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Cytogenetic studies suggested that chromosome 15q11-q13 might be a candidate region that increases the risk of autism. Previous association studies in Caucasian populations identified the risk variants of genes in this region. However, the association of these genes with autism in Chinese Han population remains unclear. Herein, 512 autism trios were utilized for a family-based association study of 41 tag single nucleotide polymorphisms (SNPs) in this region to explore the association between protein-coding genes on chromosome 15q11-q13 and autism in Chinese Han population. Furthermore, we sequenced these autism-related genes to detect rare variants in 512 autism trios and 575 healthy controls. Our results showed that the C allele of rs7180500 in GABRG3 was a risk variant for autism (p = 0.00057). The expression quantitative trait loci (eQTL) analysis revealed that the C allele of rs7180500 might be associated with the expression of GABRG3 in the cerebellum (Braineac: p = 0.0048; GTEx: p = 0.0010). Moreover, the sequencing identified two rare variants rs201602655 (p.Val233Met) and rs201427468 (p.Pro365Ser) in GABRG3 and six rare variants in GABRB3 in autistic patients. Among these variants, rs201602655 (p.Val233Met) in GABRG3 were observed in 9 of 512 autistic children and 2 of 575 healthy controls (Pearson χ2-test, χ2 = 5.375, p = 0.020). The functional prediction indicated that rs201602655 (p.Val233Met) might be deleterious. Thus, these findings demonstrated that GABRG3 might contribute to the pathogenesis of autism in Chinese Han population.

Autism is a pervasive neurodevelopmental disorder with high heritability. Genetic factors play crucial roles in the aetiology of autism. Dual specificity phosphatase 15 (DUSP15) has been recognised as a key regulator gene for oligodendrocytes differentiation. A previous study detected one de novo missense variant (p.Thr107Met) with probable deleterious function in exon 6 of DUSP15 among patients with autism. Therefore, we sequenced this mutation in autistic children and performed an association analysis between DUSP15 polymorphisms and autism.We performed a case-control study between 255 children affected with autism and 427 healthy controls. Four tag-single nucleotide polymorphisms (SNPs) were selected. These SNPs and the previously reported mutation in exon 6 of DUSP15 were genotyped via Sanger sequencing.Our results showed that rs3746599 was significantly associated with autism under allelic, additive and dominant models, respectively (χOur findings initially suggest that DUSP15 might be a susceptibility gene for autism in Chinese Han population.

It has been suggested that altered neurogenesis may be involved in the etiology of schizophrenia, so genes impacting on neurogenesis could be potential candidates for schizophrenia. A member of the Musashi family, the human MSI2 gene plays a substantial role in stem-cell maintenance, asymmetric division, and differentiation during neurogenesis. Our previous genome-wide association study (GWAS) implied an association of MSI2 with schizophrenia in a Han Chinese population. To further explore this association, three single-nucleotide polymorphisms (SNPs), rs9892791, rs11657292, and rs1822381, were selected for a replication study involving 921 schizophrenia cases and 1244 controls. After rigorous Bonferroni correction, two of the SNPs (rs9892791 and rs11657292) displayed significant differences in allele and genotype distribution frequencies between the case and control groups. When our GWAS and replication samples were combined, the three MSI2 SNPs were all strongly associated with schizophrenia (rs9892791: allelic P = 1.07E−5; rs11657292: allelic P = 1.95E−12; rs1822381: allelic P = 1.44E−4). These results indicate that the human MSI2 gene might be a susceptibility gene for schizophrenia and encourage future research on the functional relationship between this gene and schizophrenia.

Objective: To systematically study various surgical approaches for treating complex hypopharyngeal and/or laryngotracheal stenoses at a variety of sites and levels. Patients and Methods: We retrospectively analyzed the treatment of 17 patients with severe and complex hypopharyngeal and/or laryngotracheal stenosis at various sites and levels of severity. All of the 17 patients initially had a tracheostomy. Thirteen had failed the previous laser lysis and/or dilation treatment. Given the high severity and complexity of stenosis, all of these patients were treated by open surgical reconstruction techniques using repairing grafts (flaps), followed by stenting. Results: Thirteen of 17 patients had successful decannulation 1-8 months post-operation and had stable airway and adequate vocal and swallow function. Two patients with complex hypopharyngeal and esophageal stenosis had unsuccessful decannulation. Follow-up was lost in 1 patient with complex hypopharyngeal and esophageal stenosis and 1 patient with original hypopharyngeal stenosis and recurrent thoracotracheal stenosis. Conclusion: Despite the failure by the regular treatments using laser lysis and/or dilation therapy, severe and complex hypopharyngeal and/or laryngotracheal stenosis may be successfully treated by variable open surgical reconstruction techniques using different grafts (flaps) depending on the site and severity of the stenosis.

