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While various septin GTPases have been reported for their physiological functions, their roles in orchestrating complex cognitive/emotional functions in adult mammals remained scarcely explored. A comprehensive behavioral test battery was administered to two sexes of 12-week-old

A family history of psychiatric diseases was suggested as one risk factor for autism spectrum disorders (ASD). Our aim was to assess the association of paternal and maternal diagnosis of psychiatric disorders with the risk of ASD in offspring in Taiwan. We conducted a population-based case-control study. Using several linked national databases, we obtained 1,000,939 singleton birth records born between 2004 and 2008. We followed these children up to 2015 for cases of ASD, using diagnostic codes in the National Health Insurance databases. There were 8,933 ASD cases and each case was matched to ten controls by sex and year of birth. We extracted their parental diagnosis of psychiatric disorders and performed conditional logistic regression models to assess the association of interest. Our sample included 8,933 cases and 89,330 controls. Eighty-six percent of the sample were boys. After adjustment for parental age, family income, and urbanization, we found that parental psychiatric diseases were significantly associated with ASD, including schizophrenic and psychotic disorders, mood, anxiety and personality disorders, with adjusted odds ratios ranging from 1.32 to 2.39. Notably, the effect estimates were all larger for maternal diagnosis than paternal diagnosis when stratified by mothers or fathers. Cases of ASD are more likely to be born to parents with psychiatric disorders than their counterparts. Maternal psychiatric diagnosis seems to have a larger influence than paternal diagnosis. Both genetics and maternal environmental factors may contribute to the association observed between parental psychiatric diseases and child ASD.

Objective: Cystic hygromas are frequently encountered in fetus with Turner syndrome (TS). Nevertheless, identification of genetic loci responsible for the cystic hygroma has been problematic. Here, we tried to elucidate the candidate gene for cystic hygroma through a rare case of complex Y chromosomal rearrangements involving duplication of partial Yq and monosomy of partial Yp. Case report: A 30-year-old woman, gravida 1 para 0, was diagnosed with fetal cystic hygroma at 12 weeks of gestation. The genetic analysis of the product of conception revealed complex rearrangement of Y chromosome: microdeletion in Yp11.2p11.31 and microduplicatin in Yq11.223q11.23. The deleted region spans about 6.25 Mb and includes 76 genes, including SRY. The duplicated region spans about 4.76 Mb and includes 145 genes. Conclusion: From this rare case with non-mosaic complex Y-chromosome rearrangements, we could narrow down Turner stigmata critical region to Yp11.2～p11.3. We also propose RPS4Y1 as lymphedema candidate gene.

Objective: To examine changes in the number and causes of maternal deaths after the introduction of pregnancy checkbox on the death certificate in January 2014 in Taiwan. Materials and methods: We first used the cause-of-death (COD) mortality data for years 2010 through 2017 to examine the number of deaths by item of pregnancy checkbox. We then compared the distribution of the causes of maternal deaths before and after the introduction of pregnancy checkbox. Results: Between 2014 and 2017, 111 women died, for whom the certifiers indicated the following in the pregnancy checkbox items: 2 (pregnant at the time of death; n = 10), 3 (died within 42 days after the termination of pregnancy; n = 64), and 4 (died between 43 days and 1 year after the termination of pregnancy; n = 37). However, in only 61 of the 111 deaths, the certifiers reported pregnancy or delivery-related diagnosis in the COD section of the death certificate—5 each for items 2 and 4 and 51 for item 3. The number of maternal deaths was 55 in 2010–2013; this number increased to 82 in 2014–2017. A decline in the percentage of maternal deaths from obstetric hemorrhage was noted from 38% (21/55) in 2010–2013 to 21% (17/82) in 2014–2017. Conclusion: The number of maternal deaths increased, and the distribution of causes of maternal deaths changed after the introduction of pregnancy checkbox. Additional studies are required to examine the possible misclassification of pregnancy-associated deaths indicated in the pregnancy checkbox. Keywords: Cause-of-death, Death certificate, Pregnancy checkbox, Pregnancy-associated deaths, Maternal deaths

SEPTIN12 (SEPT12) is a testis-enriched gene that is downregulated in the testis of infertile men with severe spermatogenic defects. While SEPT12 is involved in spermatogenic failure and sperm motility disorder, SEPT12 transcriptional regulation is still unknown. Here we report the promoter region of SEPT12 as a 245 bp segment upstream of the transcription start site. One androgen receptor (AR) and two estrogen receptor α (ERα) binding sites in this region were initially identified by bioinformatics prediction and confirmed by chromatin immunoprecipitation assay. Truncated ERα or AR binding sites decreased the promoter activity, which indicated that the ERα and AR are essential for the SEPT12 promoter. On the other hand, the promoter activity was enhanced by the treatment with 17β-estradiol (E2) and 5α-dihydrotestosterone (5α-DHT). Thus, one androgen and two estrogen hormone responsive elements located in the promoter of SEPT12 gene can regulate SEPT12 expression. Two single nucleotide polymorphisms (SNPs), rs759992 T > C and rs3827527 C > T, were observed in the SEPT12 gene promoter region and were able to decrease the promoter activity. In conclusion, the current work identified the promoter of the human SEPT12 gene and provided key evidence about its transcriptional regulation via E2 and 5α-DHT. Since SEPT12 has an important role in spermatogenesis, SEPT12 expression analysis can be developed as a potential tool for the assessment of environmental or food pollution by hormones or for the evaluation of the risk of endocrine-disrupting chemicals (EDCs) in general.

Placental mesenchymal dysplasia (PMD) and partial hydatidiform mole (PHM) placentas share similar characteristics, such as placental overgrowth and grape-like placental tissues. Distinguishing PMD from PHM is critical because the former can result in normal birth, while the latter diagnosis will lead to artificial abortion. Aneuploidy and altered dosage of imprinted gene expression are implicated in the pathogenesis of PHM and also some of the PMD cases. Diandric triploidy is the main cause of PHM, whereas mosaic diploid androgenetic cells in the placental tissue have been associated with the formation of PMD. Here, we report a very special PMD case also presenting with trophoblast hyperplasia phenotype, which is a hallmark of PHM. This PMD placenta has a normal biparental diploid karyotype and is functionally sufficient to support normal fetal growth. We took advantage of this unique case to further dissected the potential common etiology between these two diseases. We show that the differentially methylated region (DMR) at NESP55, a secondary DMR residing in the GNAS locus, is significantly hypermethylated in the PMD placenta. Furthermore, we found heterozygous mutations in NLRP2 and homozygous variants in NLRP7 in the mother’s genome. NLRP2 and NLRP7 are known maternal effect genes, and their mutation in pregnant females affects fetal development. The variants/mutations in both genes have been associated with imprinting defects in mole formation and potentially contributed to the mild abnormal imprinting observed in this case. Finally, we identified heterozygous mutations in the X-linked ATRX gene, a known maternal–zygotic imprinting regulator in the patient. Overall, our study demonstrates that PMD and PHM may share overlapping etiologies with the defective/relaxed dosage control of imprinted genes, representing two extreme ends of a spectrum.

