Ming-Song Tsai

Clonal Amniotic Fluid-Derived Stem Cells Express Characteristics of Both Mesenchymal and Neural Stem Cells

Abstract Recent evidence has shown that amniotic fluid may be a novel source of fetal stem cells for therapeutic transplantation. We previously developed a two-stage culture protocol to isolate a population of amniotic fluid-derived mesenchymal stem cells (AFMSCs) from second-trimester amniocentesis. AFMSCs maintain the capacity to differentiate into multiple mesenchymal lineages and neuron-like cells. It is unclear whether amniotic fluid contains heterogeneous populations of stem cells or a subpopulation of primitive stem cells that are similar to marrow stromal cells showing the behavior of neural progenitors. In this study, we showed a subpopulation of amniotic fluid-derived stem cells (AF-SCs) at the single-cell level by limiting dilution. We found that NANOG- and POU5F1 (also known as OCT4)-expressing cells still existed in the expanded single cell-derived AF-SCs. Aside from the common mesenchymal characteristics, these clonal AF-SCs also exhibit multiple phenotypes of neural-derived cells such as NES, TUBB3, NEFH, NEUNA60, GALC, and GFAP expressions both before and after neural induction. Most importantly, HPLC analysis showed the evidence of dopamine release in the extract of dopaminergic-induced clonal AF-SCs. The results of this study suggest that besides being an easily accessible and expandable source of fetal stem cells, amniotic fluid will provide a promising source of neural progenitor cells that may be used in future cellular therapies for neurodegenerative diseases and nervous system injuries.

Functional Network Analysis of the Transcriptomes of Mesenchymal Stem Cells Derived from Amniotic Fluid, Amniotic Membrane, Cord Blood, and Bone Marrow

Using high‐density oligonucleotide microarrays and functional network analyses, we examined whether MSCs derived from four different origins exhibited unique gene expression profiles individually and then compared the gene expression profiles of all MSCs with those of fetal organs. Our results indicated that within each group of MSCs from the same origin, the variability of the gene expression levels was smaller than that between groups of different origins. Functional genomic studies revealed the specific roles of MSCs from different origins. Our results suggest that amniotic fluid MSCs may initiate interactions with the uterus by upregulating oxytocin and thrombin receptors. Amniotic membrane MSCs may play a role in maintaining homeostasis of fluid and electrolytes by regulating the networks of endothelin, neprilysin, bradykinin receptors, and atrial natriuretic peptide. Cord blood MSCs may be involved in innate immune systems as the neonatal defense system against the earliest encountered pathogens. Adult bone marrow MSCs may be an important source not only of all blood lineages but also of bone formation. However, in spite of the different gene expression profiles seen in MSCs derived from different origins, a set of core gene expression profiles was preserved in these four kinds of MSCs. The core signature transcriptomes of all MSCs, when contrasted against those of fetal organs, included genes involved in the regulation of extracellular matrix and adhesion, transforming growth factor‐β receptor signaling, and the Wnt signaling pathways.

Neonatal outcomes of intrauterine nonylphenol exposure—A longitudinal cohort study in Taiwan

BACKGROUND Nonylphenol (NP) is an environmental hormone with proven estrogenic effects. Although its adverse effects on animals are well documented, the effects of NP exposure on humans remain unclear, and those on the human foetus are completely unknown. This study explores the effects of intrauterine NP exposure on neonates. METHODS A cohort of pregnant women was established in a medical centre in northern Taiwan. Urine samples from the first, second, and third trimesters of gestation were collected. Urinary NP concentration was measured by high-performance liquid chromatography coupled with fluorescent detection. Neonatal outcomes were evaluated immediately after delivery. A mixed-effects model using a generalised estimating equation was applied to assess the association between gestational age, maternal body weight, and maternal NP concentration throughout the three trimesters. A multivariable regression model was used to determine the association between maternal NP level in urine in each trimester and neonatal outcomes. RESULTS In total, 162 singleton pregnant women completed this study through delivery. The geometric mean of creatinine-adjusted urinary NP concentrations were 4.27 μg/g, 4.21 μg/g, and 4.10 μg/g in the first, second, and third trimesters, respectively. Pregnant women whose urinary NP concentrations were above the median in the second trimester had low maternal weight gain (β=-1.55 kg, p=0.02) and short neonatal body length (β=-0.47 cm, p=0.04). Women with an above-median urinary NP concentration had an odds ratio of having a small for gestational age (SGA) neonate of 7.81 (p<0.05). CONCLUSIONS This study indicates that maternal high NP exposure in the second trimester is associated with SGA, decreased foetal body length at birth, and low maternal weight gain. The effects of this endocrine-disrupting substance on pregnant women and foetuses should be a concern during gestation.

