFs secrete ∼6-fold higher amounts of the CXC-type chemokine, GROα, than IMR 90, a human lung fibroblast line, which does not support hESC growth. Furthermore, immunocytochemistry and immunoblot approaches revealed that hESCs express CXCR, a GROα receptor. We used this information to develop defined culture medium for feeder-free propagation of hESCs in an undifferentiated state. Cells passaged as small aggregates and maintained in the GROα-containing medium had a normal karyotype, expressed pluripotency markers, and exhibited apical-basal polarity, i.e., had the defining features of pluripotent hESCs. They also differentiated into the three primary (embryonic) germ layers and formed teratomas in immunocompromised mice. hESCs cultured as single cells in the GROα-containing medium also had a normal karyotype, but they downregulated markers of pluripotency, lost apical-basal polarity, and expressed markers that are indicative of the early stages of neuronal differentiation-ßIII tubulin, vimentin, radial glial protein, and nestin. These data support our hypothesis that establishing and maintaining cell polarity is essential for the long-term propagation of hESCs in an undifferentiated state and that disruption of cell-cell contacts can trigger adoption of a neuronal fate.

Health-related quality of life and sagittal balance at two to 25 years after posterior transfixation for high-grade dysplastic spondylolisthesis.

AIMS: High-grade dysplastic spondylolisthesis is a disabling disorder for which many different operative techniques have been described. The aim of this study is to evaluate Scoliosis Research Society 22-item (SRS-22r) scores, global balance, and regional spino-pelvic alignment from two to 25 years after surgery for high-grade dysplastic spondylolisthesis using an all-posterior partial reduction, transfixation technique. METHODS: SRS-22r and full-spine lateral radiographs were collected for the 28 young patients (age 13.4 years (SD 2.6) who underwent surgery for high-grade dysplastic spondylolisthesis in our centre (Scottish National Spinal Deformity Service) between 1995 and 2018. The mean follow-up was nine years (2 to 25), and one patient was lost to follow-up. The standard surgical technique was an all-posterior, partial reduction, and S1 to L5 transfixation screw technique without direct decompression. Parameters for segmental (slip percentage, Dubousset's lumbosacral angle) and regional alignment (pelvic tilt, sacral slope, L5 incidence, lumbar lordosis, and thoracic kyphosis) and global balance (T1 spino-pelvic inclination) were measured. SRS-22r scores were compared between patients with a balanced and unbalanced pelvis at final follow-up. RESULTS: SRS-22r domain and total scores improved significantly from preoperative to final follow-up, except for the mental health domain that remained the same. Slip percentage improved from 75% (SD 15) to 48% (SD 19) and lumbosacral angle from 70° (SD 11) to 101° (SD 11). Preoperatively, 35% had global imbalance, and at follow-up all were balanced. Preoperatively, 63% had an unbalanced pelvis, and at final follow-up this was 32%. SRS-22r scores were not different in patients with a balanced or unbalanced pelvis. However, postoperative pelvic imbalance as measured by L5 incidence was associated with lower SRS-22r self-image and total scores (p = 0.029). CONCLUSION: In young patients with HGDS, partial reduction and transfixation improves local lumbosacral alignment, restores pelvic, and global balance and provides satisfactory long-term clinical outcomes. Higher SRS-22r self-image and total scores were observed in the patients that had a balanced pelvis (L5I < 60°) at two to 25 years follow-up. Cite this article: Bone Jt Open 2021;2(3):163-173.

Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease.

The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring's health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.

Spinal deformity in patients with DiGeorge syndrome.

STUDY DESIGN: Retrospective review of a case series. OBJECTIVE: To present the clinical characteristics and treatment of spinal deformity in DiGeorge syndrome. SUMMARY OF BACKGROUND DATA: There are no data on the development of spinal deformity in this condition. A high rate of wound infection could be expected after spinal surgery due to congenital thymic hypoplasia. METHODS: The medical records and spinal radiographs of 4 consecutive patients were reviewed. All patients were followed for a minimum of 2.5 years after spinal surgery. RESULTS: The mean age at diagnosis of spinal deformity was 9.9 years. The type of deformity was not uniform but the curves progressed in all patients requiring a spinal arthrodesis at a mean age of 16.1 years. Two patients developed a thoracolumbar scoliosis and underwent an anterior spinal arthrodesis with instrumentation, which produced a good outcome. The remaining 2 patients developed a double thoracic and lumbar scoliosis with increased thoracic kyphosis. Brace treatment was unsuccessful to control the deformity in one of these patients. Both patients underwent a posterior spinal arthrodesis with segmental instrumentation, which achieved satisfactory correction of the scoliosis with no loss of correction or detected pseudarthrosis at follow-up. However, both patients developed junctional kyphosis above the proximal end of the instrumentation. This was asymptomatic and nonprogressive; therefore, cephalad extension of the fusion was not required. Irradiated blood products were administered in all patients to prevent graft-versus-host disease. The postoperative course was uncomplicated and none of the patients developed wound healing problems or infections. CONCLUSIONS: The development of spinal deformity in patients with DiGeorge syndrome may be associated to the presence of marked ligamentous laxity and congenital cardiac disease. There is significant variability on the pattern of spinal deformity, which in our series was progressive in all patients and required surgical correction with no perioperative complications.

