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1.  Surfactant Protein-A as an Anti-Inflammatory Component in the Amnion: Implications for Human Pregnancy1 
The mechanism of mouse parturition is thought to involve myometrial infiltration by amniotic fluid (AF) macrophages, activated by surfactant protein-A (SP-A). In humans, the concentration of AF SP-A decreases during labor, and no fetal macrophages are found in the myometrium after labor. Therefore, it appears that the mechanisms of labor in mice and humans are different. We investigated a potential role for SP-A in human pregnancy and parturition by examining SP-A expression patterns in AF and amnion. High molecular weight (HMW; >250 kD) oligomeric SP-A was increased in AF with advancing gestation. Interestingly, these oligomers were more abundant in placental amnion before labor at term, while they increased primarily in reflected amnion during labor (p<0.05). Immunoblotting showed a binding of HMW SP-A in AF to amnion. In C57BL/6 mice, oligomeric SP-A was also readily detected in AF from E15 onwards, but not in amnion. Macrophage density in mice myometrium did not change with advancing gestational age. Microarray analysis of human amnion explants incubated with SP-A revealed a molecular signature of inhibited cytokine-cytokine receptor interaction with down-regulation of IL-1β, CXCL2, and CXCL5 mRNA expression. The findings herein strongly suggest that SP-A signals amniotic anti-inflammatory response via amniotic fluid during pregnancy. We propose that a SP-A interaction among amniotic fluid, placental amnion, and reflected amnion is a unique mechanism for immunoregulation in human pregnancy akin to that established in lung biology. However, amniotic fluid SP-A and fetal macrophages by themselves do not seem to be exclusive effectors of parturition in humans.
This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org.
doi:10.4049/jimmunol.0903867
PMCID: PMC3103775  PMID: 20439915
human; inflammation; mucosa; macrophages; reproductive immunology
2.  Morphologic Alteration of Metastatic Neuroblastic Tumor in Bone Marrow after Chemotherapy 
Korean Journal of Pathology  2013;47(5):433-442.
Background
The aim of this study is to evaluate the histologic features of metastatic neuroblastic tumors (NTs) in bone marrow (BM) before and after chemotherapy in comparison with those of primary NTs.
Methods
A total of 294 biopsies from 48 children diagnosed with NTs with BM metastasis were examined. There were 48 primary neoplasm biopsies, 48 BM biopsies before chemotherapy, 36 primary neoplasm excisional biopsies after chemotherapy, and 162 BM biopsies after chemotherapy.
Results
Metastatic NTs in BM before chemotherapy were composed of undifferentiated and/or differentiating neuroblasts, but had neither ganglion cells nor Schwannian stroma. Metastatic foci of BM after chemotherapy were found to have differentiated into ganglion cells or Schwannian stroma, which became more prominent after further cycles of chemotherapy. Persistence of NTs or tumor cell types in BM after treatment did not show statistically significant correlation to patients' outcome. However, three out of five patients who newly developed poorly differentiated neuroblasts in BM after treatment expired due to disease progression.
Conclusions
Metastatic NTs in BM initially consist of undifferentiated or differentiating neuroblasts regardless of the primary tumor subtype, and become differentiated after chemotherapy. Newly appearing poorly differentiated neuroblasts after treatment might be an indicator for poor prognosis.
doi:10.4132/KoreanJPathol.2013.47.5.433
PMCID: PMC3830990  PMID: 24255631
Neuroblastoma; Bone marrow; Drug therapy; Neoplasm metastasis; Histology
3.  Methylome of Fetal and Maternal Monocytes and Macrophages at the Feto-Maternal Interface 
Problem
Decidual macrophages (dMϕ) of the mother and placental macrophages (Hofbauer cells, HC) of the fetus are deployed at a critical location: the feto-maternal interface. This study was conducted to compare DNA methylome of maternal and fetal monocytes, dMϕ, and HC, and thereby to determine the immunobiological importance of DNA methylation in pregnancy.
Methods of Study
Paired samples were obtained from normal pregnant women at term not in labor and their own neonates. Maternal monocytes (MM) and fetal monocytes (FM) were isolated from peripheral blood of mothers and from fetal cord blood, respectively. dMϕ and HC were obtained from the decidua of fetal membranes and placenta, respectively. DNA methylation profiling was done using the Illumina Infinium Human Methylation27 BeadChip. Quantitative real-time PCR and western blot were performed for validation experiments.
Results
1) Significant differences in DNA methylation were found in each comparison (MM vs. FM, 65 loci; dMϕ vs. HC, 266 loci; MM vs. dMϕ, 199 loci; FM vs. HC, 1,030 loci). 2) Many of the immune response-related genes were hypermethylated in fetal cells (FM and HC) compared to maternal cells (MM and dMϕ). 3) Genes encoding markers of classical macrophage activation were hypermethylated and genes encoding alternative macrophage activation were hypomethylated in dMϕ and HC compared to MM and FM, respectively. 4) mRNA expressions of DNMT1, DNMT3A, and DNMT3B were significantly lower in dMϕ than in HC. 5) 5-azacytidine treatment increased expression of INCA1 in dMϕ.
Conclusions
The findings herein indicate that DNA methylation patterns change during monocyte-macrophage differentiation at the feto-maternal interface. It is also suggested that DNA methylation is an important component of biological machinery conferring an anti-inflammatory phenotype to macrophages at the feto-maternal interface.
doi:10.1111/j.1600-0897.2012.01108.x
PMCID: PMC3479407  PMID: 22385097
Decidua; DNA methylation; DNA methyltransferase; Epigenetics; Epigenome; Hofbauer cell; Placenta; Pregnancy
4.  Optical Coherence Tomographic Observation of Morphological Features of Neointimal Tissue after Drug-Eluting Stent Implantation 
Yonsei Medical Journal  2014;55(4):944-952.
