Biomedical subjects

Yeon Mee Kim

Publications and source records attributed to Yeon Mee Kim.

At least 19 recordsLinked to original sources

PubMed2006

Genetic origin and proportion of basal plate surface-lining cells in normal and abnormal pregnancies.

The human placenta is a transient organ, the villous surface of which is in direct contact with the maternal circulation during pregnancy. Thus, the syncytiotrophoblast and the basal plate-lining cells are considered continuous with the endothelial layer of the maternal vasculature. Two types of cells are found on the surface of the basal plate: trophoblasts (of fetal origin) and endothelial cells of putative maternal origin. Histologic abnormalities have been described in the basal plate of the placenta obtained from patients with preeclampsia and intrauterine growth restriction. Moreover, endothelial cell dysfunction and intravascular inflammation are key features of preeclampsia. The objectives of this study were to: (1) determine the origin of the endothelial cells located in the basal plate surface of the placenta (from male fetuses); and (2) analyze the relative proportion of the intervillous surface of the basal plate occupied by trophoblasts and endothelial cells. Immunohistochemistry and morphometry were performed in placentas from women in the following clinical groups: (1) normal-term pregnancies (n = 15); (2) severe preeclampsia at term (n = 15); (3) small-for-gestational-age (SGA) neonates delivered at term (n = 15); (4) preterm deliveries (<37 weeks) without inflammation (n = 5); and (5) preterm preeclampsia (n = 5). Laser capture microdissection and polymerase chain reaction were used to determine the allelic pattern of the amelogenin gene of the endothelial cells on the intervillous surface of the basal plate. Our results showed that: (1) the endothelial cells lining the basal plate in placentas of male fetuses were uniformly of maternal origin; and (2) in placentas from uncomplicated pregnancies, the median proportion of trophoblasts and endothelial cells covering the surface of the basal plate were 27.7% and 46.5%, respectively. The remaining area of the intervillous surface of the basal plate was composed of fibrin and anchoring villi. Of interest, placentas from women who delivered an SGA neonate had a higher proportion of trophoblasts and a lower proportion of endothelial cells lining the basal plate than those from normal pregnancies (P < .05). The same tendency was observed in placentas from patients with preeclampsia. This study demonstrates that endothelial cells of maternal origin cover the intervillous surface of the basal plate of the placenta, along with trophoblasts of fetal origin. The proportion of this surface lined by trophoblasts is greater in placentas from SGA and preeclampsia than in normal pregnancy. We propose that this change reflects a compensatory mechanism whereby the basal plate surface covered by injured endothelial cells is replaced by trophoblasts or results from a failure of trophoblastic involution in abnormal pregnancies. Our observations also suggest that the lining of the basal plate can provide information about the pathology of endothelial cells in complications of pregnancy.

Adolescent↗

PubMed2006

Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature.

OBJECTIVE: The purpose of this study was to identify which biological processes may be involved in normal labor. STUDY DESIGN: Transcriptional profiles for chorioamniotic membranes (n = 24) and blood (n = 20) were generated from patients at term with no labor (TNL) and in labor (TIL). RESULTS: Expression of 197 transcripts (P < or = .02) differentiated TIL and TNL chorioamniotic membrane samples. Gene Ontology analysis indicated that TIL samples had increased expression of multiple chemokines and transcripts associated with neutrophil and monocyte recruitment. Microarray results were verified using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) with independent samples. Transcriptional profiles from blood RNA revealed no Gene Ontology category enrichment of discriminant probe sets. CONCLUSION: Labor induces gene expression changes consistent with localized inflammation, despite the absence of histologically detectable inflammation.

Adult↗

PubMed2006

Fetal macrophages are not present in the myometrium of women with labor at term.

OBJECTIVE: The basic mechanisms responsible for human parturition remain to be elucidated. The influx of fetal leukocytes into the myometrium has been recently proposed to be a crucial event in the onset of murine parturition. Surfactant protein-A has been implicated in the initiation of labor. In mice, it is thought that surfactant protein-A induces migration and subsequent activation of amniotic fluid macrophages of fetal origin, which then invades the myometrium. The present study was conducted to determine whether fetal macrophages invade the myometrium of women in labor. STUDY DESIGN: Placental bed biopsy specimens were obtained from patients in labor who delivered male neonates at term (n = 7). Myometrial sections of postpartum hysterectomy specimens obtained from women who delivered of male neonates (n = 3) were also analyzed. Formalin-fixed, paraffin-embedded sections were immunostained for CD68 or CD14 (which are markers for macrophages); immunoreactive myometrial macrophages were specifically procured by laser capture microdissection. Sex typing was done by polymerase chain reaction for the amelogenin gene with genomic DNA that was isolated from the macrophages. Chromogenic in situ hybridization with a Y chromosome-specific probe was also performed on paraffin-embedded histologic sections. RESULTS: Amelogenin allelotypes of the macrophages were consistent with female alleles in all cases that were tested, indicating a maternal origin. Chromogenic in situ hybridization demonstrated the absence of Y chromosome-positive mononuclear cells in the myometrium in all cases. CONCLUSION: These observations, from a limited number of cases, suggest that migration of fetal macrophages from the amniotic cavity or the chorioamniotic membranes into the myometrium does not occur during human labor. The trafficking of fetal macrophages in labor seems to be different in humans and mice.

