Objective: Neural tube defects [NTDs] are severe congenital anomalies. The etiology of NTDs is not fully known, and studies on the potential risk factors of NTDs present inconsistent results. Thus, we conducted a systematic review and meta-analysis to investigate the maternal, paternal, and neonatal risk factors for NTDs. Study design: We systematically reviewed relative original studies published through October 6, 2018 available in Pubmed, Embase and the Cochrane Library without restrictions for language. The selected studies measured maternal, paternal, and neonatal risk factors and examined their associations with NTDs. A meta-analysis, including subgroup analysis and sensitivity analysis, was conducted to estimate the pooled effect measures. Two reviewers independently extracted data using a predesigned data collection form. Results: Forty-five studies were eligible for inclusion in the meta-analysis, and twelve potential risk factors were analyzed. The factors that were associated with NTDs risk included stressful life events (odds ratio [OR],1.61; 95% confidence interval [CI], 1.24-2.08; p < 0.001; I-2 = 59.2%], low maternal education level [OR, 1.42; 95% CI, 1.19-1.70; p < 0.001; I-2 = 47.7%], pregestational diabetes [OR, 2.24; 95% CI, 1.21-4.12; p < 0.010; I-2 = 56.3%], low paternal age [OR, 1.41; 95% CI, 1.10-1.81; p = 0.007; I-2 = 0.0%], low birth weight [OR, 5.53; 95% CI, 1.95-15.70; p = 0.001; I-2 = 98.5%], and neonatal female gender [OR, 1.54; 95% CI, 1.10-2.14; p = 0.012; I-2 = 67.8%]. Conclusion: Stressful life events, pregestational diabetes, low birth weight, and neonatal female gender are risk factors associated with NTDs. Low maternal education level and low paternal age are factors that are moderately associated with NTDs. Further cohort studies are required to verify the factors associated with NTDs and control the risk of this severe birth defect.
Background: The goal of this study was to investigate the effect of estradiol in mediation of electroencephalogram (EEG) abnormality induced by etomidate in neonatal rats. Methods: Sprague-Dawley rats were anesthetized using intraperitoneal etomidate for 2 h on postnatal days (P) 4, 5, or 6 and recorded electroencephalogram in two ways. First, pups were recorded EEG two and a half hours under etomidate anesthesia, in subgroups, estradiol receptor antagonist ICI182780 and estradiol synthase inhibitor formestane were given subcutaneously in male rats 15 min prior to etomidate. Second, pups were anesthetized with etomidate for 2 h on P4,5 or 6 and then recovered from anesthesia, EEG were recorded for one hour in two postnatal periods of P9-P11 and P14-P16. Subgroup rats that received bumetanide, NKCC1 inhibitor, to test the NKCC1-GABAAR signaling effect on neonatal brain development, negative control groups and maternally separated for 2 h on P4, 5, or 6 were studied in 16 groups. Each group's n was = 8. Results: Male pups showed more severe seizure-like activities than female pups in P4-P6 under etomidate anesthesia. Pups pretreated with ICI182780 and formestane showed a less abnormalities of EEG in male rats. Etomidate caused seizure-like activity in P4-P6 could extend to P9-P11, but not seen in P14-P16, Pretreated with bumetanide only alleviated abnormalities in male pups other than female in P9-P11. Conclusions: Estradiol involves in the NKCC1-GABA(A)R mediated seizure-like activity caused by etomidte in neonatal rats and these the abnormality lasts near two weeks.
Background: The second trimester is a period of neurogenesis and neuronal migration, which may be affected by exposure to anesthetics. Studies have suggested that multiple anesthetic exposures may have a significant impact on neuronal migration. Methods: Pregnant C57BL/6 mice at embryonic day 14.5 were randomly divided into four groups: Con x 1, Sev x 1, Con x 2, and Sev x 2. Cortical neuronal migration in offspring mice was detected by GFP immunostaining, and the number of cells in the cortex was analyzed. Results: Dual exposure to sevoflurane, not single sevoflurane exposure, caused neuronal migration deficits. Dual exposure to sevoflurane increased the expression of prostaglandin D2 synthase (Ptgds). Furthermore, Ptgds siRNA attenuated neuronal migration deficits induced by dual sevoflurane exposure. Conclusion: Our study suggests that multiple sevoflurane exposures in pregnant mice may induce neuronal migration deficits in offspring mice. Additional studies comprising long-term behavioral tests are required to confirm the effects of sevoflurane exposure during pregnancy.
Tyrosine hydroxylase (TH) deficiency is a rare autosomal recessive inborn error of dopamine transmission, which the deficient gene is at the chromosome 11, also called'Segawa Syndrome'. TH converts tyrosine into L-DOPA, which is the direct precursor of catecholamine biosynthesis. TH deficiency causes a neurological disease with primary extrapyramidal signs and a variable response to L-DOPA. We report three patients in China who were diagnosed with Tyrosine hydroxylase (TH) deficiency by genetic testing and clinical manifestations. After L-DOPA treatment, their condition had sustained improvement.
