Maternal Metformin Treatment Reprograms Maternal High-Fat Diet-Induced Hepatic Steatosis in Offspring Associated with Placental Glucose Transporter Modifications.

Maternal high-fat (HF) diet exposure in utero may affect fetal development and cause metabolic problems throughout life due to lipid dysmetabolism and oxidative damage. Metformin has been suggested as a potential treatment for body weight reduction and nonalcoholic fatty liver disease, but its reprogramming effect on offspring is undetermined. This study assesses the effects of maternal metformin treatment on hepatic steatosis in offspring caused by maternal HF diet. Female rats were fed either a control or an HF diet before conception, with or without metformin treatment during gestation, and placenta and fetal liver tissues were collected. In another experiment, the offspring were fed a control diet until 120 d (adult stage). Metformin treatment during pregnancy ameliorates placental oxidative stress and enhances placental glucose transporter 1 (GLUT1), GLUT3, and GLUT4 expression levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Maternal metformin treatment was shown to reprogram maternal HF diet-induced changes in offspring fatty liver with the effects observed in adulthood as well. Further validation is required to develop maternal metformin therapy for clinical applications.

Coronary Dilatation and Endothelial Inflammation in Neonates Born to Mothers with Preeclampsia.

OBJECTIVES: To investigate the cardiovascular features and endothelium in neonates born to mothers with preeclampsia. STUDY DESIGN: In this combined observational cohort and case-control study, neonates born to mothers with normotension and mothers with preeclampsia were recruited at a neonatal intensive care unit of a tertiary medical center. Cardiovascular measurements by echocardiography and the clinical measures upon admission were analyzed. Vascular cell adhesion molecule-1 expression in umbilical arteries and in in vitro endothelial cell stimulation with plasma were examined. Continuous data were compared using nonparametric analysis, and their relationships were analyzed using linear regression. Binary logistic regression was performed in the model of adjustment of birth body weight and for multivariate analysis. RESULTS: In the cohort, almost all cardiovascular segments positively correlated to birth weight. Notably, neonates (n = 65) of mothers with preeclampsia had significantly larger coronary arteries at birth than neonates of mothers with normotension (n = 404) (median size of left main coronary artery 1.36 mm versus 1.08 mm, p <0.001; median size of right coronary artery, RCA 1.25 mm versus 1.0 mm, p <0.001). The size of the right coronary artery positively correlated to the maternal antepartum diastolic blood pressure (r = 0.298, P = .018) and was associated with in-hospital death (P < .001). Meanwhile, endothelial vascular cell adhesion molecule-1 expression was significantly increased in the umbilical arteries of the preeclamptic group and following preeclamptic cord-plasma stimulation. The latter also correlated with their relative coronary sizes. CONCLUSIONS: Neonates of mothers with preeclampsia had distinctive coronary dilatation at birth. Coronary size might be useful as a severity index of neonatal endothelial inflammation as a result of maternal preeclampsia.

Mid-Term Follow-Up of Transcatheter Closure for Coronary Cameral Fistula in Pediatrics.

BACKGROUND: Coronary cameral fistula (CCF), a rare abnormal coronary communication to cardiac chambers, may lead to coronary steal phenomenon and increase cardiac overload. We investigated the clinical and cardiovascular characteristics in children before and after transcatheter closure. METHODS: We retrospectively reviewed pediatric patients with CCFs diagnosed by echocardiography in a tertiary medical center between 1998 and 2019. Basic information, echocardiogram, catheterization and interventional procedures were obtained from medical charts. RESULTS: A total of 12 pediatric subjects were included. The median ages at diagnosis and catheterization were 0.2 and 2.8 years, respectively. All CCFs were unilateral and single with varying degrees of coronary artery dilatation and aneurysm formation and diagnosed by echocardiography. The median follow-up periods before and after catheterization were 2.5 and 7.3 years, respectively. Seven of the CCFs originated from the left side. The drainage sites were all right hearts. Before catheterization, the median size of the proximal end of the fistula was 3.1 mm, concomitant with enlargement of conduit coronary arteries. Eleven of the 12 patients underwent transcatheter closure using coils in six and vascular plugs in five. Only one patient had a significant increase in pulmonary-to-systemic flow ratio. The size of conduit coronary artery gradually decreased and the size of ipsilateral coronary branch increased after closure. CONCLUSIONS: Transcatheter occlusion for CCFs in children is safe and effective. The morphology of CCFs varies with the degrees of dilation, tortuosity, and aneurysmal formation. After occlusion, alterations in the size of coronary arteries may be a prognostic indicator.