Female↗

PubMed2006

Tissue microarray: an effective high-throughput method to study the placenta for clinical and research purposes.

OBJECTIVE: Tissue microarray (TMA) technology allows simultaneous examination of the expression of many molecular markers (protein, mRNA, DNA, etc.) with high-throughput. The application of this technology, to date, has been largely confined to the study of cancer. Placental pathology poses unique challenges because of the size of the organ, its complex anatomy, as well as its histological heterogeneity. The objective of this study was to assess the feasibility and efficiency of TMAs for immunohistochemistry and in situ hybridization of placental tissues. STUDY DESIGN: TMAs were constructed using an automated tissue arrayer. Standard 0.6-mm or 1-mm microarray needles were used. Villous parenchyma, basal plate, and chorioamniotic membranes were targeted in each block. Five mum-thick TMA sections underwent immunohistochemical analysis of both cytoplasmic and nuclear antigens using a panel of antibodies against a variety of cytoplasmic [cytokeratin-7, vascular endothelial growth factor (VEGF), and protein Z], membranous (endoglin), and nuclear (c-fos and c-jun) antigens. mRNA in situ hybridization for surfactant protein A (SP-A) and chromogenic in situ hybridization for the Y chromosome (DYZ1) were also performed. RESULTS: Validation of TMA immunoreactivity demonstrated comparable results with corresponding whole sections. When a two-tiered scoring system (positive/negative) was employed, there was agreement between two and three cores and whole tissue sections (kappa>0.7). When a three-tiered scoring system (negative, weak-positive, or strong-positive) was used, the data from three cores showed the highest agreement with whole tissue sections (kappa >0.7). In situ hybridization experiments for mRNA and DNA were also successful in that the signals were readily detectable. Successful transfer from the donor block to the recipient block differed according to the anatomical compartment. The transfer efficiency of villous parenchyma, basal plate, and chorioamniotic membranes were 96.9% (875/903), 76.7% (115/150), and 75.4% (224/297), respectively. CONCLUSION: TMA is a practical and effective tool for high-throughput molecular analysis of the human placenta. Duplicate and triplicate cores offer agreement with whole tissue sections for two-category distinction immunostaining. TMA also affords relevant results from in situ hybridization experiments for mRNA and DNA. The major advantages are the conservation of tissues and reagents, simultaneous comparison of molecular markers in different anatomical compartments of the placenta, and reduction of experimental error.

Biomarkers↗

PubMed2006

Normal and abnormal transformation of the spiral arteries during pregnancy.

This article reviews the anatomy and physiology of the uterine circulation, with emphasis on the remodeling of spiral arteries during normal pregnancy, and the timing and anatomical pathways of trophoblast invasion of the spiral arteries. We review the definitions of the placental bed and basal plate of the placenta, their relevance to the study of the physiologic transformation of the spiral arteries, as well as the methods to obtain and examine placental bed biopsy specimens. We also examine the role of the extravillous trophoblast in normal and abnormal pregnancies, and the criteria used to diagnose failure of physiologic transformation of the spiral arteries. Finally, we comment on the use of uterine artery Doppler velocimetry as a surrogate marker of chronic uteroplacental ischemia.

Arteries↗

PubMed2005

A short cervix in women with preterm labor and intact membranes: a risk factor for microbial invasion of the amniotic cavity.

