A Subset of Paracrine Factors as Efficient Biomarkers for Predicting Vascular Regenerative Efficacy of Mesenchymal Stromal/Stem Cells.

Mesenchymal stromal/stem cells (MSCs) have been developed as a promising source for cell-based therapies of ischemic disease. However, there are some hurdles in their clinical application such as poor cell engraftment and inconsistent stem cell potency. In this study, we sought to find biomarkers for predicting potency of MSCs for proangiogenic therapy to improve their beneficial effects. Large variations were observed in proangiogenic factor secretion profiles of conditioned media derived from nine different donor-derived Wharton's jelly (WJ)-derived MSCs and 8 factors among 55 angiogenesis-related factors were secreted at considerable levels. Two distinct WJ-MSCs that had the lowest or the highest secretion of these eight factors showed corresponding proangiogenic activities in in vitro angiogenesis assays. When four additional different donor-derived WJ-MSCs were further examined, proangiogenic activities in migration and tube formation of endothelial cells and in in vivo Matrigel plug assay were highly consistent with secretion levels of four major factors (angiogenin, interleukin-8, monocyte chemoattractant protein-1, and vascular endothelial growth factor). Such correlation was also observed in vascular regenerative effect in a mouse hind limb ischemia model. Blocking of these four factors by neutralizing antibodies or knockdown of them by siRNA treatment resulted in significant inhibition of proangiogenic activities of not only WJ-MSCs, but also bone marrow-derived MSCs. These results suggest that these four factors may represent efficient biomarkers for predicting vascular regenerative efficacy of MSCs. Stem Cells 2019;37:77-88.

Determining optimal gestational weight gain in the Korean population: a retrospective cohort study.

BACKGROUND: The World Health Organization (WHO) international body mass index (BMI) cut-off points defining pre-pregnancy BMI categories in the Institute of Medicine (IOM) guidelines are not directly applicable to Asians. We aimed to define the optimal gestational weight gain (GWG) for the Korean population based on Asia-specific BMI categories. METHODS: Data from 2702 live singleton deliveries in three tertiary centers between 2010 and 2011 were analyzed retrospectively. A multivariable logistic regression analysis was conducted to determine the lowest aggregated risk of composite perinatal outcomes based on Asia-specific BMI categories. The perinatal outcomes included gestational hypertensive disorder, emergency cesarean section, and fetal size for gestational age. In each BMI category, the GWG value corresponding to the lowest aggregated risk was defined as the optimal GWG. RESULTS: Among the study population, 440 (16.3%) were underweight (BMI < 18.5), 1459 (54.0%) were normal weight (18.5 ≤ BMI < 23), 392 (14.5%) were overweight (23 ≤ BMI < 25) and 411 (15.2%) were obese (BMI ≥ 25). The optimal GWG by Asia-specific BMI category was 20.8 kg (range, 16.7 to 24.7) for underweight, 16.6 kg (11.5 to 21.5) for normal weight, 13.1 kg (8.0 to 17.7) for overweight, and 14.4 kg (7.5 to 21.9) for obese. CONCLUSION: Considerably higher and wider optimal GWG ranges than recommended by IOM are found in our study in order to avoid adverse perinatal outcomes. Revised IOM recommendations for GWG could be considered for Korean women according to Asian BMI categories. Further prospective studies are needed in order to determine the optimal GWG for the Korean population.

Teratogenic Effect of Radotinib: Case Report.

BACKGROUND: Simultaneous presentation of pregnancy and chronic myeloid leukemia (CML) is rare. Tyrosine kinase inhibitors (TKIs) are rarely used in pregnancy. There is almost no information on the effect of recently developed TKIs on the fetus. CASE REPORT: A 22-year-old woman became pregnant while using radotinib, a novel TKI for CML. She was concerned about the possible teratogenic effect of radotinib; hence the first pregnancy was terminated. The patient underwent full-term delivery at the second pregnancy. The infant had facial deformity and congenital laryngomalacia. CONCLUSION: We witnessed structural abnormality when the patient used radotinib during the first trimester of pregnancy. When radotinib is prescribed for women of childbearing age, thorough education about contraception is necessary.

