Transcriptional factor PU.1 regulates decidual C1q expression in early pregnancy in human

"Copyright: © 2015 Madhukaran, Kishore, Jamil, Teo, Choolani and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms."C1q is the first recognition subcomponent of the complement classical pathway, which in addition to being synthesized in the liver, is also expressed by macrophages and dendritic cells (DCs). Trophoblast invasion during early placentation results in accumulation of debris that triggers the complement system. Hence, both early and late components of the classical pathway are widely distributed in the placenta and decidua. In addition, C1q has recently been shown to significantly contribute to feto-maternal tolerance, trophoblast migration, and spiral artery remodeling, although the exact mechanism remains unknown. Pregnancy in mice, genetically deficient in C1q, mirrors symptoms similar to that of human preeclampsia. Thus, regulated complement activation has been proposed as an essential requirement for normal successful pregnancy. Little is known about the molecular pathways that regulate C1q expression in pregnancy. PU.1, an Ets-family transcription factor, is required for the development of hematopoietic myeloid lineage immune cells, and its expression is tissue-specific. Recently, PU.1 has been shown to regulate C1q gene expression in DCs and macrophages. Here, we have examined if PU.1 transcription factor regulates decidual C1q expression. We used immune-histochemical analysis, PCR, and immunostaining to localize and study the gene expression of PU.1 transcription factor in early human decidua. PU.1 was highly expressed at gene and protein level in early human decidual cells including trophoblast and stromal cells. Surprisingly, nuclear as well as cytoplasmic PU.1 expression was observed. Decidual cells with predominantly nuclear PU.1 expression had higher C1q expression. It is likely that nuclear and cytoplasmic PU.1 localization has a role to play in early pregnancy via regulating C1q expression in the decidua during implantation

Evaluation of preferences of women and healthcare professionals in Singapore for implementation of noninvasive prenatal testing for Down syndrome

INTRODUCTION: Invasive prenatal diagnosis (IPD) has long been used to prenatally diagnose Down syndrome (DS), but is associated with a small risk of miscarriage. Meanwhile, noninvasive prenatal testing (NIPT) is a highly sensitive screening test using cell-free DNA in maternal blood for detection of DS that removes the risk of miscarriage, but confers a small risk of false-positive and false-negative results. Their implementations into clinical practice require an understanding of stakeholder preferences. METHODS: A total of 69 health professionals (HPs) and 301 women took part in a discrete choice experiment (DCE) in which preferences for four prenatal test attributes (accuracy, time of results, risk of miscarriage and amount of information provided) were assessed, and conditional logit regression was used to analyse data. Data on demographics and ranked preferences for test attributes were collected, and a direct choice between NIPT, IPD or neither test was given. RESULTS: Women showed a preference for test safety, whereas HPs prioritised test accuracy above all other attributes. When offered a direct choice between NIPT, IPD or neither test, women aged over 35 years, those with previous miscarriage or who knew a child with DS were more likely to choose NIPT than IPD. Chinese women preferred NIPT whereas Indian women preferred IPD. CONCLUSION: Our data highlight the need for patient-specific counselling, taking into account previous experiences and cultural factors. Since women and HPs prioritise different test attributes, it is essential that HPs recognise these differences in order to provide non-biased counselling

Dealing with uncertain results from chromosomal microarray and exome sequencing in the prenatal setting: an international cross-sectional study with healthcare professionals.

OBJECTIVES: To conduct qualitative interviews with healthcare providers working in different countries to understand their experiences of dealing with uncertain results from prenatal chromosome microarray analysis (CMA) and exome sequencing (ES). METHODS: Semi-structured interviews with 31 healthcare providers who report or return prenatal CMA and/or ES results (clinicians, genetic counsellors and clinical scientists) in six countries with differing healthcare systems; Australia (4), Denmark (5), Netherlands (6), Singapore (4), Sweden (6) and United Kingdom (6). The topic guide explored the main sources of uncertainty and their management. RESULTS: There was variation in reporting practices both between and across countries for variants of uncertain significance (VUS), however, there was broad agreement on reporting practices for incidental findings. There was also variation in who decides what results are reported (clinical scientists or clinicians). Technical limitations and lack of knowledge (to classify variants and of prenatal phenotypes) were significant challenges, as were turnaround times and lack of guidelines. CONCLUSION: Health professionals around the globe are dealing with similar sources of uncertainty, but managing them in different ways, Continued dialogue with international colleagues on ways of managing uncertain results is important to compare and contrast the benefits and limitations of the different approaches. This article is protected by copyright. All rights reserved