The association between maternal nonylphenol exposure and parity on neonatal birth weight: A cohort study in Taiwan

BACKGROUND The aim of this study was to explore the association between NP exposure and parity and their effect on neonatal birth weight. METHODS A cohort of pregnant women was established in a medical center in North Taiwan. Urinary NP concentration was determined by high-performance liquid chromatography coupled with fluorescent detection and adjusted using creatinine. A multivariable regression model was fit to determine the association between the maternal NP level in each trimester and neonatal birth weight. The odds ratios (ORs) of infant birth weight below the 10th, 25th, and 50th percentiles, comparing pregnant women with the different NP exposure levels, was estimated using a logistic regression. RESULTS Of the 162 pregnant women in the study, 99 were multiparas and 63 were primiparas. After adjusting for other covariates, the NP level in the second trimester had a significant association with birth weight in the primiparas (β = -182.49 g, p value = 0.02). The OR of low infant birth weight, comparing pregnant women with different NP levels, was increased by decreasing the cutoff percentile for birth weight (OR = 1.18 for the 50th percentile, 2.12 for the 25th percentile, and 7.81 for the 10th percentile). The odds of primiparas with high NP level having a low neonatal birth weight increased to 3.87, 11.77, and 9.40 for the three different percentiles (p value < 0.05). CONCLUSION Maternal NP exposure level is associated with an increased risk of low neonatal weight. Primiparas are especially at risk, and the second trimester of pregnancy may be the critical stage of exposure.

Pregnancy Outcomes of Taiwanese Women with Gestational Diabetes Mellitus: A Comparison of Carpenter-Coustan and National Diabetes Data Group Criteria

AIMS To evaluate the pregnancy outcome of pregnant women in whom the 100-g oral glucose tolerance test (OGTT) met the criteria of Carpenter and Coustan (C&C) but not those of the National Diabetes Data Group (NDDG) for diagnosis of gestational diabetes mellitus (GDM). METHODS The medical records of 10,990 singleton pregnancies, delivered at Cathay General Hospital, Taiwan, between 2001 and 2008, were reviewed retrospectively. All pregnant women followed the two-step diagnostic algorithm for GDM; that is, women with a positive (>or=140 mg/dL) 50-g glucose challenge test (GCT) underwent a 100-g OGTT at 24-28 weeks of gestation. The pregnancies were classified as follows: group 1, women without GDM; group 2, women with GDM meeting the C&C criteria but not the NDDG criteria; and group 3, women with GDM diagnosed by NDDG criteria. RESULTS Of the pregnancies, 10,116 (92%), 489 (4.4%), and 385 (3.5%) were classified into groups 1, 2, and 3, respectively. Women with GDM by the C&C criteria but not by the NDDG criteria had an increase in macrosomia compared with women without GDM, 22 (4.5%) infants vs. 236 (2.3%) infants, respectively (p < 0.05); however, there were no associated adverse complications. If the C&C criteria were used, the incidence of GDM increased to 874 (7.9%) pregnancies. GDM as defined by either NDDG or C&C criteria identified pregnancies complicated by macrosomia, cesarean section, and gestational hypertension compared with the healthy population (p < 0.05). CONCLUSIONS In a Taiwanese population, using C&C criteria has no added advantages over using NDDG criteria.

Pregnancy outcomes in unselected singleton pregnant women with an increased risk of first‐trimester Down's syndrome

Background.  The purpose of this study was to assess outcomes in pregnancies with a positive screen of first‐trimester combined test (nuchal translucency, pregnancy‐associated plasma protein‐A and free beta‐human chorionic gonadotropin).

Low Maternal Serum Levels of Pregnancy-associated Plasma Protein-A During the First Trimester are Associated with Subsequent Preterm Delivery with Preterm Premature Rupture of Membranes

OBJECTIVE To assess the relationship between the first-trimester maternal serum pregnancy-associated plasma protein-A (PAPP-A) levels and pregnancies complicated by preterm delivery. MATERIALS AND METHODS The correlation between PAPP-A levels and gestational age at delivery was analyzed by linear regression. The probabilities of low PAPP-A multiples of the median (MoM) levels between preterm delivery and control population were analyzed by logit model. RESULTS A positive correlation was noted between the first-trimester PAPP-A MoM levels and gestational age at delivery between 34-38 weeks (p < 0.001). Lower PAPP-A MoM level had a significantly higher likelihood of preterm delivery (p < 0.05). When preterm premature rupture of membranes (PPROM) and preterm labor (PTL) were analyzed separately, there was an increasing likelihood of PPROM with decreasing PAPP-A MoM levels (p < 0.05), but not for PTL with intact membranes. CONCLUSION Low maternal serum PAPP-A levels during the first trimester may reflect a trophoblast invasion defect in the maternal-fetal interface, resulting in subsequent preterm delivery, particularly in those of PPROM.