Purpose
The impacts of different time courses and the degree of neointimal growth on neointimal morphology have not yet been sufficiently investigated. Therefore, we evaluated the morphological features of neointimal tissue after drug-eluting stent (DES) implantation using optical coherence tomography (OCT).
Materials and Methods
The morphological features of neointimal tissue in stented segments with a maximal percentage of cross-sectional area (CSA) stenosis of neointima were evaluated in 507 DES-treated lesions with >100 µm mean neointimal thickness on follow-up OCT. Neointimal tissue was categorized as homogeneous, heterogeneous, layered, or neoatherosclerotic.
Results
In lesions with <50% of neointimal CSA stenosis, homogeneous neointima (68.2%) was predominant, followed by heterogeneous neointima (14.1%) and layered neointima (14.1%). In lesions with ≥50% of neointimal CSA stenosis, layered neointima was most frequently observed (68.3%), followed by neoatherosclerotic neointima (25.2%). In subgroup analysis of lesions with ≥50% of neointimal CSA stenosis, 89.5% of the lesions with a stent age <30 months were layered neointima, while 62.3% of the lesions with a stent age ≥30 months were neoatherosclerotic neointima.
Conclusion
This study suggests that the OCT-detected morphology of DES neointimal tissue was different according to the follow-up time course and degree of neointimal hyperplasia.
doi:10.3349/ymj.2014.55.4.944
PMCID: PMC4075398  PMID: 24954322
Optical coherence tomography; stent; coronary artery disease
5.  Peripheral CD300a+CD8+ T Lymphocytes with a Distinct Cytotoxic Molecular Signature Increase in Pregnant Women with Chronic Chorioamnionitis 
Problem
CD300a is an immunomodulatory molecule of the immunoglobulin receptor superfamily expressed in the leukocytes of myeloid and lymphoid lineages. However, its biological function on CD8+ T lymphocytes remains largely unknown. This study was conducted to assess the biological significance of CD300a expression in T lymphocytes and to determine whether its expression in peripheral T lymphocytes changes in pregnant women presenting with anti-fetal rejection.
Methods of Study
Microarray analysis was performed using total RNA isolated from peripheral CD300a+ and CD300a− T lymphocytes. Flow cytometric analysis of the peripheral blood samples of pregnant women and pathologic examination of the placentas were conducted.
Results
A large number of genes (N = 1,245) were differentially expressed between CD300a− and CD300a+ subsets of CD8+ T lymphocytes, which included CCR7, CD244, CX3CR1, GLNY, GZMB, GZMK, IL15, ITGB1, KLRG1, PRF1, and SLAMF7. Gene Ontology analysis of differentially expressed genes demonstrated enrichment of biological processes such as immune response, cell death, and signal transduction. CD300a expression in CD8+ T lymphocytes was coupled to a more cytotoxic molecular signature. Of note, the proportion of CD300a+CD8+ T lymphocytes increased in pregnant women with chronic chorioamnionitis (anti-fetal rejection of the chorioamniotic membranes; P < 0.05).
Conclusion
The findings of this study strongly suggest an increase of systemic T lymphocyte-mediated cytotoxicity in pregnant women with chronic chorioamnionitis as a manifestation of maternal anti-fetal rejection.
doi:10.1111/j.1600-0897.2011.01088.x
PMCID: PMC3479405  PMID: 22077960
placenta; maternal anti-fetal rejection; prematurity; preterm birth; transcriptome
6.  Poly(styrene)-b-poly(DL-lactide) copolymer-based nanoparticles for anticancer drug delivery 
Poly(styrene)-b-poly(DL-lactide) (PS-PDLLA) copolymer-based nanoparticles (NPs) of a narrow size distribution, negative zeta potential, and spherical shape were fabricated for the delivery of docetaxel (DCT). The particle size was consistently maintained in serum for 24 hours and a sustained drug release pattern was observed for 10 days in the tested formulations. The cytotoxicity of the developed blank NPs was negligible in prostate cancer (PC-3) cells. Cellular uptake and distribution of the constructed NPs containing a hydrophobic fluorescent dye was monitored by confocal laser scanning microscopy (CLSM) for 24 hours. Anti-tumor efficacy of the PS-PDLLA/DCT NPs in PC-3 cells was significantly more potent than that of the group treated with commercially available DCT, Taxotere® (P<0.05). Blood biochemistry tests showed that no serious toxicity was observed with the blank NPs in the liver and kidney. In a pharmacokinetic study of DCT in rats, in vivo clearance of PS-PDLLA/DCT NPs decreased while the half-life in blood increased compared to the Taxotere-treated group (P<0.05). The PS-PDLLA NPs are expected to be a biocompatible and efficient nano-delivery system for anticancer drugs.
doi:10.2147/IJN.S62806
PMCID: PMC4051715  PMID: 24940058
docetaxel; prolonged blood circulation; prostate cancer
7.  Comparison of Full Lesion Coverage versus Spot Drug-Eluting Stent Implantation for Coronary Artery Stenoses 
Yonsei Medical Journal  2014;55(3):584-591.
Purpose
The aim of this study was to evaluate and compare the long-term clinical outcomes of the spot drug-eluting stent (DES) implantation strategy, which is used to minimize implanted stent length and the number of stents, versus full lesion coverage for treatment of coronary artery stenoses.
Materials and Methods
We evaluated 1-year clinical outcomes of 1619 patients with stent implantation for a single coronary lesion. They were divided into two groups: those treated by full lesion coverage (n=1200) and those treated with the spot stenting strategy (n=419). The combined occurrence of 1-year target vessel failure (TVF), including cardiac death, target-vessel related myocardial infarction, or ischemia-driven target-vessel revascularization was evaluated.