The study aimed to investigate the pathologic mechanism of functional brain regions in attention-deficit hyperactivity disorder (ADHD) patients through making comparisons of normal and ADHD children from the perspective of the network nodes of brain network and the intensity of functional connection between bilateral of hemispheres by resting-state functional magnetic resonance imaging (fMRI). Thirty-five ADHD and forty-two children were examined by resting-state functional magnetic resonance imaging (fMRI) scans. Data analysis was done via the degree centrality (DC) and voxel-mirrored homotopic connectivity (VMHC) approaches. Compared with healthy subjects, the ADHD group exhibited significantly decreased DC values in the right posterior cingulate gyrus, left medial superior frontal gyrus, right inferior parietal gyrus, right middle frontal gyrus, left superior frontal gyrus and right superior frontal gyms. Children with ADHD also exhibited some areas with increased DC values compared with healthy children. These regions included the cerebellar anterior lobe, right middle occipital cortex, left middle cingulate gyrus and right middle cingulate gyrus. VMHC analysis all revealed positive activation in a range of brain regions when comparing ADHD and normal children, suggesting that the VMHC scores of children with ADHD were higher in the bilateral superior frontal lobe, bilateral middle occipital lobe, and bilateral cerebellar anterior lobes. This work provides a new approach for examining the neural mechanisms underlying ADHD, demonstrating that the DC and VMHC methods enabled more comprehensive analysis that can be cross-checked.
Over the last three decades, advances in medical and surgical techniques have proven life saving and life improving for young children. Consequently, early and repeated exposure to general anesthetics in childhood has increased. However, accumulating evidence suggests that general anesthetics may be neurotoxic in children. Of particular concern is the neurotoxicity fetuses may suffer from maternal exposure to sevoflurane during surgeries and fetal intervention procedures performed during the second trimester, as this can cause neurodevelopmental impairment in offspring. In this review we demonstrate that the pathology associated with fetal toxicity resulting from exposure to sevoflurane during pregnancy involves oxidative stress, neuroinflammation, neuroapoptosis, and alteration of synaptic properties. The mechanisms remain to be elucidated, but may include increased tau protein phosphorylation and abnormal methylation. These findings highlight the need for a global and comprehensive understanding of the potential neurotoxicity of anesthetic exposure in fetuses and its long-term effects.
Embryonic development is a critical period wherein brain neurons are generated and organized. Maternal dietary folate, a cofactor in one-carbon metabolism, modulates neurogenesis and apoptosis in foetal brain neurons. We hypothesized that aberrant neuronal apoptosis may affect the development of the central nervous system during maternal folic acid deficiency, with evident effects because maternal folic acid deficiency modulates the microRNA-34a associated with Bcl-2 pathway during embryonic development. Four-week-old female Sprague-Dawley rats were divided randomly into two groups (10 rats per group): a folate-deficient diet group and a folate-normal diet group. The diets were administered to the rats 60 d before mating, which was continued for the pregnant dams until parturition. Maternal folic acid deficiency increased neuronal apoptosis in the hippocampus and the cortex in the offspring. Furthermore, maternal folic acid deficiency increased the ratio of cleaved caspase-3/caspase-3, followed by an increase in caspase-3 activity. Moreover, maternal folic acid deficiency downregulated Bcl-2 and upregulated Bax, and this effect associate with maternal folic acid deficient increases expression of microRNA-34a. Together, the present results indicate that maternal folic acid deficiency stimulates neuronal apoptosis via microRNA-34a associated with Bcl-2 signalling in rat offspring.
Objective: To identify candidate genes for the clinical diagnosis of floppy infant syndrome (FIS) using single nucleotide polymorphism (SNP) array in a specific FIS family. Methods: SNP array analysis of the whole chromosome copy number was performed in the proband (III1). Multiple polymerase chain reaction (PCR) combined with denaturing high-performance liquid chromatography (DHPLC) was used to validate the array data. Results: A large 5.818182 Mb duplication (Xq13.1: 67987646-73805828), which encompasses 66 known genes, was found in III1. The start and end points of the duplication were confirmed with an SNP array. Duplicated genes with potential roles in central and/or peripheral nervous system development (HDAC8, PHKA1, TAF1, DLG3, KIF4A, IGBP1, PIA1, and SLC16A2) were confirmed by multiple PCR-DHPLC in III1. The patient's mother and grandmother carry duplications in these eight genes, but only on one X chromosome, while the patient's aunt does not carry any of the duplications. Conclusion: Based on the location of the eight candidate genes in Xq13.1, the large duplication found by SNP array does indeed exist and is predicted to be both novel and pathogenic. Moreover, we recommend SNP array as the first option for genetic diagnosis of both large-scale and rare/complicated diseases, such as FIS.