Evaluation of endothelial dysfunction, endothelial plasma markers, and traditional metabolic parameters in children with adiposity.

BACKGROUND/PURPOSE: To investigate the correlations among endothelial function assessment parameters, asymmetric dimethylarginine (ADMA)-related biomarkers, and traditional risk factors in adipose children. METHODS: We enrolled adipose children aged 7-18 years between July 2014 and August 2016 as well as normal-weight controls from the outpatient clinic. Vascular measurements including echocardiography, carotid intima media thickness, pulse wave velocity (PWV), and flow-mediated dilation (FMD) were measured. Venous blood samples including traditional metabolic and endothelial dysfunction parameters were analyzed. Participants were grouped as adipose vs. normal-weight and as adipose with hypertension vs. adipose without hypertension. Clinical presentations, laboratory data, and cardiovascular measurement were compared. RESULTS: Of the 105 enrolled children, 85 were adipose. Adipose children had higher systolic blood pressure, larger left ventricular (LV) mass, and adverse traditional metabolic biomarkers. FMD was significantly reduced (8.25 (5.32-12.06) % vs. 12.49 (7.18-16.58) %, p = 0.018) in the adipose group. PWV was markedly increased (4.65 (4.2-5.5) m/sec vs. 3.95 (3.38-4.35) m/sec, p < 0.001) in the hypertensive adipose children. Endothelial dysfunction parameters were not significantly changed in this study. CONCLUSION: Adipose children were at higher risk of hypertension and LV hypertrophy. FMD, PWV and traditional cardiovascular biomarkers can detect subtle vascular changes. Hypertension is an important sign of arterial involvement in adipose children. Although ADMA-related biomarkers were not statistically significant, future studies are needed to confirm its correlation with adiposity and hypertension in children. The early detection and prevention of endothelial dysfunction may decrease the rate of progression to cardiovascular consequences in later life.

Left Ventricle Decompression Strategies in Pediatric Peripheral Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is widely used in patients with potentially reversible acute cardiac and/or pulmonary failure who are unresponsive to conventional treatment. Patients with profound left ventricular (LV) dysfunction under venous-arterial (V-A) ECMO may experience LV distention, pulmonary edema, and thrombus formation. It is critical to unload the left ventricle to prevent such complications. The aim of this study was to identify the risks, timing and methods of LV decompression in pediatric peripheral ECMO. METHODS: Between August 2006 and November 2017, 51 patients received peripheral ECMO support in our pediatric intensive care unit. All of them were less than 18 years of age and non-cardiotomy surgery-related. We retrospectively reviewed the patients' clinical presentations, decompression methods and outcomes. RESULTS: The overall success rate of ECMO removal was 76.5% (39/51), and the survival rate after discharge was 62.7% (32/51). The myocarditis group had the most favorable outcomes among the ECMO patients (100% survival). LV decompression was needed in 12 patients who had profound LV dysfunction under V-A ECMO. Five patients received medical treatment successfully, and the other 7 patients underwent intra-aortic balloon pump (IABP) procedures. In the IABP group, 1 patient still needed further pigtail-decompression. All of our decompression patients survived with good neurological outcomes (Glasgow Outcome Scale 5). CONCLUSIONS: The patients with profound LV dysfunction under peripheral VA ECMO were at risk of thromboembolic events and LV decompress was needed. If medical decompression fails, IABP is a feasible approach for LV decompression in pediatric peripheral ECMO.

Clinical utility and diagnostic accuracy of palm-held, mini-sized ultrasonocardiographic scanner in congenital heart disease.

