Abstract Objective To analyze the performance of the first trimester Down syndrome screening in a single medical center in Northern Taiwan. Materials and methods From April 1999 to June 2012, a total ...of 25,104 pregnant women at gestational age of 10 weeks to 13 weeks 6 days received first trimester “combined test” for Down syndrome screening. The test combines the ultrasound scan of nuchal translucency thickness and maternal biochemical serum levels of pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (β-hCG). A positive screen was defined as an estimated Down syndrome risk ≥1/270, and either chorionic villous sampling or amniocentesis was performed for fetal chromosomal analyses. Results Seventy-eight of the 25,104 pregnancies were proven to have fetal chromosome anomalies. The detection rates for trisomy 21, trisomy 18, Turner syndrome, and other chromosome anomalies were 87.5% (21/24), 69.2% (9/13), 81.8% (9/11), and 60% (18/30), respectively, with a false positive rate (FPR) of 5.4% (1353/25,026). Further evaluation of the detection rates for trisomy 21, by gestational age at 11, 12, and 13 weeks, were 92.3%, 87.5%, and 66.7%, respectively. Conclusion The first trimester combined test is an effective screening tool for Down syndrome detection with an acceptable low false positive rate. The best timing of screening will be between 11 and 12 weeks' gestation.
Summary
Objectives Outcome of the first‐trimester Down syndrome screening in younger population was less reported before. We present the outcome of this screening in Taiwanese women younger than 35 ...years old. We also test whether or not the first‐trimester Down syndrome screening of women <35 years of age and women >35 years old routinely receiving amniocentesis is cost‐effective compared with all pregnant women screened with this test in the setting of increased maternal age.
Methods From 1999 to 2007, the first‐trimester Down syndrome screening including nuchal thickness, pregnancy‐associated plasma protein A and free β‐hCG are provided to 10 811 singleton women <35 years of age with the cut‐off of 1/270. A cost‐effectiveness analysis of young women receiving this screening and older women undergo amniocentesis versus all women undergo this screening was performed in Taiwan population from 1987 to 2006, in which advanced age pregnancies increased from 2.8% to 11.6% of total pregnancies.
Results Detection rates of trisomy 21, trisomy 18, Turner syndrome and other chromosome anormalies in women <35 years of age are 87.5% (14/16), 50% (2/4), 80% (8/10) and 63% (12/19), respectively, with a false‐positive rate of 5.5% (590/10 811). As advanced age pregnancies reached 11.6%, the average cost per one case averted for all women screened ranged from $77 204 to $98 421, while the cost ranged from $99 647 to $116 433 for only women <35 years of age receiving this screening.
Conclusions In an aging population, the first‐trimester Down syndrome screening should be implemented for all pregnant women when it is available.
Human chorionic gonadotropin (hCG) is composed of a common α subunit and a placenta-specific β subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated ...syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cyclic AMP (cAMP). Although the ubiquitous activating protein 2 (AP2) transcription factors TFAP2A and TFAP2C may regulate hCGβ expression, it remains unclear how cAMP stimulates placenta-specific hCGβ gene expression and trophoblastic differentiation. Here we demonstrated that the placental transcription factor glial cells missing 1 (GCM1) binds to a highly conserved promoter region in all six hCGβ paralogues by chromatin immunoprecipitation-on-chip (ChIP-chip) analyses. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate the hCGβ promoter through a GCM1-binding site (GBS1), which also constitutes a previously identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between the hCGβ promoter and GCM1 but not TFAP2C. Indeed, the hCG-cAMP-protein kinase A (PKA) signaling pathway also stimulates Ser269 and Ser275 phosphorylation of GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the fusogenic protein syncytin-1, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCGβ expression and cell differentiation.
Preeclampsia is a major pregnancy-specific disorder affecting 5-7% of pregnancies worldwide. Although hypoxia caused by incomplete trophoblast invasion and impaired spiral arterial remodeling is ...thought to be a major cause of preeclampsia, how hypoxia affects placental development remains uncertain. GCM1 (glial cells missing homolog 1) is a transcription factor critical for placental development. In preeclampsia, GCM1 and its target genes syncytin 1 and placental growth factor, important for syncytiotrophoblast formation and placental vasculogenesis, are all decreased. Here we present evidence that GCM1 is a major target of hypoxia associated with preeclampsia. We show that hypoxia triggers GCM1 degradation by suppressing the phosphatidylinositol 3-kinase-Akt signaling pathway, leading to GSK-3β activation. Activated GSK-3β phosphorylates GCM1 on Ser³²², which in turn recruits the F-box protein FBW2, leading to GCM1 ubiquitination and degradation. Importantly, the GSK-3β inhibitor LiCl prevented hypoxia-induced GCM1 degradation. Our study identifies a molecular basis for the disrupted GCM1 transcription network in preeclampsia and provides a potential avenue for therapeutic intervention.