Objective: Particulate matter (PM) as an environmental pollutant is suspected to be associated with autism spectrum disorder (ASD). The aim of this study was to assess whether exposures to PM2.5 during the first three years of life in relation to the risk and degree of the severity of ASD. Methods: A total of two hundred and ninety-seven 3-6 years old Chinese children (99 confirmed autism cases and 198 their age-gender matched control subjects) were included. Children's exposures to PM2.5 (particulate matter with aerodynamic diameter < 2.5 mu m) during the first three years after birth were estimated. Logistic regression analysis was used to examine the PM2.5-ASD association. Results: The mean levels of PM2.5 exposures in ASD and typical developmental children during the first three years of life were 89.8[standard deviations (SD): 6.1] mu g/m(3) and 87.3(6.6) mu g/m(3), respectively (p = 0.002). A statistically significant positive correlation was found between the serum levels of PM2.5 and the Childhood Autism Rating Scale (CARS) score indicating severity of autism (r = 0.259; p = 0.010). Based on the receiver operating characteristic (ROC) curve, the optimal cutoff value of PM2.5 levels as an indicator for auxiliary diagnosis of ASD was projected to be 89.5ug/m(3), which yielded a sensitivity of 65.4% and a specificity of 63.2%, with the area under the curve at 0.61 (95% confidence intervals [CIs], 0.54-0.68; P < 0.001). Multivariate analysis models were used to assess ASD risk according to PM2.5 quartiles (the lowest quartile [Q1] as the reference), with the adjusted odds ratios (ORs) (95% CIs) were recorded. As shown in the Table 2, the 3rd and 4th quartile of PM2.5 were compared against the Q1, and the risks were increased by 103% (OR = 2.03; 95%CI: 1.13-5.54; p = 0.015) and 311% (4.15; 2.04-9.45; p = 0.002), respectively. Conclusions: To conclude, the evidence from this study allowed us to conclude that there was an association between PM2.5 exposure and ASD risk and severity.
Background: Maternal infection during pregnancy is known to adversely affect foetal development, but previous studies have rarely investigated the impact of gynaecological diseases during pregnancy on offspring during adulthood. Vaginitis is one of the most prevalent gynaecological diseases during pregnancy. Methods: The effect of maternal vaginal inflammation on offspring was simulated by inducing maternal vaginal infection. We performed a transvaginal injection of lipopolysaccharide (LPS) in pregnant mice to induce vaginitis and investigated their offspring by means of behavioural tests and molecular and cellular measurements. Results: Behavioural tests revealed that the offspring of mothers transvaginally injected with LPS exhibited sex dependent differences. Male offspring showed increased anxiety-related behaviours, including reduced time exploring the open arm in the elevated plus maze test and light chamber in the light-dark box test. Serum levels of corticosterone were increased in LPS male offspring, indicating activation of the hypothalamic-pituitary adrenal (HPA) axis. Corticotropin-releasing hormone (CRH) protein expression and c-Fos positive cells were increased in the hypothalamic paraventricular nucleus (PVN) in LPS male offspring, which presented with an increased number of microglia. Conclusion: This study suggests that prenatal vaginal infection increases anxiety-like behaviour in male offspring, possibly via activation of the HPA axis.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that begins in infancy. Although the etiology and pathogenesis are poorly understood, many studies have shown that ASD is closely related to structural and functional defects in the nervous system, especially synaptic transmission. The endocannabinoid (eCB) system is an important regulatory system of the central nervous system that regulates neurotransmission and synaptic plasticity and plays an important role in emotional and social responses and cognitive function. The relationship between eCB system and ASD has attracted increasing attention from scholars. In this review, we discuss the complex lipid signaling network of the eCB system, intracellular transport pathways, abnormal expression and association with various neurological diseases, and direct and indirect evidence for the link between eCB and ASD. Collectively, the findings to date indicate that the eCB system plays a key role in the pathophysiology of ASD and can provide new insights into potential interventions and rehabilitation strategies for ASD.
Cytology and histology obstacles have been the main barriers to multiple tissues injury repair. In search of the most promising treatment strategies for spinal cord injury (SCI), stem cell-based transplantation coupled with various materials/technologies have been explored extensively to enhance SCI repair. Chitosan (CS) has demonstrated immense potential for widespread application in the form of scaffolds and micro-particles for SCI repair. The current review summarizes the evidences for stem cell-based transplantation and CS in SCI repair. Stem cells transplantation, which plays a key role in the repair of SCI, mainly results from its neural differentiation potential and neurotrophic effects. Application of CS enhances the survival of grafted stem cells, up-regulates the expression level of neurotrophic factors and heightens the neural differentiation of stem cells as well as the functional recovery of spinal cord. Meanwhile, CS can also be exploited as growth factors/RNA carriers to control the release of regenerating molecules which are beneficial to damage spinal cord repair.
