Objective To explore the clinical and pathological features and the diagnosis of childhood Alport syndrome (AS). Methods A retrospective analysis was performed on clinical data of 91 children with AS. Results Hematuria was observed in all 91 patients, of whom 86 were accompanied with proteinuria. Sixty-one children with X-Linked AS (XL-AS) had positive family history. Renal biopsy was performed on 82 children. Mild to moderate mesangial proliferation was observed in 74 cases. Small amounts of immune complexes deposits in the glomerular mesangial area were observed in 48 cases. Glomerular basement membrane (GBM) attenuation, thickening and layering were observed in 53 cases by electron microscopy (EM). In 63 cases receiving renal tissue type IV collagen α3 and α5 chain immunofluorescence detection, 58 were diagnosed with AS, including 53 cases of XL-AS and 5 cases of autosomal recessive AS. In 91 cases of AS, 58 were diagnosed as AS by renal tissue type IV collagen α3 and α5 chain immunofluorescence, 21 were diagnosed by EM, one was diagnosed by skin biopsy, and 12 were diagnosed by gene detection. Six novel mutations of COL4A5 gene were found. Forty-five cases were misdiagnosed before the diagnosis of AS. Forty-one of the 45 cases received steroids and/or immunosuppressant therapy. Conclusions The clinical manifestations and pathological changes are not specific in children with AS, resulting in a higher rate of misdiagnosis. Typical lesions of GBM under EM are only observed in a part of patients. There is a high novel mutation rate of COL4A5 in the detected AS children.

Objective To study the association between fluid overload and acute kidney injury (AKI) after congenital heart disease surgery in infants. Methods A retrospective analysis was performed on 88 infants aged less than 6 months who underwent a radical surgery for congenital heart disease. The treatment outcomes were compared between the infants with AKI after surgery and those without. The effect of cumulative fluid overload on treatment outcomes 2 days after surgery was analyzed. The risk factors for the development of AKI after surgery were assessed by logistic regression analysis. Results Compared with those without AKI after surgery, the patients with AKI had younger age, lower body weights, higher serum creatinine levels and higher vasoactive-inotropic score, as well as longer durations of intraoperative extracorporeal circulation and aortic occlusion (P < 0.05). Compared with those without AKI after surgery, the patients with AKI had a higher transfusion volume, a higher incidence rate of low cardiac output syndrome, a longer duration of mechanical ventilation, a longer length of stay in the intensive care unit (ICU), a longer length of hospital stay, a higher application rate of extracorporeal membrane oxygenation, a higher 30-day mortality rate, and higher levels of cumulative fluid overload 2 and 3 days after surgery (P < 0.05). The logistic regression analysis showed that fluid overload and low cardiac output syndrome were major risk factors for the development of AKI after surgery. The children with cumulative fluid overload > 5% at 2 days after surgery had a higher incidence rate of low cardiac output syndrome, a longer duration of mechanical ventilation, a longer length of stay in the ICU, a longer length of hospital stay, and a higher mortality rate (P < 0.05). Conclusions Infants with fluid overload after surgery for congenital heart disease tend to develop AKI, and fluid overload may be associated with poor outcomes after surgery.

Objective To study the association between the single nucleotide polymorphisms (SNPs) of the ninth exon Val279Phe of platelet-activating factor acetylhydrolase (PAF-AH) gene and gastrointestinal bleeding in children with Henoch-Schönlein purpura (HSP). Methods A total 516 children with HSP were enrolled, among whom 182 had gastrointestinal bleeding and 334 had no gastrointestinal bleeding. PCR was used to investigate the distribution of genotypes and alleles in the SNPs of Val97Phe. The plasma PAF-AH activity was measured, as well as the levels of platelet-activating factor (PAF), granular membrane protein-140 (GMP-140), β-thromboglobulin (β-TG), and platelet factor 4 (PF4). Results The Val279Phe genotype and allele frequencies were in Hardy-Weinberg equilibrium, and the homozygous genotype TT and heterozygotes accounted for 0.97% and 6.05% respectively. The gastrointestinal bleeding group had a significantly higher allele frequency than the control group (5.22% vs 3.33%; P < 0.01). The HSP patients with GG genotype in the gastrointestinal bleeding group had significantly higher levels of plasma PAF and GMP-140 than those in the non-gastrointestinal bleeding group (P < 0.05), while the non-gastrointestinal bleeding group had a significantly higher PAF-AH activity than the gastrointestinal bleeding group (P < 0.05). There were no significant differences in β-TG and PF4 between the two groups (P > 0.05). Conclusions Val279Phe gene polymorphisms in PAF-AH are associated with PAF-AH activity and PAF and GMP-140 levels and may be a risk factor for HSP with gastrointestinal bleeding.