OBJECTIVE: The purpose of this study was to determine whether there was a relationship between sonographic cervical length and the presence of culture-proven microbial invasion of the amniotic cavity in women with preterm labor and intact membranes. STUDY DESIGN: Ultrasonography and amniocentesis were performed in 401 patients admitted with preterm labor (22-35 weeks) and cervical dilatation of < or = 3 cm, as assessed by digital examination. Cervical length was determined by transvaginal ultrasound at admission. Outcome variables were the presence of microbial invasion of the amniotic cavity (defined as a positive amniotic fluid culture) and the occurrence of preterm delivery before 35 weeks. Contingency tables, chi2 test, receiver-operator characteristic (ROC) curves, and logistic regression were used for statistical analysis. RESULTS: The prevalence of microbial invasion of the amniotic cavity was 7% (28/401). Spontaneous preterm delivery (< or = 35 weeks) occurred in 21.4% (82/384) of patients. ROC curve analysis showed a significant relationship between the frequency of microbial invasion of the amniotic cavity and the length of the uterine cervix (area under the curve: 0.77; P < .005). Patients with a cervical length < 15 mm had a higher rate of a positive amniotic fluid culture than patients with a cervical length > or = 15 mm (26.3% [15/57] vs. 3.8% [13/344], respectively; P < .05). Moreover, patients with a short cervix (defined as < 15 mm) were more likely to deliver spontaneously before 35 weeks, 32 weeks, within 7 days, and within 48 hours of admission ( P < .05 for all comparisons). Forty percent of patients (161/401) had a cervical length > or = 30 mm. These patients had a very low risk of microbial invasion of the amniotic cavity (1.9% [3/161]), spontaneous delivery < or = 35 weeks (4.5% [7/154]), < or = 32 weeks (2.6% [2/76]), within 7 days (1.9% [3/154]), and within 48 hours (0% [0/154]) of admission. CONCLUSION: Endovaginal ultrasonographic examination of the uterine cervix in women with preterm labor identifies patients at increased risk for intrauterine infection.

Adult↗

PubMed2005

Expression of bone morphogenetic protein 2 in normal spontaneous labor at term, preterm labor, and preterm premature rupture of membranes.

OBJECTIVE: Genome-wide screening studies of the chorioamniotic membranes unexpectedly identified an increase in the expression of bone morphogenetic protein 2 in spontaneous labor at term. The objective of this study was to determine whether bone morphogenetic protein 2 messenger RNA and protein expression are altered in the chorioamniotic membranes of patients with term labor, preterm labor, and preterm premature rupture of membranes. STUDY DESIGN: Chorioamniotic membranes were obtained from patients at term (with and without labor), with preterm labor (with and without histologic chorioamnionitis), and with preterm premature rupture of membranes (with and without histologic chorioamnionitis). The expression of bone morphogenetic protein 2 was studied by real-time quantitative reverse transcriptase-polymerase chain reaction (n = 88) and immunohistochemistry (n = 124). Nonparametric statistics were used for analysis. Primary amnion cells obtained from women at term not in labor were treated with bone morphogenetic protein 2 to examine whether there was increased prostaglandin E2 expression. RESULTS: The median bone morphogenetic protein 2 messenger RNA and protein expression were significantly higher in the membranes of patients with spontaneous labor at term than in those of patients not in labor at term (P < .001 for both). Bone morphogenetic protein 2 messenger RNA and protein expression were increased in patients with preterm labor with histologic chorioamnionitis than in those without histologic chorioamnionitis (P < .05 and P < .001, respectively). There was no difference in bone morphogenetic protein 2 messenger RNA and protein expression in patients with preterm premature rupture of membranes, regardless of chorioamnionitis (P = .13 and P = .08, respectively). There was a correlation between bone morphogenetic protein 2 and cyclooxygenase 2 protein expression in chorioamniotic membranes (R = .34; P < .001). CONCLUSION: Bone morphogenetic protein 2 messenger RNA and protein expression are increased in the chorioamniotic membranes of patients with spontaneous labor at term and patients with preterm labor associated with histologic chorioamnionitis. Its expression pattern and biologic effects strongly suggest that bone morphogenetic protein 2 is involved in human parturition.

Amnion↗

PubMed2005

Maternal plasma osteoprotegerin concentration in normal pregnancy.

OBJECTIVE: Pregnancy is associated with major changes in calcium metabolism because the neonatal skeleton contains approximately 30 g of calcium, which are largely deposited in the third trimester. Osteoprotegerin (OPG) acts as a decoy receptor for the "Receptor Activator of Nuclear Factor-kappaB Ligand" (RANKL), which is an essential factor for bone remodeling. This study was conducted to determine whether there were changes in maternal plasma OPG concentration during normal pregnancy. STUDY DESIGN: A cross-sectional study was performed in 433 patients of reproductive age (40 nonpregnant and 393 pregnant). Pregnant patients were classified into 4 groups according to gestational age: group 1: 11 to 14 weeks (n = 100); group 2: 15 to 18 weeks (n = 99); group 3: 27 to 30 weeks (n = 100); and group 4: 37 to 42 weeks (n = 94). Plasma OPG concentrations were measured with the use of a sensitive and specific immunoassay. Nonparametric statistics were used for analysis. RESULTS: OPG was detected in the plasma of all women tested. The median OPG concentration was significantly higher in term patients than in those in early pregnancy (median: 6.63 pmol/L [range: 1.57-25.57] vs median: 3.98 pmol/L [range: 0.41-13.71], P < .001). There was no significant difference in plasma OPG concentrations between nonpregnant women and those in groups 1 or 2 (nonpregnant women median: 3.86 pmol/L [range: 1.64-15.29] vs group 1 median: 3.98 pmol/L [range: 0.41-13.71] vs group 2 median: 3.87 pmol/L [range: 1.14-69.83], P = .75). CONCLUSION: The median maternal plasma OPG concentration is higher in the third trimester than in the first trimester of pregnancy. OPG may be involved in the regulation of bone turnover during pregnancy.