Autism is a complex neurodevelopmental disorder with high heritability. Previous genome-wide association studies (GWAS) demonstrated that some single-nucleotide polymorphisms (SNPs) were significantly associated with autism, while other studies focusing on these GWAS hits showed inconsistent results. Besides, the association between these variants and autism in the Chinese Han population remains unclear. Therefore, this family-based association study was performed in 640 Chinese Han autism trios to investigate the association between autism and 7 SNPs with genome-wide significance in previous GWAS (rs4307059 near MSNP1AS, rs4141463 in MACROD2, rs2535629 in ITIH3, rs11191454 in AS3MT, rs1625579 in MIR137HG, rs11191580 in NT5C2, and rs1409313 in CUEDC2). The results showed a nominal association between the T allele of rs4307059 and autism under both additive model (T>C, Z = 2.250, P = .024) and recessive model (T>C, Z = 2.109, P = .035). The findings provided evidence that rs4307059 near MSNP1AS might be a susceptibility variant for autism in the Chinese Han population.

BACKGROUND Antipsychotic-induced weight gain (AIWG) is a serious concern in therapy with antipsychotic medications. To identify single nucleotide polymorphisms (SNPs) associated with AIWG, we conducted a genome-wide association study (GWAS) for antipsychotic treatment. METHODS The discovery cohort consisted of 534 patients with schizophrenia, who underwent 8-week treatment with antipsychotics and were genotyped using the Illumina Human 610-Quad BeadChip. The independent replication cohort consisted of 547 patients with schizophrenia, treated with similar antipsychotics, and genotyped using the Sequenom MassARRAY platform. Two hundred and thirty-six drug-naive patients treated with risperidone or quetiapine were analyzed independently. Additionally, we conducted pathway and expression analyses using several public bioinformatics databases. RESULTS After correction for age and gender, the top 2 genome-wide significant SNPs with AIWG were located in the PTPRD gene (protein tyrosine phosphatase, receptor type D, 9p24-p23; rs10977144, P GWAS = 9.26E-09; rs10977154, P GWAS = 4.53E-08). The third most significant SNP was in the GFPT2 gene (glutamine-fructose-6-phosphate amidotransferase 2, 5q35.3; rs12386481, P GWAS = 1.98E-07). These results were validated in the replication cohort (rs10977144, P Replication = 4.30E-03; rs10977154, P Replication = 6.33E-03; rs12386481, P Replication =7.65E-03). These results were also verified in those patients initially exposed to risperidone and quetiapine (rs10977144, P = 1.97E-05; rs10977154, P = 2.04E-05; rs12386481, P = 1.97E-04). Pathway analyses showed that AIWG may involve in multiple pathways related to metabolic processes. Moreover, PTPRD mRNA might be highly expressed in brain regions, and the SNPs (rs10977144, rs1097154) also showed significant expression quantitative trait locus effects. CONCLUSIONS Our findings indicate that PTPRD polymorphisms might modulate AIWG.

Multiple epidermal growth factor-like-domains 10 (MEGF10), a critical member of the apoptotic engulfment pathway, mediates axon pruning and synapse elimination during brain development. Previous studies indicated that synaptic pruning deficit was associated with autism-related phenotypes. However, the relationship between MEGF10 and autism remains poorly understood. Disease-associated variants are significantly enriched in the transcription regulatory regions. These include the transcription start site (TSS) and its cis-regulatory elements. To investigate the role of MEGF10 variants with putative transcription regulatory function in the etiology of autism, we performed a family-based association study in 410 Chinese Han trios. Our results indicate that three single nucleotide polymorphisms (SNPs), rs4836316, rs2194079 and rs4836317 near the TSS are significantly associated with autism following Bonferroni correction (p = 0.0011, p = 0.0088, and p = 0.0023, respectively). Haplotype T-A-G (rs4836316-rs2194079-rs4836317) was preferentially transmitted from parents to affected offspring (ppermutation = 0.0055). Consistently, functional exploration further verified that the risk allele and haplotype might influence its binding with transcription factors, resulting in decreased transcriptional activity of MEGF10. Our findings indicated that the risk alleles and haplotype near the MEGF10 TSS might modulate transcriptional activity and increase the susceptibility to autism.

Autism is a pervasive neurodevelopmental disorder diagnosed in early childhood. The genetic factors might play an important role in its pathogenesis. Previous studies revealed that Reelin ( RELN ) polymorphisms were associated with autism. However, the roles of genes in Reelin signaling pathway for autism are largely unknown. As several knockout mice models in which the Reelin pathway genes (i.e. DAB1 , VLDLR / APOER2 , FYN / SRC and CRK / CRKL ) are deficient have the similar phenotype as the reeler mice ( Reelin −/− ), we hypothesized that the Reelin signaling pathway genes might play roles in the etiology of autism. Therefore, we conducted a family-based association study. Sixty-two tagged single nucleotide polymorphisms (SNPs) covering 15 genes in Reelin pathway were genotyped in 239 trios, and 14 significant SNPs were further investigated in the additional 188 trios. In the total 427 trios, we found significant genetic association between autism and four SNPs in DAB1 (rs12035887 G: p = 0.0006; rs3738556 G: p = 0.0044; rs1202773 A: p = 0.0048; rs12740765 T: p = 0.0196). After the Bonferroni correction, SNP rs12035887 remained significant. Furthermore, the haplotype constructed with rs1202773 and rs12023109 in DAB1 showed significant excess transmission in both individual and global haplotype analyses ( p = 0.0052 and 0.0279, respectively). Our findings suggested that variations in DAB1 involved in the Reelin signaling pathway might contribute to genetic susceptibility to autism with Chinese Han decent, supporting the defect in the Reelin signaling pathway as a predisposition factor for autism.

