Parental alcohol use and brain volumes in early- and late-onset alcoholics.

BACKGROUND: Studies have shown that alcoholics have smaller brain volumes than non-alcoholic cohorts, but an effect of family history (FH) of heavy drinking on brain volume has not been demonstrated. We examined the relationship between an FH of heavy drinking and both brain shrinkage as measured by the ratio of brain volumes to intracranial volume (ICV) as well as maximal brain growth as measured by ICV in early-onset and late-onset alcoholics. METHODS: With T1-weighted resonance imaging, we measured ICV, brain volume, and white and gray matter volume in adult treatment-seeking late-onset and early-onset alcoholics with either a positive or a negative FH of heavy alcohol use, and in healthy control subjects. We also calculated brain shrinkage using a ratio of soft tissue volumes to ICV. RESULTS: The FH positive alcoholic patients had significantly smaller ICVs than FH negative patients, suggesting smaller premorbid brain growth. Brain shrinkage did not correlate with FH. Late-onset alcoholics showed a greater difference in ICV between FH positive and FH negative patients than early-onset alcoholics. Late-onset FH positive patients also had significantly lower IQ scores than late-onset FH negative patients, and IQ scores were correlated with ICV. CONCLUSIONS: These data provide evidence that parental alcohol use might increase risk for alcoholism in offspring in part by a genetic and/or environmental effect that might be related to reduced brain growth.     

C2H2-171 : A novel human cDNA representing a developmentally regulated poz domain/zinc finger protein preferentially expressed in brain

We describe a novel human zinc finger cNDA, C2H2-171. This cDNA represents an mRNA which encodes a protein of 484 amino acids and a calculated molecular weight of 54 kD. Four zinc finger-like domains are found in the C-terminal end of the protein. At the N-terminus, C2H2-171 contains a POZ/tramtrack-like domain similar to that found in the tumor associated zinc finger proteins LAZ-3/BCL-6 and PLZ-F, as well as in non-zinc finger proteins. C2H2-171 RNA is preferentially expressed in the brain, and increases during the course of murine development, with maximal expression in the adult. C2H2-171 RNA is differentially expressed in brain regions, with the highest level of expression in the cerebellum. C2H2-171 RNA was expressed at high levels in primary cerebellar granule cell neurons compared to astrocytes. The gene encoding C2H2-171 is highly conserved in vertebrates, and maps to the terminus of human chromosome 1 (1q44-ter). This chromosomal location is associated with a number of cytogenetic aberrations including those involving brain developmental anomalies and tumorigenesis. These data suggest that C2H2-171 may play an important role in vertebrate brain development and function.     

Neuropathology of schizophrenia: A mini review

The neuropathology of schizophrenia remains obscure despite the fact that many neuropathologists have investigated this area for over 100 years. While remarkable progress has been made in the neuropathological study of neurodegenerative diseases including Alzheimer's disease, progress in studying the neuropathological entity of schizophrenia has not kept pace; the phrase “schizophrenia is the graveyard of neuropathologists” has been stated in the field. Since the 1980s, the morphological or functional abnormalities in the brains of schizophrenia patients have been reported by means of CT or MRI and with advanced functional brain image technology such as positron emission tomography or single photon emission computed tomography. Results from such imaging studies have led to neuropathological examination of the post mortem brains of schizophrenia patients being undertaken again. These neuroimaging studies have influenced the neuropathological investigation of the schizophrenic brain. Not only the classical microscopic observation of neuropathology, but also measurement and statistical analysis using computer imaging software or using immunohistological techniques has been performed. Based on the neuropathological studies of schizophrenia over the last 20 years, it is clear that schizophrenia is not a pure functional disease without organic factors. Reports of neuropathological abnormalities in the post mortem schizophrenic brain indicated they were found in almost all areas of the brain, but there are more reports describing the temporal lobe and frontal lobe compared to those describing other areas of the brain. These observed neuropathological abnormalities are explained rationally by the hypothesis of a neurodevelopmental disorder in this disease. In recent molecular biology studies, several putative candidate genes were reported, and some of these genes might have the function of neurodevelopment or making neuronal networks. It is important to consider together these findings with morphometric studies in neuropathological observation, neuroimaging studies and genome studies to pursue the etiology of schizophrenia from various perspectives.     