Complete septate uterus, obstructed hemivagina, and ipsilateral adnexal and renal agenesis in pregnancy.

Most cases of double uterus with obstructed hemivagina and ipsilateral renal agenesis were diagnosed at adolescents after menarche. This is the first reported case of complete septate uterus with obstructed hemivagina and ipsilateral renal agenesis in addition to ipsilateral agenesis of fallopian tube and ovary in which the diagnosis was delayed until pregnancy. The pregnancy was uneventful in spite of intermittent vaginal spotting. During the cesarean section, the septum of the uterus was resected and about a 3-cm×3-cm window was made on the vaginal septum to allow an opening for the obstructed vaginal discharge. We followed the patient up for one and half years, and she has not had symptoms such as dysmenorrhea or abnormal vaginal bleeding.

Congenital chylothorax and pulmonary hypertension complicated with heart failure and hepatopathy.

Respiratory difficulty resulting from congenital chylothorax is usually relieved by postnatal thoracentesis, closed chest drainage, and oxygen therapy. However, early occurrence of congenital chylothorax or accumulation of a large amount of chylous fluid sometimes leads to pulmonary hypoplasia or persistent pulmonary hypertension of the newborn, which requires further customized mechanical ventilatory support. In these cases, conventional mechanical ventilation is primarily used during initial treatment and is later replaced by high-frequency ventilation, but the advantages of inhaled nitric oxide treatment have rarely been described. This case suggests the benefits of inhaled nitric oxide in patients with congenital chylothorax, even when mechanical ventilation cannot improve respiratory distress because of severe pulmonary hypertension of the newborn leading to right cardiac dysfunction and possibly cholestasis.

Obstructive sleep apnea screening and perinatal outcomes in Korean pregnant women.

PURPOSE: This study was intended to evaluate the attributable risk of obstructive sleep apnea (OSA) by a sleep questionnaire to adverse pregnancy outcomes. METHODS: This was a prospective, cohort study in Korean pregnant women. Berlin questionnaire was employed for symptom-based OSA screening during the third trimester and obstetric outcome data were obtained in 276 deliveries. The relationship between symptom-based OSA and outcomes were explored using SPSS version 18.0 and stratified by obesity (BMI strata <30 and ≥30). Our primary outcome was the compound occurrence of SGA (fetal) or preeclampsia (maternal). Multivariate models were applied in controlling for potential confounders. RESULTS: The overall prevalence of OSA was 32.2 % and it was significantly related with the higher maternal BMI, more body weight at delivery, and weight gain during pregnancy (p = 0.007, p = 0.003, p = 0.005, respectively). There were no significant differences in the primary outcomes according to the positivity of OSA by screening, regardless of the stratification by obesity. The cesarean delivery rate was significantly higher in the OSA positive group (36.0 vs 22.5 %, p = 0.018), but it was not significant in the each strata of obesity. In multivariate analysis, the outcomes of birth weight, preeclampsia, cesarean delivery, and small for gestational age were also not different according to the positivity of OSA. CONCLUSIONS: It seems that the prevalence of OSA by a sleep questionnaire is overestimating OSA in Korean pregnant women. Polysomnography might be needed to diagnose OSA and to evaluate the relationship between OSA and the occurrence of SGA or preeclampsia.

Gene expression pattern of human chorion-derived mesenchymal stem cells during adipogenic differentiation.