Maternal exposure to a high-magnitude earthquake during pregnancy influences pre-reading skills in early childhood

Exposure to an adverse prenatal environment can influence fetal development and result in long-lasting changes in the offspring. However, the association between maternal exposure to stressful events during pregnancy and the achievement of pre-reading skills in the offspring is unknown. Here we examined the association between prenatal exposure to the Chilean high-magnitude earthquake that occurred on February 27th, 2010 and the development of early reading precursors skills (listening comprehension, print knowledge, alphabet knowledge, vocabulary, and phonological awareness) in children at kindergarten age. This multilevel retrospective cohort study including 3280 children, of whom 2415 were unexposed and 865 were prenatally exposed to the earthquake shows substantial evidence that maternal exposure to an unambiguously stressful event resulted in impaired pre-reading skills and that a higher detrimental effect was observed in those children who had been exposed to the earthquake during the first trimester of gestation. In addition, females were more significantly affected by the exposure to the earthquake than their male peers in alphabet knowledge; contrarily, males were more affected than females in print knowledge skills. These findings suggest that early intervention programs for pregnant women and/or children exposed to prenatal stress may be effective strategies to overcome impaired pre-reading skills in children

Maternal exposure to a high-magnitude earthquake during pregnancy influences pre-reading skills in early childhood

Exposure to an adverse prenatal environment can influence fetal development and result in long-lasting changes in the offspring. However, the association between maternal exposure to stressful events during pregnancy and the achievement of pre-reading skills in the offspring is unknown. Here we examined the association between prenatal exposure to the Chilean high-magnitude earthquake that occurred on February 27th, 2010 and the development of early reading precursors skills (listening comprehension, print knowledge, alphabet knowledge, vocabulary, and phonological awareness) in children at kindergarten age. This multilevel retrospective cohort study including 3280 children, of whom 2415 were unexposed and 865 were prenatally exposed to the earthquake shows substantial evidence that maternal exposure to an unambiguously stressful event resulted in impaired pre-reading skills and that a higher detrimental effect was observed in those children who had been exposed to the earthquake during the first trimester of gestation. In addition, females were more significantly affected by the exposure to the earthquake than their male peers in alphabet knowledge; contrarily, males were more affected than females in print knowledge skills. These findings suggest that early intervention programs for pregnant women and/or children exposed to prenatal stress may be effective strategies to overcome impaired pre-reading skills in children

A comparison of intrauterine haemopoietic cell transplantation and lentiviral gene transfer for the correction of severe β-thalassaemia in a HbbTh3/+ murine model

Major haemoglobinopathies place tremendous strain on global resources. Intrauterine haemopoietic cell (IUHCT) and gene (IUGT) therapies can potentially reduce perinatal morbidities with greater efficacy than postnatal therapy alone. We performed both procedures in the thalassaemic HbbTh3/+ murine model. Intraperitoneal delivery of coisogenic cells at E13-14 produced dose-dependent chimerism. High-dose adult bone marrow (BM) cells maintained 0.2-3.1% chimerism over ~24 weeks and treated heterozygotes demonstrated higher chimerism than wild-type pups (1.6 vs. 0.7%). Fetal liver cells produced higher chimerism compared to adult BM when transplanted at the same doses, maintaining 1.8-2.4% chimerism over ~32 weeks. We boosted transplanted mice postnatally with adult BM cells following busulfan conditioning. Engraftment was maintained at >1% only in recipients which were chimeric prior to boosting. IUHCT-treated non-chimeras and non-IUHCT mice showed micro- or no chimerism. Additional fludarabine treatment produced higher chimerism than busulfan alone. Engraftment was more effective following higher starting chimerism prior to boosting and in heterozygotes. Chimeric heterozygotes expressed 2.2-15.1% donor cells with eventual decline at 24 weeks (vs. <1% in non-chimeras) and demonstrated improved haematological indices and smaller spleens compared to untreated heterozygotes. Intravenous delivery of GLOBE lentiviral-vector expressing HBB (human β-globin) resulted in vector concentration of 0.001-0.6 copies/cell. Most haematological indices were higher in treated than untreated heterozygotes including haemoglobin and mean corpuscular volume, though still lower than in wild-types. Thus both direct IUGT and IUHCT strategies can be used to achieve haematological improvement but require further dose optimisation. IUHCT will be useful combined with postnatal transplantation to further enhance engraftment