Results
The spot DES implantation group had a shorter stent length (23.14±9.70 mm vs. 25.44±13.24 mm, respectively; p<0.001) and a fewer number of stents (1.09±0.30 vs. 1.16±0.41, respectively; p<0.001), even though the average lesion length was similar to the full lesion coverage group (21.36±10.30 mm vs. 20.58±10.97 mm, respectively; p=0.206). Spot DES implantation was superior to full DES coverage with respect to 1-year TVF (1.4% vs. 3.3%, p=0.044). Cox proportional hazard model analysis showed that the risk for 1-year TVF was almost 60% lower among patients who received spot DESs compared to those who received full DES coverage after adjustment for other risk factors (HR=0.40, 95% confidence interval=0.17-0.98; p=0.046).
Conclusion
Minimizing stent length and the number of stents with overlapping by spot DES implantation may result in reduced rates of 1-year TVF, compared with full DES coverage.
doi:10.3349/ymj.2014.55.3.584
PMCID: PMC3990086  PMID: 24719123
Drug-eluting stents; percutaneous coronary intervention; coronary artery disease
8.  Clinical Outcomes in Patients with Intermediate Coronary Stenoses: MINIATURE Investigators (Korea MultIceNter TrIal on Long-Term Clinical Outcome According to the Plaque Burden and Treatment Strategy in Lesions with MinimUm Lumen ARea lEss Than 4 mm2 Using Intravascular Ultrasound) 
Korean Circulation Journal  2014;44(3):148-155.
Background and Objectives
We evaluated the two-year clinical outcomes in patients with angiographically intermediate lesions according to the plaque burden and treatment strategy.
Subjects and Methods
We prospectively enrolled patients with angiographically intermediate lesions (diameter stenosis 30-70%) with an intravascular ultrasound (IVUS) minimum lumen area (MLA) <4 mm2 with 50-70% plaque burden of 16 Korean percutaneous coronary intervention centers. Patients were divided into medical therapy group (n=85) and zotarolimus-eluting stent group (ZES; Resolute) group (n=74). We evaluated the incidences of two-year major adverse cardiovascular events (MACE).
Results
A two-year clinical follow-up was completed in 143 patients and MACE occurred in 12 patients. There were no significant differences in the incidences of death (1.3% vs. 3.0%, p=0.471), target vessel-related non-fatal myocardial infarction (0.0% vs. 0.0%, p=1.000) and target vessel revascularizations (7.8% vs. 4.5%, p=0.425) between medical and ZES groups. Independent predictors of two-year MACE included acute myocardial infarction {odds ratio (OR)=2.87; 95% confidence interval (CI) 1.43-6.12, p=0.014}, diabetes mellitus (OR=2.46; 95% CI 1.24-5.56, p=0.028) and non-statin therapy (OR=2.32; 95% CI 1.18-5.24, p=0.034).
Conclusion
Medical therapy shows comparable results with ZES, and myocardial infarction, diabetes mellitus and non-statin therapy were associated with the occurrence of two-year MACE in patients with intermediate lesion with IVUS MLA <4 mm2 with 50-70% of plaque burden.
doi:10.4070/kcj.2014.44.3.148
PMCID: PMC4037636  PMID: 24876855
Coronary artery disease; Atherosclerotic plaque; Intravascular ultrasonography
9.  Interleukin-33 in the Human Placenta 
Objective
Interleukin-33 (IL-33) is the newest member of the IL-1 cytokine family, a group of key regulators of inflammation. The purpose of this study was to determine whether IL-33 is expressed in the human placenta and to investigate its expression in the context of acute and chronic chorioamnionitis.
Methods
Placental tissues were obtained from five groups of patients: (1) normal pregnancy at term without labor (n=10); (2) normal pregnancy at term in labor (n=10); (3) preterm labor without inflammation (n=10); (4) preterm labor with acute chorioamnionitis (n=10); and (5) preterm labor with chronic chorioamnionitis (n=10). Immunostaining was performed to determine IL-33 protein expression patterns in the placental disk, chorioamniotic membranes, and umbilical cord. mRNA expression of IL-33 and its receptor IL1RL1 (ST2) was measured in primary amnion epithelial and mesenchymal cells (AECs and AMCs, n=4) and human umbilical vein endothelial cells (HUVECs, n=4) treated with IL-1β (1ng/ml and 10ng/ml) and CXCL10 (0.5ng/ml and 1ng/ml or 5ng/ml).
Results
1) Nuclear IL-33 expression was found in endothelial and smooth muscle cells in the placenta, chorioamniotic membranes, and umbilical cord; 2) IL-33 was detected in the nucleus of CD14+ macrophages in the chorioamniotic membranes, chorionic plate, and umbilical cord, and in the cytoplasm of myofibroblasts in the Wharton’s jelly; 3) acute (but not chronic) chorioamnionitis was associated with the presence of IL-33+ macrophages in the chorioamniotic membranes and umbilical cord; 4) expression of IL-33 or IL1RL1 (ST2) mRNA in AECs was undetectable; 5) IL-33 mRNA expression increased in AMCs and HUVECs after IL-1β treatment but did not change with CXCL10 treatment; and 6) IL1RL1 (ST2) expression decreased in AMCs and increased in HUVECs after IL-1β but not CXCL10 treatment.
Conclusions
IL-33 is expressed in the nucleus of placental endothelial cells, CD14+ macrophages, and myofibroblasts in the Wharton’s jelly. IL-1β can induce the expression of IL-33 and its receptor. Protein expression of IL-33 is detectable in macrophages of the chorioamniotic membranes in acute (but not chronic) chorioamnionitis.
doi:10.3109/14767058.2012.735724
PMCID: PMC3563729  PMID: 23039129
alarmin; chorioamnionitis; interleukin-1 family; pregnancy; preterm birth; preterm labor
10.  Prospective and Systematic Analysis of Unexpected Requests for Non-Cardiac Surgery or Other Invasive Procedures during the First Year after Drug-Eluting Stent Implantation 
Yonsei Medical Journal  2014;55(2):345-352.