PURPOSE: The aim of this study was to identify the adipocyte-specific gene expression patterns in chorion-derived mesenchymal stem cells during adipogenic differentiation. MATERIALS AND METHODS: Chorionic cells were isolated from the third trimester chorions from human placenta at birth and identified morphologically and by fluorescence-activated cell sorting analysis. After inducing adipogenic differentiation for 28 days, cells at days 3, 10, 21 and 28 were analyzed by Oil red O staining and RNA extraction in order to assess the expression levels of adipocyte marker genes, including CCAAT-enhancer binding protein α (C/EBPα), peroxisome proliferator- activated receptor γ (PPARγ), fatty acid binding protein 4 (FABP4) and Glycerol-3-phosphate dehydrogenase (GPD2). Cells not induced for differentiation were compared with the induced cells as a control group. RESULTS: Chorion-derived cells showed the same pattern as fibroblasts, and expressed CD73, CD105, and CD166 antigens, but not CD45, CD34, and HLA-DR antigens. On day 3 after differentiation, cells began to stain positively upon Oil red O staining, and continuously increased in lipid granules for 4 weeks. The expression level of C/EBPα increased 4.6 fold on day 3 after induction, and continued to increase for 4 weeks. PPARγ was expressed at a maximum of 2.9 fold on day 21. FABP4 and GPD2 were significantly expressed at 4.7- and 3.0-fold, respectively, on day 21, compared to controls, and further increased thereafter. CONCLUSION: Human chorion-derived mesenchymal stem cells exhibited the sequential expression pattern of adipocyte marker genes during differentiation, corresponding to adipogenesis.

Comparison of outcomes after typical and atypical eclampsia: a retrospective study.

OBJECTIVE: To evaluate the characteristics, clinical features and maternal-perinatal outcomes after atypical eclampsia. METHODS: In a retrospective study, we compared demographics, clinical characteristics and outcomes between typical and atypical eclampsia. RESULTS: Of 90 eclamptic patients, 56 had typical eclamptic features and 34 had atypical features. Compared to typical eclampsia, atypical eclampsia had higher gestational age (37.6 ± 3.3 vs. 34.6 ± 4.2 weeks, p = 0.001), a higher incidence of no antenatal risk factors [25 (73.5%) vs. 12 (21.4%), p < 0.001], less antepartum seizures [11 (32.4%) vs. 45 (80.4%), p < 0.001], a lower incidence of prodromal symptoms [20 (58.5%) vs. 49 (87.5%), p = 0.002], and a higher incidence of no lesion in brain imaging [16 (47.1%) vs. 12 (21.4%), p = 0.010). Although atypical eclampsia was associated with a lower odd ratio (OR) in composite perinatal complications (OR = 0.22, 95% CI = 0.08-0.60, p = 0.003), composite maternal complications did not differ between the two groups (OR = 0.52, 95% CI = 0.08-0.60, p =0.191). CONCLUSIONS: Maternal outcomes did not differ between the two groups. Therefore, more attention should be focused on atypical eclampsia.

Sleep disturbances in Korean pregnant and postpartum women.

This was a prospective, cohort study in Korean pregnant and postpartum women, to estimate the prevalence and patterns of sleep disturbances. The survey was composed of the following validated sleep questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Women's Health Initiative Insomnia Rating Scale, Berlin Questionnaire for sleep disordered breathing, the international restless leg syndrome (IRLS) Study Group criteria, and the Johns Hopkins Telephone Diagnostic Interview Form (JHTDIF) for RLS. Statistical analyses were performed using SPSS version 18.0. Six hundred eighty-nine women completed sleep surveys. The overall percentage of women with very poor sleep quality (a PSQI score greater than 10), clinically significant insomnia (a total score of 9 or more), excessive daytime sleepiness (a total ESS score of 10 or more), short sleep duration (less than 7 hours per night) were 80.7%, 50.5%, 34.0% and 29.5%, respectively, and all of three parameters became increased as pregnancy progressed and after delivery ( p = 0.002, 0.001, and 0.001, respectively). The overall positive rates in Berlin and RLS questionnaires were 25.4% and 19.4%. In conclusion, sleep disturbances are prevalent among Korean pregnant and postpartum women, and increase significantly as pregnancy progresses and after delivery.

Antenatal sonographic features of ileal atresia.