Background: The regulation of thyroid hormones in the early stages of gestation plays a crucial role in the outcome of a pregnancy. Furthermore, thyroid hormones are fundamental for the fetal development of all organs, including endocrine hormone changes in uterus. Endocrine disrupting chemicals have been shown to have an effect on thyroid hormone homeostasis in newborns, which affects their later development. Few studies have proposed how phthalates could alter thyroid function through several mechanisms and the possible effects on thyroid hormone homeostasis of phthalates on pregnant women. However, the effects of cord blood phthalates and prenatal phthalate exposure on thyroid hormones in newborns remain unclear. Objectives: We aim to follow up on our previous established subjects and determine the correlation between phthalate exposure and thyroid hormones in pregnant women and newborns. Materials and methods: We recruited 61 pregnant women from the Obstetrics and Gynecology Department of a medical hospital in southern Taiwan and followed up. High performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was used to analyze urine samples for five phthalate metabolites. Serum levels of thyroid hormones were analyzed using electrochemoluminescence immunoassay (ECLIA) method. We used Spearman and Pearson correlation coefficients to evaluate the correlation between each phthalate metabolites in serum and the thyroid hormone levels in fetus and parturient. Finally, multiple logistic regression was used to explore the relationship between hormones and their corresponding phthalate metabolites in cord blood. Results: High MBP in cord blood was correlated with negative cord serum TSH in newborns (r = −0.25, p &lt, 0.06). By using multiple linear regression after adjusting for potential confounders (gestational and maternal age), cord serum MBP levels showed a negative association with cord serum TSH (β = 0.217, p &lt, 0.05), cord serum T4 (β = 1.71, p &lt, 0.05) and cord serum T4 × TSH (β = 42.8, p &lt, 0.05), respectively. Conclusion: We found that levels of cord serum TSH and T4 in newborns was significantly negatively associated with cord serum MBP levels after adjusting for significant covariate. The fall in TSH in newborns may potentially be delaying their development.

AIM To examine the association of maternal chronic hypertension and pregnancy-induced hypertension (PIH)/preeclampsia with childhood neurodevelopmental disorders (NDDs) in a large-scale population-based cohort. METHOD We conducted a linked Taiwan National Health Insurance Research Database cohort study of children born between 2004 and 2008 (n=877 233). Diagnoses of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), developmental delay, intellectual disability, cerebral palsy (CP), and epilepsy/infantile spasms were identified from birth to the end of 2015. Cox proportional hazards models were fitted with adjustment for potential confounders to estimate the effect of maternal hypertensive disorder of pregnancy on childhood outcomes. RESULTS Compared with the offspring of unexposed mothers, offspring of mothers with chronic hypertension or PIH/preeclampsia exhibited increased risk of developing a wide spectrum of NDDs. Chronic hypertension was associated with increased risks of ADHD (hazard ratio 1.22, 95% confidence interval [CI] 1.13-1.​31), developmental delay (1.29, 1.21-1.38), intellectual disability (1.67, 1.43-1.95), CP (1.45, 1.14-1.85), and epilepsy/infantile spasms (1.31, 1.10-1.56) in the offspring, whereas PIH/preeclampsia was associated with increased risks of ASD (1.27, 1.12-1.43), ADHD (1.23, 1.17-1.29), developmental delay (1.29, 1.24-1.35), intellectual disability (1.53, 1.37-1.71), CP (1.44, 1.22-1.70), and epilepsy/infantile spasms (1.36, 1.22-1.52) in the offspring after adjustment for potential confounders. The co-occurrence of maternal diabetes, preterm deliveries, or fetal growth restriction further increased the risk. INTERPRETATION Chronic hypertension or PIH/preeclampsia seems to be sufficient to increase the risk of childhood NDDs. What this paper adds Children exposed to maternal hypertensive disorders have a higher cumulative incidence of neurodevelopmental disorders (NDDs) than unexposed children. Chronic hypertension or pregnancy-induced hypertension/preeclampsia seems to be sufficient to increase the risk of childhood NDDs. Co-occurrence of maternal diabetes, preterm deliveries, or fetal growth restriction further increases the risk.

Septins are GTP-binding proteins that form heteromeric filaments for proper cell growth and migration. Among the septins, septin7 (SEPT7) is an important component of all septin filaments. Here we show that protein kinase A (PKA) phosphorylates SEPT7 at Thr197, thus disrupting septin filament dynamics and ciliogenesis. The Thr197 residue of SEPT7, a PKA phosphorylating site, was conserved among different species. Treatment with cAMP or overexpression of PKA catalytic subunit (PKACA2) induced SEPT7 phosphorylation, followed by disruption of septin filament formation. Constitutive phosphorylation of SEPT7 at Thr197 reduced SEPT7‒SEPT7 interaction, but did not affect SEPT7‒SEPT6‒SEPT2 or SEPT4 interaction. Moreover, we noted that SEPT7 interacted with PKACA2 via its GTP-binding domain. Furthermore, PKA-mediated SEPT7 phosphorylation disrupted primary cilia formation. Thus, our data uncover the novel biological function of SEPT7 phosphorylation in septin filament polymerization and primary cilia formation.

Septins are GTP-binding proteins that form heteromeric filaments for proper cell growth and migration. Among these septins, septin7 (SEPT7) is an important component of all septin filaments. Here we showed that protein kinase A (PKA) phosphorylates SEPT7 at Thr197 thus disrupting septin filament dynamics and ciliogenesis. The PKA targeting site at Thr197 of SEPT7 was conserved among species. Treatment of cAMP or overexpression of PKA catalytic subunit (PKACA2) induced SEPT7 phosphorylation. SEPT7 phosphorylation at Thr197 disrupted septin filament formation by reducing SEPT7-SEPT7 interaction, but not affected SEPT7-SEPT6-SEPT2 or SEPT4 interaction. Besides, overexpression of phosphomimetic SEPT7 mutant (T197E) disrupted endogenous SEPT7 filaments suggesting T197E had dominant negative effect on septin filament polymerization. We also identified SEPT7 interacted with the PKACA2 via the GTP-binding domain. Furthermore, PKA-mediated SEPT7 phosphorylation disrupted primary cilia formation. Thus, our data uncover the novel biological function of SEPT7 phosphorylation in septin filament polymerization and primary cilia formation.