Associations between polyfluoroalkyl substance and organophosphate flame retardant exposures and telomere length in a cohort of women firefighters and office workers in San Francisco.

BACKGROUND: Environmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential marker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA. METHODS: We measured serum levels of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters and office workers who participated in the 2014-15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length. RESULTS: Regression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA ( ß (95%CI) = 0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis(2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (-0.14(-0.28, -0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and levels of exposure between the two groups and/or potential unmeasured confounding. CONCLUSION: Our findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes.

Trisomy 21 is Associated with Caspase-2 Upregulation in Cytotrophoblasts at the Maternal-Fetal Interface.

Impaired placentation is implicated in poor perinatal outcomes associated with Trisomy 21. Earlier studies revealed abnormal cytotrophoblast differentiation along the invasive pathway as a contributing mechanism. To further elucidate the causes, we evaluated Caspase-2 expression at the protein level (immunolocalization and immunoblot) in samples from Trisomy 21 (n = 9) and euploid (n = 4) age-matched placentas. Apoptosis was investigated via the TUNEL assay. An immunolocalization approach was used to characterize Caspase-3, Fas (CD95), and Fas ligand in the same samples. Caspase-2 was significantly overexpressed in Trisomy 21 placentas, with the highest expression in villous cores and invasive cytotrophoblasts. Immunolocalization showed that Caspase-3 had a similar expression pattern as Caspase-2. Using the TUNEL approach, we observed high variability in the number of apoptotic cells in biopsies from different regions of the same placenta and among different placentas. However, Trisomy 21 placentas had more apoptotic cells, specifically in cell columns and basal plates. Furthermore, Caspase-2 co-immunolocalized with Fas (CD95) and FasL in TUNEL-positive extravillous cytotrophoblasts, but not in villous cores. These results help explain the higher levels of apoptosis among placental cells of Trisomy 21 pregnancies in molecular terms. Specifically, the co-expression of Caspase-2 and Caspase-3 with other regulators of the apoptotic process in TUNEL-positive cells suggests these molecules may cooperate in launching the observed apoptosis. Among trophoblasts, only the invasive subpopulation showed this pattern, which could help explain the higher rates of adverse outcomes in these pregnancies. In future experiments, this relationship will be further examined at a functional level in cultured human trophoblasts.

A proteomic approach identifies early pregnancy biomarkers for preeclampsia: novel linkages between a predisposition to preeclampsia and cardiovascular disease.

Preeclampsia (PE) is a common, potentially life-threatening pregnancy syndrome triggered by placental factors released into the maternal circulation, resulting in maternal vascular dysfunction along with activated inflammation and coagulation. Currently there is no screening test for PE. We sought to identify differentially expressed plasma proteins in women who subsequently develop PE that may perform as predictive biomarkers. In seven DIGE experiments, we compared the plasma proteome at 20 wk gestation in women who later developed PE with an appropriate birth weight for gestational age baby (n=27) or a small for gestational age baby (n=12) to healthy controls with uncomplicated pregnancies (n=57). Of the 49 differentially expressed spots associated with PE-appropriate for gestational age, PE-small for gestational age or both (p<0.05, false discovery rate corrected), 39 were identified by LC-MS/MS. Two protein clusters that accurately (>90%) classified women at risk of developing PE were identified. Immunoblots confirmed the overexpression of fibrinogen gamma chain and alpha-1-antichymotrypsin in plasma prior to PE. The proteins identified are involved in lipid metabolism, coagulation, complement regulation, extracellular matrix remodeling, protease inhibitor activity and acute-phase responses, indicating novel synergism between pathways involved in the pathogenesis of PE. Our findings are remarkably similar to recently identified proteins complexed to high-density lipoprotein and linked to cardiovascular disease.

Spinal deformity in patients with Sotos syndrome (cerebral gigantism).

