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HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

Gestational diabetes mellitus (GDM) is a severe global issue that requires immediate attention. MicroRNA expression abnormalities are possibly disease-specific and may contribute to GDM pathological processes. To date, there is limited data on miRNA profiling in GDM, especially that involves a longitudinal study. Here, we performed miRNA expression profiling in the entire duration of pregnancy (during pregnancy until parturition and postpartum) using a miRNA- polymerase chain reaction array (miRNA-PCRArray) and in-silico analysis to identify unique miRNAs expression and their anticipated target genes in Malay maternal serum. MiRNA expression levels and their unique potential as biomarkers were explored in this work. In GDM patients, the expression levels of hsa-miR-193a, hsa-miR-21, hsa-miR-23a, and hsa-miR-361 were significantly increased, but miR-130a was significantly downregulated. The area under the curve (AUC) and receiver operating characteristic (ROC) curve study demonstrated that hsa-miR-193a (AUC = 0.89060 ± 04,470, P = 0.0001), hsa-miR-21 (AUC = 0.89500 ± 04,411, P = 0.0001), and miR-130a (AUC = 0.6939 ± 0.05845, P = 0.0025) had potential biomarker features in GDM. In-silico analysis also revealed that KLF (Kruppel-Like family of transcription factor), ZNF25 (Zinc finger protein 25), AFF4 (ALF transcription elongation factor 4), C1orf143 (long intergenic non-protein coding RNA 2869), SRSF2 (serine and arginine rich splicing factor 2), and ZNF655 (Zinc finger protein 655) were prominent genes targeted by the common nodes of miR23a, miR130, miR193a, miR21, and miR361.Our findings suggest that circulating microRNAs in the first trimester has the potential for GDM screening in the Malay population. [ABSTRACT FROM AUTHOR]

Background: Induction of labour (IOL) in low‐risk nulliparas at 39 weeks reduces caesarean delivery. Multiparas with ripe cervixes typically have vaginal delivery within eight hours. Delivery at night and weekend are associated with higher maternal and neonatal mortality. Aims: To evaluate IOL in full‐term multiparas with ripe cervixes to achieve delivery at normal working hours and improve maternal satisfaction. Methods: A randomised trial was performed in a tertiary hospital in Malaysia. Low‐risk multiparas with ripe cervixes (Bishop score ≥6) were recruited at 38+4–40+0 weeks, then randomised to planned labour induction at 39+0 weeks or expectant care. Primary outcomes were delivery during 'normal working hours' 09:00–17:00 hours, Monday–Friday and patient satisfaction by visual numerical rating scale. Results: For IOL (n = 80) vs expectant care (n = 80) arms respectively, primary outcomes of delivery at normal working hours was 27/80 (34%) vs 29/78 (37%), relative risk (RR) 0.9, 95% CI 0.5–1.7, P = 0.41, patient satisfaction was 8.0 ± 1.8 vs 7.8 ± 1.6, P = 0.41; presentation for spontaneous labour or rupture of membranes were 27/80 (34%) vs 70/79 (89%), RR 0.4, 95% CI 0.3–0.5, P < 0.001; and for labour induction 52/80 (65%) vs 15/79 (19%), RR 3.4, 95% CI 2.1–5.5, P < 0.001. Caesarean delivery was 8/80 (10%) vs 4/79 (5%), RR 2.0, 95% CI 0.62–6.3, P = 0.25; and mean birthweight was 3.1 ± 0.3 vs 3.3 ± 0.4 kg, P = 0.06 for IOL vs expectant care, respectively. Conclusion: Labour induction in low‐risk multiparas does not increase births during working hours or improve patient satisfaction. Antenatal clinic visits and non‐birth hospitalisation were significantly reduced. [ABSTRACT FROM AUTHOR]

