[Genetic analysis of a family of Van der Woude syndrome].

OBJECTIVE: To analyze clinical and genetic features of a family affected with Van der Woude syndrome. METHODS: The umbilical cord blood of the proband and the peripheral blood of the parents were used for the whole exon sequencing to find the candidate gene.Peripheral blood of 9 members of the family were collected for Sanger sequencing verification, bioinformatics analysis and genotype-phenotype correlation analysis. RESULTS: The proband was diagnosed with cleft lip and palate by ultrasound. His father and grandmother had hollow lower lip and all other family members did not have the similar phenotype. A missense c.263A>G (p.N88S) mutation was found in exon 4 of IRF6 gene in the proband, his father and his grandmother.The mutation was not found in other family members. CONCLUSIONS: A missense c.263A>G (p.N88S) mutation in IRF6 gene probably underlies the pathogenesis of Van der Woude syndrome in the family and the mutation has been firstly discovered in China.

Alternative splicing of the androgen receptor in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders and a leading cause of female subfertility. The mechanism underlying the pathophysiology of PCOS remains to be illustrated. Here, we identify two alternative splice variants (ASVs) of the androgen receptor (AR), insertion and deletion isoforms, in granulosa cells (GCs) in ∼62% of patients with PCOS. AR ASVs are strongly associated with remarkable hyperandrogenism and abnormalities in folliculogenesis, and are absent from all control subjects without PCOS. Alternative splicing dramatically alters genome-wide AR recruitment and androgen-induced expression of genes related to androgen metabolism and folliculogenesis in human GCs. These findings establish alternative splicing of AR in GCs as the major pathogenic mechanism for hyperandrogenism and abnormal folliculogenesis in PCOS.

Highly elevated serum CA-125 levels in patients with non-malignant gynecological diseases.

PURPOSES: To identify patients with highly elevated serum CA-125 levels and analyze their clinical characteristics. METHODS: Patients with non-malignant gynecologic disease (NMGDs, n = 41), in whom serum CA-125 levels were over 1,000 IU/ml were retrospectively enrolled in the study. Seventy-one patients with epithelial ovarian cancer (EOC), in whom, serum CA-125 levels were over 1,000 IU/ml were included as the comparison group. Clinical parameters were compared between the two groups. RESULTS: In NMGDs group, 43.90% of the patients had endometriosis. The median of serum CA-125 level in NMGDs was much lower than that of EOC subjects (P < 0.001). Compared to EOC group, the patients in NMGDs group were much younger (P < 0.001) and had fewer histories of pelvic masses (P < 0.001) but had more clinical complaints such as acute abdominal symptoms (P < 0.001) and/or abnormal vaginal bleeding (P = 0.022). Clinical progresses of these two groups were correlated with changes of serum CA-125 levels by follow-up for up to 386 days. CONCLUSIONS: High levels of serum CA-125 were found not only in the EOC, but also in some NMGDs, especially in the reproductive patients with complaints of acute abdomen symptoms or abnormal vaginal bleeding.

Comparison of reproducibility of manual and sphere contour methods for the measurement of vascularization in cervical carcinoma using the virtual organ computer-aided analysis II system.

OBJECTIVE: The purpose of this study was to investigate the reproducibility of virtual organ computer-aided analysis II software (GE Healthcare, Milwaukee, WI), an integrated tool for 3-dimensional power Doppler angiography (3D-PDA), in measuring vascularization of cervical carcinoma under manual and automatic sphere contour modes. METHODS: Eighty patients with cervical carcinoma were prospectively examined by observer 1 using transvaginal 3D-PDA. For each patient, measurements of the vascularization index, flow index, and vascularization-flow index were repeated twice under both manual and automatic sphere contour modes. Forty patients were randomly selected for another round of examination by observer 2 under the same setting. The reproducibility of vascularization measurements was assessed by the intraclass correlation coefficient (intra-CC), interclass correlation coefficient (inter-CC), and 95% limits of agreement (LOAs). Various analysis of variance models were used to estimate the contribution of each factor (observer, contour mode, and patient) to measurement variance. RESULTS: For each observer, the manual contour mode outperformed the automatic sphere contour mode in reproducibility (intra-CC, 0.96 to 0.99 versus 0.77 to 0.94). In addition, repeated measurements of the manual mode had a smaller SD and a narrower LOA. For the manual contour mode, interobserver agreement was comparable with intraobserver agreement (inter-CC, 0.91 to 0.98, versus intra-CC, 0.96 to 0.99). However, the interobserver agreement was significantly smaller than the intraobserver agreement for the automatic sphere contour mode (inter-CC, 0.51 to 0.85, versus intra-CC, 0.77 to 0.94; P = .001). CONCLUSIONS: The manual contour mode for 3D-PDA vascular measurements has better interobserver and intraobserver reproducibility than the automatic sphere contour mode. It is especially useful for measuring tumor tissues with irregular shapes and vascularity.

Intratumoral blood flow analysis in epithelioid trophoblastic tumors.