A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions.

Disrupted-In-Schizophrenia-1 (DISC1) is a promising candidate gene for schizophrenia (SZ) and bipolar disorder (BP), but its basic biology remains to be elucidated. Accumulating genetic evidence supports that DISC1 is associated with some aspects of cognitive functions relevant to SZ and BP. Here, we provide a summary of the current updates in biological studies of DISC1. Disrupted-In-Schizophrenia-1, preferentially expressed in the forebrain, has multiple isoforms with potential posttranslational modifications. Disrupted-In-Schizophrenia-1 protein occurs in multiple subcellular compartments, which include the centrosome, microtubule fractions, postsynaptic densities, actin cytoskeletal fractions, the mitochondria, and the nucleus. Recent studies have clarified that DISC1 mediates at least centrosome-dynein cascade and cyclic adenosine monophosphate (cAMP) signaling. Furthermore, both cytogenetic and cell biological studies consistently suggest that an overall loss of DISC1 function (either haploinsufficiency or dominant-negative, or both) may be associated with SZ and BP. On the basis of these findings, production of DISC1 genetically engineered mice is proposed as a promising animal model for SZ and BP. Several groups are currently generating DISC1 mice and starting to characterize them. In this review, the advantages and disadvantages of each animal model are discussed.     

Pituitary volume in pediatric obsessive-compulsive disorder.

BACKGROUND: Abnormalities in the limbic-hypothalamic-pituitary-adrenal (LHPA) axis have been implicated in the pathogenesis of obsessive-compulsive disorder (OCD). To our knowledge, however, no prior study has measured pituitary gland volume in OCD. METHODS: Volumetric magnetic resonance imaging studies were conducted in 31 psychotropic drug-na?ve children (10 boys, 21 girls) aged 8-17 years and 31 case-matched healthy comparison subjects. RESULTS: Pituitary volume was significantly smaller in patients with OCD as compared with healthy control subjects (11% smaller). Smaller pituitary volume in patients with OCD was associated with increased compulsive but not obsessive symptom severity. Boys with OCD had smaller pituitary gland volumes compared with control boys (20% smaller). No significant differences in pituitary volume were observed between girls with OCD and control girls. Boys with OCD had significantly smaller pituitary volumes than girls with OCD (31% smaller), whereas control boys also had smaller pituitary gland volumes compared with control girls (21% smaller). CONCLUSIONS: These findings provide new evidence of reduced pituitary volume in pediatric OCD that seems to be more prominent in male patients. The observed alterations in pituitary volume are consistent with neuroendocrine studies that have reported abnormalities in the LHPA axis in OCD.     

SOX5: Lamb–Shaffer syndrome—A case series further expanding the phenotypic spectrum

To delineate further the clinical phenotype of Lamb–Shaffer Syndrome (LSS) 16 unpublished patients with heterozygous variation in SOX5 were identified either through the UK Decipher database or the study team was contacted by clinicians directly. Clinical phenotyping tables were completed for each patient by their responsible clinical geneticist. Photos and clinical features were compared to assess key phenotypes and genotype–phenotype correlation. We report 16 SOX5 variants all of which meet American College of Medical Genetics/Association for Clinical Genomic Science ACMG/ACGS criteria class IV or V. 7/16 have intragenic deletions of SOX5 and 9/16 have single nucleotide variants (including both truncating and missense variants). The cohort includes two sets of monozygotic twins and parental gonadal mosaicism is noted in one family. This cohort of 16 patients is compared with the 71 previously reported cases and corroborates previous phenotypic findings. As expected, the most common findings include global developmental delay with prominent speech delay, mild to moderate intellectual disability, behavioral abnormalities and sometimes subtle characteristic facial features. We expand in more detail on the behavioral phenotype and observe that there is a greater tendency toward lower growth parameters and microcephaly in patients with single nucleotide variants. This cohort provides further evidence of gonadal mosaicism in SOX5 variants; this should be considered when providing genetic counseling for couples with one affected child and an apparently de novo variant.     