The aim of this study was to evaluate the in vivo impacts of maternal n-3 polyunsaturated fatty acids (PUFAs) deficiency during pregnancy on the proliferation of neural progenitor cells (NPCs) in the developing cerebral cortex of fetal rats. Our results showed that about 5 weeks of maternal dietary n-3 PUFAs deprivation resulted in a substantial n-3 PUFA deficiency in fetal rat cerebral cortex. Importantly, by two survival schemes and two quantitative methods, we found that maternal intake of n-3 PUFAs deficient diet during the gestation significantly inhibited the proliferation of NPCs in fetal rat cerebral cortex. Moreover, the decreased cortical NPCs proliferation induced by nutritional n-3 PUFAs restriction did not originate from the increased NPCs apoptosis. Finally, our observations indicated that the down-regulation of cyclin E protein might be involved in the inhibitory effects of maternal n-3 PUFAs deficient diet on the proliferation of cortical NPCs. These findings highlight the importance of maternal intake of appropriate n-3 PUFAs and deepen our understanding of the exact effects of n-3 PUFAs on mammalian brain development
Objectives: Tangshan earthquake which had a magnitude of 7.8 killed approximately 250,000 people in China in 1976. In the present study, we sought to determine the prevalence and risks of mental disorders in adults who experienced earthquake as an infant or in the prenatal period. Methods: This cross-sectional cohort study recruited participants based on the urban resident registry of Tangshan, Hebei province, 2013 using a multistage stratified cluster sampling method with selection probabilities proportional to size. We recruited subjects who were born between July 29, 1975 and April 28, 1978 that was one year before and 1.9 years after the occurrence of Tangshan Earthquake, respectively. Current psychiatric diagnoses and lifetime psychiatric diagnoses were obtained through the Structured Clinical Interview for DSM-IV Axis I Disorders Patient Research Version. Unconditional logistic regression analysis was performed to analyze risk factors of mental disorders. Results: Totally1380 subjects were included with 392 subjects exposed to the earthquake in the fetal period, 399 subjects who experienced the earthquake during their infancy, and 589 subjects who had no exposure to the earthquake. Twenty-one (2.7%; current 1.9%) subjects exposed to earthquake were diagnosed with major depressive disorderversus 2.3% (current 1.5%) in the non-exposure group. Five (0.6%; current 0.6%) subjects with exposure to earthquake had bipolar disorder versus 0.9% in the non-exposure group. Thirteen (1.6%; current 1.6%) subjects with exposure to earthquake had schizophreniaversus 0.2% in the non-exposure group (P = 0.006). Furthermore, 5.2% (current 3.7%) subjects with exposure to earthquake had anxiety disorders versus 5.7% (current 3.9%) in the non-exposure group. Moreover, 8.1% (current 7.0%)subjects with exposure to earthquake had alcohol use disorders versus 7.1% (current 5.3%) in the non-exposure group. Furthermore, the prevalence of schizophrenia of the prenatal exposure group (2.3%) was significantly higher than the other two groups (chi(2) = 10.273, P = 0.006); however, no statistically significant difference was found in the current and lifetime prevalence of other DSM-IV axis I disorders among the three groups (P > 0.05). Our multivariate regression analysis showed that prenatal earthquake stress exposure was not a significant risk of any of the lifetime or current DSD-IV axis I disorders. Conclusion: Adults who were exposed to earthquake in the prenatal period had a significantly higher rate of schizophrenia than those who were not exposed or who experienced earthquake in their infancy. No statistically significant difference was found in the current and lifetime prevalence of other DSM-IV axis I disorders between those exposed and those not exposed to earthquake. Furthermore, prenatal earthquake stress exposure was not a significant risk of any of the lifetime or current DSD-IV axis I disorders.
The BTBR T + Itpr3tf/J (BTBR) mouse has developmental disorders in the central nervous system and many aberrant neuroanatomical structures. However, identification of the pathological mechanisms underlying these abnormal neuroanatomical structures in the brains of BTBR mice is still lacking. Posttranslational modifications (PTMs) are known to be involved in the regulation of diverse cellular processes, and evidence shows that some types of PTMs are associated with the development of the central nervous system. In this study, we detected four novel PTMs in the cerebral cortex of BTBR mice as compared to C57BL/6 J (B6) mice using western blotting. Results revealed that lysine crotonylation and succinylation were elevated in the cerebral cortex of BTBR mice compared to levels in B6 mice. We speculate that elevated profiles of lysine crotonylation and succinylation may be involved in mechanisms related to neuroanatomical abnormalities in cerebral cortex of BTBR mice.