The placental transcription factor glial cell missing 1 (GCM1) and its target gene syncytin-1 are involved in cAMP-stimulated trophoblastic fusion for syncytiotrophoblast formation. GCM1 DNA-binding ...activity is inhibited by sumoylation, whereas GCM1 stability is decreased by deacetylation. cAMP enhances GCM1 desumoylation through the Epac1/Rap1/CaMKI signaling cascade and CaMKI is known to down-regulate class IIa HDAC activity. In this paper, we study whether the Epac1/Rap1/CaMKI signaling cascade regulates GCM1 activity and placental cell fusion through class IIa HDACs. Interaction and co-localization of GCM1 and HDAC5 were characterized by co-immunoprecipitation analysis and immunofluorescence microscopy (IFM). Regulation of GCM1 transcription activity and syncytin-1 expression by HDAC5 was studied by transient expression. Phospho-specific antibodies against HDAC5, RNA interference and IFM were used to examine the de-repression of GCM1 activity, syncytin-1 expression and cell-cell fusion by Epac1/Rap1/CaMKI signaling cascade in placental BeWo cells expressing constitutively active Epac1 and CaMKI. We demonstrate that both GCM1 and HDAC5 are expressed in the syncytiotrophoblast layer of full-term placenta and the nuclei of BeWo cells. The interaction between HDAC5 and GCM1 facilitates GCM1 deacetylation and suppresses its transcriptional activity. In contrast, Epac1 stimulates HDAC5 phosphorylation on Ser259 and Ser498 in a Rap1- and CaMKI-dependent manner leading to nuclear export of HDAC5 and thereby de-repression of GCM1 transcriptional activity. Importantly, HDAC5 suppresses syncytin-1 expression and cell-cell fusion in BeWo cells, which is counteracted by Epac1 and CaMKI. Our results reveal a new layer of regulation of GCM1 activity and placental cell fusion through the Epac1/Rap1/CaMKI signaling cascade by restraining HDAC5 from interacting with and mediating GCM1 deacetylation.
To evaluate the ability of a tumor-head volume ratio to predict outcome and incidence of hydrops in fetuses with sacrococcygeal teratoma.
Seventy-one sonograms were reviewed retrospectively from 28 ...fetuses with sacrococcygeal teratoma managed in our institution. Head volume (HV) and total tumor volume were calculated from sonograms. Amount of cystic tumor was estimated to determine solid tumor volume (STV) for the STV/HV ratio.
Twenty percent of sonograms with STV/HV <1 and 97.3% with STV/HV >1 were associated with 1 or more abnormal sonographic signs (p = 0.000). Overall mortality was 11/27 (41%). There was no mortality in fetuses with a ratio of <1, while 11/18 (61%) of fetuses with ratio >1 died (p = 0.003).
The STV/HV ratio may be used to identify fetuses with a high risk of a poor outcome due to high-output cardiac failure and hydrops, and may help guide management.
Chromosome 22q11 deletion syndrome (22q11DS) causes a developmental disorder during the embryonic stage, usually because of hemizygous deletions. The clinical pictures of patients with 22q11DS vary ...because of polymorphisms: on average, approximately 93% of affected individuals have a de novo deletion of 22q11, and the rest have inherited the same deletion from a parent. Methods using multiple genetic markers are thus important for the accurate detection of these microdeletions.
We studied 12 babies suspected to carry 22q11DS and 18 age-matched healthy controls from unrelated Taiwanese families. We determined genomic variance using microarray-based comparative genomic hybridization (array-CGH), quantitative real-time polymerase chain reaction (qPCR) and multiplex ligation-dependent probe amplification (MLPA).
Changes in genomic copy number were significantly associated with clinical manifestations for the classical criteria of 22q11DS using MPLA and qPCR (p < 0.01). An identical deletion was shown in three affected infants by MLPA. These reduced DNA dosages were also obtained partially using array-CGH and confirmed by qPCR but with some differences in deletion size.
Both MLPA and qPCR could produce a clearly defined range of deleted genomic DNA, whereas there must be a deleted genome that is not distinguishable using MLPA. These data demonstrate that such multiple genetic approaches are necessary for the unambiguous molecular detection of these types of complicated genomic syndromes.
The aim of this study was to develop a cell-based bone-regeneration approach evaluated by molecular imaging and immunohistochemistry.
Genetically modified NIH3T3 embryonic fibroblasts carrying ...enhanced green fluorescent protein (NIH3T3-G) were predifferentiated into osteoblastlike cells using platelet-rich plasma (PRP) medium, followed by intraosseous transplantation into ovariectomized senescence-accelerated mouse prone substrain 8 (OVX-SAMP8 mice).
PRP-conditioned NIH3T3-G (PRP/NIH3T3-G) engraftment prevented the development of osteoporosis. Molecular imaging and immunohistochemistry demonstrated the migration of NIH3T3-G cells from the implantation site throughout the skeleton. In situ analyses revealed coexpression of osteopontin and green fluorescent protein in the newly formed bone tissue, demonstrating that the transplant restored the bone trabecular architecture and mineral density in treated OVX-SAMP8 mice. Interestingly, the life span of OVX-SAMP8 mice receiving PRP/NIH3T3-G transplantation was significantly prolonged and similar to that of the congenic senescence-resistant strain of mice.
This unique and yet simple approach could potentially be applied to the treatment of senile postmenopausal osteoporosis and perhaps inborn genetic syndromes associated with accelerated aging, such as Hutchinson-Gilford progeria syndrome, and for the prolongation of life expectancy in general.
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