There is no apparently changed after overexpression of RAB18 in cortical neuronal migration. A Representative coronal section showing migration of transfected neurons 4 d after electroporated at E14.5 with GFP plasmid together with indicated constructs. Scale bar: 100 μm. B Quantitative analysis of GFP positive neurons in different cortical regions in A. Data represent the mean ± SEM (n = 3). (PDF 76 kb)

The distributions of neurons do not have apparent differences after suppression of RAB3GAP2 at E18.5. A Representative coronal section showing migration of transfected neurons 4 d after electroporated at E14.5 with GFP plasmid together with indicated constructs. Scale bar: 100 μm. B Quantitative analysis of GFP positive neurons in different cortical regions in A. Data represent the mean ± SEM (n = 3). (PDF 70 kb)

There is no apparently changed after RAB18 deficiency in GluR1, KDEL and GRASP65 protein expression levels. A Immunoblot analysis of cortical neurons infected with indicated plasmids with the indicated antibodies. B-D The graphs separately indicate the ratios of GluR1 / Tuj1, KDEL / Tuj1, and GRASP65 / Tuj1 in A. Data represent the mean ± SEM and the experiment was performed at least four times. (PDF 57 kb)

Overexpression of DN-RAB18 (S22N) mildly impairs the neuronal migration at E18.5. A Representative coronal section showing migration of transfected neurons 4 d after electroporated at E14.5 with GFP plasmid together with indicated constructs. Scale bar: 100 μm. B Quantitative analysis of GFP positive neurons in different cortical regions in A. Data represent the mean ± SEM (n = 3); * p

Cortical neuronal migration is mildly affected by overexpression of N-cadherin. A Representative coronal section showing migration of transfected neurons 3 d after electroporated at E14.5 with GFP plasmid together with indicated constructs. Scale bar: 100 μm. B Quantitative analysis of GFP positive neurons in different cortical regions in A. Data represent the mean ± SEM (n = 3); ** p

There is no apparently changed after silencing RAB18 in radial glial organization, progenitor proliferation and survival. A, B Cerebral cortical sections at E18.5 and E16.5 which were electroporated at E14.5 with the indicated constructs together with GFP plasmid, were immunostained with antibodies against nestin or Ki67. Scale bars: (A), 100 μm; (B), 40 μm. C Quantification of the ratio of Ki67 and GFP double positive cells to total GFP positive cells in SVZ/VZ (Ki67 index). No significant differences between pSUPER and shRAB18-3 groups are found. Data are shown as the mean ± SEM (n = 3). D Immunostaining for cleaved caspase-3 (Asp175) shows no detectable apoptotic cell in RAB18 silencing brains at E16.5 which were electroporated at E14.5. Scale bars: 40 μm. (PDF 210 kb)

microRNAs (miRNAs) play a vital role in development via the post-transcriptional regulation of most genes. Variation in the miRNA machinery pathway proteins which mediate the biogenesis, maturation, transportation, and functioning of miRNAs might be relevant to human traits. In this work, we explored the role of 59 miRNA machinery genes in schizophrenia (SZ). Association analysis of 967 single nucleotide polymorphisms within these genes detected that an intronic polymorphism of EIF4ENIF1, rs7289941, was significantly associated with SZ (P=4.10E-5). We failed to replicate this result in a validation sample comprising 1027 healthy controls and 1012 SZ cases, and the combined data yielded nominal significance (P=0.013). We conducted a gene-based association analysis using VEGAS and SKAT, and found seven associated genes in total, including EIF4ENIF1, PIWIL2, and DGCR8, but none survived correction for multiple testing. Taken together, our data do not provide strong support for the association of common variants within miRNA machinery genes with SZ in the Han Chinese population, but implicate several promising candidate genes for further research.

Radial migration of pyramidal neurons is an important event during the development of cerebral cortex. Neurons experience series of morphological and directional transitions to get to their final laminar positions. Here we report that the histone methyltransferase enhancer of zest homolog 2 (Ezh2) is involved in the regulation of cortical radial migration. We show that Ezh2 knockdown leads to disturbed neuronal orientation, which results in the impairment of radial migration. Further results reveal that this migration deficiency may be due to the derepression of Reelin transcription in the migrating neurons. Our study provides evidence that epigenetic regulation of Reelin by Ezh2 maintains appropriate Reelin expression pattern to fulfill proper orientation of migrating neurons.