AIM: The purpose of this study was to determine the antenatal sonographic features of ileal atresia. MATERIAL AND METHODS: We identified neonates with surgically-confirmed ileal atresia who had antenatal sonography performed in our institution between 1 January 1999 and 30 June 2009. The antenatal sonography images and reports were reviewed. RESULTS: Sixteen neonates had surgically-confirmed ileal atresia in our institution in 11 years. Seven fetuses (43.7%) did not have any intestinal abnormalities detected antenatally on ultrasonography. Nine fetuses (56.3%) had various sonographic features of ileal atresia, including multiple dilated bowel loops, ascites, cysts, and polyhydramnios with or without associated anomalies. Six of nine fetuses had multiple dilated bowel loops and two fetuses had ascites. One fetus had a large, cystic, mixed, echogenic dilatation of bowel. Polyhydramnios was present in three fetuses. Heart anomalies, kidney anomalies, or hydrops were present in four fetuses. Eight of 16 fetuses (50%) had other intestinal problems, including intussusceptions in one fetus, small bowel malrotation, meconium pseudocyst volvulus, meconium peritonitis, and a congenital band. CONCLUSION: The prenatal sonographic features of ileal atresia are not simple. Various sonographic findings are shown and ileal atresia was detected in about 60% of cases.

Korean-specific parameter models for calculating the risk of Down syndrome in the second trimester of pregnancy.

The purpose of the current study was to propose a Korean-specific parameter set for calculating the risk of Down syndrome in the second trimester of pregnancy and to determine the screening performances of triple and quadruple tests in Korean women. Using the data on triple or quadruple screening from three hospitals in Korea during 7 yr, we re-converted the concentrations of four serum markers to multiple of median values according to gestational age and maternal weight. After re-calculating the risk of Down syndrome in each pregnancy by multiplying maternal age-specific risk by the likelihood ratio values for the serum markers, screening performances and optimal cut-off values of triple and quadruple tests were analyzed. Among 16,077 pregnancies, 23 cases had Down syndrome (1.4/1,000 deliveries). Compared to the previous program, the tests with new parameters had improved screening performance. The triple and quadruple tests had detection rates of 65.2% and 72.7%, respectively, at a false-positive rate of 5%. The optimal cut-off value for the quadruple and triple tests was 1:250. We have presented a Korean-specific parameter set for Down syndrome screening. The proposed screening test using this parameter set may improve the performance of Down syndrome screening for Korean women.

Comparison of cervical parameters by three-dimensional ultrasound according to parity and previous delivery mode.

BACKGROUND: We would like to find out that whether the patient's parity, previous delivery mode and previous labor could influence cervical parameters. Cervical length, volume and width were measured using two-dimensional (2D) and three-dimensional (3D) transvaginal ultrasound on normal pregnant women. METHOD: This study was conducted between January 2009 and December 2010 in singleton pregnant women who were admitted for routine antenatal care at hospitals in affiliation with the Catholic University, Seoul, Korea. The study group was classified by parity (nullipara and multipara) and previous delivery mode (cesarean section group and vaginal delivery group). The previous cesarean section group was divided by elective group who did not undergo labor and labor group who underwent labor. Cervical parameters such as cervical length, volume and width were measured using 2D and 3D ultrasound examinations in the first and second trimesters and the results were analyzed between those groups mentioned above. RESULTS: One hundred and twenty-one pregnant women in their 1st trimester and 233 pregnant women in their 2nd trimester (a total of 354) were enrolled in this study. Cervical parameters were not statistically significant from parity, nor previous delivery mode and previous labor in 1st trimester. Cervical volumes were not statistically significant from nullipara and elective cesarean section groups (35.96±9.81 vs. 34.73±9.75 cm3), but the nullipara groups were significantly lowered in the vaginal group (35.96±9.81 vs. 43.10±11.87 cm3) in 2nd trimester. For the nullipara group, cervical widths were not statistically significant in the elective cesarean section group but these were significantly lower than labor and previous vaginal group in the 2nd trimester. CONCLUSION: The cervical volume and width have an influence on parity, previous delivery mode and labor in the 2nd trimester.