BACKGROUND/PURPOSE: To investigate whether a palm-held ultrasonocardiographic scanner would be useful for screening and follow-up in congenital heart disease (CHD). METHODS: We retrospectively reviewed the echocardiographic images from June 1, 2014 to November 1, 2014. All patients underwent two ultrasonographic examinations including palm-held scanner examination and standard echocardiography. To compare the quality of the two instruments, we developed a diagnostic scoring system ranging from 1 point to 10 points, with 10 points indicating the best quality. Two experienced echocardiographers retrospectively reviewed all recorded images blindedly and gave each examination a score. Comparisons of diagnostic score between two equipments were performed. RESULTS: A total of 262 patients' images were reviewed. All cardiac lesions could be detected with both instruments. The mean diagnostic score of palm-held scanner and standard echocardiography were 8.20±0.53 versus 9.64±0.37 (p<0.05) in color image and 7.00±1.05 versus 8.56±1.14 (p<0.05) in gray-scale two-dimensional image, respectively. When we compared the score between the two instruments in individual CHDs, we found standard echocardiography had better quality except for detecting muscular ventricular septal defect and pulmonary regurgitation. CONCLUSION: The diagnostic sensitivity of palm-held scanner in detecting CHD was very good. Despite both instruments having a high diagnostic score in detecting CHD, standard echocardiography had better quality. Traditional echocardiography is still the standard tool for CHD evaluation. However, the palm-held scanner can support physical examination for initial screening and follow-up, and offer cardiologists an opportunity to visualize and listen to the heart at any time.

Mid- to long-term follow-up of pediatric patients with coronary artery fistula.

BACKGROUND/PURPOSE: To investigate mid- to long-term outcomes in children with coronary artery fistula (CAF). METHODS: We retrospectively reviewed the medical records of patients seen between September 1996 and August 2011. We enrolled those diagnosed with CAF via echocardiography (Philips SONOS 7500 system and Philips IE33) or angiography. The mean follow time was 42.58 ± 3.4 months (range, 1-166 months). For comparative purposes, participants were grouped as acquired versus congenital, and symptomatic versus asymptomatic. We also measured the size of the coronary artery (CA) in patients with CA dilatation (CAD). RESULTS: Out of 122 CAF patients, spontaneous closure was detected in 37 patients at 21.59 ± 3.45 months after diagnosis. This timeframe did not differ between the acquired and congenital groups (21.64 ± 6.26 months vs. 21.57 ± 4.15 months; p = 0.991). Ninety patients were asymptomatic and remained so; their spontaneous closure rate was 28.89%. Moreover, 24 patients had CAD, including 17 with Kawasaki disease and seven with congenital CAF. The CAs of all congenital-CAF-plus-CAD patients were initially > 5 mm; these patients underwent percutaneous transcatheter intervention, and their CA sizes decreased significantly (6.11 ± 0.79 mm vs. 3.76 ± 0.36 mm; p = 0.002). CONCLUSION: With the advanced sensitivity of echocardiography, CAF can be detected more easily than ever before. Most patients with small CAFs are asymptomatic and may experience spontaneous closure. Therefore, management of CAF depends on symptoms; if patients are asymptomatic and have small CAFs, intervention may not be necessary, especially in acquired cases. However, if patients present with symptoms or persistent dilatation of the proximal CA, surgical or percutaneous closure should be performed.

Predictors of Atrial Septal Defect Occluder Dislodgement.

The aim of this study was to identify the factors that influence atrial septal occluder dislodgement in adults and children.From June 2003 to June 2013, a total of 213 patients (115 adults and 98 children) diagnosed with secundum atrial septal defects (ASD) underwent transcatheter closure of their defects with an atrial septal occluder (ASO) in our hospital. The ASO was implanted under transesophageal echocardiography (TEE) guidance. Ten patients suffered from ASO dislodgement, and the other 203 patients comprised the successful group. We compared the preprocedural data related to general demographics, defects, margins, and minor post-implantation complications between the two groups with the goal of identifying the factors that affected ASO dislodgement.Univariate logistic regression analyses identified a high Qp/Qs value, the Qp/Qs ratio > 3.13, ASO size, ASO size greater than 32 mm, ASO size/BSA ratio > 15.13 and IAS erosion, floppiness or aneurysm formation as factors with significant predictive value. Multivariate analysis revealed that a Qp/Qs ratio > 3.13, and interatrial septum (IAS) erosion, floppiness and aneurysm formation post-implantation were independent predictors of ASO dislodgement (P = 0.001 and P = 0.006, respectively) in both adults and children.Percutaneous device closure of ASDs is safe and effective in the current era. The Qp/Qs ratio > 3.13 and IAS erosion, floppiness or aneurysm formation post-implantation might be predictors of ASO dislodgement in adults and children.

High citrulline-to-arginine ratio associated with blood pressure abnormalities in children with early chronic kidney disease.