First-trimester ultrasound diagnosis of Meckel-Grüber syndrome

1. Frantzel O. Angeborener Defect der Rechten Lungenarterie. Virchows Arch Pathol Anat. 1868;/42:/420. 2. Harkel AT, Blom NA, Ottenkamp J. Isolated unilateral absenceof a pulmonary artery. Chest. 2002;/122:/1471 7. 3. Bouros D, Pare P, Panagou P, Tsintiris K, Siafakas N. The varied manifestation of pulmonary artery agenesis inadulthood. Chest. 1995;/108:/670 6. 4. Pool PE, Vogel JHK, Blount SG Jr. Congenital unilateral absence of a pulmonary artery: the importance of flow inpulmonary hypertension. Am J Cardiol. 1962;/10:/706 32. 5. Stiller RJ, Soberman S, Turetsky A, Lockwood C, Haddad R. Agenesis of the pulmonary artery: an unusual cause of dyspnea in pregnancy. Am J Obstet Gynecol. 1988;/158:/ 172 3. 6. Ferrari M, Karrazi R, Lampronti G, Biasin C, Zuccali V, Olivieri M, et al. Effect of changing position on arterial oxygenation in a patient with agenesis of the left pulmonary artery. Respiration. 1997;/64:/371 4. 7. Ko T, Gatz MG, Reisz GR. Congenital unilateral absence of a pulmonary artery: a report of two adult cases. Am Rev Respir Dis. 1990;/141:/795 8. 8. Weiss BM, Zemp L, Seifert B, Hess OM. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol. 1998;/31:/ 1650 7.

Concurrent exposures to nonylphenol, bisphenol A, phthalates, and organophosphate pesticides on birth outcomes: A cohort study in Taipei, Taiwan

Prenatal exposure to phenols, phthalates (PAEs), and organophosphate (OP) pesticides may increase the risk of abnormal birth outcomes. However, many previous studies have examined exposure to a limited number of chemical classes or exposure profiles limited to a specific stage of pregnancy. This study aims to characterize the concurrent exposure scenario throughout pregnancy by simultaneously monitoring internal doses of several endocrine-disrupting compounds (EDCs), including 2 phenols (nonylphenol (NP) and bisphenol A (BPA)), 9 PAEs, and 6 OP pesticide metabolites and to assess the relationships between concurrent exposure to EDCs and infant birth weight, length, and head and chest circumference. One hundred and sixty two women provided three spot urine samples at approximately 11 and 26weeks gestation and at delivery. We applied multivariable linear regression and ridge regression models to estimate the effects of separate and correlated exposures. Multivariable linear regression models revealed that women with short birth-length infants had significantly higher urinary second-trimester NP levels (50th percentile, 5.03μg/g creatinine) (β=-0.47cm; 95% CI=-0.93 to -0.01). Similarly significant relationships were observed between second-trimester mono-methyl phthalate (MMP) exposure and short birth length, second-trimester ΣPAEs and short birth length, second-trimester ΣPAEs exposure and reduced head and chest circumference, second-trimester diethylphosphate (DEP) exposure and reduced birth weight and length, and second-trimester ΣDEPs exposure and short birth length. Women with urinary BPA above the 75th percentile or ΣPAEs levels above the 50th percentile in the third trimester had infants with significantly reduced head circumference. These observations suggest that the second trimester may be the critical stage of susceptibility for fetal development. In ridge regression models, for which women with fewer measures for exposure to NP, BPA, MMP, ΣPAEs, DEP and ΣDEPs simultaneously were available, no relationships were found with infant size at birth. Additional studies with larger sample sizes are warranted.

The critical fetal stage for maternal manganese exposure

Prenatal exposure and the health effects of that exposure have been intensively studied for a variety of environmental pollutants and trace elements. However, few studies have compared susceptibilities among the three trimesters of gestation. Manganese (Mn) is a naturally occurring and abundant trace element in the environment. Although the effects of Mn on animals are well documented, knowledge of the effects of Mn exposure on pregnant women and fetuses remains limited. A longitudinal study was conducted by collecting blood samples during all three trimesters, and Mn exposure was completely characterized during gestation. The aims of this study were to examine the effects of maternal Mn exposure on neonatal birth outcomes and to explore the critical stage of these effects. In total, 38, 76 and 76 samples were obtained from singleton pregnant women in their first, second and third trimesters, respectively. The cohort of pregnant women was selected at a medical center in northern Taiwan. Erythrocyte samples were collected during the first, second and third trimesters of gestation. Erythrocyte Mn concentrations were measured by inductively coupled plasma mass spectrometry. Neonatal birth outcomes were evaluated immediately after delivery. A multivariate regression model was used to determine the associations between maternal Mn levels in erythrocytes in each trimester and neonatal birth outcomes. The geometric mean concentrations of Mn were 2.93 μg/dL, 3.96 μg/dL and 4.41 μg/dL in the first, second and third trimesters, respectively. After adjusting for potential confounders, a consistently negative association was found between maternal Mn levels throughout the three trimesters and birth outcomes. Log-transformed Mn levels in maternal erythrocytes in the second trimester were significantly associated with neonatal birth weight, head and chest circumferences, respectively (β=-556.98 g, p=0.038; β=-1.87 cm, p=0.045; β=-2.74 cm, p=0.024). Despite the limited sample size in the first trimester, negative effects of maternal Mn levels on birth weight (β=-1108.95 g, p<0.01) and chest circumference (β=-4.40 cm, p=0.019) were also observed.