Septins play important roles in regulating development and differentiation. Septin 7 (SEPT7) is a crucial component in orchestrating the septin core complex into highly ordered filamentous structures. Here, we showed that genetic depletion of SEPT7 or treatment with forchlorfenuron (FCF; a compound known to affect septin filament assembly) led to reduced the S phase entry in cell models and zebrafish embryos. In addition to colocalizing with actin filaments, SEPT7 resided in the centrosome, and SEPT7 depletion led to aberrant mitotic spindle pole formation. This mitotic defect was rescued in SEPT7-deficient cells by wild-type SEPT7, suggesting that SEPT7 maintained mitotic spindle poles. In addition, we observed disorganized microtubule nucleation and reduced cell migration with SEPT7 depletion. Furthermore, SEPT7 formed a complex with and maintained the abundance of p150glued , the component of centriole subdistal appendages. Depletion of p150glued resulted in a phenotype reminiscent of SEPT7-deficient cells, and overexpression of p150glued reversed the defective phenotypes. Thus, SEPT7 is a centrosomal protein that maintains proper cell proliferation and microtubule array formation via maintaining the abundance of p150glued .

Additional file 1: Figure S1. Study flow diagram. Figure S2. Adjusted odds ratios (ORs) for pregnancy outcomes according to paternal and maternal age categories, among male and female fetuses.

Recurrent pregnancy loss (RPL) is the termination of pregnancies, usually before 20 weeks of gestation, and is defined as the loss of two or more pregnancies. In Taiwan, after 2011 di-2-ethylhexyl phthalate (DEHP) exposure episode, more reproductive-aged women still expose to high levels of DEHP and di-butyl phthalate (DBP) than have women of other age groups. Phthalates might be involved in the RPL pathogenesis. This study assessed the association of phthalate exposure with RPL risk in reproductive-aged Taiwanese women. This study recruited 103 patients diagnosed by a physician with RPL of unknown etiology and 76 controls from the Department of Obstetrics and Gynecology at a medical center in southern Taiwan between August 2013 and August 2017. Urine samples were analyzed for 11 phthalate metabolites through liquid chromatography–tandem mass spectrometry; subsequently, principal component analysis (PCA) and hierarchical clustering analysis were performed to determine the main sources of phthalate exposure. Finally, multivariate logistic regression was used to determine the RPL risk. The creatinine-unadjusted median levels of mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) in RPL/control were 9.8/5.3, 27.2/13.1, 11.4/8.1, and 12.9/9.5 ng/mL, respectively; furthermore, ΣDBPm and ΣDEHPm in RPL/control were 0.18/0.10 and 0.15/0.12 nmol/mL, respectively. PCA revealed three primary components of phthalate exposure: diethyl phthalates (DEP), DEHP, and DBP. Plastic food container use and medication were identified as the main phthalate exposure sources. After adjustment for potential confounding factors (urinary creatinine, age, age at menarche, education, and plastic food container use), we found that the urinary level of ΣDBPm was significantly associated with elevated risk for RPL (OR = 2.85, p = 0.045). Our findings supported the hypothesis that exposure to phthalates increases RPL risk. The development of a strategy to reduce phthalate exposure among reproductive-aged women should be emphasized.

Background Worldwide several studies have examined the associations of fetal sex, paternal age and maternal age with pregnancy outcomes, with the evidence regarding paternal age being less consistent. Although in Taiwan we keep good records on birth certificates, these issues have been seldom researched. Our objective was to assess the association of fetal sex and parental age with gestational hypertension/preeclampsia, eclampsia and preterm delivery in the Taiwanese population. Methods We conducted a nationwide study and included 1,347,672 live births born between 2004 and 2011 in Taiwan. Gestational hypertension/preeclampsia and eclampsia were ascertained based on the International Classification of Diseases codes; preterm delivery ( Results The prevalence was 2.27% for gestational hypertension/preeclampsia, 0.07% for eclampsia and 6.88% for preterm delivery. After considering other parent’s age and covariates, we observed a significantly stepped increase in the risk of both gestational hypertension/preeclampsia and preterm delivery as paternal and maternal age increased. For example, fathers aged ≥50 years were associated with a significantly higher risk of gestational hypertension/preeclampsia (odds ratio [OR]: 1.60, 95% CI: 1.39, 1.84) and preterm delivery (OR: 1.38, 95% CI: 1.27, 1.51) than fathers aged 25–29 years. Analysis on fetal sex showed that relatively more female births were linked to gestational hypertension/preeclampsia and more male births linked to preterm delivery, compared to the whole population. Conclusions We found both paternal and maternal age, as well as fetal sex, were associated with the risk of pregnancy outcomes. Some findings on fetal sex contradicted with previous research using non-Asian samples, suggesting that ethnicity may play a role in the association of fetal sex and pregnancy outcomes. Besides, there is a need to counsel couples who are planning their family to be aware of the influence of both advanced maternal and paternal age on their pregnancy outcomes.

Phthalates, which are commonly used in flexible plastics and consumer products, have been reported to be toxic to reproductive and developmental function in mammals. Past studies have focused on the toxic effects on male reproduction, with only a few studies conducted on the risks that cumulative exposure to phthalates have on the female reproductive system. We recruited 260 patients with recurrent pregnancy loss (RPL) of unknown etiology and 203 controls from the clinics of Obstetrics and Gynecology at a medical center in southern Taiwan from 2013 to 2020. The daily intake of phthalates was estimated from urine samples using the back-calculation method, after which the cumulative risk was determined using multiple hazard indices, including a dose-addition model, a receptor effect model, and a hazard index approach. The patients with RPL had a significantly higher cumulative exposure to phthalates (p

Preeclampsia is a severe gestational hypertensive disorder that occurs after 20 weeks' of gestation. It involves several maternal systems, such as cardiovascular, renal, coagulatory systems, and poses a major threat to the maternal and fetal health. Recent clinical evidence showed that aspirin is an effective preventative treatment for reducing the incidence of premature preeclampsia among high-risk pregnant women, however, the mechanism of drug action is not clear. miR-200 family has been shown to be associated with preeclampsia and upregulated in the plasma and placenta of preeclamptic patients. Here we revealed that miR-200 family inhibited trophoblast invasion and epithelial-mesenchymal transition (EMT) process by stimulating epithelial marker expression (E-cadherin and ZO-1) and repressing mesenchymal marker expression (ZEB1 and TGFβ1). Similarly, EMT markers in the placenta of preeclamptic patients showed higher E-cadherin and lower ZEB1 and TGF-β1 protein expression. Moreover, aspirin was shown to suppress miR-200 family and these miR-200 family-mediated cell functions, including cell invasion and EMT changes, were completely reversed. In conclusion, this study demonstrates the effect of miR-200 family on trophoblast invasion and EMT. For the first time, aspirin was shown to fully reverse miR-200-mediated trophoblast biology and act through the network signaling of TGF-β1/ZEB1/miR-200. These results provide a plausible mechanism explaining aspirin's effect on preeclampsia prevention and a therapeutic target for disease intervention.