Adult↗

PubMed2005

Toll-like receptor 4: a potential link between "danger signals," the innate immune system, and preeclampsia?

OBJECTIVE: Toll-like receptors (TLRs) recognize microbial ligands and host products that are released during tissue damage, the so-called "danger signals." This study was conducted to determine whether changes in TLR-4 and TLR-2 expressions can be detected in the trophoblasts at the placental bed of women with and without preeclampsia. STUDY DESIGN: Placental bed biopsy specimens were obtained from women with: (1) normal term pregnancies with and without labor (each n = 20); (2) preeclampsia who delivered preterm (n = 15); and (3) preterm labor and intact membranes with and without chorioamnionitis (each n = 15). The expression pattern of TLR-4 and TLR-2 in the trophoblasts was analyzed by double immunohistochemistry. RESULTS: (1) The median percentage of TLR-4 positive interstitial trophoblasts was significantly higher in patients with preeclampsia than in patients with preterm labor without or with histologic chorioamnionitis (P = .0002 and P = .02, respectively). (2) The median percentage of TLR-2 positive interstitial trophoblasts was not different among the study groups (P>.05). (3) TLR-4 positive trophoblasts were also frequently immunoreactive to activated nuclear factor-kappaB, tumor necrosis factor-alpha, and M30 (a specific apoptosis antigen for trophoblast). (4) Lipopolysaccharide treatment inhibited the migration of trophoblast cell lines in vitro. CONCLUSION: TLR-4 protein expression is increased in interstitial trophoblasts of patients with preeclampsia. We propose that "danger signals" at the feto-maternal interface, which are recognized by trophoblasts through TLR-4, may play a key role in the creation of a local abnormal cytokine milieu. This suggests a novel mechanism that links the activation of the innate immune system through TLR-4 and preeclampsia.

Cell Movement↗

PubMed2005

Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia.

OBJECTIVE: Accumulating evidence suggests that the balance between vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and their receptors is important for effective vasculogenesis, angiogenesis, and placental development. Recently, the soluble form of VEGFR-1 (sVEGFR-1), an antagonist to VEGF and PIGF, has been implicated in the pathophysiology of pre-eclampsia. Plasma sVEGFR-1 concentration is elevated in pre-eclampsia at the time of clinical diagnosis and correlates with the severity of the disease. The purpose of this study was to determine whether the concentrations of sVEGFR-1 in plasma of pre-eclamptic patients change prior to the clinical manifestations of the disease. METHODS: A longitudinal case-control study was conducted in normal pregnant women (n = 44) and patients with pre-eclampsia (n = 44). Blood sampling was performed at six intervals: (1) 7-16 weeks; (2) 16-24 weeks; (3) 24-28 weeks; (4)28-32 weeks; (5) 32-36 weeks; and (6) more than 37 weeks of gestation. To examine the relationship between plasmasVEGFR-1 concentration and interval to clinical diagnosis of pre-eclampsia, plasma samples of pre-eclamptic patients at different gestational ages were stratified according to the interval from blood sampling to clinical development of the disease into five groups: (1) at clinical manifestation; (2) 2-5 weeks; (3) 6-10 weeks; (4) 11-16 weeks; and (5) 17-25 weeks before clinical manifestations. Plasma concentrations of sVEGFR-1 were determined by enzyme-linked immunoassay. Parametric statistics and repeated measure procedures were used for the analysis. RESULTS: The mean plasma sVEGFR-1 concentration in pre-eclamptic patients before the clinical manifestation of the disease was significantly higher than in normal pregnant women at 24-28, 28-32, and 32-37 weeks of gestation (p = 0.02,p < 0.001, and p < 0.001, respectively). In contrast, no significant differences in the mean plasma sVEGFR-1 concentration between patients with pre-eclampsia and normal pregnant women were observed both at 7-16 weeks and 16-24 weeks of gestation (p= 0.1 and p= 0.9). Similarly, the mean plasma sVEGFR-1 concentration was significantly higher in pre-eclamptic patients than in normal pregnant women at clinical manifestation, at 2-5 weeks (mean 3.8 weeks), and at 6-10 weeks (mean 8.2 weeks) prior to the development of clinical pre-eclampsia (p < 0.001, p < 0.001, and p = 0.002,respectively). Among patients with early-onset pre-eclampsia (defined as gestational age of 34 weeks or less), the mean plasma sVEGFR-1 concentration was significantly higher in pre-eclampsia (before clinical diagnosis) than in normal pregnant women at 24-28 (mean 26.4) weeks of gestation (p = 0.008). In contrast, among patients with the late-onset disease(defined as gestational age of more than 34 weeks), plasma sVEGFR-1 concentration in pre-clinical pre-eclampsia was significantly higher than in normal pregnant women at 28-32 (mean 30.2) weeks of gestation (p < 0.001). CONCLUSIONS: Plasma sVEGFR-1 concentration is elevated in pre-eclampsia prior to the clinical diagnosis of the disease. This elevation began 6-10 weeks prior to the clinical manifestations, and the increase was more pronounced at 2-5 weeks before the diagnosis, as well as at clinical presentation. Furthermore, in early-onset pre-eclampsia, plasma concentration ofsVEGFR-1 is elevated earlier than the late-onset disease.