Database for exploration of functional context of genes implicated in ovarian cancer

Ovarian cancer (OC) is becoming the most common gynecological cancer in developed countries and the most lethal gynecological malignancy. It is also the fifth leading cause of all cancer-related deaths in women. The identification of diagnostic biomarkers and development of early detection techniques for OC largely depends on the understanding of the complex functionality and regulation of genes involved in this disease. Unfortunately, information about these OC genes is scattered throughout the literature and various databases making extraction of relevant functional information a complex task. To reduce this problem, we have developed a database dedicated to OC genes to support exploration of functional characterization and analysis of biological processes related to OC. The database contains general information about OC genes, enriched with the results of transcription regulation sequence analysis and with relevant text mining to provide insights into associations of the OC genes with other genes, metabolites, pathways and nuclear proteins. Overall, it enables exploration of relevant information for OC genes from multiple angles, making it a unique resource for OC and will serve as a useful complement to the existing public resources for those interested in OC genetics. Access is free for academic and non-profit users and database can be accessed at http://apps.sanbi.ac.za/ddoc/

SERS-based detection of haptoglobin in ovarian cyst fluid as a point-of-care diagnostic assay for epithelial ovarian cancer

Purpose: To evaluate haptoglobin (Hp) in ovarian cyst fluid as a diagnostic biomarker for epithelial ovarian cancers (EOCs) using surface-enhanced Raman spectroscopy (SERS)-based in vitro diagnostic assay for use in an intraoperative setting. Methods: SERS-based method was used to detect and quantify Hp in archived ovarian cyst fluids collected from suspicious ovarian cysts and differentiate benign tumors from EOCs. The diagnostic performance of SERS-based assay was verified against the histopathology conclusions and compared with the results of CA125 test and frozen sections. Results: Hp concentration present in the clinical cyst fluid measured by SERS was normalized to 3.3 mg/mL of standard Hp. Normalized mean values for patients with benign cysts were 0.65 (n=57) and malignant cysts were 1.85 (n=54), demonstrating a significantly (P<0.01) higher Hp in malignant samples. Verified against histology, Hp measurements using SERS had a sensitivity of 94% and specificity of 91%. Receiver operating characteristic curve analysis of SERS-based Hp measurements resulted in area under the curve of 0.966±0.03, establishing the robustness of the method. CA125 test on the same set of patients had a sensitivity of 85% and specificity of 90%, while frozen section analysis on 65 samples had 100% sensitivity and specificity. Conclusion: With a total execution time of <10 minutes and consistent performance across different stages of cancer, the SERS-based Hp detection assay can serve as a promising intraoperative EOC diagnostic test.National Medical Research Council (NMRC), Singapore; Bio-Medical Research Council of Agency for Science, Technology and Research (A*STAR), and the NHIC Innovation to Develop (I2D

Factors associated with mobile health information seeking among Singaporean women

This study examined effects of age and social psychological factors on women’s willingness to be mobile health information seekers. A national survey of 1,878 Singaporean women was conducted to obtain information on women’s mobile phone usage, experiences of health information seeking, and appraisals of using mobile phones to seek health information. Results showed that young, middle-aged, and older women exhibited distinct mobile phone usage behaviors, health information-seeking patterns, and assessments of mobile health information seeking. Factors that accounted for their mobile information-seeking intention also varied. Data reported in this study provide insights into mobile health interventions in the future