OBJECTIVE: The purpose of this series was to describe the transvaginal color pulsed Doppler sonographic features of epithelioid trophoblastic tumors (ETTs) and to evaluate whether there were specific sonographic criteria to accurately distinguish them from other lesions. METHODS: Seven cases of ETTs treated in the Women's Hospital of Zhejiang University were retrospectively analyzed. Doppler indices, including the Pourcelot resistive index (RI), pulsatility index (PI), and peak systolic to diastolic velocity (S/D) ratio from blood flow signals within the tumors were calculated from each waveform sample by using the software of the ultrasound machines. RESULTS: Patients with ETTs had heterogeneously echoic masses and highly abnormal flow patterns. The mean PI, RI, and S/D ratio for the patients were 0.57 (range, 0.22-1.09), 0.42 (range, 0.2-0.7), and 1.89 (range, 1.25-3.40), respectively. CONCLUSIONS: The clinical usefulness of intratumoral blood flow assessment in ETTs is yet to be established. However, the multiparameter sonographic approach can help in diagnosis of an ETT.

Heterochronic bilateral ectopic pregnancy after ovulation induction.

Ectopic pregnancy is identified with the widely-applied assisted reproductive technology (ART). Bilateral ectopic pregnancy is a rare form of ectopic pregnancy which is difficult to be diagnosed at the pre-operation stage. In this paper, we presented an unusual case of heterochronic bilateral ectopic pregnancy after stimulated intrauterine insemination (IUI), where there has been a delay of 22 d between the diagnoses of the two ectopic pregnancies. Literature was reviewed on the occurrence of bilateral ectopic pregnancy during the past four years in the MEDLINE database. We found 16 cases of bilateral ectopic pregnancy reported since 2008, and analyzed the characteristics of those cases of bilateral ectopic pregnancy. We emphasize that ovulation induction and other ARTs may increase the risk of bilateral ectopic pregnancy. Because of the difficulty in identification of bilateral ectopic pregnancy by ultrasonography, the clinician should be aware that the treatment of one ectopic pregnancy does not preclude the occurrence of a second ectopic pregnancy in the same patient and should pay attention to the intra-operation inspection of both side fallopian tubes in any ectopic pregnancy case.

Cardiovascular dysfunction in offspring of ovarian-hyperstimulated women and effects of estradiol and progesterone: a retrospective cohort study and proteomics analysis.

CONTEXT: The cardiovascular dysfunction in children born with assisted reproductive technologies has been of great concern. However, the association of ovarian hyperstimulation syndrome (OHSS), a complication of assisted reproductive technologies, with worse cardiovascular functions and underlying mechanism remains unknown. OBJECTIVES: The objective of the study was to assess the cardiovascular functions of children born to mothers with OHSS and investigate the underlying regulator(s). DESIGN AND SETTING: This was a retrospective cohort recruited in a university hospital. PARTICIPANTS AND METHODS: We assessed the cardiovascular functions by Doppler echography in 42 children born to OHSS women, 34 children of mothers with non-OHSS in vitro fertilization, and 48 spontaneously conceived (SC) children (mean age ∼ 4.5 y). Groups were matched for gestational age at delivery and birth weight. An isobaric tag for relative and absolute quantitation-labeled proteomics analysis was performed with another set of umbilical arteries from OHSS and SC pregnancies (n = 3 for both groups). RESULTS: Children of OHSS mothers showed a significantly decreased mitral ratio of early to late mitral peak velocities, reduced systolic and diastolic diameters of common carotid arteries, and impaired flow-mediated dilation compared with non-OHSS in vitro fertilization and SC children. Intima-media thickness and arterial stiffness indices were similar in the three groups. In the proteomics study, 1640 proteins were identified from OHSS and SC umbilical arteries, and 40 differentially expressed proteins were selected for further analysis. Estradiol and progesterone were identified as activated upstream regulators. CONCLUSIONS: Children born to ovarian-hyperstimulated women displayed cardiovascular dysfunctions. The underlying mechanisms may involve the effects of supraphysiological estradiol and progesterone levels.

Proteomic analysis on the alteration of protein expression in the placental villous tissue of early pregnancy loss.

Early pregnancy loss is the most common complication of human reproduction. Given the complexities of early development, it is likely that many mechanisms are involved. Knowledge of differences in protein expression in parallel profiling is essential to understand the comprehensive pathophysiological mechanism underlying early pregnancy loss. To identify proteins with different expression profiles related to early pregnancy loss, we applied a proteomic approach and performed two-dimensional gel electrophoresis (2-DE) on six placental villous tissues from patients with early pregnancy loss and six from normal pregnant women, followed by comparison of the silver-stained 2-DE profiles. It was found that 13 proteins were downregulated and 5 proteins were upregulated significantly (P < 0.05) in early pregnancy loss as determined by spot volume. Among them, 10 downregulated and 2 upregulated spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Anomalies of these proteins, including three principal antioxidant enzymes (copper/zinc-superoxide dismutase, peroxiredoxin 3, and thioredoxin-like 1 protein), S100 calcium binding protein, galectin-1, chorionic somatomammotropin hormone 1, transthyretin, fas inhibitory molecule, eukaryotic translation elongation factor, RNA-binding protein, ubiquitin-conjugating enzyme E2N, and proteasome beta-subunit, indicate widespread failure in cell regulations and processes such as antioxidative defense, differentiation, cell proliferation, metabolism, apoptosis, transcription, and proteolysis in early pregnancy loss. This study has identified several proteins that are associated with placentation and early development, shedding a new insight into the proteins that may be potentially involved in the pathophysiological mechanisms underlying early pregnancy loss.