BACKGROUND: Nitric oxide (NO) is involved in hypertension and chronic kidney disease (CKD). NO synthase can metabolize L-arginine (ARG) to generate NO and L-citrulline (CIT). Two methylated ARG derivatives, asymmetric and symmetric dimethylarginine, are also involved in NO deficiency. Thus it was hypothesized that their combined ratios relate to blood pressure (BP) abnormalities in children with early CKD. METHODS AND RESULTS: The relationship between these ARG metabolites in plasma was examined using 24-h ambulatory BP monitoring (ABPM) profile in children and adolescents with CKD stages 1-3 (n=44). Approximately 20.4% (9/44) of children with CKD stages 1-3 were diagnosed with hypertension on clinical BP measurement, and 77.3% (33/44) had BP abnormalities on ABPM, including increased BP load, nocturnal BP non-dipping, and nocturnal hypertension. Children with CKD stages 2-3 were more prevalent with abnormal BP on ABPM, and had a higher level of CIT and CIT-to-ARG ratio than those with stage 1. Furthermore, high CIT-to-ARG ratio was significantly correlated with abnormal ABPM profile, including nocturnal hypertension, increased diastolic BP load, and nocturnal BP non-dipping. Higher CIT level was significantly correlated with increased diastolic BP load and overall ABPM profile. CONCLUSIONS: Plasma CIT-to-ARG ratio may serve as a useful marker of cardiovascular outcome in children with early CKD.

Eosinophil-derived neurotoxin is elevated in patients with amyotrophic lateral sclerosis.

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons in the brainstem, motor cortex, and spinal cord. Oxidative stress and neuroinflammation have been implicated in the pathophysiology of ALS. Members of the family of damage-associated molecular patterns, including reactive oxygen species, high-mobility group box 1, and eosinophil-derived neurotoxin (EDN), may participate in pathological conditions. In this study, we aim to discover new biomarker for detecting ALS. MATERIALS AND METHODS: We examined 44 patients with ALS, 41 patients with Alzheimer's disease, 41 patients with Parkinson's disease, and 44 healthy controls. The concentration of serum EDN was measured using an enzyme-linked immunosorbent assay. RESULTS: EDN levels were significantly increased 2.17-fold in the serum of patients with ALS as compared with healthy controls (P < 0.05). No correlation between the levels of serum EDN and various clinical parameters of ALS was found. Moreover, the levels of serum EDN in patients with Parkinson's disease and Alzheimer's disease and healthy controls were similar. CONCLUSION: A higher level of serum EDN was found specifically in patients with ALS, indicating that EDN may participate in the pathophysiology of ALS.

Small-bore pigtail catheters for the treatment of primary spontaneous pneumothorax in young adolescents.

OBJECTIVE: Small-bore pigtail catheters have been found to be effective in the treatment of primary spontaneous pneumothorax (PSP) in adults. The aim of this study was to compare the effectiveness of small-bore pigtail and large-bore catheters in the treatment of PSP in young adolescents. MATERIALS AND METHODS: Young adolescents (<18 years) with initial PSP were treated with aspiration (control group), small-bore pigtail catheters or large-bore catheters. Treatment was determined on a case-by-case basis with parental consultation. Success rate, recurrence rate (within 12 months), duration of hospital stay, duration of catheter insertion, and complications were analysed. MAIN RESULTS: There were 41 patients treated: aspiration, n=8; small-bore pigtail catheters, n=10; large-bore catheters, n=23. Demographic and baseline clinical characteristics were similar between groups. The success rates were 50.0% and 65.2% in the small-bore pigtail and large-bore catheter groups, respectively. Corresponding recurrence rates were 20.0% and 56.5%. There was no difference between the small-bore pigtail and large-bore catheter groups in the duration of hospital stay in patients for whom treatment was successful; however, the duration of catheter insertion was significantly shorter in the small-bore pigtail catheter group compared with the large-bore catheter group in patients for whom treatment was successful (p<0.05). There were no major complications in either catheter treatment group and few minor complications (small-bore pigtail catheter, n=2; large-bore catheter, n=4). CONCLUSIONS: The findings suggest that small-bore pigtail catheters may be as effective as large-bore catheters for the initial treatment of PSP in young adolescents.

Brefeldin a effectively inhibits cancer stem cell-like properties and MMP-9 activity in human colorectal cancer Colo 205 cells.