M1 macrophage differentiation plays a crucial role in enhanced inflammation during pregnancy, which may lead to pregnancy complications. Therefore, modulation of macrophage differentiation toward the M2 phenotype is desirable to ensure a successful pregnancy. Medroxyprogesterone acetate (MPA) is a potent progestin with an anti-inflammatory property, but its effect on macrophage differentiation is unknown. This study aimed to examine whether MPA can induce an M2 macrophage differentiation by using the human monocytes cell line THP-1 or primary monocytes. THP-1 cells were primed with phorbol-12-myristate-13 acetate (PMA) to initiate macrophage differentiation. By incubating with MPA, the cells (denoted as MPA-pTHP-1) underwent M2 macrophage differentiation with downregulations of CD11c, IL-1β and TNF-α, and upregulations of CD163 and IL-10; while cells incubated with progesterone (P4) did not show the M2 phenotype. Primary monocytes treated with MPA also had the same M2 phenotype. Moreover, M1 macrophages derived from IFN-γ/LPS-treated THP-1 cells, which had high levels of IL-1b and iNOS, and low levels of IL-10 and IDO, were reversed to the M2 phenotype by the MPA treatment. We also found that the MPA-pTHP-1 promoted the decidualization of endometrial stromal cells and the invasion of trophoblast cells. To mimic conditions of exposure to various pathogens, MPA-pTHP-1 cells were stimulated by different types of TLR ligands. We found they produced lower levels of IL-1β and TNF-α, as well as a higher level of IL-10, compared to untreated cells. Finally, we found the level of phosphorylated ERK in the MPA-pTHP-1 cells was increased, but its IL-10 production was suppressed by either the progesterone/glucocorticoid antagonist (Mifepristone) or MEK inhibitor (U0126). Taken together, MPA could drive monocyte differentiation toward an M2 phenotype that mimics decidual macrophages. This finding holds great potential to combat chronic endometrial inflammation.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder resulting from mutations in the dystrophin gene. The mdx/utrn−/− mouse, lacking in both dystrophin and its autosomal homologue utrophin, is commonly used to model the clinical symptoms of DMD. Interestingly, these mice are infertile but the mechanisms underlying this phenomenon remain unclear. Using dystrophin deficient mdx mouse and utrophin haplodeficient mdx/utrn+/− mouse models, we demonstrate the contribution of Dp427 (full-length dystrophin) and utrophin to testis and epididymis development, as well as spermatogenesis. We show that Dp427 deficiency disturbed the balance between proliferation and apoptosis of germ cells during spermatogenesis, which was further disrupted with utrophin haplodeficiency, deciphering a compensatory role of utrophin for dystrophin in the male reproductive system. In the spermatozoa, we have found a compensatory response of utrophin to dystrophin deficiency - namely the upregulation and relocation of utrophin to the flagellar midpiece. This study demonstrates the contribution of Dp427 and utrophin in male fertility, suggesting a potential pathology in DMD patients.

In 1979, more than 2000 persons ingested rice oil contaminated with polychlorinated biphenyls and polychlorinated dibenzofurans; this event was called the “Yucheng accident.” An increased percentage of oligospermia, reduced ability of sperm to penetrate oocytes, and reduced percentage of male offspring were reported in Yucheng men. This study examined whether the sperm sex ratio and chromosome aneuploidy are responsible for our observed findings in Yucheng men. In 1999–2000, Yucheng men and their neighborhood referents aged 37–50 years were recruited for physical examination, followed by semen analysis. The semen samples were analyzed for chromosomal aneuploidy through fluorescent in situ hybridization according to an established procedure in our laboratory. A total of 50 Yucheng men and 34 neighborhood referents volunteered to participate in the study. Although abnormal morphology was mildly increased, no differences were observed in sperm percentages, with normal numbers of chromosomes X, Y, and 8 in the two groups. The percentage of sperm with aneuploidy of the sex chromosomes or chromosome 8 and of that with diploidy did not vary between both groups. The normal X/Y sperm ratio was not different between the groups. However, among Yucheng men, 8% had a normal X/Y sperm ratio of >1.4, and no neighborhood referent showed such an elevated X/Y ratio. Chromosomal aneuploidy was not elevated in Yucheng men. The mechanisms underlying the reduced sperm capability of oocyte penetration and changed offspring sex ratio in Yucheng men remain undetermined.

Macrophage polarization, regulated appropriately, may play important roles in successful pregnancy. In the face of the vital roles of decidua macrophages in pregnancy, it is insufficient to recognize the trigger of macrophage differentiation and polarization. We aimed to explore the link between the NLRP7 gene and macrophage polarization in human deciduas. Here, we enrolled the endometrial tissues from eight pregnant women in the first trimester. We found that NLRP7 was abundant in endometrial tissues and that NLRP7 was expressed in decidual macrophages of the first-trimester pregnancy. NLRP7 was predominately expressed in the decidual M2 macrophages, as compared with the M1 macrophages. Furthermore, our results suggest that NLRP7 is associated with decidual macrophage differentiation. NLRP7 over-expression suppresses the expression of M1 markers and enhances the expression of the M2 markers. Considering that NLRP7 relates to decidualization and macrophage differentiation, we propose that NLRP7 is a primate-specific multitasking gene to maintain endometrial hemostasis and reproductive success. This finding may pave the way for therapies of pathological pregnancies.

Gestational diabetes mellitus (GDM) is a type of unbalanced glucose tolerance that occurs during pregnancy, which affects approximately 10% of pregnancies worldwide. Fetuin-A is associated with insulin resistance, and the concentration of circulating fetuin-A increases in women with GDM, however, the role of fetuin-A in the placenta remains unclear. In this study, we enrolled placental samples from twenty pregnant women with GDM and twenty non-GDM pregnant women and found that the abundance of fetuin-A was upregulated in terms of mRNA and protein levels. Fetuin-A inhibited placental cell growth by inducing apoptosis and inhibiting S phase entry. Irregular alignment of mitotic chromosomes and aberrant mitotic spindle poles were observed. In addition, centrosome amplification was induced by fetuin-A treatment, and these amplified centrosomes nucleated microtubules with disorganized microtubule arrays in placental cells. Furthermore, fetuin-A inhibited autophagy, and thus blocked the growth of the primary cilium, a cellular antenna that regulates placenta development and differentiation. Thus, our study uncovered the novel function of fetuin-A in regulating placental cell growth and ciliogenesis.

The main objective of this study was to evaluate the potential genetic effects of SEPT14 on male infertility through sequencing the SEPT14 coding region. To address this research gap, 254 men with sperm abnormalities and 116 normozoospermic men were recruited, and the whole-coding regions of SEPT14 were sequenced. Two heterozygous mutations, p.Ala123Thr (3/254 vs. 0/116) and p.Ile333Thr (3/254 vs. 0/116), were identified in these cases. A high percentage of defective sperm heads was found in sperm with mutated SEPT14. Both mutations are highly evolutionarily conserved among vertebrates. The results of a fine morphological and chromatin structural analysis indicated severely malformed sperm heads with abnormal chromatin packaging through transmission electron microscopy and Toluidine blue staining. Compared with controls, high DNA fragmentation was demonstrated in sperm from cases carrying SEPT14 mutations using the comet assay. In addition, these two mutations in SEPT14 affected its polymerization ability in vitro. These data revels that the two SEPT14 missense mutations impaired sperm head morphology and induced DNA damage. Our study suggests that genetic variant of SEPT14 is one of the effects for human sperm formation and male fertility.