Purpose
Unexpected requests for non-cardiac surgery requiring discontinuation of dual antiplatelet therapy (DAPT) frequently occur in daily clinical practice. The objectives of this study were to evaluate prevalence, timing and clinical outcomes of such unexpected requests for non-cardiac surgery or other invasive procedures during the first year after drug-eluting stents (DESs) implantation.
Materials and Methods
We prospectively investigated the prevalence, timing and clinical outcomes of unexpected requests for non-cardiac surgery or other procedures during the first year after DESs implantation in 2117 patients.
Results
The prevalence of requested non-cardiac surgery or invasive procedures was 14.6% in 310 requests and 12.3% in 261 patients. Among 310 requests, those were proposed in 11.3% <1 month, 30.0% between 1 and 3 months, 36.8% between 4 and 6 months and 21.9% between 7 and 12 months post-DES implantation. The rates of actual discontinuation of DAPT and non-cardiac surgery or procedure finally performed were 35.8% (111 of 310 requests) and 53.2% (165 of 310 requests), respectively. On multivariate regression analysis, the most significant determinants for actual discontinuation of DAPT were Endeavor zotarolimus-eluting stent implantation with 3-month DAPT (OR=5.54, 95% CI 2.95-10.44, p<0.001) and timing of request (OR=2.84, 95% CI 1.97-4.11, p<0.001). There were no patients with any death, myocardial infarction, or stent thrombosis related with actual discontinuation of DAPT.
Conclusion
Those unexpected requests with premature discontinuation of DAPT were relatively common and continuously proposed during the first year following DES implantation. No death, myocardial infarction or stent thrombosis occurred in patients with actual discontinuation of DAPT.
doi:10.3349/ymj.2014.55.2.345
PMCID: PMC3936620  PMID: 24532502
Antiplatelet therapy; drug-eluting stents; coronary artery disease
11.  The Frequency, Clinical Significance, and Pathological Features of Chronic Chorioamnionitis: A Lesion Associated with Spontaneous Preterm Birth 
Acute chorioamnionitis (ACA) is a well-established lesion of the placenta in cases with intra-amniotic infection. In contrast, the clinicopathologic significance of chronic chorioamnionitis (CCA) is unclear. This study was conducted to determine the frequency and severity of CCA in normal pregnancy and various pregnancy complications. Placentas from the following patient groups were studied: 1) term not in labor (TNL; n=100), 2) term in labor (TIL; n=100), 3) preterm labor (PTL; n=100), 4) preterm prelabor rupture of the membranes (PPROM; n=100), 5) preeclampsia at term (TPE; n=100), 6) preterm preeclampsia (PPE; n=100), and 7) small-for-gestational-age at term (SGA; n=100). Amniotic fluid CXCL10 concentration was measured in 64 patients. CXCL9, CXCL10, and CXCL11 mRNA expressions in the chorioamniotic membranes were assessed by real-time quantitative RT-PCR. The frequency of CCA in PTL and PPROM groups was 34% and 39%, respectively, which was higher than those of normal term placentas (TNL 19%, TIL 8%; p<0.05 each). The frequency of CCA in TPE, PPE and SGA groups was 23%, 16%, and 13%, respectively. Concomitant villitis of unknown etiology (VUE) was found in 38.2% and 35.9% of PTL and PPROM cases with CCA, respectively. Interestingly, the median gestational age of preterm CCA cases was higher than that of ACA cases (p<0.05). The median amniotic fluid CXCL10 concentration was higher in cases with CCA than in those without, in both PTL and PPROM groups (p<0.05 and p<0.01, respectively). CXCL9, CXCL10, and CXCL11 mRNA expression in the chorioamniotic membranes was also higher in CCA cases than in those without CCA (p<0.05). We propose that CCA defines a common placental pathologic lesion among the PTL and PPROM groups, especially in cases of late preterm birth. Its association with VUE and the chemokine profile in amniotic fluid suggests an immunological origin, akin to transplantation rejection and graft-versus-host disease in the chorioamniotic membranes.
doi:10.1038/modpathol.2010.73
PMCID: PMC3096929  PMID: 20348884
Chorioamnionitis; amniotic fluid; pregnancy; CXCL9; CXCL10; CXCL11
12.  Percutaneous Cardiopulmonary Support in Refractory No-Reflow with Cardiogenic Shock after Coronary Stenting in Acute Myocardial Infarction 
Yonsei Medical Journal  2010;51(4):599-601.
Coronary no-reflow is defined as inadequate myocardial perfusion of a given coronary segment without angiographic evidence of mechanical vessel obstruction. No-reflow is visualized angiographically as a reduction in thrombolysis in myocardial infarction (TIMI) flow grade and is typically accompanied by chest pain, electrocardiographic changes with ST-segment shift and possible hemodynamic compromise. No-reflow during primary percutaneous coronary intervention (PCI) results in increasing mortality and morbidity. Therefore, treatment of noreflow is associated with improved clinical outcomes. Generally, the treatment of no-reflow is based on pharmacotherapy. In this case, despite maximal pharmacotherapy and intraaortic balloon pump (IABP), refractory no-reflow accompanied with cardiogenic shock was successfully treated with percutaneous cardiopulmonary support (PCPS).
doi:10.3349/ymj.2010.51.4.599
PMCID: PMC2880277  PMID: 20499430
No-reflow; percutaneous cardiopulmonary support; acute myocardial infarction
13.  The Initial Extent of Malapposition in ST-Elevation Myocardial Infarction Treated with Drug-Eluting Stent: The Usefulness of Optical Coherence Tomography 
Yonsei Medical Journal  2010;51(3):332-338.