Background. Adipocytokines participate in regulating the inflammatory response in glucose homeostasis and type 2 diabetes. However, among these peptides, the role of adipocyte-specific fatty-acid-binding protein (AFABP), chemerin, and secreted protein acidic and rich in cysteine (SPARC) in gestational diabetes (GDM) has not been fully investigated. Method. The maternal fasting level of adipocytokines of 53 subjects with GDM and 43 normal pregnant (NGDM) was measured using multiplex immunoassay at 24–28 weeks, before delivery, immediate postpartum, and 2–6 months postpuerperium. Results. Higher levels of AFABP were associated with a 3.7-fold higher risk of GDM. Low chemerin levels were associated with a 3.6-fold higher risk of GDM. Interleukin-10 (IL-10) was inversely associated with the risk of GDM. SPARC had no association with GDM. AFABP was directly correlated to interleukin-6 (r = 0.50), insulin resistance index (r = 0.26), and body mass index (r = 0.28) and inversely correlated to C-reactive protein (r = − 0.27). Chemerin levels were directly and strongly correlated with IL-10 (r = 0.41) and interleukin-4 (r = 0.50) and inversely correlated to insulin resistance index (r = − 0.23) in GDM but not NGDM. In the longitudinal assessment, there were no significant differences in AFABP and chemerin concentrations of both studied groups. Conclusion. AFABP and chemerin were associated with a higher risk of GDM. These adipocytokines were related to insulin resistance, body mass index, and inflammation in pregnant women diagnosed with GDM. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factors (FGFs); FGF-21 and FGF-23, have been proposed to be associated with metabolic syndrome. However, data on the role of these peptides in gestational diabetes mellitus (GDM) are limited. Therefore, this study was designed to assess the association of serum FGF-21 and FGF-23 with the risk of GDM. Furthermore, we evaluated the circulation of these peptides in pregnancy and post-puerperium. Materials and methods: Fifty-three pregnant subjects with GDM and 43 normal glucose tolerance (NGT) pregnant women participated in this study. Serum FGF-21 and FGF-23 were measured during pregnancy and post-puerperium. Results: FGF-21 and FGF-23 were low in GDM compared to NGT during pregnancy. There were no significant differences in the level of these peptides post-puerperium. Using logistic regression, FGF-23 [odds ratio (OR) 0.70 (95% confidence interval [CI]: 0.50–0.96)] was inversely associated with GDM, so a 1-μg/mL decrease in FGF-23 levels was associated with a 1.4-fold increased risk of developing GDM and this remained statistically significant after adjustment for confounders [adjusted OR (aOR) 0.70 (95% CI: 0.50–0.98)]. There was no association of FGF-21 with the development of GDM risk. Conclusions: Lower FGF-23 concentrations could be involved in the pathophysiology of GDM. FGF-21, even though associated with metabolic risk factors in pregnancy, may not be a fundamental factor in GDM. [ABSTRACT FROM AUTHOR]

Background. Defects in incretin have been shown to be related to the pathogenesis of type 2 diabetes. Whether such a deficiency happens in gestational diabetes mellitus (GDM) remains to be confirmed. We assessed the association of fasting glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) with GDM. We also studied the longitudinal circulation of these peptides during pregnancy and afterwards. Methods. 53 women with GDM (30 managed with diet only (GDM-diet) and 23 treated with insulin (GDM-insulin)) and 43 pregnant women with normal glucose tolerance (NGDM) were studied, with GIP and GLP-1 levels measured at 24–28 weeks (E1), prior (E2) and after (E3) delivery, and postpuerperium (E4). Results. Basal GIP was shown to be low in GDM groups compared to NGDM in E1, and in E4 for GDM-diet. GLP-1 was low in GDM groups during pregnancy and afterwards. At E1, serum GIP and GLP-1 were inversely associated with GDM and participants with lower levels of GIP (<0.23 ng/mL) and GLP-1 (<0.38 ng/mL) had a 6 (95% CI 2.5-14.5)- and 7.6 (95% CI 3.0-19.1)-fold higher risk of developing GDM compared with the higher level, respectively. In the postpuerperium, when there is a drop in β-cell function, participants with previous GDM (pGDM) presented lower GLP-1 (in both GDM subgroups) and lower GIP in GDM-diet subgroup compared to controls. Conclusion. There is an independent, inverse association between fasting incretins and higher risk of GDM. Furthermore, lowered levels of these peptides may play an important role in the abnormality of glucose regulation following pregnancy. [ABSTRACT FROM AUTHOR]

Introduction: Diabetes mellitus (DM) has been associated with sperm damage. In view of the fact that quercetin possesses antioxidant and anti-inflammatory activities, this compound may help to protect sperm against damage in DM. In this study, in-vivo effects of quercetin on sperm parameters in DM were investigated.Material and Methods: Quercetin (10, 25 and 50 mg/kg/b.w.) was given orally to streptozotocin-nicotinamide induced adult male diabetic rats for 28 days. Following treatment completion, rats were sacrificed and sperm were harvested from the cauda epididymis. Sperm count, motility, viability, hyperosmotic swelling (HOS) tail-coiled sperm and morphology were assessed. Levels of lipid peroxidation (LPO) and anti-oxidative enzymes (SOD, CAT and GPx) in sperm with and without H2O2 incubation were determined by biochemical assays. Expression levels of SOD, CAT and GPx mRNAs in sperm were evaluated by qPCR. Sperm DNA integrity was estimated by flow cytometry while expression levels of the inflammatory markers NF-κβ and TNF-α in sperm were determined by Western blotting.Results: In diabetic rats receiving quercetin, sperm count and motility, viability and HOS tail-coiled sperm increased (p < 0.05) while sperm with abnormal morphology decreased. Moreover, sperm SOD, CAT, GPx activities and their mRNA expression levels increased while sperm LPO, NF-κβ and TNF-α levels decreased. In normal and diabetic rat sperm incubated with H2O2, a further increase in MDA and further decreases in SOD, CAT and GPx were observed, and these were ameliorated by quercetin treatment.Conclusions: In-vivo administration of quercetin to diabetic rats helps to ameliorate sperm damage and improves sperm morphology and functions in DM. [ABSTRACT FROM AUTHOR]

