Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies.

Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

Association of Polymorphisms in FSHR, INHA, ESR1, and BMP15 with Recurrent Implantation Failure.

Recurrent implantation failure (RIF) refers to two or more unsuccessful in vitro fertilization embryo transfers in the same individual. Embryonic characteristics, immunological factors, and coagulation factors are known to be the causes of RIF. Genetic factors have also been reported to be involved in the occurrence of RIF, and some single nucleotide polymorphisms (SNPs) may contribute to RIF. We examined SNPs in FSHR, INHA, ESR1, and BMP15, which have been associated with primary ovarian failure. A cohort of 133 RIF patients and 317 healthy controls consisting of all Korean women was included. Genotyping was performed by Taq-Man genotyping assays to determine the frequency of the following polymorphisms: FSHR rs6165, INHA rs11893842 and rs35118453, ESR1 rs9340799 and rs2234693, and BMP15 rs17003221 and rs3810682. The differences in these SNPs were compared between the patient and control groups. Our results demonstrate a decreased prevalence of RIF in subjects with the FSHR rs6165 A>G polymorphism [AA vs. AG adjusted odds ratio (AOR) = 0.432; confidence interval (CI) = 0.206-0.908; p = 0.027, AA+AG vs. GG AOR = 0.434; CI = 0.213-0.885; p = 0.022]. Based on a genotype combination analysis, the GG/AA (FSHR rs6165/ESR1 rs9340799: OR = 0.250; CI = 0.072-0.874; p = 0.030) and GG-CC (FSHR rs6165/BMP15 rs3810682: OR = 0.466; CI = 0.220-0.987; p = 0.046) alleles were also associated with a decreased RIF risk. Additionally, the FSHR rs6165GG and BMP15 rs17003221TT+TC genotype combination was associated with a decreased RIF risk (OR = 0.430; CI = 0.210-0.877; p = 0.020) and increased FSH levels, as assessed by an analysis of variance. The FSHR rs6165 polymorphism and genotype combinations are significantly associated with RIF development in Korean women.

Genetic Variations miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G and the Risk of Recurrent Pregnancy Loss in Korean Women

This study investigated the genetic association between recurrent pregnancy loss (RPL) and microRNA (miRNA) polymorphisms in miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G in Korean women. Blood samples were collected from 381 RPL patients and 281 control participants, and genotyping of miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G was carried out by TaqMan miRNA RT-Real Time polymerase chain reaction (PCR). Four polymorphisms were identified, including miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G. MiR-10a dominant model (AA vs. AT + TT) and miR-499bGG genotypes were associated with increased RPL risk (adjusted odds ratio [AOR] = 1.520, 95% confidence interval [CI] = 1.038−2.227, p = 0.032; AOR = 2.956, 95% CI = 1.168−7.482, p = 0.022, respectively). Additionally, both miR-499 dominant (AA vs. AG + GG) and recessive (AA + AG vs. GG) models were significantly associated with increased RPL risk (AOR = 1.465, 95% CI = 1.062−2.020, p = 0.020; AOR = 2.677, 95% CI = 1.066−6.725, p = 0.036, respectively). We further propose that miR-10aA>T, miR-30cA>G, and miR-499bA>G polymorphisms effects could contribute to RPL and should be considered during RPL patient evaluation.

Genetic Polymorphisms in the 3'-Untranslated Regions of SMAD5, FN3KRP, and RUNX-1 Are Associated with Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) is typically defined as two or more consecutive pregnancy losses prior to 20 weeks of gestation. Although the causes of idiopathic RPL are not completely understood, vascular development and glucose concentration were reported to correlate with the pregnancy loss. The TGF-ß signaling pathway which plays a significant role in pregnancy is activated by the interaction between high glucose and SMAD signaling and affects the vascular cells. SMAD5 and RUNX-1 are involved in the TGF-ß signaling pathway and contribute to advanced glycation end products (AGEs) production and vascular development. FN3KRP, a newly described gene, is also associated with vascular diseases and suggested to relate to AGEs. Therefore, in the present study, we investigated associations between RPL risk and genetic polymorphisms of SMAD5, FN3KRP, and RUNX-1 in 388 women with RPL and 280 healthy control women of Korean ethnicity. Participants were genotyped using real-time polymerase chain reaction and restriction fragment length polymorphism assay to determine the frequency of SMAD5 rs10515478 C>G, FN3KRP rs1046875 G>A, and RUNX-1 rs15285 G>A polymorphisms. We found that women with RPL had lower likelihoods of the FN3KRP rs1046875 AA genotype (adjusted odds ratio (AOR), 0.553; p = 0.010) and recessive model (AOR, 0.631; p = 0.017). Furthermore, combination analysis showed that SMAD5 rs10515478 C>G and FN3KRP rs1046875 G>A mutant alleles were together associated with reduced RPL risk. These findings suggest that the FN3KRP rs1046875 G>A polymorphism has a significant role on the prevalence of RPL in Korean women. Considering that it is the first study indicating a significant association between FN3KRP and pregnancy disease, RPL, our results suggest the need for further investigation of the role of FN3KRP in pregnancy loss.