Adult↗

PubMed2005

Normal pregnancy is characterized by systemic activation of the complement system.

BACKGROUND: The complement system, a major component of innate immunity, has recently been implicated in the mechanisms of fetal loss and placental inflammation in the anti-phospholipid antibody syndrome. Inhibition of complement has been proposed as an absolute requirement for normal pregnancy. Yet, pregnancy is characterized by a generalized activation of the innate immune system. This study was conducted to determine whether or not normal pregnancy is associated with complement activation in the maternal circulation. METHODS: Anaphylatoxins (C3a, C4a and C5a) were determined in the plasma of normal pregnant (20-42 wks; n=134) and non-pregnant women (n=40). These complement split products (C3a, C4a and C5a) were measured using specific immunoassays. Non-parametric statistics were used for analysis. RESULTS: 1) The median plasma concentrations of C3a, C4a and C5a were significantly higher in normal pregnant women than in non-pregnant women (all p<0.001); 2) the concentration of C3a, C4a and C5a did not change with gestational age (p>0.05); and 3) the median plasma concentration of C3a had a positive correlation with the plasma C4a and C5a concentrations (r=0.36, p<0.001 and r=0.35, p<0.001, respectively). CONCLUSION: 1) Normal human pregnancy is associated with evidence of complement activation, as determined by higher concentrations of the anaphylatoxins C3a, C4a and C5a in the maternal circulation; and 2) we propose that physiologic activation of the complement system during pregnancy is a compensatory mechanism aimed at protecting the host against infection.

Adolescent↗

PubMed2005

Increased concentration of the complement split product C5a in acute pyelonephritis during pregnancy.

OBJECTIVE: Pregnant women with acute pyelonephritis develop acute respiratory distress syndrome (ARDS) more frequently than non-pregnant women. The reasons for this remain unknown. The complement system is a complex set of self-assembling proteins that have been implicated in the pathophysiology of ARDS and sepsis. The purpose of this study was to determine if activation of the complement system occurs in pregnant women with acute pyelonephritis. METHODS: A cross-sectional study was conducted to determine the plasma concentrations of C3a, C4a and C5a (i.e., complement split products) in pregnant patients with acute pyelonephritis (n=38) and normal pregnant women (n=38). The complement split products C3a, C4a and C5a were measured using ELISA. Data were analyzed using non-parametric statistics. RESULTS: 1) The median plasma concentration of C5a in pregnant patients with acute pyelonephritis was significantly higher than that in normal pregnant women (p<0.001); 2) there was no statistical difference in the median plasma concentration of C3a and C4a between the two groups (p>0.05); and 3) concentrations of C3a, C4a and C5a were not different among patients with acute pyelonephritis with and without bacteremia. CONCLUSIONS: 1) Pyelonephritis in pregnant women is associated with an increased plasma concentration of C5a, but not C3a and C4a; and 2) an excess of C5a can predispose pregnant women to develop ARDS and multi-organ failure in pyelonephritis. This finding may have clinical implications since blocking C5a improves ARDS in experimental sepsis.

Acute Disease↗

PubMed2005

Monocyte chemotactic protein-1 is increased in the amniotic fluid of women who deliver preterm in the presence or absence of intra-amniotic infection.