Objective To investigate the renal function of small-for-gestational-age (SGA) infants at the early stage after birth. Methods A total of 40 preterm SGA infants, 33 full-term SGA infants, 80 preterm appropriate-forgestational-age (AGA) infants, and 33 full-term AGA infants were included in this study. The following indices were compared between the SGA infants and AGA infants within 48 hours after admission:blood urea nitrogen (BUN), serum creatinine (SCr), estimated glomerular filtration rate (eGFR), blood pressure, urine volume per body weight, and proteinuria. Results The preterm SGA group had a significantly lower BUN level than the preterm AGA group (P < 0.05). However, there were no significant differences in SCr level, eGFR, and blood pressure between the two groups (P > 0.05). The full-term SGA group had a significantly higher SCr level and a significantly lower eGFR than the full-term AGA group (P < 0.05). However, there were no significant differences in BUN level and blood pressure between the two groups (P > 0.05). There was no significant difference in urine volume per body weight between the preterm SGA and preterm AGA groups (P > 0.05) and between the full-term SGA and full-term AGA groups (P > 0.05). There was no significant difference in the incidence of proteinuria between the preterm SGA and preterm AGA groups (P > 0.05). Proteinuria was not present in the SGA full-term and AGA full-term groups. Conclusions SCr and eGFR can be used as the diagnostic indices for early renal damage of SGA infants. The renal function is worse in full-term SGA infants than in full-term AGA infants.

Objective To investigate the clinical value of humidified high-flow nasal cannula (HHFNC) as a respiratory support after extubation by comparing it with nasal continuous positive airway pressure (NCPAP) in neonates with meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of the newborn (PPHN). Methods A total of 78 neonates with MAS and PPHN were randomly administered with HHFNC or NCPAP immediately after extubation. The following indices were compared between the two groups:blood gas parameters, duration of noninvasive ventilation, rate of extubation failure, and incidence of complications, such as nasal damage, abdominal distension, and intraventricular hemorrhage. Results There were no significant differences in the rate of extubation failure, PaO₂, PCO₂, and PaO₂/FiO₂ ratio at one hour after NCPAP or HHFNC, duration of noninvasive ventilation, time to full enteral feeding, length of hospital stay, and incidence of intraventricular hemorrhage between the two groups (P > 0.05). The HHFNC group had significantly lower incidence of nasal damage (5.0% vs 31.6%; P < 0.05) and incidence of abdominal distension (7.5% vs 34.2%; P < 0.05) than the NCPAP group. Conclusions Both NCPAP and HHFNC can be used as the sequential therapy for neonates with MSA and PPHN after extubation, and they both have a definite effect. As a new strategy of respiratory support, HHFNC is better tolerated, and has fewer side effects than NCPAP.

Objective To analyze the clinical features of 6 children with Duchenne muscular dystrophy (DMD) and review related literature, and to provide a basis for early diagnosis and effective treatment of this disease. Methods A retrospective analysis was performed on the clinical data of 6 children with DMD who were admitted to the First Affiliated Hospital of Nanjing Medical University from January 2010 to October 2015. Results All the 6 cases were boys without a family history of DMD, and the age of diagnosis of DMD was 1.2-11.5 years. All patients had insidious onset and increases in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase, creatine kinase (CK), and creatine kinase-MB, particularly CK, which was 3.3-107.2 times the normal level. Their gene detection results all showed DMD gene mutation. The gene detection results of two children's mothers showed that they carried the same mutant gene. The muscle biopsy in one case showed that the pathological changes confirmed the diagnosis of DMD. The level of CK in one case declined by 77.0% 5 days after umbilical cord blood mesenchymal stem cell transplantation. Conclusions For boys with abnormal serum enzyme levels and motor function, DMD should be highly suspected. It should be confirmed by CK and DMD gene detection as soon as possible. And the progression of the disease could be delayed by early intervention for protecting the remaining normal muscle fibers.