Objective: Interleukin 1 receptor type 2 (IL1R2) regulates the inflammatory pathway that results in preterm delivery. We aim to investigate the impact of IL1R2 gene polymorphisms on the risk of preterm delivery.Method: A total of 664 women with spontaneous preterm and term deliveries were genotyped for IL1R2 gene polymorphisms (rs2072476A/G, rs2071008G/T, rs2072474C/T) using Sequenom MassARRAY platform.Results: Ethnic-specific analysis revealed a significant association between the G allele of IL1R2 rs2072476 polymorphism and reduced risk of PTB in the Indian ethnic subgroup (OR: 3.7, 95% CI: 1.3-11.3, p = 0.017). The odds of G allele occurring among Indian women with term delivery (>37 weeks) was three times higher than those with preterm delivery (<37 weeks). Genotype analysis showed a significant association between the GG genotype of IL1R2 rs2072476 polymorphism and term delivery in the Indian women.Conclusion: This study shows disparity in the occurrence of preterm birth due to the differences in the genotype of the women. Particularly, Indian women with the minor allele of IL1R2 rs2072476 polymorphisms were more likely to deliver at term (>37 weeks). These findings suggest the possible influence of maternal IL1R2 gene polymorphism on the risk of preterm delivery. [ABSTRACT FROM AUTHOR]

Background: Preterm birth (PTB) is the largest cause of neonatal mortality and morbidity in the world. Ethnicity disparity in the occurrence of PTB has been associated with the cytokine function. In this study, we aimed at examining cytokine levels in women with spontaneous preterm and term births. Method: Women with spontaneous preterm birth (SPTB) between 24 and 31 weeks (n = 40) and women with spontaneous term birth between 37 and 41 weeks (n = 40) admitted to the University of Malaya Medical Centre from 2011 to 2013 were involved in this study. Plasma proteins were determined for 35 cytokines using ProcartaPlex™ immunoassay. Protein levels were compared between women with SPTB and women with term birth. Result: Six specific cytokines were significantly high among women with SPTB. This includes TNFA (odds ratio (OR) 3.4, 95% confidence interval (CI) 2.0-6.0, p = 0.001), MCP-3 (OR 2.5, 95% CI 1.29-4.67, p = 0.007), IL16 (OR 2.4, 95% CI 1.34-4.30, p = 0.003), IL17A (OR 2.3, 95% CI 1.28-4.06, p = 0.005), IFNG (OR 3.8, 95% CI 2.0-8.0, p = 0.001), and farctalkine (OR 2.1, 95% CI 1.17-4.22, p = 0.031), respectively. Conclusion: This study identifies high levels of specific cytokines in women with PTB. These inflammatory biomarkers may play an important role in the mechanisms that result in uterine contraction and PTB. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Adipose tissue-derived stromal cells (ASCs) natively reside in a relatively low-oxygen tension (i.e., hypoxic) microenvironment in human body. Low oxygen tension (i.e., in situ normoxia), has been known to enhance the growth and survival rate of ASCs, which, however, may lead to the risk of tumourigenesis. Here, we investigated the tumourigenic potential of ASCs under their physiological condition to ensure their safe use in regenerative therapy. Human ASCs isolated from subcutaneous fat were cultured in atmospheric O2 concentration (21% O2) or in situ normoxia (2% O2). We found that ASCs retained their surface markers, tri-lineage differentiation potential, and self-renewal properties under in situ normoxia without altering their morphology. In situ normoxia displayed a higher proliferation and viability of ASCs with less DNA damage as compared to atmospheric O2 concentration. Moreover, low oxygen tension significantly up-regulated VEGF and bFGF mRNA expression and protein secretion while reducing the expression level of tumour suppressor genes p16, p21, p53, and pRb. However, there were no significant differences in ASCs telomere length and their relative telomerase activity when cultured at different oxygen concentrations. Collectively, even with high proliferation and survival rate, ASCs have a low tendency of developing tumour under in situ normoxia. These results suggest 2% O2 as an ideal culture condition for expanding ASCs efficiently while maintaining their characteristics. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the temporal and case-controlled correlations of anxiety, depression and stress with hyperemesis gravidarum Study Design: We performed a longitudinal cohort study of women with hyperemesis gravidarum using the Depression, Anxiety and Stress Scale (DASS-21) to evaluate psychological distress at hospitalization and in the third trimester of pregnancy (from 28 weeks gestation). Third pregnancy trimester controls were recruited from routine antenatal clinic attendees who were matched to gestational age at the second DASS-21 assessment in the HG cohort. Results: The prevalences of nausea and vomiting, depression, anxiety and stress caseness in newly hospitalised hyperemesis gravidarum women were 100% and 100%, 19%, 69% and 21% which by the third trimester had fallen to 15.7% and 9.9%, 4%, 19% and 3% and in third trimester controls were 15.9% and 14.2%, 14%, 61% and 20% respectively. Within the hyperemesis gravidarum cohort, nausea, vomiting depression, anxiety and stress reduced significantly by an absolute 84.3% (95% CI 76.2%–89.8%), 90.1% (82.8%–94.2%), 14.9% (7.2%–23.0%), 49.6% (38.6%–58.7%) and 18.2% (10.4%–26.4%) respectively between hospitalization for hyperemesis gravidarum and at the third trimester. In the third trimester, when comparing the hyperemesis gravidarum cohort to controls, the risk of nausea or vomiting was similar but depression, anxiety and stress were significantly lower: adjusted odds ratio AOR 0.10 (95% CI 0.03–0.5), 0.11 (0.05–0.23) and 0.08 (0.02–0.33) respectively. Conclusion: Our study revealed a reassuring pattern of a strong rebound from depression, anxiety and stress in women with hyperemesis gravidarum such that by the third pregnancy trimester the level of psychological distress was even lower than in controls. This observation imply that much of the psychological distress in acute hyperemesis gravidarum is self-limiting and probably in the causal pathway of hyperemesis gravidarum. Care in women with hyperemesis gravidarum should focus on the relief of nausea and vomiting. [ABSTRACT FROM AUTHOR]