Primary coenzyme Q10 deficiency-7 (COQ10D7) is a rare mitochondrial disease caused by biallelic mutations in COQ4. Here we report the largest cohort of COQ10D7 to date, with 11 southern Chinese patients confirmed with biallelic COQ4 mutations. Five of them have the classical neonatal-onset encephalo-cardiomyopathy, while the others have infantile onset with more heterogeneous clinical presentations. We also identify a founder mutation COQ4 (NM_016035.5): c.370G>A, p.(Gly124Ser) for COQ10D7, suggesting a higher chance of occurrence in the southern Chinese. This study helps improve understanding of the clinical spectrum of this disorder.

Recent studies suggested that prophylactic aspirin prior to 16 weeks of gestation in high-risk patients may reduce the risk of developing preeclampsia; however, the exact mechanism of aspirin's effect on the pathophysiology of preeclampsia is not clear. This study was designed to investigate the effect of aspirin on trophoblast cell function and its effect on soluble fms-like tyrosine kinase 1 (sFlt-1) production to elucidate the preventive mechanisms for preeclampsia.We used two human trophoblastic cell lines (HTR-8/SVneo and JAR) and freshly isolated cytotrophoblasts from normal and preeclamptic placenta at term to determine the effect of aspirin on trophoblast cell function. Trophoblasts were pretreated with aspirin, and then cell functions and sFlt-1 expression were assessed. Our results showed that aspirin promoted trophoblast invasion not only in HTR-8/SVneo and JAR cells, but also in isolated cytotrophoblasts. sFlt-1 production was repressed by aspirin in a dose-dependent manner. By adding Flt-1 recombinant protein, the trophoblast invasion ability was inhibited in HTR-8/SVneo cells, which was reversed by Flt-1 small interfering ribonucleic acid knockdown. In addition, metalloproteinase 2/9 expression and activity were activated by aspirin but inhibited by sFlt-1. Aspirin also downregulated Akt phosphorylation, and trophoblast invasiveness was facilitated under Akt inhibitor treatment.Aspirin enhances cell invasiveness and inhibits sFlt-1 production in trophoblasts. Moreover, sFlt-1 itself also inhibits trophoblast invasion. Our novel findings suggest that the preeclampsia prevention effect of aspirin may be exerted through these two mechanisms.

Male infertility is observed in approximately 50% of all couples with infertility. Intracytoplasmic sperm injection (ICSI), a conventional artificial reproductive technique for treating male infertility, may fail because of a severe low sperm count, immotile sperm, immature sperm, and sperm with structural defects and DNA damage. Our previous studies have revealed that mutations in the septin (SEPT)-coding gene SEPT12 cause teratozoospermia and severe oligozoospermia. These spermatozoa exhibit morphological defects in the head and tail, premature chromosomal condensation, and nuclear damage. Sperm from Sept12 knockout mice also cause the developmental arrest of preimplantation embryos generated through in vitro fertilization and ICSI. Furthermore, we found that SEPT12 interacts with SPAG4, a spermatid nuclear membrane protein that is also named SUN4. Loss of the Spag4 allele in mice also disrupts the integration nuclear envelope and reveals sperm head defects. However, whether SEPT12 affects SPAG4 during mammalian spermiogenesis remains unclear. We thus conducted this study to explore this question. First, we found that SPAG4 and SEPT12 exhibited similar localizations in the postacrosomal region of elongating spermatids and at the neck of mature sperm through isolated murine male germ cells. Second, SEPT12 expression altered the nuclear membrane localization of SPAG4, as observed through confocal microscopy, in a human testicular cancer cell line. Third, SEPT12 expression also altered the localizations of nuclear membrane proteins: LAMINA/C in the cells. This effect was specifically due to the expression of SEPT12 and not that of SEPT1, SEPT6, SEPT7, or SEPT11. Based on these results, we suggest that SEPT12 is among the moderators of SPAG4/LAMIN complexes and is involved in the morphological formation of sperm during mammalian spermiogenesis.

Aim The purpose of this study was to investigate the effectiveness of empathic caring on sleep quality, depression, stress, and social support in women with recurrent miscarriage. Materials and methods Sixty-two eligible women were randomly assigned to either the experimental group (n = 31), which received three face-to-face nursing counseling sessions, or the control group (n = 31). Outcome measures included the Pittsburgh Sleep Quality Index, Edinburgh Prenatal Depression Scale, Perceived Stress Scale, and Interpersonal Support Evaluation List. Results Paired-sample t-tests revealed that, after receiving nursing counseling, the participants in the experimental group showed significant decreases in stress and depression. However, no significant mean differences were found in the control group between the pretest and the 12-week posttest for any of the four outcome measures. Conclusion Clinical healthcare professionals may incorporate empathic caring into health-promotion protocols to assist women with recurrent miscarriage to improve their psychosocial health.

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an important regulator for embryo implantation and placental development, and is clinically associated with several obstetric disorders related to insufficient or inappropriate trophoblast invasion, such as recurrent abortion, preeclampsia, and intrauterine fetal growth restriction. This study was performed to identify the microRNAs targeting EG-VEGF, and evaluate the regulatory effect on trophoblast biology. miR-346 and miR-582-3p were initially identified via bioinformatic tools, and their specific binding sites on the EG-VEGF 3'UTR were further confirmed using dual luciferase and a co-transfection assays. miR-346 and miR-582-3p were demonstrated not only to suppress EG-VEGF expression, but also inhibit trophoblast invasion and migration in the JAR and HTR-8/SVneo cell lines. We further evaluated the effect of microRNAs in HTR-8/SVneo cells coexpressing EG-VEGF and miR-346 or miR-582-3p on matrix metalloproteinase (MMP 2 and MMP 9) and the tissue inhibitors of metalloproteinase (TIMP 1 and TIMP 2) using RT-PCR, western blotting and gelatin zymography. TIMP 1 and TIMP 2 were not affected by the two microRNAs, whereas the expressions and activities of MMP 2 and MMP 9 were significantly downregulated, which in turn inhibited the invasion ability of trophoblasts. In conclusion, miR-346 and miR-582-3p regulate EG-VEGF-induced trophoblast invasion through repressing MMP 2 and MMP 9, and may become novel diagnostic biomarkers or therapeutic targets for EG-VEGF-related obstetric disorders. © 2016 BioFactors, 43(2):210-219, 2017.