STUDY DESIGN: Retrospective review of a case series. OBJECTIVE: To present the clinical characteristics and progression of spinal deformity in patients with Sotos syndrome. SUMMARY OF BACKGROUND DATA: There is limited information on the development of spinal deformity and the need for treatment in this condition. METHODS: The medical records and spinal radiographs of 5 consecutive patients were reviewed. All patients were followed to skeletal maturity (mean follow-up: 6.6 y). RESULTS: The mean age at diagnosis of spinal deformity was 11.9 years (range: 5.8 to 14.5) with 4 patients presenting in adolescence. The type of deformity was not uniform. Two patients presented in adolescence with relatively small and nonprogressive thoracolumbar and lumbar scoliosis, which required observation but no treatment until the end of spinal growth. Three patients underwent spinal deformity correction at a mean age of 11.7 years (range: 6 to 15.4). The first patient developed a double structural thoracic and lumbar scoliosis and underwent a posterior spinal arthrodesis extending from T3 to L4. Five years later, she developed marked degenerative changes at the L4/L5 level causing symptomatic bilateral lateral recess stenosis and affecting the L5 nerve roots. She underwent spinal decompression at L4/L5 and L5/S1 levels followed by extension of the fusion to the sacrum. The second patient developed a severe thoracic kyphosis and underwent a posterior spinal arthrodesis. The remaining patient presented at the age of 5.9 years with a severe thoracic kyphoscoliosis and underwent a 2-stage antero-posterior spinal arthrodesis. CONCLUSIONS: The development of spinal deformity is a common finding in children with Sotos syndrome and in our series it occurred in adolescence in 4 out of 5 patients. There is significant variability on the pattern of spine deformity, ranging from a scoliosis through kyphoscoliosis to a pure kyphosis, and also the age at presentation and need for treatment.

Placental Structure in Preterm Birth Among HIV-Positive Versus HIV-Negative Women in Kenya.

BACKGROUND: Preterm birth (PTB) is a major cause of infant morbidity and mortality in developing countries. Recent data suggest that in addition to Human Immunodeficiency Virus (HIV) infection, use of antiretroviral therapy (ART) increases the risk of PTB. As the mechanisms remain unexplored, we conducted this study to determine whether HIV and ART were associated with placental changes that could contribute to PTB. SETTING: We collected and evaluated placentas from 38 HIV-positive women on ART and 43 HIV-negative women who had preterm deliveries in Nairobi, Kenya. METHODS: Anatomical features of the placentas were examined at gross and microscopic levels. Cases were matched for gestational age and compared by the investigators who were blinded to maternal HIV serostatus. RESULTS: Among preterm placentas, HIV infection was significantly associated with thrombosis (P = 0.001), infarction (P = 0.032), anomalies in cord insertion (P = 0.02), gross evidence of membrane infection (P = 0.043), and reduced placental thickness (P = 0.010). Overall, preterm placentas in both groups were associated with immature villi, syncytial knotting, villitis, and deciduitis. Features of HIV-positive versus HIV-negative placentas included significant fibrinoid deposition with villus degeneration, syncytiotrophoblast delamination, red blood cell adhesion, hypervascularity, and reduction in both surface area and perimeter of the terminal villi. CONCLUSIONS: These results imply that HIV infection and/or ART are associated with morphological changes in preterm placentas that contribute to delivery before 37 weeks. Hypervascularity suggests that the observed pathologies may be attributable, in part, to hypoxia. Further research to explore potential mechanisms will help elucidate the pathways that are involved perhaps pointing to interventions for decreasing the risk of prematurity among HIV-positive women.

Human embryonic stem cells as a model system for studying the effects of smoke exposure on the embryo.

Human embryonic stem cells (hESCs) share many characteristics including pluripotency with cells of the early embryo and so are potentially useful tools for studying the harmful effects of xenobiotics during early development. Here, we used hESCs as a model system to test the effects of nicotine on the pluripotent population of cells that forms the whole body. Specifically, we exposed hESCs (H7 and H9) to various concentrations of nicotine ranging from 0.1 to 6microM. We evaluated the effects in terms of cell adhesion, integrin expression, hESC colony morphology, markers of pluripotency and survival. The results revealed a significant negative impact of nicotine in the dose range between 1.8 and 3.7microM on all the endpoints analyzed. The observed effects were reversed by the addition of the nicotine antagonist d-tubocurarine, suggesting that the effects are receptor mediated. Together these results offer new explanations in terms of embryo toxicity for the large negative impact of cigarette smoke exposure on a woman's reproductive capacity.

Dielectric Properties of Bio-Based Diphenolate Ester Epoxies.

Thermoset bio-based diglycidyl ether of diphenolate esters (DGEDP) exhibit comparable mechanical properties as petroleum-derived diglycidyl ether of bisphenol A (DGEBA), whereas DGEDP is derived from levulinic acid, a safe and readily renewable feedstock. To determine the potential replacement of DGEBA as dielectric materials, a series of DGEDP-esters (i.e., methyl, ethyl, propyl, and butyl esters) were synthesized and studied. Broadband dielectric spectroscopy revealed that DGEDP-propyl has the highest dielectric constant in the series, comparable to DGEBA. Differences in the dielectric properties of DGEDP-esters is attributed to the interplay of segmental, small local, and side-chain motions on one hand and free volume and steric hindrance on the other.