Background: External cephalic version (ECV) is offered to reduce the number of Caesarean delivery indicated by breech presentation which occurs in 3-4% of term pregnancies. ECV is commonly performed aided by the application of aqueous gel or talcum powder to the maternal abdomen. We sought to compare gel with powder during ECV on achieving successful version and increasing tolerability. Method: We enrolled 95 women (= 36 weeks gestation) on their attendance for planned ECV. All participants received terbutaline tocolysis. Regional anaesthesia was not used. ECV was performed in the standard fashion after the application of the allocated aid. If the first round (maximum of 2 attempts) of ECV failed, crossover to the opposing aid was permitted. Results: 48 women were randomised to powder and 47 to gel. Self-reported procedure related median [interquartile range] pain scores (using a 10-point visual numerical rating scale VNRS; low score more pain) were 6 [5-9] vs. 8 [7-9] P = 0.03 in favor of gel. ECV was successful in 21/48 (43.8%) vs. 26/47 (55.3%) RR 0.6 95% CI 0.3-1.4 P = 0.3 for powder and gel arms respectively. Crossover to the opposing aid and a second round of ECV was performed in 13/27 (48.1%) following initial failure with powder and 4/21 (19%) after failure with gel (RR 3.9 95% CI 1.0-15 P = 0.07). ECV success rate was 5/13 (38.5%) vs. 1/4 (25%) P = 0.99 after crossover use of gel or powder respectively. Operators reported higher satisfaction score with the use of gel (high score, greater satisfaction) VNRS scores 6 [4.25-8] vs 8 [7-9] P = 0.01. Conclusion: Women find gel use to be associated with less pain. The ECV success rate is not significantly different. [ABSTRACT FROM AUTHOR]

Objective: To develop and validate a food frequency questionnaire (FFQ) to estimate the genistein intake in a Malaysian population of pregnant women. Method: A single 24-h dietary recall was obtained from 40 male and female volunteers. A FFQ of commonly consumed genistein-rich foods was developed from these recalls, and a database of the genistein content of foods found in Malaysia was set up. The FFQ was validated against 7-d food diary (FD) kept by 46 pregnant women and against non-fasting serum samples obtained from 64 pregnant women. Reproducibility was assessed by comparing the responses on two FFQs administered approximately 1 month apart. Results: The Pearson correlation coefficient between FFQ1 and FD was 0.724 and that between FFQ2 and FD was 0.807. Classification into the same or adjacent quintiles was 78% for FFQ1 versus FD and 88% for FFQ2 versus FD. A significant dose -- response relation was found between FFQ-estimated genistein intake and serum levels. Conclusion: The FFQ developed is a reliable, valid tool for categorising people by level of genistein intake. [ABSTRACT FROM AUTHOR]