Objective To study the values of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in predicting the sensitivity to intravenous immunoglobulin (IVIG) in Kawasaki disease (KD). Methods A retrospective cohort study was conducted in 404 children with newly diagnosed KD. The data on routine blood tests, NLR, and PLR were collected before and after IVIG treatment. The receiver operating characteristic (ROC) curve was used to determine the cut-off values of NLR and PLR in predicting the insensitivity to IVIG. A logistic regression analysis was used to identify independent predictive factors for insensitivity to IVIG. Results Of all patients, 31 were insensitive to IVIG. Compared with the IVIG sensitivity group, the IVIG insensitivity group had a significantly higher incidence rate of coronary artery ectasia (P < 0.01), a shorter course of disease when IVIG therapy was initiated (P < 0.05), and significantly higher NLR, PLR, and C-reactive protein (CRP) level before and after treatment (P < 0.05). The optimal cut-off values for NLR and PLR to predict IVIG insensitivity were 4.36 and 162 before IVIG treatment and 1.45 and 196 after treatment. The multivariate regression analysis showed that the course of disease before IVIG treatment, CRP before IVIG treatment, and NLR and PLR before and after IVIG treatment were independent predictive factors for IVIG insensitivity. Conclusions NLR and PLR can be used to predict IVIG insensitivity in children with KD.

Objective To investigate the clinical features of invasive candidiasis in children and the risk factors for Candida bloodstream infection. Methods A retrospective study was performed on 134 children with invasive candidiasis and hospitalized in 5 tertiary hospitals in Urumqi, China, between January 2010 and December 2015. The Candida species distribution was investigated. The clinical data were compared between the patients with and without Candida bloodstream infection. The risk factors for Candida bloodstream infection were investigated using multivariate logistic regression analysis. Results A total of 134 Candida strains were isolated from 134 children with invasive candidiasis, and non-albicans Candida (NAC) accounted for 53.0%. The incidence of invasive candidiasis in the PICU and other pediatric wards were 41.8% and 48.5% respectively. Sixty-eight patients (50.7%) had Candida bloodstream infection, and 45 patients (33.6%) had Candida urinary tract infection. There were significant differences in age, rate of use of broad-spectrum antibiotics, and incidence rates of chronic renal insufficiency, heart failure, urinary catheterization, and NAC infection between the patients with and without Candida bloodstream infection (P < 0.05). The multivariate logistic regression analysis showed that younger age (1-24 months) (OR=6.027) and NAC infection (OR=1.020) were the independent risk factors for Candida bloodstream infection. Conclusions The incidence of invasive candidiasis is similar between the PICU and other pediatric wards. NAC is the most common species of invasive candidiasis. Candida bloodstream infection is the most common invasive infection. Younger age (1-24 months) and NAC infection are the risk factors for Candida bloodstream infection.