Autism spectrum disorder (ASD) is a group of severe neurodevelopmental disorders. Epigenetic factors play a critical role in the etiology of ASD. Enhancer of zest homolog 2 (EZH2), which encodes a histone methyltransferase, plays an important role in the process of chromatin remodeling during neurodevelopment. Further, EZH2 is located in chromosome 7q35-36, which is one of the linkage regions for autism. However, the genetic relationship between autism and EZH2 remains unclear. To investigate the association between EZH2 and autism in Chinese Han population, we performed a family-based association study between autism and three tagged single nucleotide polymorphisms (SNPs) that covered 95.4% of the whole region of EZH2. In the discovery cohort of 239 trios, two SNPs (rs740949 and rs6464926) showed a significant association with autism. To decrease false positive results, we expanded the sample size to 427 trios. A SNP (rs6464926) was significantly associated with autism even after Bonferroni correction (p=0.008). Haplotype G-T (rs740949 and rs6464926) was a risk factor for autism (Z=2.655, p=0.008, Global p=0.024). In silico function prediction for SNPs indicated that these two SNPs might be regulatory SNPs. Expression pattern of EZH2 showed that it is highly expressed in human embryonic brains. In conclusion, our findings demonstrate that EZH2 might contribute to the genetic etiology of autism in Chinese Han population.

GM1 ganglioside was reported to mediate the amyloid beta-protein (Abeta) secretion and accumulation in the pathogenesis of Alzheimer's disease (AD). The objective of this project was to comprehend the underlying molecular changes related to amyloid beta-protein precursor (APP) processing pathway induced by GM1. Using suppression subtractive hybridisation (SSH), we detected one prominent sequence with increased expression in human neuroblastoma cells that stably transfected with human APP695 cDNA treated with GM1. This transcript has high identity to human Ubiquilin 1 gene. Differential expression was initially confirmed by dot blot hybridization. This result was further authenticated with quantitative real-time polymerase chain reaction (RT-PCR) analysis. Furthermore, using Western blots, we discovered that GM1 stimulated the expression of Ubiquilin 1 in human neuroblastoma cells and rat cortical neurons while other gangliosides Asialo-GM1 and GD1b did not. Ubiquilin 1 is one of the candidate genes of AD, which have been shown to modulate the gamma-secretase components in the proteolytic processing of APP, and is therefore a putative candidate for further investigation of GM1 mechanisms in the etiology and pathology of AD.

Plaques containing amyloid beta-peptides (Abeta) are a major feature in Alzheimer's disease (AD), and GM1 ganglioside is an important component of cellular plasma membranes and especially enriched in lipid raft. GM1-bound Abeta (GM1/Abeta), found in brains exhibiting early pathological changes of AD including diffuse plaques, has been suggested to be involved in the initiation of amyloid fibril formation in vivo by acting as a seed. However, the role of GM1 in amyloid beta-protein precursor (APP) processing is not yet defined. In this study, we report that exogenous GM1 ganglioside promotes Abeta biogenesis and decreases sAPPalpha secretion in SH-SY5Y and COS7 cells stably transfected with human APP695 cDNA without affecting full-length APP and the sAPPbeta levels. We also observe that GM1 increases extracellular levels of Abeta in primary cultures of mixed rat cortical neurons transiently transfected with human APP695 cDNA. These findings suggest a regulatory role for GM1 in APP processing pathways.

A number of studies have indicated that 8p22-p12 is likely to harbor schizophrenia susceptibility loci. In this region, the candidate gene of interest, neuregulin 1 (NRG1), may play a role in the pathogenesis of schizophrenia. Then in the present study, we performed the linkage disequilibrium to determine the association between three genetic variants (SNPs: rs3924999, rs2954041, SNP8NRG221533) on NRG1 gene and schizophrenia in 246 Chinese Han schizophrenic family trios using PCR-based restriction fragment length polymorphism method and denaturing high-performance liquid chromatography. The transmission disequilibrium test analysis for each variant showed a significant difference between two transmitted alleles even after Bonferroni correction (rs3924999, P=0.007752; rs2954041, P=0.0009309; SNP8NRG221533, P=0.012606). The global chi(2) test for haplotype transmission also revealed a strong association (chi(2)=46.068, df=7, P&

Autism is a pervasive neurodevelopmental disorder. CDK5 (cyclin-dependent kinase 5) and its interacting molecules are involved in neurodevelopment. We performed a family-based association analysis between CDK5, NDEL1, and LIS1 polymorphisms and autism in a Chinese Han population. Our study did not detect a significant association. It indicated that common genetic variations in these genes might not play a role in the genetic predisposition to autism.

Objective To investigate the effects of anteroposterior cricoid spliting interposition costal grafting for moderate and severe laryngotracheal stenosis in children. Methods From 1995 to 2005, 87 children (aged 1.2 to 14 years) with moderate and severe glottic and subglottic stenosis were retrospectively studied. They were operated with cricoid spliting laryngotracheal reconstruction in our hospital. All of 87 patients were tracheostomy-dependent before surgery. Results Eighty-five patients (95%) were successfully decannnulated and got an effective phonation. The follow-up time was more than 5 years. The effect of operation was satisfactory and the growth and development of children was normal. Conclusion Anteroposterior cricoid split interposition costal cartilage graft is a safe and effective treatment method for moderate and severe glottic and subglottic stenosis in children.