Association Study between Mucin 4 (MUC4) Polymorphisms and Idiopathic Recurrent Pregnancy Loss in a Korean Population.

Recurrent pregnancy loss (RPL) is the loss of two or more consecutive pregnancies before 20 weeks of gestational age. Our study investigated whether mucin 4 (MUC4) polymorphisms are associated with RPL. MUC polymorphisms (rs882605 C>A, rs1104760 A>G, rs2688513 A>G, rs2258447 C>T, and rs2291652 A>G) were genotyped in 374 women with RPL and 239 controls of Korean ethnicity using polymerase chain reaction-restriction fragment length polymorphism analysis and the TaqMan probe SNP genotyping assay. Differences in genotype frequencies between cases of RPL and the controls were compared. MUC4 rs882605 C>A and rs1104760 A>G polymorphisms were associated with increased incidence of RPL in three and four or more pregnancy loss patients. The haplotype analyses showed a tendency for the allelic effect including the association of MUC4 rs882605 A and rs1104760 G alleles with increased incidence of RPL. In addition, the MUC4 rs882605 CA/MUC4 rs2258447 CC genotype combination was associated with increased RPL prevalence. The two exonic polymorphisms lead to amino acid changes of protein and may act as pathogenic variants for RPL. In conclusion, the MUC4 rs882605 C>A and MUC4 rs1104760 A>G polymorphisms were associated with the susceptibility of RPL and we considered them as potential biomarkers for RPL.

Genetic Polymorphisms in miR-604A>G, miR-938G>A, miR-1302-3C>T and the Risk of Idiopathic Recurrent Pregnancy Loss.

The purpose of this study was to investigate whether polymorphisms in five microRNAs (miRNAs), miR-604A>G, miR-608C>G, 631I/D, miR-938G>A, and miR-1302-3C>T, are associated with the risk of idiopathic recurrent pregnancy loss (RPL). Blood samples were collected from 388 patients with idiopathic RPL (at least two consecutive spontaneous abortions) and 227 control participants. We found the miR-604 AG and AG + GG genotypes of miR-604, the miR-938 GA and GA + AA genotypes of miR-938, and the miR-1302-3CT and CT + TT genotypes of miR-1302-3 are less frequent than the wild-type (WT) genotypes, miR-604AA, miR-938GG, and miR-1302-3CC, respectively, in RPL patients. Using allele-combination multifactor dimensionality reduction (MDR) analysis, we found that eight haplotypes conferred by the miR-604/miR-608/miR-631/miR-938/miR-1302-3 allele combination, A-C-I-G-T, A-C-I-A-C, G-C-I-G-C, G-C-I-G-T, G-G-I-G-C, G-G-I-G-T, G-G-I-A-C, G-G-D-G-C, three from the miR-604/miR-631/miR-938/miR-1302-3 allele combination, A-I-G-T, G-I-G-C, G-I-A-T, one from the miR-604/miR-631/miR-1302-3 allele combination, G-I-C, and two from the miR-604/miR-1302-3 allele combination, G-C and G-T, were less frequent in RPL patients, suggesting protective effects (all p < 0.05). We also identified the miR-604A>G and miR-938G>A polymorphisms within the seed sequence of the mature miRNAs and aligned the seed sequences with the 3'UTR of putative target genes, methylenetetrahydrofolate reductase (MTHFR) and gonadotropin-releasing hormone receptor (GnRHR), respectively. We further found that the binding affinities between miR-604/miR-938 and the 3'UTR of their respective target genes (MTHFR, GnRHR) were significantly different for the common (miR-604A, miR-938G) and variant alleles (miR-604G, miR-938A). These results reveal a significant association between the miR-604A>G and miR-938G>A polymorphisms and idiopathic RPL and suggest that miRNAs can affect RPL in Korean women.