The clinical significance of digital examination-indicated cerclage in women with a dilated cervix at 14 0/7-29 6/7 weeks.

OBJECTIVE: This study was to compare pregnancy outcomes between cerclage and expectant management in wemen with a dilated cervix. DESIGN: Retrospective multicenter cohort study. SETTING: Five hospitals of Catholic University Medical Center Network in Korea. POPULATION: A total of 173 women between 14 0/7 and 29 6/7 weeks' gestation with cervical dilation of 1 cm or greater by digital examination. METHODS: Pregnancy outcomes were compared according to cerclage or expectant management, with the use of propensity-score matching. MAIN OUTCOME MEASURES: Primary outcome was time from presentation until delivery (weeks). Secondary outcomes were gestational age at delivery, neonatal survival, morbidity, preterm birth, and so on. RESULTS: Of 173 women, 116 received a cerclage (cerclage group), and 57 were managed expectantly without cerclage (expectant group). Cervical dilation at presentation, and the use of amniocentesis performed to exclude subclinical chorioamnionitis differed between two groups. In the overall matched cohort, there was significant difference in the time from presentation until delivery (cerclage vs. expectant group, 10.6±6.2 vs. 2.9±3.2 weeks, p <0.0001). While there was no significant difference in the neonatal survival between two groups, there were lower neonatal morbidity as well as higher pregnancy maintenance rate at 28, 32, 34 and 37 weeks' gestation in the cerclage group, compared with the expectant group. CONCLUSION: This study suggests that digital examination-indicated cerclage appears to prolong gestation and decrease neonatal morbidity, compared with expectant management in women with cervical dilation between 14 0/7 and 29 6/7 weeks.

Monoamniotic twins with one fetal anencephaly and cord entanglement diagnosed with three dimensional ultrasound at 14 weeks of gestation.

A 29-year-old pregnant woman with parity 0-0-0-0 was diagnosed with monoamniotic twin pregnancy discordant for anencephaly at 14 weeks gestation. Umbilical cord entanglement, which is an important cause of fetal death in monoamniotic twins, was confirmed by three-dimensional ultrasound. Cesarean section was performed at 34 weeks of gestation, and the normal newborn infant was discharged without any complications. We report a case of monoamniotic twin pregnancy discordant for anencephaly and diagnosed with cord entanglement by three-dimensional ultrasound at 14 weeks of gestation, and now report it along with a literature review.

Pregnancy outcomes and appropriate timing of pregnancy in 183 pregnancies in Korean patients with SLE.

This study was undertaken to investigate the pregnancy outcomes in patients with systemic lupus erythematosus (SLE) and the appropriate timing of pregnancy. We performed a retrospective evaluation of 183 pregnancies with SLE at Catholic University Medical Center during the 13-year period from 1998 to 2010. Pregnancy outcomes were compared according to SLE characteristics. The predictive value of the different cut-off points of the stable period before conception on adverse pregnancy outcomes was calculated by ROC (Receiver operating characteristics) curve analysis. In multivariate analysis, the presence of antiphospholipid antibodies (aPLs) increased the risk of pregnancy loss (p<0.0001) and premature birth (p=0.0040). Active disease at conception increased the risk of premature birth (p< 0.0001) and complications (IUGR, PIH, or both) (p= 0.0078). The other predictor of complications was found to be lupus flare (p=0.0252). At a cut-off level of stable period of 4 months before conception, sensitivity and specificity were 70.8% and 53.2%, 71.4% and 61.5%, and 63.6 % and 59.8 %, respectively on reducing pregnancy loss, premature birth, and complications. Pregnancies with aPLs, active disease at conception and SLE flares are at a higher risk of adverse outcomes. It is essential that disease activity remains stable at least 4 months before conception, for favorable pregnancy outcomes.

The sonographic umbilical cord coiling in late second trimester of gestation and perinatal outcomes.