Schizophrenia (SZ) is a severe mental disorder characterized by multiple neurodevelopmental dysfunctions including a breakdown of thinking process and a deficit of typical emotional responses. Ataxin-2 (ATXN2) plays vital roles in cell proliferation and growth, and functional mutations of ATXN2 cause neurodegenerative phenotypes, including spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). To explore the possible role of ATXN2 in SZ, we conducted a two-stage study to examine the association of ATXN2 polymorphisms with SZ in the Han Chinese population. Association analysis of seven SNPs in 768 patients and 1348 controls revealed two associated SNPs, including rs630511 (P=1.76E-4) and rs7969300 (P=5.08E-4). We examined these two SNPs in a validation sample of 1957 patients and 1509 controls, and observed an association of rs7969300 with SZ (P=5.03E-3). The SNP rs7969300 is a non-synonymous SNP causing a Ser to Asn substitution, which is predicted to increase the protein stability of ATXN2. Our data suggest that the ATXN2 gene may confer vulnerability for SZ, adding further evidence for the genetic variants within the developmental pathway in the illness.

Schizophrenia (SZ) is a neurodevelopmental disorder in which altered immune function typically plays an important role in mediating the effect of environmental insults and regulation of inflammation. The breast cancer suppressor protein associated protein (BRAP) is suggested to exert vital effects in neurodevelopment by modulating the mitogen-activated protein kinase cascade and inflammation signaling. To explore the possible role of BRAP in SZ, we conducted a two-stage study to examine the association of BRAP polymorphisms with SZ in the Han Chinese population. In stage one, we screened SNPs in BRAP from our GWAS data, which detected three associated SNPs, with rs3782886 being the most significant one (P = 2.31E-6, OR = 0.67). In stage two, we validated these three SNPs in an independently collected population including 1957 patients and 1509 controls, supporting the association of rs3782886 with SZ (P = 1.43E-6, OR = 0.73). Furthermore, cis-eQTL analysis indicates that rs3782886 genotypes are associated with mRNA levels of aldehyde dehydrogenase 2 family (ALDH2) (P = 0.0039) and myosin regulatory light chain 2 (MYL2) (P < 1.0E-4). Our data suggest that the BRAP gene may confer vulnerability for SZ in Han Chinese population, adding further evidence for the involvement of developmental and/or neuroinflammatory cascades in the illness.

Growing evidence suggests that the methylenetetrahydrofolate reductase (MTHFR) may play a role in the pathogenesis of schizophrenia. Recent studies suggested that the MTHFR 677T, as a risk allele, has an impact on brain activation and memory function in schizophrenia patients. To confirm further the association between this functional polymorphism and schizophrenia, we detected genotypes of MTHFR C677T polymorphism in 1002 schizophrenic patients and 1036 controls of Chinese Han population, by using direct DNA sequencing method. To explore further effects of MTHFR C677T polymorphism on memory and brain function in schizophrenia, 33 schizophrenia patients and 29 healthy participants were selected from above samples to be assessed with MRI scanning and episodic memory (EM) examination. The case-control association study results showed that the MTHFR C677T was associated with schizophrenia ( χ 2 = 14.11, P = 1.74 × 10 −4 , OR = 0.79; 95% CI = 0.70–0.89). We also found that the MTHFR 677T allele had a load-dependent effect on EM in schizophrenic patients, but not in healthy control participants. Further analysis on gray matter density (GMD) revealed significant diagnostic effects in bilateral frontal cortices, bilateral insula, left medial temporal cortex and bilateral occipital cortices, effects of MTHFR genotype in the right insula, right inferior frontal gyrus, right rolandic opercula, right parahippocampal gyrus and right medial temporal pole, and effects of genotype-diagnosis interaction in the right temporal gyrus. Our findings suggested that the MTHFR 677T allele might have effect on risk of schizophrenia, memory impairment and GMD changes in patients.

Chromosome 6p21-p22.1, spanning the extended major histocompatibility complex (MHC) region, is a highly polymorphic, gene-dense region. It has been identified as a susceptibility locus of schizophrenia in Europeans, Japanese, and Chinese. In our previous two-stage genome-wide association study (GWAS), polymorphisms of zinc finger with KRAB and SCAN domains 4 (ZKSCAN4), nuclear factor-κB-activating protein-like (NKAPL), and piggyBac transposable element derived 1 (PGBD1), localized to chromosome 6p21-p22.1, were strongly associated with schizophrenia. To further investigate the association between polymorphisms at this locus and schizophrenia in the Chinese Han population, we selected eight other single-nucleotide polymorphisms (SNPs) distributed in or near these genes for a case-control association study in an independent sample of 902 cases and 1,091 healthy controls in an attempt to replicate the GWAS results. Four of these eight SNPs (rs12214383, rs1150724, rs3800324, and rs1997660) displayed a nominal difference in allele frequencies between the case and control groups. The association between two of these SNPs and schizophrenia were significant even after Bonferroni correction (rs12000: allele A>G, P = 2.50E-04, odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.12-1.45; rs1150722: allele C>T, P = 4.28E-05, OR = 0.55, 95% CI = 0.41-0.73). Haplotype ATTGACGC, comprising these eight SNPs (rs2235359, rs2185955, rs12214383, rs12000, rs1150724, rs1150722, rs3800324, and rs1997660), was significantly associated with schizophrenia (P = 6.60E-05). We also performed a combined study of this replication sample and the first-stage GWAS sample. The combined study revealed that rs12000 and rs1150722 were still strongly associated with schizophrenia (rs12000: allele G>A, P(combined) = 0.0019, OR = 0.81; rs1150722: allele G>A, P(combined) = 3.00E-04, OR = 0.61). These results support our findings that locus 6p21-p22.1 is significantly associated with schizophrenia in the Chinese Han population and encourage further studies of the functions of these genetic factors.