Fronto-limbic white matter microstructural changes in psychiatrically healthy adults with childhood trauma

Childhood trauma (CT) may influence brain white matter microstructure; however, few studies have examined the differential impact of distinct CT types on white matter microstructure in psychiatrically healthy adults living in a developing country. In adults without significant medical or psychiatric disorders, we investigated the association(s) between CT, including abuse and neglect, and fractional anisotropy (FA) of limbic tracts previously shown to be associated with CT. Participants underwent diffusion tensor imaging and completed the Childhood Trauma Questionnaire. Multivariate analysis of variance models were used to test the effects of total overall CT, as well as CT subtypes, on FA in six fronto-limbic tracts, adjusting for age, sex, and educational level. The final sample included 69 adults (age 47 ± 17 years; 70% female). Overall, CT had a significant main effect on FA for tracts of interest (p < .001). Greater CT severity was associated with lower FA for the bilateral and left stria terminalis (uncorrected) as well as the bilateral, left, and right anterior limb of the internal capsule (ALIC; corrected). Exposure to total non-violent/deprivational trauma specifically was associated with lower FA of the bilateral, left, and right ALIC, suggesting that distinct types of CT are associated with differential white matter changes in apparently healthy adults. The ALIC predominantly carries fibers connecting the thalamus with prefrontal cortical regions. Microstructural alterations in the ALIC may be associated with functional brain changes, which may be adaptive or increase the risk of accelerated age-related cognitive decline, maladaptive behaviors, and subsyndromal psychiatric symptoms.     

去水卫矛醇对斑马鱼神经发育毒性评价

目的 探讨去水卫矛醇(dianhydrogalactitol,DAG)诱导斑马鱼胚胎及幼鱼神经发育毒性作用及其机制。方法 在一般毒性评价的基础上,对斑马鱼胚胎进行相应的分组暴露给药,采用幼鱼的自主运动反应、光照刺激反应等试验观察DAG对斑马鱼神经及行为的影响;通过脑部组织病理学检查、吖啶橙染色,观察DAG对斑马鱼脑部的组织影响;利用实时荧光定量PCR方法测定斑马鱼幼鱼体内多巴胺神经元相关基因(DAT、TH、GCH1)及神经抑/促凋亡相关基因(Bax、Bcl-2)的相对表达量。结果 DAG在20,40,75 mg·mL^-1下能明显抑制斑马鱼的自主运动,且自主运动抑制率呈现明显的浓度相关性;DAG在20,40,75 mg·mL^-1下对斑马鱼反应速度有较明显的抑制作用,反应能力下降率呈现浓度相关性;DAG各浓度组斑马鱼脑组织形态变小,但组织结构均未见显著异常;采用吖啶橙染色检测斑马鱼整体胚胎细胞凋亡情况,发现给药组头部绿色荧光比对照组明显,说明细胞凋亡增多,且细胞凋亡呈剂量依赖性增加,与表观一致;DAG在75,150,300,425,600 mg·L^-1下可导致斑马鱼幼鱼多巴胺能神经元相关基因DAT、TH、GCH1的mRNA相对表达量下调,Bax/Bcl-2的RNA相对表达量随着给药浓度增加而上升。结论 高浓度DAG对斑马鱼胚胎和幼鱼具有神经发育毒性作用,可能与多巴胺能神经元的抑制作用有关。     

硫酸软骨素蛋白聚糖的研究进展

硫酸软骨素蛋白聚糖（CSPGs）是硫酸软骨素（CS）和核心蛋白共价连接的糖复合物,存在于细胞表面和结缔组织中。近年来,CSPGs领域快速发展,CSPGs不仅作为软骨、椎间盘、脑和角膜等复杂基质的结构成分发挥作用,还可作用于多种生物活性分子,参与血管生成、炎症反应、肿瘤发生以及神经的发育和修复等生理病理过程。研究表明,CS糖链的种类、相对分子质量以及硫酸化程度等均会影响CSPGs的生物学功能。此外,CSPGs已被认为是肿瘤、中枢神经系统损伤等疾病治疗的靶点以及诊断潜在的生物标志物。按照CSPGs在细胞中的定位,对典型CSPGs的结构、功能及其作为疾病诊断和治疗靶点等生物学意义的最新研究进展进行综述,旨在为CSPGs在疾病治疗中的应用提供参考。