Purpose
The aim of this study is to identify the extent of initial malapposition using optical coherence tomography (OCT) in ST-elevation myocardial infarctions (STEMI) treated with different types of drug-eluting stents (DES).
Materials and Methods
Twenty four STEMI patients that underwent primary percutaneous coronary intervention (PCI) were enrolled. The OCT and intravascular ultrasound (IVUS) were performed within 72 hours after the primary PCI. Distances between the endo-luminal surface of the strut reflection and the vessel wall and the extent of malapposition were measured and analyzed.
Results
Sirolimus-eluting stents (SES), paclitaxel-eluting stents (PES) and zotarolimus-eluting stents (ZES) were deployed in 7 patients (29%), 7 patients (29%) and 10 patients (42%). In total, 4951 struts in 620 mm single-stent segments were analyzed (1463 struts in SES, 1522 in PES, and 1966 in ZES). In strut analysis by OCT, the incidence of malapposition was 17 % (860/4951) and in stent analysis by IVUS, malapposition rate was 21% (5/24). The malapposition rate of strut level using OCT in 5 patients who had malapposition in IVUS was significantly higher than the 19 of those who had not (32 ± 5% vs. 12 ± 6%, p = 0.001). In addition, the frequency of malapposition was also significantly different (28% in SES, 11% in PES, 10% in ZES, p = 0.001). The use of SES was an independent predictor of malapposed struts.
Conclusion
The incidence of malapposition using OCT was quite prevalent in STEMI after primary PCI with DES implantation and SES has especially higher rates of malapposition compared to other DESs.
doi:10.3349/ymj.2010.51.3.332
PMCID: PMC2852787  PMID: 20376884
Malapposition; drug eluting stent; coherence tomography; optical; myocardial infarction
14.  Villitis of Unknown Etiology is Associated with a Distinct Pattern of Chemokine Up-regulation in the Feto-maternal and Placental Compartments: Implications for Conjoint Maternal Allograft Rejection and Maternal Anti-fetal Graft-versus-Host Disease1 
The co-presence of histoincompatible fetal and maternal cells is a characteristic of human placental inflammation. Villitis of unknown etiology (VUE), a destructive inflammatory lesion of villous placenta, is characterized by participation of Hofbauer cells (placental macrophages) and maternal T cells. In contrast to acute chorioamnionitis of infection-related origin, the fundamental immunopathology of VUE is unknown. This study was performed to investigate the placental transcriptome of VUE and to determine whether VUE is associated with systemic maternal and/or fetal inflammatory response(s). Comparison of the transcriptome between term placentas without and with VUE revealed differential expression of 206 genes associated with pathways related to immune response. The mRNA expression of a subset of chemokines and their receptors (CXCL9, CXCL10, CXCL11, CXCL13, CCL4, CCL5, CXCR3, CCR5) was higher in VUE placentas than in normal placentas (p < 0.05). Analysis of blood cell mRNA showed a higher expression of CXCL9 and CXCL13 in the mother, and CXCL11 and CXCL13 in the fetus of VUE cases (p < 0.05). The median concentrations of CXCL9, CXCL10, and CXCL11 in maternal and fetal plasma were higher in VUE (p < 0.05). Comparison of preterm cases without and with acute chorioamnionitis revealed elevated CXCL9, CXCL10, CXCL11, and CXCL13 concentrations in fetal plasma (p < 0.05), but not in maternal plasma with chorioamnionitis. We report for the first time the placental transcriptome of VUE. A systemic derangement of CXC chemokines in maternal and fetal circulation distinguishes VUE from acute chorioamnionitis. We propose that VUE be a unique state combining maternal allograft rejection and maternal antifetal graft-vs-host disease mechanisms.
doi:10.4049/jimmunol.0803834
PMCID: PMC2754231  PMID: 19265171
human; inflammation; chemokines; graft versus host disease; transplantation
15.  Immunoglobulin G4 Non-Related Sclerosing Disease with Intracardiac Mass Mimicking Mitral Stenosis: Case Report 
Journal of Korean Medical Science  2013;28(12):1830-1834.
The cardiovascular system may be one of the target organs of both immunoglobulin G4 related and non-related systemic multifocal fibrosclerosis. We present a case of IgG4 non-related systemic multifocal fibrosclerosis mimicking mitral stenosis on echocardiography. For a more detailed differential diagnosis, we used multimodal imaging techniques. After surgical biopsy around the abdominal aortic area in the retroperitoneum, histological examination revealed IgG4 non-related systemic multifocal fibrosclerosis. We describe the multimodal imaging used to diagnose IgG4 non-related systemic multifocal fibrosclerosis and a positive response to steroid treatment. There have been no previous case reports of IgG4 non-related systemic multifocal fibrosclerosis with intracardiac involvement. Here, we report a case of IgG4 non-related systemic multifocal fibrosclerosis mimicking mitral stenosis.
doi:10.3346/jkms.2013.28.12.1830
PMCID: PMC3857383  PMID: 24339717
Immunoglobulin G4 Non-Related Sclerosing Disease; Periaortitis; Left Atrium Mass; Mitral Valve Stenosis
16.  Adenocarcinoma Arising in Gastric Heterotopic Pancreas: A Case Report 
Journal of Korean Medical Science  2004;19(1):145-148.