Aims: Genetics play a major role in the etiology of schizophrenia (SZ). Catechol-O-methyltransferase (COMT) is one of the promising candidate genes for SZ. A nonsynonymous single-nucleotide polymorphism (SNP), rs4680, causing a Valine (Val) to Methionine (Met) substitution, has been widely studied in relation to psychiatric phenotypes, including SZ, but with conflicting results. We conducted a two-stage study to examine the association of COMT polymorphisms with SZ in the Han Chinese population. Results: Association analysis of nine SNPs in 768 patients and 1348 controls failed to detect any positive markers or haplotypes. Then, we tested rs4680 in a validation sample of 963 patients and 992 controls, and no significant association was observed, but the cases significantly deviated from Hardy–Weinberg equilibrium (p=5.7e-4). There was no association of rs4680 with SZ in the combined sample (n=4071, p=0.110, odds ratio=1.08). Conclusions: Our results do not support the association of COMT with SZ in the Han Chinese population.

Myosin Vb (MYO5B) has recently been implicated in the etiology of bipolar disorder in a genome-wide association study (GWAS). This gene is involved in amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit glutamate receptor 1 (GluR1) recycling and plays an important role in the primary excitatory neurotransmission. Dysfunction of the brain glutamate system has been postulated to be involved in the pathophysiology in schizophrenia. To further investigate the association between MYO5B polymorphisms and schizophrenia, we genotyped nine single nucleotide polymorphisms (SNPs) in an independent sample of 1463 individuals with schizophrenia and 1563 healthy control subjects, and detected three SNPs and two haplotype blocks which displayed significant association with schizophrenia. This association was further strengthened by the results of meta-analysis. Our data strongly supported that the MYO5B gene might be associated with schizophrenia in the Chinese Han population and they have implications for understanding the glutamate hypothesis of schizophrenia.

To discuss the function and operative method of silicon T tube in laryngotracheal reconstruction.Two hundred and ninety-seven patients of laryngotracheal stenosis were operated with laryngotracheal reconstruction in our department. All of patients were tracheostomy dependent before reconstruction and were placed a silicon T-tube stenting for 3 to 6 months after reconstruction.Two hundred and eighty-nine patients (97.3%) were successfully decannulated with good airway patency and effective phonation. They were followed up from 1 to 10 years, and no recurrence was found.Silicon T-tube is an effective and safe stent for laryngotracheal reconstruction. Paying attention to some application details may avoid the complication and obtain a satisfactory effect.

Objectives/Hypothesis: To investigate and treat the late complications of using nickel–titanium alloy stents in laryngotracheal, bronchial, and esophageal stenosis patients who developed severe laryngotracheal stenosis (SLS). Study Design: Retrospective clinical study. Methods: Thirteen patients with SLS or tracheoesophageal fistula secondary to insertion of a nickel–titanium alloy stent for treatment of laryngotracheal, bronchial, or esophageal stenosis treated between May 2004 and March 2010 were retrospectively analyzed. Of the 13 total patients, nine had one stent placed, and four had two stents placed. The late complications observed were glottic and/or subglottic extension of cervical tracheal stenosis (n = 6), new stricture of the thoracic trachea (n = 4), severe left bronchial stricture with massive left pulmonary collapse (n = 1), and cervical tracheoesophageal fistula (n = 2). Results: Six patients with glottic and/or subglottic to cervical tracheal stenosis underwent successful laryngotracheal reconstruction. Two patients with subglottic and upper thoracic tracheal stenosis were successfully treated by staged operation for the stenosis. Two patients with subglottic and distal thoracic tracheal stenosis are still undergoing treatment. One patient with severe left bronchial stricture and massive left pulmonary collapse has been treated but has not achieved full recovery. One patient with cervical tracheoesophageal fistula underwent successful repair but died later from metastatic disease. One patient with tracheoesophageal fistula died from massive hemorrhage and asphyxiation induced by the stent, which had not been removed. Conclusions: The nickel–titanium alloy stents should be used with extreme caution in patients with laryngotracheal, bronchial, or esophageal stenosis treatment that can be corrected by surgical therapy. Laryngoscope, 2012