Cancer stem cells (CSCs) are a small subset of cancer cells with indefinite potential for self-renewal and the capacity to drive tumorigenesis. Brefeldin A (BFA) is an antibiotic that is known to block protein transport and induce endoplasmic reticulum (ER) stress in eukaryotic cells, but its effects on colorectal CSCs are unknown. We investigated the inhibitory effect of BFA on human colorectal cancer Colo 205 cells. We found that BFA effectively reduced the survival of suspension Colo 205 cells (IC50 = ~15 ng/mL) by inducing apoptosis, and inhibited the clonogenic activity of Colo 205 CSCs in tumorsphere formation assay and soft agar colony formation assay in the same nanogram per milliliter range. We also discovered that at such low concentrations, BFA effectively induced endoplasmic reticulum (ER) stress response as indicated by the increased mRNA expression of ER stress-related genes, such as glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP). Finally, we found that BFA reduced the activity of matrix metallopeptidase 9 (MMP-9). These findings suggest that BFA can effectively suppress the progression of colorectal cancer during the tumorigenesis and metastasis stages. These results may lead to the development of novel therapies for the treatment of colorectal cancer.

Predictors for Regression of Large Secundum Atrial Septal Defects Diagnosed in Infancy.

PUPOSE: To determine predictive factors of spontaneous closure or size reduction in large secundum-type atrial septal defects (ASD) diagnosed in infancy prior to catheterization or surgical intervention. METHODS: From June 2003 to October 2009, 59 infants diagnosed with secundum-type ASDs measuring ≥ 8 mm in the first year of life were retrospectively enrolled. We reviewed medical records, as well as electrocardiography and echocardiography findings. Patients were divided into 2 groups according to the last ASD size: group A (n = 23), ASD reduction in size to < 5 mm or spontaneous closure; group B (n = 36), size of ASD remained ≥ 5 mm. RESULTS: The ASDs spontaneously closed in 10 (17%) patients at a median age of 26.0 ± 5.1 months (range, 15-58 months), or decreased to < 5 mm in 13 (22%) (range, 6-27 months) patients. There was a significant difference in age at diagnosis between the 2 groups (p = 0.014). Patients in group A were younger than those in group B at the time of diagnosis. Changes in ASD size (p < 0.001) and body weight percentile (p = 0.01) were also significantly different fromthe 6-month follow-up. ASD diameter of ≥ 10 mm was a negative predictive factor for size reduction (p = 0.017). CONCLUSIONS: Spontaneous closure or size reduction of large ASDs was not uncommon in patients diagnosed during infancy. Patients with initial ASD sizes between 8 and 10 mm who were younger at the time of diagnosis and showed better weight gain were more likely to have favorable outcomes. KEY WORDS: Infancy; Large secundum atrial septal defect; Natural course; Spontaneous closure.

Diallyl disulfide induces Ca2+ mobilization in human colon cancer cell line SW480.

Diallyl disulfide (DADS), one of the major organosulfur compounds of garlic, is recognized as a group of potential chemopreventive compounds. In this study, we examines the early signaling effects of DADS on human colorectal cancer cells SW480 loaded with Ca(2+)-sensitive dye fura-2. It was found that DADS caused an immediate and sustained rise of [Ca(2+)](i) in a concentration-dependent manner (EC(50) = 232 µM). DADS also induced a [Ca(2+)](i) elevation when extracellular Ca(2+) was removed, but the magnitude was reduced by 45%. Depletion of intracellular Ca(2+) stores with 2 µM carbonylcyanide m-chlorophenylhydrazone, a mitochondrial uncoupler, didn't affect DADS's effect. In Ca(2+)-free medium, the DADS-induced [Ca(2+)](i) rise was abolished by depleting stored Ca(2+) with 1 µM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor). DADS-caused [Ca(2+)](i) rise in Ca(2+)-containing medium was not affected by modulation of protein kinase C activity. The DADS-induced Ca(2+) influx was blocked by nicardipine (10 µM). U73122, an inhibitor of phospholipase C, abolished ATP (but not DADS)-induced [Ca(2+)](i) rise. These findings suggest that DADS induced a significant rise in [Ca(2+)](i) in SW480 colon cancer cells by stimulating both extracellular Ca(2+) influx and thapsigargin-sensitive intracellular Ca(2+) release via as yet unidentified mechanisms.