Hyaluronan-coated surfaces preserve the proliferation and differentiation potential of mesenchymal stem cells by prolonging their G1-phase transit, which maintains cells in a slow-proliferative mode. Mitochondria are known to play a crucial role in stem cell self-renewal and differentiation. In this study, for the first time, the metabolic mechanism underlying the hyaluronan-regulated slow-proliferative maintenance of stem cells was investigated by evaluating mitochondrial functions. Human placenta-derived mesenchymal stem cells (PDMSCs) cultured on hyaluronan-coated surfaces at 0.5, 3.0, 5.0, and 30 µg/cm2 were found to have an average 58% higher mitochondrial mass and an increase in mitochondrial DNA copy number compared to noncoated tissue culture surfaces (control), as well as a threefold increase in the gene expression of the mitochondrial biogenesis-related gene PGC-1α. Increase in mitochondrial biogenesis led to a hyaluronan dose-dependent increase in mitochondrial membrane potential, ATP content, and oxygen consumption rate, with reactive oxygen species levels shown to be at least three times lower compared to the control. Although hyaluronan seemed to favor mitochondrial function, cell entry into a hyaluronan-regulated slow-proliferative mode led to a fivefold reduction in ATP production and coupling efficiency levels. Together, these results suggest that hyaluronan-coated surfaces influence the metabolic proliferative state of stem cells by upregulating mitochondrial biogenesis and function with controlled ATP production. This more efficiently meets the energy requirements of slow-proliferating PDMSCs. A clear understanding of the metabolic mechanism induced by hyaluronan in stem cells will allow future applications that may overcome the current limitations faced in stem cell culture.

Aim Recurrent miscarriage is considered a major life event. The main purposes of this study were to compare the differences in stress, anxiety, social support, sleep quality and depressive symptoms in couples experiencing recurrent miscarriage compared to peers who experience full-term normal childbirth in southern Taiwan. Methods Convenience sampling and snowball sampling were used respectively to recruit 78 couples with and 80 couples without recurrent miscarriage from October 2014 to July 2015. Five structured questionnaires including Perceived Stress Scale, State- Anxiety Inventory, Interpersonal Support Evaluation List, Pittsburgh Sleep Quality Index and Edinburgh Depression Scale were administered. Results Women who experienced recurrent miscarriage perceived significantly higher levels of stress, anxiety and depressive symptoms than their husbands. Women in the recurrent miscarriage group reported significantly greater depressive symptoms than women of the other group. A stepwise multiple regression analysis indicated key predictors of depressive symptoms among women of childbearing age, accounting for 62.9% of the variance, were anxiety, stress, social support and history of recurrent miscarriage. Conclusion Women with recurrent miscarriage suffer mild to moderate depressive symptoms and a greater incidence of depression than their peers who experienced normal childbirth. Health professionals can use the knowledge gained from these findings to evaluate women with recurrent miscarriage for stress, anxiety and depressive symptoms and develop supportive interventions.

The sperm annulus, a septin-based ring structure, is important for reproductive physiology. It is composed of SEPT12-based septin core complex followed by assembling as octameric filament. In clinical examinations, mutations of Septin12 result in male infertility, immotile sperm, as well as sperm with defective annuli. The dynamic assembly of septin filaments is regulated by several post-translational modifications, including sumoylation, acetylation, and phosphorylation. Here, we briefly review the biological significance and the regulation of SEPT12 phosphorylation in the mammalian sperm physiology. During mammalian spermiogenesis, the phosphorylation of SEPT12 on Ser198 residue is important in regulating mammalian annulus architectures. SEPT12 phosphomimetic knock-in mice displayed poor male fertility due to weak sperm motility and loss of the sperm annulus. SEPT12 is phosphorylated via Protein kinase A (PKA), and its phosphorylation interfered with SEPT12 polymerization into complexes and filaments. Taken together, the phosphorylation status of SEPT12 is crucial for its function in regulating the mammalian sperm physiology.

An increasing number of studies have revealed that phthalate exposure alters thyroid hormone homeostasis in the general population, but there is insufficient evidence of the effect of longitudinal maternal phthalate exposure on maternal and fetal thyroid hormones during pregnancy. We longitudinally assessed the effect of prenatal phthalate exposure in pregnant women on umbilical cord and maternal thyroid hormones at three trimesters during pregnancy. We recruited 98 pregnant women and collected urine and blood samples at three trimesters in an obstetrics clinic in Southern Taiwan from 2013 to 2014. We analyzed the concentrations of 11 urinary phthalate metabolites, including monoethylhexyl phthalate, mono-(2-ethyl-5-oxo-hexyl) phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-n-butyl phthalate, monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), using online liquid chromatography-tandem mass spectrometry. The cord and maternal serum levels of thyroxine (T4), free T4, triiodothyronine (T3), thyroid-stimulating hormone (TSH), and thyroxine-binding globulin were measured using an electrochemiluminescence immunoassay. A mixed-model analysis was utilized to assess the effect of longitudinal phthalate exposure on thyroid hormones and adjusted for significant covariates. We found that urinary MiBP (β=-0.065, 95% confidence interval (CI): -0.124, -0.005), and MEOHP (β=-0.083, 95% CI: -0.157, -0.009) were significantly negatively associated with serum TSH. Urinary MECPP was inversely related to serum T3 (β=-0.027, 95% CI: -0.047, -0.006). Urinary MEP (β=0.014, 95% CI: -0.001, 0.028) and MiBP (β=0.033, 95% CI: 0.018, 0.049) were positively related to free T4. We found that cord serum T3 (β=0.067, 95% CI: 0.003, 0.131) and free T4 (β=0.031, 95% CI: 0.001, 0.062) levels had significant positive associations with maternal ΣDBPm levels at the second trimester. We concluded that different phthalates exposure windows during gestation may alter cord and serum thyroid hormone homoeostasis.