OBJECTIVE: Pro-inflammatory chemokines have been associated with preterm parturition. Monocyte chemotactic protein-1 (MCP-1) is a chemokine capable of recruiting monocytes/macrophages into sites of inflammation, as well as stimulating the respiratory burst required for macrophage activation. MCP-1 transcripts and immuno-reactivity are expressed by uterine tissues (i.e., decidual cells and myometrium) and, thus, may participate in the process of labor. This study was conducted to determine if preterm labor leading to preterm delivery and intra-amniotic infection (IAI) are associated with changes in the amniotic fluid concentrations of MCP-1. STUDY DESIGN: A cross-sectional study was designed to examine the amniotic fluid concentrations of MCP-1 in women in two groups: 1) those presenting with preterm labor with intact membranes; and 2) those with preterm prelabor rupture of membranes (PROM). Amniotic fluid was obtained by transabdominal amniocentesis from 131 women in preterm labor with intact membranes and 105 women with preterm PROM. IAI was defined by a positive amniotic fluid culture for microorganisms. Group 1 included women with preterm labor and intact membranes (n=131), and was subdivided into the following groups: a) delivery at term in the absence of IAI (n=42); b) preterm delivery (< 37 weeks) in the absence of IAI (n=58); and c) preterm delivery in the presence of IAI (n=31). Group 2 consisted of women with PROM (n=105), and was subdivided into women with (n=51) and without (n=54) IAI. Non-parametric statistics were used for data analysis. RESULTS: 1) Immuno-reactive MCP-1 was detected in all amniotic fluid samples; 2) IAI, regardless of the membrane status, was associated with a significantly higher median amniotic fluid concentration of immuno-reactive MCP-1 than those without IAI (p<0.001 for both comparisons); 3) women in preterm labor who delivered preterm without IAI had a significantly higher median amniotic fluid concentration of immuno-reactive MCP-1 than those who delivered at term (p<0.001); 4) histological chorioamnionitis was associated with increased amniotic fluid concentrations of immuno-reactive MCP-1; and 5) a significant relationship existed between the amniotic fluid concentrations of immuno-reactive MCP-1 and the interval from amniocentesis to delivery. CONCLUSIONS: Amniotic fluid concentrations of immuno-reactive MCP-1 were increased in women in preterm labor with IAI, those without IAI who delivered preterm, and those who displayed acute inflammatory lesions in the extra-placental membranes. These findings suggest that MCP-1 may play a role in preterm labor regardless of the presence of IAI.

Adolescent↗

PubMed2005

Evidence supporting that the excess of the sVEGFR-1 concentration in maternal plasma in preeclampsia has a uterine origin.

BACKGROUND: Preeclampsia has been considered an anti-angiogenic state. Two factors have been implicated in the genesis of this state: soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and placental growth factor (PlGF). Indeed, the concentrations of PlGF, an angiogenic factor, are lower in preeclampsia than in normal pregnancy, while the opposite is the case for the anti-angiogenic factor, sVEGFR-1. The source of the excess sVEGFR-1 has not yet been determined. Since the placenta could be a source of sVEGFR-1, we conducted a study to determine whether there is a gradient in the plasma concentration of sVEGFR-1 and PlGF between the uterine vein and the antecubital vein in both patients with preeclampsia and normal pregnant women. METHODS: A cross-sectional study was performed to determine the plasma concentrations of sVEGFR-1 and PlGF in the uterine and antecubital vein of patients with preeclampsia (n = 9) and normal pregnant women at term (n = 9). Plasma samples were collected from antecubital and uterine veins at the time of cesarean section. The concentrations of sVEGFR-1 and PlGF were determined using specific enzyme-linked immunoassays. The differences of plasma concentrations of sVEGFR-1 and PlGF between uterine and antecubital veins in both groups were compared by paired t-tests. RESULTS: Patients with preeclampsia had a significantly higher mean plasma concentration of sVEGFR-1 in the uterine vein than in the antecubital vein (uterine vein: mean 13,675 +/- 5,684 pg/ml vs. antecubital vein: mean 10,234 +/- 4,700 pg/ml; paired t-tests, p = 0.04). In contrast, among normal pregnant women at term, there was no significant difference in plasma concentrations of sVEGFR-1 between the uterine and antecubital veins (uterine vein: mean 1,918 +/- 665 pg/ml vs. antecubital vein: mean 1,750 +/- 475 pg/ml; paired t-tests, p = 0.1). The mean plasma concentration of sVEGFR-1, either in the antecubital or uterine vein, was significantly higher in preeclampsia than in normal pregnancy (unpaired t-tests; both p < 0.001). There was no significant difference in the mean plasma concentration of PlGF between the uterine and the antecubital veins in both the preeclamptic (uterine vein, mean +/- SD: 129 +/- 106 pg/ml vs. antecubital vein, mean +/- SD: 82 +/- 43 pg/ml; paired t-tests, p = 0.2) and normal pregnancy groups (uterine vein, mean +/- SD: 331 +/- 254 pg/ml vs. antecubital vein, mean +/- SD: 319 +/- 259 pg/ml; paired t-tests, p = 0.4). The mean plasma concentration of PlGF, either in the uterine or antecubital vein, was lower in preeclampsia than in normal pregnancy (unpaired t-tests; p = 0.008 and 0.02 respectively). CONCLUSIONS: Plasma concentration of sVEGFR-1 was higher in the uterine vein than in the antecubital vein in women with preeclampsia. This provides evidence supporting the concept that the uterus is a potential source of the excess circulating sVEGFR-1 concentration in preeclamptic women.