A heterotopic pancreas in the gastrointestinal tract is mostly found incidentally and its malignant transformation is extremely rare. We describe the second case of adenocarcinoma arising in a gastric heterotopic pancreas of an asymptomatic 35-yr-old man in Korea. Esophagogastroduodenoscopy revealed a submucosal tumor with an irregular central umbilication in the gastric antrum. A wedge resection specimen demonstrated a submucosal oligolocular cystic mass (1.7×1.4×1.2 cm) with a solid portion. Microscopically, the cystic portion was composed of dilated pancreaticobiliary type ducts with adjacent small foci of periductal glandular structures. The adenocarcinoma components in the solid area infiltrated the proper muscle and the overlying mucosa of the stomach. The transitional area between the benign ductal structures and the adenocarcinoma component was found. The follow-up course was uneventful 5 months postoperatively.
doi:10.3346/jkms.2004.19.1.145
PMCID: PMC2822253  PMID: 14966359
Adenomyoma; Stomach Neoplasms; Adenocarcinoma
17.  Comparison of Three BRAF Mutation Tests in Formalin-Fixed Paraffin Embedded Clinical Samples 
Korean Journal of Pathology  2013;47(4):348-354.
Background
Recently, BRAF inhibitors showed dramatic treatment outcomes in BRAF V600 mutant melanoma. Therefore, the accuracy of BRAF mutation test is critical.
Methods
BRAF mutations were tested by dual-priming oligonucleotide-polymerase chain reaction (DPO-PCR), direct sequencing and subsequently retested with a real-time PCR assay, cobas 4800 V600 mutation test. In total, 64 tumors including 34 malignant melanomas and 16 papillary thyroid carcinomas were analyzed. DNA was extracted from formalin-fixed paraffin embedded tissue samples and the results of cobas test were directly compared with those of DPO-PCR and direct sequencing.
Results
BRAF mutations were found in 23 of 64 (35.9%) tumors. There was 9.4% discordance among 3 methods. Out of 6 discordant cases, 4 cases were melanomas; 3 cases were BRAF V600E detected only by cobas test, but were not detected by DPO-PCR and direct sequencing. One melanoma patient with BRAF mutation detected only by cobas test has been on vemurafenib treatment for 6 months and showed a dramatic response to vemurafenib. DPO-PCR failed to detect V600K mutation in one case identified by both direct sequencing and cobas test.
Conclusions
In direct comparison of the currently available DPO-PCR, direct sequencing and real-time cobas test for BRAF mutation, real-time PCR assay is the most sensitive method.
doi:10.4132/KoreanJPathol.2013.47.4.348
PMCID: PMC3759634  PMID: 24009630
BRAF mutation; Melanoma; Real-time polymerase chain reaction; Sanger sequencing; Dual-priming oligonucleotide-PCR
18.  Use of Drug-eluting Stents Versus Bare-metal Stents in Korea: A Cost-minimization Analysis Using Population Data 
Objectives
The goal of this study was to perform an economic analysis of a primary stenting with drug-eluting stents (DES) compared with bare-metal stents (BMS) in patients with acute myocardial infarction (AMI) admitted through an emergency room (ER) visit in Korea using population-based data.
Methods
We employed a cost-minimization method using a decision analytic model with a two-year time period. Model probabilities and costs were obtained from a published systematic review and population-based data from which a retrospective database analysis of the national reimbursement database of Health Insurance Review and Assessment covering 2006 through 2010 was performed. Uncertainty was evaluated using one-way sensitivity analyses and probabilistic sensitivity analyses.
Results
Among 513 979 cases with AMI during 2007 and 2008, 24 742 cases underwent stenting procedures and 20 320 patients admitted through an ER visit with primary stenting were identified in the base model. The transition probabilities of DES-to-DES, DES-to-BMS, DES-to-coronary artery bypass graft, and DES-to-balloon were 59.7%, 0.6%, 4.3%, and 35.3%, respectively, among these patients. The average two-year costs of DES and BMS in 2011 Korean won were 11 065 528 won/person and 9 647 647 won/person, respectively. DES resulted in higher costs than BMS by 1 417 882 won/person. The model was highly sensitive to the probability and costs of having no revascularization.
Conclusions
Primary stenting with BMS for AMI with an ER visit was shown to be a cost-saving procedure compared with DES in Korea. Caution is needed when applying this finding to patients with a higher level of severity in health status.
doi:10.3961/jpmph.2013.46.4.201
PMCID: PMC3740225  PMID: 23946878
Myocardial infarction; Drug-eluting stents; Costs and cost analysis; Pharmaceutical economics
19.  Deletion of the last five C-terminal amino acid residues of connexin43 leads to lethal ventricular arrhythmias in mice without affecting coupling via gap junction channels 
Basic research in cardiology  2013;108(3):348.
The cardiac intercalated disc harbors mechanical and electrical junctions as well as ion channel complexes mediating propagation of electrical impulses. Cardiac connexin43 (Cx43) co-localizes and interacts with several of the proteins located at intercalated discs in the ventricular myocardium. We have generated conditional Cx43D378stop mice lacking the last five C-terminal amino acid residues, representing a binding motif for zonula occludens protein-1 (ZO-1), and investigated the functional consequences of this mutation on cardiac physiology and morphology. Newborn and adult homozygous Cx43D378stop mice displayed markedly impaired and heterogeneous cardiac electrical activation properties and died from severe ventricular arrhythmias. Cx43 and ZO-1 were co-localized at intercalated discs in Cx43D378stop hearts, and the Cx43D378stop gap junction channels showed normal coupling properties. Patch clamp analyses of isolated adult Cx43D378stop cardiomyocytes revealed a significant decrease in sodium and potassium current densities. Furthermore, we also observed a significant loss of Nav1.5 protein from intercalated discs in Cx43D378stop hearts. The phenotypic lethality of the Cx43D378stop mutation was very similar to the one previously reported for adult Cx43 deficient (Cx43KO) mice. Yet, in contrast to Cx43KO mice, the Cx43 gap junction channel was still functional in the Cx43D378stop mutant. We conclude that the lethality of Cx43D378stop mice is independent of the loss of gap junctional intercellular communication, but most likely results from impaired cardiac sodium and potassium currents. The Cx43D378stop mice reveal for the first time that Cx43 dependent arrhythmias can develop by mechanisms other than impairment of gap junction channel function.
doi:10.1007/s00395-013-0348-y
PMCID: PMC3678986  PMID: 23558439
Connexin43; Zonula occludens protein-1; Nav1.5; Intercalated disc
20.  Functional Properties of Mouse Connexin30.2 Expressed in the Conduction System of the Heart 
Circulation research  2005;96(11):1169-1177.