Background Nucleotide-binding oligomerization domain (NACHT), leucine rich repeat (LRR) and pyrin domain (PYD) 7 containing protein, NLRP7, is a member of the NLR family which serves as innate immune sensors. Mutations and genetic variants of NLRP7 have been found in women with infertility associated conditions, such as recurrent hydatidiform mole, recurrent miscarriage, and preeclampsia. Decidualization of endometrial stromal cells is a hallmark of tissue remodeling to support embryo implantation and proper placental development. Given defective decidualization has been implicated in miscarriage as well as preeclampsia, we aimed to explore the link between the NLRP7 gene and decidualization. Methods Endometrial samples obtained from pregnant women in the first trimester and non-pregnant women were used to study NLRP7 expression pattern. The human telomerase reverse transcriptase (hTERT)-immortalized human endometrial stromal cells (T-HESCs) were used to study the effect of NLRP7 on decidualization. Decidualization of T-HESCs was induced with 1 μM medroxyprogesterone acetate (MPA) and 0.5 mM 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cAMP). siRNA was used to knock down NLRP7 while lentiviral vectors were used to overexpress NLRP7 in cells. NLRP7 expression was detected by immunofluorescence, qRT-PCR, and Western blotting. Decidualization markers, Insulin-like growth factor-binding protein 1 (IGFBP-1) and prolactin (PRL), were detected by qRT-PCR and ELISA. Nuclear translocation of NLRP7 was detected by the subcellular fractionation and confocal microscopy. The effect of NLRP7 on progesterone receptor (PR) activity was evaluated by a reporter system. Results NLRP7 was up-regulated in the decidual stromal cells of human first-trimester endometrium. After in vitro decidualization, T-HESCs presented with the swollen phenotype and increased expressions of IGFBP-1 and PRL. Knockdown or over-expression of NLRP7 reduced or enhanced the decidualization, respectively, according to the expression level of IGFBP-1. NLRP7 was found to translocate in the nucleus of decidualized T-HESCs and able to promote PR activity. Conclusions NLRP7 was upregulated and translocated to the nucleus of the endometrial stromal cells in an in vitro decidualization model. Overexpressed NLRP7 promoted the IGFBP-1 expression and PR reporter activation. IGFBP-1 expression decreased with the knockdown of NLRP7. Therefore, we suggest that NLRP7 contributes to in vitro decidualization of endometrial stromal cells.

Leucine-rich repeats and WD repeat domain containing protein 1 (LRWD1) is a testis-specific protein that mainly expressed in the sperm neck where centrosome is located. By using microarray analysis, LRWD1 is identified as a putative gene that involved in spermatogenesis. However, its role in human male germ cell development has not been extensively studied. When checking in the semen of patients with asthenozoospermia, teratozoospermia, and asthenoteratozoospermia, the level of LRWD1 in the sperm neck was significantly reduced with a defective neck or tail. When checking the sub-cellular localization of LRWD1 in the cells, we found that LRWD1 resided in the centrosome and its centrosomal residency was independent of microtubule transportation in NT2/D1, the human testicular embryonic carcinoma, cell line. Depletion of LRWD1 did not induce centrosome re-duplication but inhibited microtubule nucleation. In addition, the G1 arrest were observed in LRWD1 deficient NT2/D1 cells. Upon LRWD1 depletion, the levels of cyclin E, A, and phosphorylated CDK2, were reduced. Overexpression of LRWD1 promoted cell proliferation in NT2/D1, HeLa, and 239T cell lines. In addition, we also observed that autophagy was activated in LRWD1 deficient cells and inhibition of autophagy by chloroquine or bafilomycin A1 promoted cell death when LRWD1 was depleted. Thus, we found a novel function of LRWD1 in controlling microtubule nucleation and cell cycle progression in the human testicular embryonic carcinoma cells. J. Cell. Biochem. 119: 314-326, 2018. © 2017 Wiley Periodicals, Inc.

Purpose LRWD1 is a protein that contains LRR and WDs domains and is important in regulating spermatogenesis. However, the roles of LRR or WDs domains in the expression of LRWD1 remain unclear. Materials and methods The NT2/D1 cells separately transfected with full length of LRWD1 gene ( LRWD WT ) or genes with deleted sequences in the LRR domain ( LRWD1 ΔLRR ), WD1 domain ( LRWD1 ΔWD1 ), WD2 domain ( LRWD1 ΔWD2 ), WD3 domain ( LRWD1 ΔWD3 ) and entire three WD domains ( LRWD1 Δ3×WD ) were applied to investigate the expression levels of LRWD1 protein by either Western blot or flow cytometry. The associated proteins in these mutated LRWD1 proteins were identified by mass spectrometry. Results Deletion of the LRR domain significantly decreased the expression of LRWD1 protein. With the treatment of MG132, the LRR domain may functions in preventing LRWD1 protein from proteasome-mediated degradation. In the co-immunoprecipitation analysis, protein receptor of tumor necrosis factor 2 (TNFR2) was specifically observed to be associated with LRR-deficient LRWD1 protein. Conclusions The LRR domain is significantly correlated to the stability of LRWD1 protein. Determining if the stability is modulated by TNFR2 is worthy of further study.

Both vascular endothelial growth factor A (VEGFA) and endocrine gland-derived vascular endothelial growth factor (EG-VEGF) systems play major roles in angiogenesis. A body of evidence suggests VEGFs regulate critical processes during pregnancy and have been associated with recurrent pregnancy loss (RPL). However, little information is available regarding the interaction of these two major major angiogenesis-related systems in early human pregnancy. This study was conducted to investigate the association of gene polymorphisms and gene-gene interaction among genes in VEGFA and EG-VEGF systems and idiopathic RPL. A total of 98 women with history of idiopathic RPL and 142 controls were included, and 5 functional SNPs selected from VEGFA, KDR, EG-VEGF (PROK1), PROKR1 and PROKR2 were genotyped. We used multifactor dimensionality reduction (MDR) analysis to choose a best model and evaluate gene-gene interactions. Ingenuity pathways analysis (IPA) was introduced to explore possible complex interactions. Two receptor gene polymorphisms [KDR (Q472H) and PROKR2 (V331M)] were significantly associated with idiopathic RPL (P

Chromosome anomalies/rearrangements of the Y chromosome seldom threaten life and are quite common. The 4.5 Mb AZFc region on Yq11.2 is one of the most polymorphic regions in the human genome. AZFc partial deletion is almost inevitably associated with impaired fertility while the functional significance of AZFc partial duplications remains controversial. In this report, a large Y chromosome with one centromere and two heterochromatic blocks was identified incidentally in two men. The first case was ascertained through surveillance for recurrent miscarriage. The second case was ascertained through amniocytes of a fetus and his father. FISH and array-based comparative genomic hybridization showed duplications of the entire AZFc region as well as Yq euchromatic region. The duplications in Case 1 and Case 2 spanned 4.8 Mb and 6.2 Mb, respectively, of the Yq euchromatic region. These two cases suggest that complete AZFc duplication could be completely benign. It awaits further investigation whether this is a bona fide chromosomal polymorphism.

Objective To establish a multilocus model for studying the effect of steroid-related genes on advanced stage endometriosis. Materials and methods A total of 121 patients with advanced stage endometriosis and 171 control women were included. Eighteen single-nucleotide polymorphisms (SNPs) from nine genes ( HSD17B1 , HSD17B2 , HSD17B5 , HSD17B6 , CYP17 , CYP19 , ER α, ER β, and PGR ) were genotyped using the TaqMan assays. Logistic regression models were used to evaluate the genetic effects, with adjustment for other covariates. Results Only the presence of the mutant CYP19 (aromatase gene) was associated with a significantly increased risk of endometriosis after adjusting for age, BMI, and parity ( p = 0.002, OR = 2.69; 95% CI = 1.44–5.02). No association was ascertained between the other investigated SNPs and endometriosis. Conclusion Polymorphisms of the aromatase gene confer susceptibility to advanced stage endometriosis in the Taiwanese Han population.