Objective To investigate the changes of pulmonary function and fractional exhaled nitric oxide (FeNO) in the standardized treatment of bronchial asthma in children. Methods A total of 254 children who were newly diagnosed with acute exacerbation of bronchial asthma were selected as asthma group, and they were divided into two subgroups:asthma with concurrent rhinitis and asthma without concurrent rhinitis. All patients received the standardized management and treatment for one year. The pulmonary function parameters included forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), maximal mid-expiratory flow (MMEF), and mid-expiratory flow at 25%, 50%, and 75% of vital capacity (MEF25, MEF50, and MEF75). The FeNO levels were measured before treatment and at 3, 6, 9, and 12 months after treatment. Another 62 healthy children were selected as the control group, and the pulmonary function and FeNO levels were measured only once. Results During one year of standardized treatment, FEV1, PEF, MMEF, MEF25, MEF50, and MEF75 gradually increased, and FeNO levels gradually decreased (P < 0.05). Indicators of large airway function, such as FEV1 and PEF, almost returned to normal after 6 months of treatment; indicators of small airway function, such as MMEF, MEF25, MEF50, and MEF75 almost returned to normal after 9 months of treatment; there were no significant differences in the above indices between the asthma group and the control group after one year of treatment (P > 0.05). However, the asthma group had a significantly higher FeNO levels than the control group after one year of treatment (P < 0.05). The asthmatic patients with concurrent rhinitis had significantly higher FeNO levels than those without concurrent rhinitis before treatment and 3 months after treatment (P < 0.05). Before treatment, there was a significant negative correlation between FeNO levels and pulmonary function parameters (P < 0.05). Conclusions With the standardized treatment of bronchial asthma in children, pulmonary function parameters gradually increase and FeNO levels gradually decrease. The recovery of large airway function occurs earlier than the recovery of small airway function. Furthermore, the effect of rhinitis on airway responsiveness should be noted.

Objective To investigate the changes in serum YKL-40 level and humoral immune function and their significance in children with recurrent pneumonia. Methods Blood samples were collected from 30 children with recurrent pneumonia (recurrent pneumonia group), 30 children with acute pneumonia (acute pneumonia group), and 30 healthy children (control group). Serum YKL-40 levels were measured by enzyme-linked immunosorbent assay. The correlation between serum YKL-40 level and laboratory indices related to humoral immune function was analyzed. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of serum YKL-40 level for recurrent pneumonia. Results The recurrent pneumonia group had a significantly higher serum YKL-40 level than the acute pneumonia and control groups (P < 0.05). The acute pneumonia group had a significantly higher serum YKL-40 level than the control group (P < 0.05). Serum levels of IgG and complement 4 in the recurrent pneumonia group were significantly lower than in the acute pneumonia group (P < 0.05). Serum YKL-40 level was negatively correlated with serum IgG level (r_s=-0.309, P=0.047) and serum complement 4 level (r=-0.324, P=0.039). The area under the ROC curve of serum YKL-40 level for diagnosing recurrent pneumonia was 0.958 (95%CI:0.921-0.994). Conclusions Humoral immune function is low in children with recurrent pneumonia. Serum YKL-40 may be involved in the occurrence of recurrent pneumonia and can be used as a reference index for diagnosing recurrent pneumonia.

Objective To systematically assess the clinical efficacy of high-frequency oscillatory ventilation (HFOV) and conventional mechanical ventilation (CMV) for treating pediatric acute respiratory distress syndrome (ARDS). Methods Data from randomized controlled trials comparing HFOV and CMV in the treatment of pediatric ARDS published before July 2016 were collected from the Cochrane Library, PubMed, Medline, CNKI, and Wanfang Data. Literature screening, data extraction, and quality assessment were performed by two independent reviewers according to the inclusion and exclusion criteria. The selected studies were then subjected to a Meta analysis using the RevMan 5.3 software. Results A total of 6 studies involving 246 patients were included. The results of the Meta analysis showed that there were no significant differences between the HFOV and CMV groups in the in-hospital or 30-day mortality rate, incidence of barotrauma, mean ventilation time, and oxygenation index (P > 0.05). However, compared with CMV, HFOV increased the PaO₂/FiO₂ ratio by 17%, 24%, and 31% at 24, 48, and 72 hours after treatment respectively, and improved oxygenation in patients. Conclusions Although the mortality rate is not reduced by HFOV in children with ARDS, this treatment can result in significant improvement in oxygenation compared with CMV. Further large-sample, multicenter, randomized clinical trials will be required to draw a definitive conclusion.