Gap junction channels composed of connexin (Cx) 40, Cx43, and Cx45 proteins are known to be necessary for impulse propagation through the heart. Here, we report mouse connexin30.2 (mCx30.2) to be a new cardiac connexin that is expressed mainly in the conduction system of the heart. Antibodies raised to the cytoplasmic loop or the C-terminal regions of mCx30.2 recognized this protein in mouse heart as well as in HeLa cells transfected with wild-type mCx30.2 or mCx30.2 fused with enhanced green fluorescent protein (mCx30.2-EGFP). Immunofluorescence analyses of adult hearts yielded positive signals within the sinoatrial node, atrioventricular node, and A-V bundle of the cardiac conduction system. Dye transfer studies demonstrated that mCx30.2 and mCx30.2-EGFP channels discriminate poorly on the basis of charge, but do not allow permeation of tracers >400 Da. Both mCx30.2 and mCx30.2-EGFP gap junctional channels exhibited weak sensitivity to transjunctional voltage (Vj) and a single channel conductance of ≈9 pS, which is the lowest among all members of the connexin family measured in HeLa cell transfectants. HeLa mCx30.2-EGFP transfectants when paired with cells expressing Cx40, Cx43, or Cx45 formed functional heterotypic gap junction channels that exhibited low unitary conductances (15 to 18 pS), rectifying open channel I-V relations and asymmetric Vj dependence. The electrical properties of homo- and hetero-typic junctions involving mCx30.2 may contribute to slow propagation velocity in nodal tissues and directional asymmetry of excitation spread in the AV nodal region.
doi:10.1161/01.RES.0000169271.33675.05
PMCID: PMC3657762  PMID: 15879306
connexin; gap junctions; mCx30.2; sinoatrial node; atrioventricular node
21.  Comparison of Early Clinical Outcomes Following Transcatheter Aortic Valve Implantation versus Surgical Aortic Valve Replacement versus Optimal Medical Therapy in Patients Older than 80 Years with Symptomatic Severe Aortic Stenosis 
Yonsei Medical Journal  2013;54(3):596-602.
Purpose
Transcatheter aortic valve implantation (TAVI) has become an attractive therapeutic strategy for severe aortic stenosis (AS) in elderly patients due to its minimally-invasive nature. Therefore, early results of its clinical outcomes in elderly Korean patients were evaluated.
Materials and Methods
We compared early clinical outcomes of TAVI, surgical aortic valve replacement (SAVR), and optimal medical therapy (OMT) in patients aged ≥80 years with symptomatic severe AS. Treatment groups were allocated as follows: TAVI (n=10), SAVR (n=14), and OMT (n=42).
Results
Baseline clinical characteristics including predicted operative mortality were similar among the three groups. However, patients with New York Heart Association functional class III or IV symptoms and smaller aortic valve area were treated with TAVI or SAVR rather than OMT. In-hospital combined safety endpoints (all-cause mortality, major stroke, peri-procedural myocardial infarction, life-threatening bleeding, major vascular complication, and acute kidney injury) after TAVI or SAVR were significantly lower in the TAVI group than in the SAVR group (10.0% vs. 71.4%, respectively, p=0.005), along with an acceptable rate of symptom improvement and device success. During the follow-up period, the TAVI group showed the lowest rate of 3-month major adverse cardiovascular and cerebrovascular events, a composite of all-cause mortality, myocardial infarction, major stroke, and re-hospitalization (TAVI 0.0% vs. SAVR 50.0% vs. OMT 42.9%, p=0.017).
Conclusion
Treatment with TAVI was associated with lower event rates compared to SAVR or OMT. Therefore, TAVI may be considered as the first therapeutic strategy in selected patients aged ≥80 years with symptomatic severe AS.
doi:10.3349/ymj.2013.54.3.596
PMCID: PMC3635628  PMID: 23549802
Aortic stenosis; transcatheter aortic valve implantation; treatment outcome
22.  Characterization of the transcriptome of chorioamniotic membranes at the site of rupture in spontaneous labor at term 
OBJECTIVE
The purpose of this study was to compare the transcriptome between the site of membrane rupture and the chorioamniotic membranes away from the site of rupture.
STUDY DESIGN
The transcriptome of amnion and chorion (n =20 each) from and distal to the site of rupture from women with spontaneous labor and vaginal delivery at term after spontaneous rupture of membranes was profiled with Illumina HumanHT-12 microarrays. Selected genes were validated with the use of quantitative reverse transcription–polymerase chain reaction.
RESULTS
Six hundred seventy-seven genes were differentially expressed in the chorion between the rupture and nonrupture sites (false discovery rate <0.1; fold change >1.5). Quantitative reverse transcription–polymerase chain reaction confirmed the differential expression in 10 of 14 genes. Enriched biological processes included anatomic structure development, cell adhesion and signal transduction. Extracellular matrix–receptor interaction was the most impacted signaling pathway.