Adult↗

PubMed2005

Idiopathic vaginal bleeding during pregnancy as the only clinical manifestation of intrauterine infection.

OBJECTIVE: To determine the frequency and clinical significance of microbial invasion of the amniotic cavity (MIAC) in patients with vaginal bleeding in the absence of placenta previa, preterm labor or preterm premature rupture of membranes (PROM). STUDY DESIGN: This retrospective cohort study included patients who presented with vaginal bleeding between 18 and 35 weeks, and underwent an amniocentesis shortly after admission for the assessment of the microbiologic status of the amniotic cavity and/or fetal lung maturity. Amniotic fluid was cultured for aerobic and anaerobic bacteria, as well as genital mycoplasmas. Patients presenting with preterm labor, preterm PROM, placenta previa, overt placental abruption, and an intrauterine device in situ were excluded, as well as those with local cervical bleeding. MIAC was defined as a positive amniotic fluid culture. Analysis was conducted with non-parametric statistics. RESULTS: One hundred and fourteen patients met the entry criteria. MIAC was detected in 14% of cases (16/114). Patients with vaginal bleeding and a gestational age < 28 weeks at the time of amniocentesis had a significantly higher frequency of MIAC than those with a gestational age 28 weeks [25% (13/52) vs. 4.8% (3/62), respectively; p < 0.01]. Ureaplasma urealyticum was the microorganism most frequently isolated from the amniotic fluid. Except for one case admitted at 33 weeks, all patients with MIAC had an early preterm delivery 32 weeks. Patients with vaginal bleeding and MIAC had a shorter procedure-to-delivery interval than those without MIAC [MIAC, median survival 19 days (95% CI 10-27 days) vs. no MIAC, median survival 50 days (95% CI 37-62 days); p < 0.0001]. Patients with vaginal bleeding and MIAC had a significantly lower gestational age at delivery and lower birth weight than those with vaginal bleeding and negative amniotic fluid cultures (for gestational age, median 25 weeks, range 21-33 weeks vs. median 37 weeks, range 19-42 weeks, respectively; p < 0.01, and for birth weight, median 750 grams, range 520-1820 grams vs. 2800 grams, range 520-4880 grams, respectively; p < 0.01), as well as a higher frequency of subsequent preterm PROM [81.3% (13/16) vs. 9.2% (9/98); p < 0.01]. CONCLUSIONS: MIAC was detected in 14% of patients with 'idiopathic' vaginal bleeding and was associated with subsequent preterm PROM and early preterm delivery. Vaginal bleeding may be the only clinical manifestation of MIAC, and it predisposes to adverse outcome.

Adult↗

PubMed2005

Macrophage migration inhibitory factor in patients with preterm parturition and microbial invasion of the amniotic cavity.