To assess the outcomes of laryngotracheal reconstruction using thyroid alar cartilage grafting in adult patients with laryngotracheal stenosis.Case series with chart review.Tertiary university hospital.Twelve adults who underwent thyroid alar cartilage graft laryngotracheal reconstruction from April 1997 to April 2009 for laryngotracheal stenosis were analyzed. The mean age of the study population was 29 years. Using the Myer-Cotton grading system, 3 patients had grade II stenosis, 7 had grade III, and 2 had grade IV. Seven of the 12 patients had subglottic stenosis, 3 had tracheal stenosis, and 2 had subglottic and upper tracheal stenosis.Nine of 12 (75%) patients were decannulated. Of the patients in whom laryngotracheal reconstruction failed, 2 had grade IV stenosis and 1 had severe grade III stenosis with a long segment of stenotic tissue. The postoperative complications were hematoma of the left laryngeal ventricle at the donor site in 1 patient, granulation tissues in the supraglottic and suprastomal region and at the graft site in 4 patients, and neck wound infection in 1 patient. Ossification of the thyroid alar cartilage was observed in 2 patients. A Ttube remained in situ for 6 to 18 months.Laryngotracheal reconstruction with thyroid alar cartilage graft could be a viable alternative for the treatment of laryngotracheal stenosis in adults. However, it should be used only in cases of limited and minor subglottic or tracheal stenosis.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders. Recent studies suggested that calcium channel genes might be involved in the genetic etiology of ASD. CACNA1A, encoding an alpha-1 subunit of voltage-gated calcium channel, has been reported to play an important role in neural development. Previous study detected that a single nucleotide polymorphism (SNP) in CACNA1A confers risk to ASD in Central European population. However, the genetic relationship between autism and CACNA1A in Chinese Han population remains unclear. To explore the association of CACNA1A with autism, we performed a family-based association study. First, we carried out a family-based association test between twelve tagged SNPs and autism in 239 trios. To further confirm the association, the sample size was expanded to 553 trios by recruiting 314 additional trios. In a total of 553 trios, we identified association of rs7249246 and rs12609735 with autism though this would not survive after Bonferroni correction. Our findings suggest that CACNA1A might play a role in the etiology of autism.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with a strong genetic component. Many lines of evidence indicated that ASD shares common genetic variants with other psychiatric disorders (for example, schizophrenia). Previous studies detected that calcium channels are involved in the etiology of many psychiatric disorders including schizophrenia and autism. Significant association between CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit) and schizophrenia was detected. Furthermore, rare mutation in CACNA1C is suggested to cause Timothy syndrome, a multisystem disorder including autism-associated phenotype. However, there is no evidence for association between CACNA1C and autism in Chinese Han population. To investigate the association between single nucleotide polymorphisms (SNP) in CACNA1C and autism, we first performed a family-based association study between eighteen SNPs in CACNA1C and autism in 239 trios. All SNPs were genotyped by using Sequenom genotyping platform. Two SNPs (rs1006737 and rs4765905) have a trend of association with autism. To further confirm the association between these two SNPs with autism, we expanded the sample size to 553 trios by adding 314 trios. Association analyses for SNPs and haplotype were performed by using family-based association test (FBAT) and Haploview software. Permutation tests were used for multiple testing corrections of the haplotype analyses (n=10,000). The significance level for all statistical tests was two-tailed (p

To evaluate the possibility and reliability of platysma pedicle flap transfer in the correction of hypopharynx stenosis,and delineate the operation skills and clinical results.Ten patients with hypopharynx stenosis underwent hypopharynx reconstruction using platysma pedicle flap.Nine of these patients had been decannulated successfully with good airway patency, good pronunciation and a good swallow.Platysma pedicle flap transfer was a single stage reconstruction, relatively simple procedure and less complication that can restore an adequate airway and a good swallow. The results indicate that the platysma pedicle flap is an ideal transplant for hypopharynx reconstruction. This method is simple, safe and reliable.

To investigate the effects of anteroposterior cricoid split interposition grafting on children with laryngotracheal stenosis.This is a retrospective study, from 1991 to 2001 years, 12 children (aged 6 years to 15 years) with laryngotracheal stenosis were operated with cricoid split laryngotracheal reconstruction at our hospital. All of 12 patients were tracheostomy dependent before reconstruction.Eleven patients (91.7%) were successfully decannulated with good airway patency and effective phonation. The follow-up period ranged from 1 to 10 years. The effect of operation is steady and the growth and development of children is normal.The anteroposterior cricoid split interposition grafting was a safe and effective method for treatment of laryngotracheal stenosis in children.