Objective To investigate the effect of air pollution on respiratory health in school-aged children in the main urban area of Chongqing, China. Methods The main urban area of Chongqing was divided into polluted area and clean area according to the air pollution data shown on the Environmental Protection Agency Website of Chongqing between 2010 and 2015. A cluster sampling method was used to select 695 third- or fourth-grade children from 2 primary schools in the clean or polluted area as study subjects, with 313 children from the clean area and 382 children from the polluted area. Pulmonary function was examined for all children and a standard American epidemiological questionnaire (ATS-DLD-78-C) was used to investigate the prevalence of respiratory diseases and symptoms. Results Compared with the clean area, the polluted area had significantly higher concentrations of inhalable particles (PM₁₀), fine particulate matter (PM_2.5), and nitric oxide (NO_X) (P < 0.05). The multivariate logistic regression analysis was performed after adjustment for confounding factors, and the results showed that compared with those in the clean area, the children in the polluted area had significantly higher risks of cough (OR=1.644), cough during cold (OR=1.596), expectoration during cold (OR=2.196), persistent expectoration (OR=1.802), and wheezing (OR=2.415). The boys and girls in the clean area had significantly higher forced vital capacity and forced expiratory volume in one second than those in the polluted area (P < 0.05). Conclusions Air pollution in the main urban area of Chongqing is associated with the increased prevalence of respiratory symptoms in school-aged children and has certain effect on children's pulmonary function.

Objective To investigate the clinical features of acute poisoning in hospitalized children. Methods A retrospective analysis was performed on the clinical data of 586 hospitalized children who were diagnosed with poisoning and discharged from the Children's Hospital of Chongqing Medical University between January 2006 and December 2015. Results The patients included 354 males and 232 females (age:24 days to 15.8 years). Of the 586 cases, 450 (76.8%) were infants and preschool children; 463 (79.0%) came from rural areas; 551 (94.0%) were hospitalized because of unintentional poisoning. The drug poisoning, pesticide poisoning, and rodenticide poisoning accounted for 221 cases (37.7%), 167 cases (28.5%), and 175 cases (29.9%) respectively. There was a significant difference in the distribution of the poisoning toxins between urban and rural children (P < 0.01), and drugs and pesticides were the most common toxins for urban and rural children respectively. There were significant differences in main clinical manifestations between the children with drug poisoning, pesticide poisoning, and rodenticide poisoning (P < 0.01), who presented with main clinical symptoms of the nervous system, digestive system, and circulatory system respectively. There was no significant difference in overall response rate between the children poisoned by different toxins. Conclusions Acute poisoning is most common in infants and preschool children. The majority of the patients are from rural areas. The majority of acute poisoning is unintentional. Poisoning by drugs is the main type of acute poisoning. There is no significant difference in overall response rate between the children poisoned by different toxins, but their clinical manifestations are different.

Objective To examine the mediating effect of self-concept between interparental conflict and mental health in children and adolescents. Methods A total of 689 students (10-18 years) were surveyed using the convenient sampling method, and their mental health, self-concept, and interparental conflict were examined by the general status questionnaire, Strengths and Difficulties Questionnaire, Self-Description Questionnaire, and Children's Perception of Interparental Conflict Scale. Structural equation modeling (SEM) and simultaneous analysis of several groups were used to construct the mediator model and analyze the data, respectively. The Bootstrap method was used to assess the significance of the mediating effects. Results Interparental conflict was positively correlated with mental health of children and adolescents (P < 0.05), but was negatively correlated with self-concept (P < 0.01). Self-concept was negatively correlated with mental health (P < 0.01). Self-concept had a partial (60%) mediating effect between interparental conflict and mental health. Academic stage, but not gender, had a regulatory role on interparental conflict, mental health, and self-concept. Conclusions Self-concept plays an important role between interparental conflict and mental health. It is necessary to improve self-concept level in children and adolescents exposed to interparental conflict.