CASP3 gene single-nucleotide polymorphism (rs72689236) and Kawasaki disease in Taiwanese children.

Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. A study from Japan reported that G to A substitution of a single-nucleotide polymorphism (SNP) located in the 5'-untranslated region of caspase 3 (CASP3) (rs72689236), which was associated with nuclear factor of activated T cell-mediated T-cell activation, is responsible for susceptibility to KD. This study was conducted to investigate whether the polymorphism of CASP3 is responsible for susceptibility and coronary artery lesion (CAL) formation in KD in the Taiwanese population. A total of 1092 subjects (341 KD patients and 751 controls) were investigated to identify an SNP of rs72689236 using Invader assays (Third Wave Technologies). Our data provided a borderline significant association between the genotypes and allele frequency of rs72689236 in control subjects and KD patients (P=0.0535 under the dominant model; P=0.0575 under the allelic model). The A allele of rs72689236 in KD patients and in patients with CAL and intravenous immunoglobulin resistance was seen in a higher frequency. Importantly, a significant association was obtained between rs72689236 and KD patients with aneurysm formation (P=0.009, under the recessive model). The A allele of rs72689236 is very likely to be a risk allele in the development of aneurysm in patients with KD.

Impact of transcatheter closure of atrial septal defects in pediatric patients on body weight.

BACKGROUND/PURPOSE: Pediatric patients with atrial septal defect (ASD) may have failure to thrive. This study aimed to investigate body weight changes in pediatric patients after transcatheter closure of ASD. METHODS: From June 2003 to September 2008, we enrolled 60 pediatric patients who underwent transcatheter closure of ASD. Changes in body weight percentile, heart rate, and resolution of right ventricular hypertrophy were compared before and after ASD closure. Patients were divided into two groups according to initial weight percentile: group A, <50(th) percentile (n = 39) and group B, ≥50(th) percentile (n = 21). Echocardiography and routine weight measurements were performed before the procedure and at 3, 6, and 12 months during follow-up. Clinical presentations, laboratory data, and outcomes were measured. RESULTS: Increased body weight percentile (41±4 vs. 48±4, p<0.01), lower heart rate (100±2 beats/min vs. 89±2beats/min, p<0.01), and resolution of right ventricular hypertrophy (59/60 vs. 1/60, p<0.01) were achieved after ASD closure at the 12-month follow-up. Patients in group A were significantly younger (4.6±0.5 years vs. 7.0±0.9 years, p = 0.016), had a higher pulmonary/systemic blood flow ratio (2.2±0.1 vs. 1.8±0.l, p = 0.044), a largerratio of ASD diameter/body surface area (25.0±1.4 vs. 16.4±1.9, p<0.01), and higher percentage of weight gain increase ≥ 5 percentile compared with patients in group B (22/39 vs. 6/21, p = 0.039). CONCLUSION: Transcatheter closure of ASD positively affects weight gain. An increase of 7 percentile weight was observed at 1 year of follow-up. Patients with a younger age, higher pulmonary/systemic blood flow ratio, and a larger ratio of ASD diameter/body surface area may have better weight gain after ASD closure.

Congenital Heart Diseases Impair Female Fertility.

Background: The objective of this research was to evaluate the fertility of Taiwanese women with diagnoses of congenital heart diseases (CHDs). The study also investigated how different forms of CHDs may have variously influenced fertility. Methods: We directed this nationwide, population-based and retrospective matched-cohort research by using data from the Taiwan National Health Insurance Research Database. The CHD group (n = 6602) included women with congenital structural heart diseases, aged 16-45 years in 2000. The non-CHD group (n = 6602) was matched according to urbanization and income. The outcomes, involving live birth, abortion, and fertility rates, were followed until the end of 2013. Poisson regression was used to evaluate the incidence rate ratios (IRRs). Results: The CHDs had an inferior rate of live births (IRR 0.74 [95% CI 0.71-0.78]) than the non-CHD group. There was also a lower fertility rate in the CHD group (IRR 0.81 [95% CI 0.78-0.84]) than the non-CHD group. Abortion rates between the two groups were similar. Conclusion: Congenital structural heart disease compromises female fertility, even among patients with simple forms of CHDs. It is suggested that pregnant patients with CHDs are early appeared to and advised personally with multidisciplinary care to improve their outcomes.