CONCLUSION
The transcriptome of fetal membranes after spontaneous rupture of membranes in term labor is characterized by region-and tissue-specific differential expression of genes that are involved in signature pathways, which include extracellular matrix–receptor interactions.
doi:10.1016/j.ajog.2010.02.045
PMCID: PMC3604885  PMID: 20452490
chorion; extracellular matrix; inflammation; labor; microarray; parturition; spontaneous rupture of membranes
23.  Dorsal-Plantar Loop Technique Using Chronic Total Occlusion Devices via Anterior Tibial Artery 
Yonsei Medical Journal  2013;54(2):534-537.
The effectiveness of below-the-knee (BTK) percutaneous transluminal angioplasty to obtain successful revascularization in patients with critical limb ischemia has been well established, and many of these patients with chronic lower-extremity disease have been treated by endovascular intervention as the firstline treatment. Dorsal-plantaer loop technique is one of the new BTK interventional techiniques, and includes recanalization of both pedal and plantar arteries and their anatomical anastomoses. This method generally needs two approaches simultaneously, including antegrade and retrograde. In this report, however, we describe a case in which dorsal-plantar loop technique with only one antegrade approach, using chronic total occlusion devices via anterior tibial artery, was used to successfully recanalize BTK arteries. We think that this new technique, which may represent a safe and feasible endovascular option to avoid more invasive, time-consuming, and riskier surgical procedures, especially in end-stage renal disease and diabetes, should be considered whenever the foot is at risk, and results of above-the-ankle percutaneous transluminal angioplasty remain unsatisfactory or insufficient to achieve limb salvage.
doi:10.3349/ymj.2013.54.2.534
PMCID: PMC3575960  PMID: 23364993
Ischemia; peripheral arterial disease; angioplasty
24.  Relationship between Angiographic Late Loss and 5-Year Clinical Outcome after Drug-Eluting Stent Implantation 
Yonsei Medical Journal  2012;54(1):41-47.
Purpose
Currently, insufficient data exist to evaluate the relationship between angiographic late loss (LL) and long-term clinical outcome after drug-eluting stent (DES) implantation. In this study, we hypothesized that angiographic LL between 0.3 and 0.6 mm correlate with favorable long-term clinical outcomes.
Materials and Methods
Patients were enrolled in the present study if they had undergone both DES implantation in single coronary vessel and a subsequent follow-up angiogram (n=634). These individuals were then subdivided into three groups based on their relative angiographic LL: group I (angiographic LL <0.3 mm, n=378), group II (angiographic LL between 0.3 and 0.6 mm, n=124), and group III (angiographic LL >0.6 mm, n=134). During a 5-year follow-up period, all subjects were tracked for critical events, defined as any cause of death or myocardial infarction, which were then compared among the three groups.
Results
Mean follow-up duration was 63.0±10.0 months. Critical events occurred in 25 subjects in group I (6.6%), 5 in group II (4.0%), and 17 in group III (12.7%), (p=0.020; group I vs. group II, p=0.293; group II vs. group III, p=0.013). In a subsequent multivariate logistic regression analysis, chronic renal failure [odds ratio (OR)=3.29, 95% confidence interval (CI): 1.48-7.31, p=0.003] and long lesion length, defined as lesion length >28 mm (OR=1.88, 95% CI: 1.02-3.46, p=0.042) were independent predictors of long-term critical events.
Conclusion
This retrospective analysis fails to demonstrate that post-DES implantation angiographic LL between 0.3 and 0.6 mm is protective against future critical events.
doi:10.3349/ymj.2013.54.1.41
PMCID: PMC3521267  PMID: 23225797
Coronary artery disease; stents; outcome assessment
25.  Maternal HLA Panel Reactive Antibodies in Early Gestation Positively Correlates with Chronic Chorioamnionitis: Evidence in Support of the Chronic Nature of Maternal Anti-fetal Rejection 
Problem
Maternal tolerance of the fetus is essential for viviparity, yet anti-fetal rejection occurs in several pregnancy complications. Chronic chorioamnionitis (CCA) is a feature of anti-fetal cellular rejection. There is a robust association between CCA and maternal seropositivity for anti-HLA panel reactive antibodies (PRA) at the time of delivery. This longitudinal study was performed to assess maternal HLA PRA status in early gestation and the temporal evolution of maternal HLA PRA in the context of CCA and thereby to determine whether HLA PRA during the course of pregnancy is useful for the detection of anti-fetal rejection.
Method of Study
Maternal sera obtained before 16 weeks of gestation and at delivery were analyzed for HLA panel reactive antibodies (PRA) in cases with (N=100) and without (N=150) CCA.
Results
IgG but not IgM HLA class I and II PRA positivity at delivery was higher in cases with CCA than in those without CCA. IgG HLA class I PRA positivity before 16 weeks of gestation was higher in cases with CCA than in those without (30.3% vs. 13.3%; p=0.001). Positive conversion (negative HLA PRA before 16 weeks of gestation but positive at delivery) of IgG HLA class I and II PRA was significantly associated with CCA. Fetal HLA class I antigen-specific antibodies were confirmed in 12 of 16 mothers tested who were sensitized to HLA class I antigens before 16 weeks of gestation.
Conclusion
Positive maternal HLA PRA before 16 weeks of gestation and the temporal evolution of maternal HLA PRA are associated with the presence of CCA at the time of delivery. Maternal IgG HLA PRA has potential to be a monitoring tool of anti-fetal rejection. Furthermore, the findings herein indicate that subsets of fetuses are exposed to alloimmune HLA antibodies for months, especially in cases with CCA.
doi:10.1111/j.1600-0897.2011.01066.x
PMCID: PMC3234997  PMID: 21951517
chronic chorioamnionitis; human leukocyte antigen; panel reactive antibody; pregnancy; preterm birth; rejection

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