The septin gene belongs to a highly conserved family of polymerizing GTP-binding cytoskeletal proteins. SEPTs perform cytoskeletal remodeling, cell polarity, mitosis, and vesicle trafficking by interacting with various cytoskeletons. Our previous studies have indicated that SEPTIN12+/+/+/− chimeras with a SEPTIN12 mutant allele were infertile. Spermatozoa from the vas deferens of chimeric mice indicated an abnormal sperm morphology, decreased sperm count, and immotile sperm. Mutations and genetic variants of SEPTIN12 in infertility cases also caused oligozoospermia and teratozoospermia. We suggest that a loss of SEPT12 affects the biological function of microtublin functions and causes spermiogenesis defects. In the cell model, SEPT12 interacts with α- and β-tubulins by co-immunoprecipitation (co-IP). To determine the precise localization and interactions between SEPT12 and α- and β-tubulins in vivo, we created SEPTIN12-transgene mice. We demonstrate how SEPT12 interacts and co-localizes with α- and β-tubulins during spermiogenesis in these mice. By using shRNA, the loss of SEPT12 transcripts disrupts α- and β-tubulin organization. In addition, losing or decreasing SEPT12 disturbs the morphogenesis of sperm heads and the elongation of sperm tails, the steps of which are coordinated and constructed by α- and β-tubulins, in SEPTIN12+/+/+/− chimeras. In this study, we discovered that the SEPTIN12-microtubule complexes are critical for sperm formation during spermiogenesis.

The dicentric Y chromosomes are the most commonly found in the structural aberration of Y chromosome. If the dicentric chromosome has completely symmetric arms, it is considered an isodicentric chromosome. The sites of breakage and fusion at Yp and Yq are variable, but breakage and fusion at the pseudo-autosomal region has never been reported. Herein we reported identification de novo isodicentric (Yq12) in a fetus. The fusion occurred at Yq pseudo-autosomal region very close the telomere and resulted in duplication of Y chromosome. The baby was grossly normal at birth. In conclusion, isodicentric Y chromosome could result from breakage and fusion at the Yq pseudo-autosomal region.

Non-mosaic trisomy 16 is rarely seen in later gestation. Herein, we report a fetus with uniparental complete trisomy 16 manifesting with asplenia syndrome, left hand deformity (only 3 deformed fingers on the left hand) and a left low-set ear. The pregnancy ended in severe placental abruption and resultant fetal demise, and maternal hypovolemic shock at 35 weeks of gestation. Only 3 non-mosaic trisomy 16 fetuses, including this case, have been reported to survive into the second or third trimester. Furthermore, this fetus would be the first case of complete trisomy 16 manifesting as asplenia syndrome.

Study question Do gene polymorphisms of two members of the human innate immune sensor nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing proteins (NLRP) family, NLRP2 and NLRP7, confer susceptibility to idiopathic recurrent miscarriage (RM)? Summary answer We found a significant association of a tag single-nucleotide polymorphism (SNP) of NLRP7 (rs26949) with idiopathic RM, while a tag SNP of NLRP2 (rs127868) showed a marginally significant association. What is known already Human NLRP2 and NLRP7 have been suggested to be maternal effect genes, regulating early embryonic development and establishment of maternal imprints. Anecdotal evidence showed women who had experienced at least three consecutive miscarriages without hydatidiform mole carried non-synonymous NLRP7 variants. Whether these two genes are associated with idiopathic RM remains obscure. Study design, size and duration In this case-controlled study, 143 women who had experienced at least two consecutive spontaneous miscarriages (n = 91 women with two miscarriages, n = 52 with three or more) and 149 controls were included between 2004 and 2010. Materials, setting, methods A total of five tag SNPs of NLRP2 and eight tag SNPs of NLRP7 were genotyped using the primer extension analysis. The deviation from the Hardy-Weinberg equilibrium was checked using χ(2) analysis. The logistic odds ratios (ORs) of RM were estimated with a 95% confidence interval (CI) in multivariate analysis after maternal age adjustment. The false discovery rate (FDR) was used to adjust for multiple testing. Tests for haplotype association with RM were performed. Gene-gene interactions among loci of the two genes were evaluated by using the multifactor dimensionality reduction (MDR) method. Main results and the role of chance One tag SNP rs269949 of NLRP7 showed significant difference between patients and controls in a recessive model (FDR P = 0.0456, age-adjusted OR (AOR) = 16.49, 95% CI = 2.00-136.11 for the GG genotype). The difference was significant in patients with two consecutive miscarriages and also in those with three or more consecutive miscarriages. Meanwhile, one tag SNP of NLRP2 (rs12768) showed marginal significance between patients and controls in a co-dominant model (FDR P = 0.0505, AOR = 2.15, 95% CI = 1.29-3.58 for the AC genotype). In the haplotype analysis, NLRP2 and NLRP7 did not show any significant difference between the patients and controls. MDR test revealed that there is no significant gene-gene interaction among loci of NLRP2 and NLRP7. Limitations, reasons for caution The results may be biased by heterogeneous ethnicities of the Taiwanese Han and a small sample size. The genetic loci responsible for the disease as well as their functional significance also await further investigation. Wider implications of the findings Our study suggests the role of the NLRP family proteins in RM. Study funding/competing interest(s) This study was supported by grants from the National Science Council of the Republic of China (NSC-100-2314-B-006-011-MY3). None of the authors have any conflicts of interest.

SummaryA fine balance between coagulation and fibrinolysis is critical in early pregnancy. Plasminogen activator inhibitor-1 (PAI-1) and angiotensin converting enzyme (ACE) are involved in the fibrinolytic process, and several studies have reported the association between their gene polymorphisms and recurrent pregnancy loss (RPL). This study was conducted to investigate the association between PAI-1 and ACE polymorphisms and idiopathic RPL, using meta-analyses. A systematic review of the published literature from the MEDLINE and EMBASE databases before April 2012 was conducted. Of 209 potentially relevant studies, 22 case-control studies comprising a total of 2,820 RPL patients and 3,009 controls were included. Among these studies were 11 reports of PAI-1 4G/5G and 11 of ACE I/D polymorphisms in patients with RPL. A significant association was found withthe ACE I/D polymorphism [summary odds ratio 1.29 (95% confidence interval 1.02–1.62)] in studies including more than two recurrent abortions. Subgroup analysis did not show significant associations with RPL in Caucasian and non-Caucasian patients. Meta-analyses of PAI-1 4G/5G polymorphism were not found associations with RPL in studies including more than two or three recurrent abortions, and in studies of Caucasian and non-Caucasian patients. In conclusion, meta-analyses showed a significant association between the ACE I/D polymorphism and idiopathic RPL. High clinical heterogeneity existed among studies of PAI-1 4G/5G, and the aggregated data failed to confer higher susceptibility to idiopathic RPL. More well-designed studies with different ethnic populations are required for future integration.