To study the success and failure factors with rib cartilage graft laryngotracheal reconstruction for severe laryngotracheal stenosis for improving the rate of successful decannulation.Thirty-six cases with severe laryngotracheal stenosis, received rib cartilage graft for laryngotracheal reconstruction during the last 18 years in our hospital, were analyzed retrospectively.Twenty-nine of the 36 patients (80.5%) were successfully decannulated after one procedure. The follow-up time ranged from 1 to 10 years. All of the 29 patients had a stable airway and normal exercise tolerance. The duration of T-tube stent was 10 days to one year (average 3 months). Seven patients (19.5%) failed to decannulate. The factors of failure were disturbance of local blood circulation, wound infection followed rib necrosis, T-tube injured mucomembrane then became a new stenosis, and restenosis for scar constitution.Laryngotracheal reconstraction with rib cartilage graft is one of effective method for severe laryngotracheal stenosis. The procedure is relatively simple, and shorter duration of stenting and higher rate of success. The drawbacks of this technique are ischemia necrosis easily occurred for isolated cartilage and required additional surgery for the donor sit. The patient with scar constitution or undertaken radiotherapy is contraindications. All the managements, appropriate selection of patients, diligent postoperative care, prevented wound infection and using T-tube properly, may increase the rate of successful decannulation. PJP].

BACKGROUND:Autism is a neurodevelopmental disorder with a high estimated heritability. ATP2B2, located on human chromosome 3p25.3, encodes the plasma membrane calcium-transporting ATPase 2 which extrudes Ca(2+) from cytosol into extracellular space. Recent studies reported association between ATP2B2 and autism in samples from Autism Genetic Resource Exchange (AGRE) and Italy. In this study, we investigated whether ATP2B2 polymorphisms were associated with autism in Chinese Han population. METHODS:We performed a family based association study between five SNPs (rs35678 in exon, rs241509, rs3774180, rs3774179, and rs2278556 in introns) in ATP2B2 and autism in 427 autism trios of Han Chinese descent. All SNPs were genotyped using the Sequenom genotyping platform. The family-based association test (FBAT) program was used to perform association test for SNPs and haplotype analyses. RESULTS:This study demonstrated a preferential transmission of T allele of rs3774179 to affected offsprings under an additive model (T>C, Z = 2.482, p = 0.013). While C allele of rs3774179 showed an undertransmission from parents to affected children under an additive and a dominant model, respectively (Z = -2.482, p = 0.013; Z = -2.591, p = 0.0096). Haplotype analyses revealed that three haplotypes were significantly associated with autism. The haplotype C-C (rs3774180-rs3774179) showed a significant undertransmission from parents to affected offsprings both in specific and global haplotype FBAT (Z = -2.037, p = 0.042; Global p = 0.03). As for the haplotype constructed by rs3774179 and rs2278556, C-A might be a protective haplotype (Z = -2.206, p = 0.027; Global p = 0.04), while T-A demonstrated an excess transmission from parents to affected offsprings (Z = 2.143, p = 0.032). These results were still significant after using the permutation method to obtain empirical p values. CONCLUSIONS:Our research suggested that ATP2B2 might play a role in the etiology of autism in Chinese Han population.

Background Loss of function mutations in RAB18, has been identified in patients with the human neurological and developmental disorder Warburg Micro syndrome. However, the function of RAB18 in brain remains unknown. Results In this study, we report that RAB18 is a critical regulator of neuronal migration and morphogenesis. Using in utero electroporation suppression of RAB18 in the mouse brain impairs radial migration. Overexpression of dominant negative RAB18 or disruption of RAB3GAP (RAB18GEF) also results in delayed neuronal migration in the developing mouse cortex and inhibition of neurite growth in vitro. Moreover, loss of RAB18 induces an acceleration of N-cadherin degradation by lysosomal pathway resulting in the decrease of surface level of N-cadherin on neurons. Conclusions RAB18 regulates neuronal migration and morphogenesis during development. Our findings highlight the critical role of RAB3GAP-RAB18 pathway in the developing cerebral cortex and might explain some of clinical features observed in patients with Warburg Micro syndrome. Electronic supplementary material The online version of this article (doi:10.1186/s13041-016-0198-2) contains supplementary material, which is available to authorized users.

Background Recent research has implicated that mutations in the neurexin-1 (NRXN1) gene on chromosome 2p16.3 might play a role in schizophrenia, autism, and nicotine dependence. In order to explore the association of NRXN1 polymorphisms with schizophrenia, we made a case-control association study in Chinese Han population. Methods We examined six tag single nucleotide polymorphisms (SNPs) spanning 116.7 kb of NRXN1 in 768 schizophrenic patients and 738 healthy control subjects. The association of NRXN1 polymorphisms with schizophrenia and the age-at-onset of this disease were explored. Results Our results showed that four SNPs of NRXN1 gene were significantly associated with schizophrenia (rs10490168: G > A, p = 0.017; rs2024513: A > G, p = 0.006; rs13382584: T > C, p = 0.009; and rs1558852: G > A, p = 0.031). Furthermore, the association of SNP rs2024513 with schizophrenia remained significance after the Bonferroni correction. Haplotypes consisting of above six SNPs also showed significantly associated with schizophrenia (global chi-square = 14.725, p = 0.022). A protective haplotype AGTGCA remained associated with schizophrenia, even after 10,000 permutation tests (empirical p-value = 0.043). However, we did not find any association with age-at-onset of schizophrenia with NRXN1 polymorphisms. Conclusions Our findings suggest that NRXN1 might represent a major susceptibility gene for schizophrenia in Chinese Han population.