Obstetrical outcomes after first-trimester chorionic villus sampling in twin pregnancies: A retrospective case-control study.

AIM: Prenatal diagnostic testing by chorionic villus sampling (CVS) is sometimes recommended for women with twin pregnancies. However, few studies have compared the outcomes between twins with CVS and control twins without intervention. This study aimed to compare the obstetrical outcomes of CVS in twin pregnancies and those in non-intervention twin pregnancies. METHODS: First-trimester transabdominal CVS was performed on dichorionic-diamniotic twins (n = 54; Group 1) between December 2006 and January 2017 at the Department of Obstetrics and Gynecology at our hospital, and the data were retrospectively analyzed. CVS risks were evaluated by comparing obstetrical outcomes with those of a control population of 155 dichorionic-diamniotic twins without intervention (Group 2). RESULTS: The difference in the overall fetal loss rate (Group 1, 7.4% vs Group 2, 3.9%; P = 0.287) between the two groups was not statistically significant. The miscarriage rate, defined as delivery at <24 gestational weeks, and early preterm delivery, defined as delivery at <34 gestational weeks, were not significant between the groups (miscarriage: Group 1, 5.6% vs Group 2, 3.2%; P = 0.428; early preterm delivery: Group 1, 11.1% vs Group 2, 9.0%; P = 0.788). The mean gestational age at delivery, birth weights and neonatal intensive care unit admission rate were not statistically significant between the groups. Thus, the overall fetal loss rate and obstetrical outcomes of Group 1 were comparable with those of Group 2. CONCLUSION: In conclusion, the overall obstetrical outcomes were not significantly different between twins with CVS and control twins with the advantage of enabling early decision-making about selective feticide in twins with CVS.

Obstetrical Outcomes of Amniocentesis or Chorionic Villus Sampling in Dichorionic Twin Pregnancies.

BACKGROUND: Under certain situations, women with twin pregnancies may be counseled to undergo invasive prenatal diagnostic testing. Chorionic villus sampling and amniocentesis are the two generally performed invasive prenatal diagnostic tests. Studies comparing procedure-related fetal loss between first-trimester chorionic villus sampling and second-trimester amniocentesis in twin pregnancies are limited. This study aimed to evaluate the procedure-related fetal loss and the obstetrical outcomes of these two procedures, chorionic villus sampling and amniocentesis in twin pregnancies. METHODS: The data from dichorionic-diamniotic twin pregnancies on which first-trimester chorionic villus sampling (n = 54) or second-trimester amniocentesis (n = 170) was performed between December 2006 and January 2017 in a single center were retrospectively analyzed. The procedure-related fetal loss was classified as loss of one or all fetuses within 4 weeks of procedure, and overall fetal loss was classified as loss of one or all fetuses during the gestation. The groups were compared with respect to the procedure-related and obstetrical outcomes. RESULTS: The difference in proportion of procedure-related fetal loss rate (1.9% for chorionic villus sampling vs. 1.8% for amniocentesis; P = 1.000) and the overall fetal loss rate (7.4% for chorionic villus sampling vs. 4.7% for amniocentesis; P = 0.489) between the two groups was not significant. The mean gestational ages at delivery were not statistically significant. CONCLUSION: Both the overall fetal loss rate and the procedure-related fetal loss rate of chorionic villus sampling and amniocentesis in dichorionic twin pregnancies had no statistical significance. Both procedures can be safely used individually.

Obstetrical outcomes of embryo reduction and fetal reduction compared to non-reduced twin pregnancies.