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Objective To explore the mechanisms of neuroprotective effects of c-Jun N-terminal kinase (JNK)/FOXO3a transcription factor signaling pathway inhibition on hypoxic-ischemic neuronal apoptosis in neonatal rats with hypoxic-ischemic brain damage (HIBD). Methods Sixty-four 7-day-old Sprague-Dawley rats were divided into four groups:hypoxia-ischemia (HI), sham-operated, JNK specific inhibitor AS601245-treated, and DMSO vehicle. Rats' cerebral cortexes were collected at 24 hours after HI. Western blot was used to detect the protein expression of JNK, p-JNK, FOXO3a, nuclear and cytoplasmic FOXO3a, Bim, and CC3. TUNEL staining was used to detect the apoptotic cells. Results Compared with the sham-operated group, p-JNK protein increased (P < 0.01), nuclear protein of FOXO3a increased (P < 0.01), cytoplasmic protein decreased (P < 0.01), and pro-apoptotic proteins Bim and CC3 increased 24 hours after HI (P < 0.01). Compared with the HI and DMSO vehicle groups, p-JNK protein was reduced (P < 0.01), nuclear protein of FOXO3a was also reduced (P < 0.01), cytoplasmic protein increased (P < 0.01), and Bim and CC3 proteins decreased (P < 0.01) in the AS601245-treated group 24 hours after HI. TUNEL positive cells were reduced in the AS601245-treated rats compared with the HI and DMSO vehicle groups 24 hours after HI (P < 0.01). Conclusions JNK activity increases in the neonatal rat brain with HI damage. JNK activity inhibition can inhibit FOXO3a translocation from cytoplasm to nucleus and downregulate the levels of pro-apoptotic proteins Bim and CC3, leading to the reduction of neuronal apoptosis.

Objective To study the effects of embryonic lead exposure on food intake and bowel movement in offspring rats and possible mechanisms. Methods Sprague-Dawley rats were given 0.1% (low-dose lead exposure group) or 0.2% (high-dose lead exposure group) lead acetate freely during pregnancy to establish an animal model of embryonic lead exposure. A blank control group was also established. The male offspring rats were enrolled in the study, and 10 male offspring rats from each group were selected to observe the changes in food intake, bowel movement, gastric emptying, intestine propulsion, and pathological inflammatory response in the gastric mucosa. Eight offspring rats were selected from each group, and electron microscopy and immunohistochemistry were used to observe the changes in the ultrastructure of jejunal microvilli and cell junction and the expression of cholecystokinin-8 (CCK-8) and motilin (MTL) in the feeding center, in order to reveal the possible mechanisms for abnormal gastrointestinal motility in offspring rats induced by embryonic lead exposure. Results Compared with the control group, the low- and high-dose lead exposure groups had a significant reduction in daily food intake, a significant increase in water content of feces, a significant reduction in fecal pellet weight, and a significant increase in small intestine propulsion (P < 0.05). The highdose lead exposure group had a significant reduction in gastric emptying ability compared with the control group (P < 0.05). Compared with the control group, the lead exposure groups had significantly greater pathological inflammatory changes in the gastric mucosa (P < 0.05), significant reductions in the number and length of the jejunal microvilli and the number of epithelial desmosome junctions (P < 0.05), a significant increase in the macula densa gap (P < 0.05), and significant increases in the expression of MTL and CCK-8 in the feeding center (P < 0.05), in a dose-dependent manner. Conclusions The degree of gastrointestinal structural injury and expression levels of MTL and CCK-8 in the feeding center are lead dose-dependent, which may be important mechanisms for changes in food intake, bowel movement, and digestive functions in offspring rats induced by embryonic lead exposure.