BACKGROUND: This study was conducted to determine whether or not the umbilical cord coiling index (UCI) during the late second trimester of gestation is associated with perinatal outcomes. METHODS: This was a retrospective study of 251 pregnancies in which a fetal anatomic survey with a recorded UCI was performed at 22-28 weeks gestation. The subjects were divided into normocoiled, hypocoiled, and hypercoiled groups and compared perinatal outcomes. RESULTS: Two hundred twenty-six patients were included. The incidence of preterm deliveries in hypocoiled group was 35%, which was significantly greater than the normocoiled groups (p=0.041). The incidence of neonates with low birth weights in the hypocoiled group was 36.4%, which was significantly greater than the normocoiled groups (p=0.044). In the hypocoiled group, 27.3% of newborns were admitted to the NICU which was significantly greater than the normocoiled and hypercoiled groups (p=0.041). After the adjustment by logistic regression analysis, only preterm delivery were significantly increased in hypocoiled group (OR=9.6, 95% CI=2.09-44.07). CONCLUSION: The hyporcoiling of the umbilical cord during the late second trimester of pregnancy suggest that the risk for preterm delivery is high, consequently the delivery of low birthweight neonates is high, and the admission to the neonatal intensive care unit is increased.

Evolution of sonographic findings in a fetus with ileal atresia.

We report a case of a meconium pseudocyst secondary to ileal atresia and midgut volvulus. Initially, a single anechoic cyst was detected on prenatal sonography. The cyst gradually increased in size during the second trimester and eventually appeared as a large mass in the lower abdomen with echogenic content and associated with bowel dilatation. This case indicates that until the mid third trimester a single sonolucent cyst without signs of bowel obstruction may be associated with congenital intestinal obstruction.

Oncostatin M as a target biological molecule of preeclampsia.

AIM: Given the presence of the cytokinetic effects of Oncostatin M (OSM), we hypothesized that placental expression of OSM and serum OSM levels are elevated in preeclampsia. To verify this hypothesis, we determined the expression of OSM in placenta and levels of OSM in plasma form women with preeclampsia and normal pregnant women. METHODS: Sixteen women with severe preeclampsia and 16 normal pregnancy women were studied. Placental tissues were immediately frozen and stored at -80 degrees C until extraction of total RNA. Total RNA was extracted and real-time quantitative PCR was carried out. Placental tissues fixed in 4% paraformaldehyde were reacted with antibodies against OSM. An independent pathologist who was blind to the origins of the samples reviewed these stained slides. The maternal serum and umbilical venous concentration of OSM were determined by commercially available ELISA analysis. RESULTS: The mRNA expression level of OSM in preeclamptic placenta was increased by 3.91 times which was significantly higher than those of the normal group (P = 0.028). OSM immunoreactivity was significantly higher in placentas of patients with preeclampsia than placentas from the normal group. The significantly greater OSM expressions were noted in cytotrophoblasts, syncytotrophoblasts and endothelium of preeclamptic placentas as compared to normal placentas (respectively, P = 0.004, 0.001 and 0.04). OSM concentration of preeclamptic women's serum was significantly higher than that of normal women's plasma (P = 0.016). However, OSM level of umbilical venous serum was not significantly different between two groups (P = 0.243) CONCLUSION: OSM may play a biological marker for severe preeclampsia, and its action may be predominantly on the trophoblasts and endothelium of placenta villi in preeclampsia.

Prenatal diagnosis of holoprosencephaly with ethmocephaly via 3-dimensional sonography.

We present the prenatal 3-dimensional (3D) sonographic findings in a case of holoprosencephaly with ethmocephaly at 32 weeks' gestation. The sonographic diagnosis was based on the intracranial findings of a single ventricle and bulb-shaped appearance of the thalami and facial abnormalities, including hypotelorism with proboscis. Chromosome study of the fetus revealed a normal female karyotype (46,XX). Postmortem examination confirmed the 3D sonographic findings. This case demonstrates that the use of 3D sonography improves the imaging and the understanding of the condition of the intracranial abnormalities and the facial anomalies.