PURPOSE: To prevent perinatal morbidity and mortality of high-order multiple pregnancy (HOMP), multifetal pregnancy reduction (MPR) is offered to some patients. In this study, we investigated whether twin pregnancies derived from MPRs carry a higher adverse obstetrical outcome compared to non-reduced control group of twins. METHODS: We retrospectively analyzed the data from HOMPs on which transvaginal ER (n = 153) at a mean gestational age of 7.6 weeks or transabdominal FR (n = 59) at a mean gestational age of 12.4 weeks was performed between December 2006 and January 2018. The risk of each procedure was evaluated by comparing obstetrical outcome with that of a control population of 157 non-reduced twins conceived by infertility treatment. RESULTS: The mean gestational ages at delivery were 35.2 weeks in the ER group, 35.7 weeks in the FR group, and 34.1 weeks in the control group (P = NS). Compared with those in the control group, the ER group had higher miscarriage (1.3% vs. 6.5%; P = 0.047; OR 0.21; 95% CI 0.45-0.898) and higher overall fetal loss (3.8% vs. 14.4%; P = 0.003; OR 0.24; 95% CI 0.09-0.60) rates. Differently compared with those in the control group, the FR group had no statistical difference in miscarriage (2.5% vs. 1.7%; P=NS) and overall fetal loss (3.8% vs. 6.8%; P=NS) rates. CONCLUSIONS: Compared with the control group, ER in twins had a higher miscarriage and fetal loss rate, whereas FR in twins was similar to the control group. So, the FR procedure is overall a better and safer approach of MPR in reducing morbidity and mortality in HOMPs.

Association between small for gestational age and intrauterine fetal death: comparing a customized South Korean growth standard versus a population-based fetal growth chart.

OBJECTIVE: To determine if a customized growth standard developed for an ethnically homogeneous South Korean population is better at identifying (SGA) fetuses at risk for intra-uterine fetal death (IUFD), compared with a current population based-growth standard. STUDY DESIGN: A retrospective cohort study comparing the identification of SGA fetuses at risk for IUFD using a customized versus a population based-chart. The association between a SGA infant defined as a birth weight <10th percentile using the South Korean population chart versus the customized chart and IUFD were compared. Intrauterine fetal death was defined as fetal demise occurring after 20 weeks gestation. Statistical analyses including OR, 95% confidence interval (CI), and screening accuracy using each chart were performed. RESULTS: The customized singleton chart identified 11 (8.2%) of the SGA pregnancies detected by the population chart and classified 15 additional fetuses as SGA. Those identified as SGA using the customized chart had an OR for IUFD that was approximately 15 times as high as those identified using the population chart. The customized chart also showed a higher sensitivity and specificity for identifying SGA pregnancies at risk for IUFD. CONCLUSION: In this ethnically homogenous population, the customized growth chart showed improved discrimination in identifying SGA pregnancies at risk for fetal death than the population-based growth chart.

Heterotopic quadruplet pregnancy: conservative management with ultrasonographically-guided KCl injection of cornual pregnancy and laparoscopic operation of tubal pregnancy.

OBJECTIVE: To discuss a case of heterotopic cornual and tubal pregnancy managed with transvaginal potassium chloride (KCl) injection of cornual pregnancy and laparoscopic operation of tubal pregnancy. METHODS: The subject was a 30-year-old woman with twin pregnancy with a left cornual and a tubal pregnancy. The heterotopic cornual pregnancy was treated with ultrasonographically-guided transvaginal injection of KCl into the thorax of ectopic fetus, and the tubal pregnancy was treated with laparoscopic left salpingectomy. RESULTS: The woman was discharged on the 6th postoperative day. After complete ablation of the cornual and tubal pregnancy, the subject had no complications or side effects for the duration of her pregnancy up to the 37th week. Elective cesarean section was performed at 37 weeks and allowed the birth of 2 boys weighing 2,500 and 2,000 g and of normal development. CONCLUSIONS: A minimally invasive approach should be considered in a hemodynamically stable patient to treat a first-trimester heterotopic pregnancy to maintain the intrauterine pregnancy with a satisfactory outcome.

Profiling of differential protein expression in angiogenin-induced HUVECs using antibody-arrayed ProteoChip.

ProteoChip has been developed as a novel protein microarray technology. So far it has been applied in new lead screening and molecular diagnostics and we expect its role to grow in the field of biology. Here, we investigated the application of ProteoChip for the study of differential protein expression profiles in angiogenin-induced human umbilical vein endothelial cells (HUVECs). Antibody microarrays constructed by immobilizing 60 distinct antibodies against signal-transducing proteins on ProteoChip base plates were used to analyze the expression pattern of cell-signaling proteins in HUVECs treated with angiogenin. The antibody microarray approach showed that angiogenin induced the up- and down-regulation of several cellular regulators related with cell proliferation. Changes in the expression of signaling proteins determined by antibody microarray were validated by Western blot analysis. In this experiment, ten up-regulated proteins and six down-regulated proteins were identified and confirmed by immunoblot analysis. Taken together, these data suggest that antibody microarrays using ProteoChip technology can be a powerful tool for high-throughput analysis of proteomes in biological samples.