Objective To study the effects of maternal folate deficiency on fetal growth and development and the methylation profiles of insulin-like growth factor system in the offspring rats. Methods Twenty-two Sprague-Dawley female rats were randomly assigned to two groups:a folate deficient group (n=12) and a control group (n=10). They were fed with folate deficient and normal diet respectively. Dams were mated after 2 weeks of feeding. Eight female rats from each group were pregnant. On the 20th day of gestation, the fetuses were delivered by caesarean section. Thirty-two fetal rats from each group were randomly selected and the body length and weight were measured. Eight fetal rats from each group were randomly selected and ELISA was used to measure the level of folate content, IGF-1 and IGFBP-3 in the fetal brain and liver. Three fetal rats from each group were randomly selected and methylated DNA immunoprecipitation sequencing (MeDIP-Seq) was used to detect the methylation level of insulin-like growth factor system in the fetal brain and liver. ELISA was used to measure the level of IGF-1 and IGFBP-3 in the maternal serum from both groups. Results The mean fetal length and weight were lower in the folate deficient group than in the control group (P < 0.05). The levels of IGF-1 and IGFBP-3 in the maternal serum, as well as folate content and IGFBP-3 in the fetal brain and liver were significantly lower in the folate deficient group than in the control group (P < 0.05). The methylation levels of IGF-1R, IGF-2R, IGFBP-2, IGFBP-5, IGFBP-6 and IGFBP-7 in the fetal brain were higher in the folate deficient group than in the control group (P < 0.05). The methylation levels of IGF-1R, IGF-2R, IGFBP-3 and IGFBP-5 in the fetal liver were higher in the folate deficient group than in the control group. The methylation of IGF-2 gene showed a significant reduction in the folate deficient group (P < 0.05). Conclusions Maternal folate deficiency may cause retardation of growth and development of the offspring, which is possibly associated with the changes of methylation profiles of insulin-like growth factors.

Objective To investigate the effect of histone acetylation/deacetylation imbalances on embryonic hearts of mice and its effect on key genes of planar cell polarity (PCP) pathway-Vangl2, Scrib and Rac1 in H9C2 cells. Methods Forty pregnant C57/B6 mice were randomly assigned into three groups:blank group (n=10), vehicle group (n=10), and valproic acid (VPA)-treated group (n=20). In the VPA-treated group, VPA, a histone deacetylase (HDAC) inhibitor, was administered to each individual dam intraperitoneally at a single dose of 700 mg/kg on embryonic day 10.5 (E10.5). The vehicle and blank groups received equivalent saline or no interventions, respectively. Dams were sacrificed on E15.5, and death rates of embryos were evaluated. Subsequently, embryonic hearts of survival fetus were removed to observe cardiac abnormalities by hematoxylin-eosin (HE) staining. H9C2 cells were cultured and allotted to the blank, vehicle, and VPA-treated groups:the VPA treated group received VPA exposure at concentrations of 2.0, 4.0 and 8.0 mmol/L; the vehicle and blank groups received equivalent saline or no interventions, respectively. HDAC1-3 as well as Vangl2, Scrib and Rac1 mRNA and protein expression levels were determined by quantitative real-time PCR and Western blot, respectively. The total HDAC activity was analyzed by colorimetric assay. Results The fetus mortality rate after VPA treatment was 31.7%, with a significantly higher rate of cardiac abnormalities in comparison with the controls (P < 0.05). In comparison with the blank and vehicle groups, HDAC1 mRNA was significantly increased at various concentrations of VPA treatment at all time points of exposure (P < 0.05), together with a reduction of protein level after 48 and 72 hours of exposure (P < 0.05). The inhibition of HDAC2 mRNA after various concentrations of VPA incubation was pronounced at 24 hours of exposure (P < 0.05), while the protein levels were reduced at all time points (P < 0.05). HDAC3 mRNA was prominently induced by VPA (4.0 and 8.0 mmol/L) at all time points of treatment (P < 0.05). In contrast, the protein level was inhibited after VPA treatment (P < 0.05). In comparison with the blank and vehicle groups, Vangl2 mRNA as well as Scrib mRNA/protein expression levels were markedly reduced after 48 and 72 hours of VPA treatment (P < 0.05), together with a reduction of protein level in Vangl2 at 72 hours (P < 0.05). Compared with the blank and vehicle groups, a significant repression in the total HDAC activity was observed in the VPA-treated group at concentrations of 4.0 and 8.0 mmol/L after 24 hours of treatment (P < 0.05), and the effect persisted up to 48 and 72 hours, exhibiting pronounced inhibition at all concentrations (P < 0.05). Conclusions VPA might result in acetylation/deacetylation imbalances by inhibiting HDAC1-3 protein expression and total HDAC activity, leading to the downregulation of mRNA and protein expression of Vangl2 and Scrib. This could be one of the mechanisms contributing to congenital heart disease.