OBJECTIVE: Macrophage migration inhibitory factor (MIF) has emerged as an important mediator of septic shock. The administration of MIF increases lethality during endotoxemia, whereas neutralization of this cytokine prevents endotoxic shock and death associated with bacterial infection. The objective of this study was to determine whether there is a change in the amniotic fluid concentration of MIF in intra-amniotic infection and human parturition. STUDY DESIGN: A cross-sectional study was conducted in women in the following categories: (1) mid-trimester (n = 84); (2) preterm labor and intact membranes who delivered at term (n = 33), who delivered preterm (n = 53) and preterm labor with intra-amniotic infection (n = 23); (3) preterm premature rupture of membranes (PROM) with (n = 25) and without intra-amniotic infection (n = 26); and (4) term with intact membranes, in labor (n = 52) and not in labor (n = 31). MIF concentrations in amniotic fluid were determined using a sensitive and specific immunoassay. MIF concentrations in maternal plasma were also determined in patients with preterm labor and intact membranes. Immunohistochemistry was conducted in chorioamniotic membranes obtained from a different set of patients presenting with preterm labor with (n = 18) and without (n = 20) histologic chorioamnionitis. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to measure MIF mRNA expression in chorioamniotic membranes of patients with preterm labor with (n = 13) and without (n = 13) histologic chorioamnionitis. Parametric and non-parametric, receiver-operating characteristic (ROC) curve, survival analysis, and Cox regression model were used for analysis. RESULTS: Immunoreactive MIF was detectable in 96% (313/327) of amniotic fluid samples. The concentration of amniotic fluid MIF at term was higher than that in the mid-trimester (p = 0.004). Intra-amniotic infection in women with preterm labor and preterm PROM was associated with a significant increase in median amniotic fluid MIF concentration (p < 0.001 and 0.004, respectively). Patients with preterm labor with sterile amniotic fluid who delivered preterm had a significantly higher median amniotic fluid MIF concentration than those who delivered at term (p = 0.007). Among patients with preterm labor with intact membranes, survival analysis indicated that the median amniocentesis-to-delivery interval was significantly shorter in patients whose amniotic fluid concentrations of MIF were above 302 ng/ml than those below this cutoff value (p < 0.001). Human parturition at term was not associated with changes in the amniotic fluid MIF concentrations (p > 0.05). There was no significant difference in median maternal plasma MIF concentrations among patients with preterm labor and intact membranes who delivered at term, those who delivered preterm, and those who had intra-amniotic infection (p > 0.05 for all comparisons). Immunohistochemistry demonstrated that MIF protein was present in amniotic epithelial cells, and the mean percentage of immunoreactive MIF-staining cells was higher in patients with histologic chorioamnionitis than in those without this lesion (p = 0.03). Similarly, the mean MIF mRNA expression was higher in chorioamniotic membranes obtained from patients with histologic chorioamnionitis than in those without this lesion (p = 0.03). CONCLUSIONS: Intra-amniotic infection and preterm parturition, but not term parturition, are associated with a significant increase in amniotic fluid MIF concentrations. Among patients with preterm labor with intact membranes, elevated amniotic fluid concentrations of MIF are associated with intra-amniotic inflammation, histologic chorioamnionitis, and shorter amniocentesis-to-delivery interval. These changes in amniotic fluid were not reflected in maternal plasma. An increased expression of MIF protein and mRNA in chorioamniotic membranes was observed in patients with histologic choricamnionitis.

Amniocentesis↗

PubMed2004

Divergent trophoblast responses to bacterial products mediated by TLRs.

Intrauterine infections have been associated with pregnancy complications that are also linked with increased trophoblast apoptosis. TLRs are key components of the innate immune system which recognize conserved sequences on the surface of pathogens and trigger effector cell functions. We hypothesize that intrauterine infections may cause the excessive trophoblast cell apoptosis observed in abnormal pregnancies and that TLR may provide a mechanism of pathogenesis. In this study we describe the expression and function of TLR-2 and TLR-4 in first trimester trophoblast cells. Although ligation of TLR4 induced cytokine production by trophoblast cells, TLR-2 activation induced apoptosis. TLR-2 mediated apoptosis was dependent upon the Fas-associated death domain, the inactivation of the X-linked inhibitor of apoptosis, and the activation of caspases 8, 9, and 3. These results suggest that certain intrauterine infections may directly induce trophoblast cell death through TLR-2. Our findings provide a novel mechanism of pathogenesis for certain pregnancy complications in which there is engagement of the innate immune system.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award.

OBJECTIVE: Soluble vascular endothelial growth factor receptor 1 (sVEGFR-1), which antagonizes VEGF functions, has been implicated in the pathophysiology of preeclampsia. The purpose of this study was to determine whether preeclampsia is associated with a change in the plasma concentration of sVEGFR-1, and, if so, whether such a change is correlated with the severity of the disease. METHODS: A cross-sectional study was conducted to determine the concentrations of sVEGFR-1 in plasma obtained from normal pregnant women (n=61) and patients with preeclampsia (n=61). Plasma concentrations of sVEGFR-1 were determined by enzyme-linked immunoassay. RESULTS: Preeclampsia had a higher median plasma concentration of sVEGFR-1 than normal pregnancy (P <.001). The median plasma concentration of sVEGFR-1 was higher in early-onset (< or =34 weeks) than late-onset (>34 weeks) preeclampsia (P=.005), and higher in severe than in mild preeclampsia (P=.002). In normal pregnancy, there was a correlation between plasma concentration of sVEGFR-1 and gestational age (r=0.5; P <.001). In contrast, there was a negative correlation between plasma concentration of sVEGFR-1 and gestational age at the onset of preeclampsia (r=-0.5; P <.001). CONCLUSION: Preeclampsia is associated with an increased plasma sVEGFR-1 concentration. The elevation of sVEGFR-1 concentration is correlated with the severity of the disease. These observations suggest the participation of VEGF and its soluble receptor in the pathophysiology of preeclampsia.

Adolescent↗