Identifying new liver X receptor alpha modulators and distinguishing between agonists and antagonists by crystal ligand pocket screening.

Background: Modulators of LXRα are of high pharmacological interest as LXRα regulates fatty acid metabolism, inflammatory processes and cancer. We aim to identify new LXRα modulators and to recognize a distinguishable feature of agonists. Results&methodology: The ligand self-dock and largest-cavity-size searching purposely located two appropriate ligand-binding sites to reach the two aims. One is identifying the new modulators from Maybridge library. 20 new compounds are confirmed by the in vitro reporter gene assay. The other is denoting an agonist by at least one best docking pose having one hydrogen bond to LXRα Helix12 His421. Conclusion: Based on the quality x-ray binding pocket, we can identify new LXRα modulators and distinguish between agonists and antagonists by molecular docking.

Synthesis and biological evaluation of thiophenylbenzofuran derivatives as potential P-glycoprotein inhibitors.

P-Glycoprotein (P-gp) overexpression is a major mechanism by which cancer cells acquire the multidrug resistance (MDR) phenotype, and is associated with poor clinical outcome in patients. In an effort to develop MDR-reversal agents, we synthesized and evaluated a series of thiophenylbenzofuran derivatives (4-31) as P-gp inhibitors, among which compounds 4, 10, and 14 represented the optimal agent in reversing the MDR phenotype. These P-gp inhibitors were dramatically effective than verapamil in sensitizing the human ABCB1-overexpressing ABCB1/Flp-In™-293 cells and MDR KBvin cells to a series of chemotherapeutic agents, including vincristine and paclitaxel, as manifested by multi-fold decreases in the respective IC50 values to therapeutically attainable levels.

MCRS2 represses the transactivation activities of Nrf1.

BACKGROUND: Nrf1 [p45 nuclear factor-erythroid 2 (p45 NF-E2)-related factor 1], a member of the CNC-bZIP (CNC basic region leucine zipper) family, is known to be a transcriptional activator by dimerization with distinct partners, such as Maf, FosB, c-Jun, JunD, etc. The transcriptional roles of CNC-bZIP family are demonstrated to be involved in globin gene expression as well as the antioxidant response. For example, CNC-bZIP factors can regulate the expression of detoxification proteins through AREs, such as expression of human gamma-glutamylcysteine synthetases (GCS), glutathione S-transferases (GST), UDP-glucuronosyl transferase (UDP-GT), NADP (H) quinone oxidoreductase (NQOs), etc. To further explore other factor(s) in cells related to the function of Nrf1, we performed a yeast two-hybrid screening assay to identify any Nrf1-interacting proteins. In this study, we isolated a cDNA encoding residues 126-475 of MCRS2 from the HeLa cell cDNA library. Some functions of MCRS1 and its splice variant-MSP58 and MCRS2 have been previously identified, such as transforming, nucleolar sequestration, ribosomal gene regulation, telomerase inhibition activities, etc. Here, we demonstrated MCRS2 can function as a repressor on the Nrf1-mediated transactivation using both in vitro and in vivo systems. RESULTS: To find other proteins interacting with the CNC bZIP domain of Nrf1, the CNC-bZIP region of Nrf1 was used as a bait in a yeast two-hybrid screening assay. MCRS2, a splicing variant of p78/MCRS1, was isolated as the Nrf1-interacting partner from the screenings. The interaction between Nrf1 and MCRS2 was confirmed in vitro by GST pull-down assays and in vivo by co-immunoprecipitation. Further, the Nrf1-MCRS2 interaction domains were mapped to the residues 354-447 of Nrf1 as well as the residues 314-475 of MCRS2 respectively, by yeast two-hybrid and GST pull-down assays. By immunofluorescence, MCRS2-FLAG was shown to colocalize with HA-Nrf1 in the nucleus and didn't result in the redistribution of Nrf1. This suggested the existence of Nrf1-MCRS2 complex in vivo. To further confirm the biological function, a reporter driven by CNC-bZIP protein binding sites was also shown to be repressed by MCRS2 in a transient transfection assay. An artificial reporter gene activated by LexA-Nrf1 was also specifically repressed by MCRS2. CONCLUSION: From the results, we showed MCRS2, a new Nrf1-interacting protein, has a repression effect on Nrf1-mediated transcriptional activation. This was the first ever identified repressor protein related to Nrf1 transactivation.