Autism,mutations, and the environment: insights from exome sequencing

References 1.Hallmayer J, Cleveland S, Torres A et al. Genetic heritability and shared environmental factors among twin pairs with utism. Arch Gen Psychiatry 2011 . DOI: 10.1001/archgenpsychiatry.2011.76. . Epub 4 July 2011. 2.Barak T, Kwan KY, Louvi A et al. Recessive LAMC3 mutations cause malformations of occipital cortical development. Nat Genet 2011 : 43 (6): 590–594. Epub 15 May 2011. 3.Zweier C, de Jong EK, Orrico A et al. CNTNAP2 and NRXN1 are mutated in autosomal‐recessive Pitt Hopkins‐like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet 2009 : 85 (5): 655–666. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations O'Roak et al. (2011) Nature Genetics 43(6):585–589. Epub 15 May 2011     

Genome-wide association study in German patients with attention deficit/hyperactivity disorder

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.     

Leu-8/CD7 antigen expression by CD3+ T cells: comparative analysis of skin and blood in mycosis fungoides/Sézary syndrome relative to normal blood values.

Deficiencies of Leu-8 and CD7 antigens are exhibited by CD3+ T cells in the skin lesions of most patients with mycosis fungoides/Sézary syndrome. To determine whether these antigenic abnormalities are limited to involved skin, we studied Leu-8/CD7 expression in 21 skin lesions of mycosis fungoides/Sézary syndrome obtained from 16 patients and compared them with their peripheral blood leukocytes obtained concurrently. There was no correlation between Leu-8/CD7 values in skin lesions versus blood. Blood values were relatively uniform; most patients had 50% or greater of CD3+, Leu-8+ T cells and CD3+, CD7+ T cells. In contrast, skin values were highly heterogeneous; most patients lacked expression of Leu-8 or CD7 by the majority of lesional CD3+ T cells. Furthermore, Leu-8/CD7 antigen deficiency was present in lesional skin in one patient with mycosis fungoides but not in her concurrently sampled pityriasis lichenoides chronica or blood. These findings suggest that Leu-8/CD7 antigen deficiencies in skin lesions of mycosis fungoides/Sézary syndrome do not represent generalized antigenic abnormalities of CD3+ T cells in other body compartments and that within the skin, these deficiencies are disease specific within individual patients with more than one dermatosis. Comparative peripheral blood immunophenotyping of the patients with mycosis fungoides/Sézary syndrome and of the control subjects indicated that the control ranges of CD3+/Leu-8+ and CD3+/CD7+ T cells (33% or greater) extend lower than reported previously (60% or greater) and suggested that leukemic involvement in patients with mycosis fungoides/Sézary syndrome may correlate with percentages of CD3+, Leu8+ and/or CD3+, CD7+ T cells that fall below the revised control range.     

Expression of bcl-2 protein and Ki-67 nuclear proliferation antigen in benign and malignant cutaneous T-cell infiltrates

The bcl-2 protein prolongs cell life by inhibiting apoptosis. Its expression has been studied in a variety of normal tissues and lymphomas but there is minimal information available concerning bcl-2 expression by benign and malignant cutaneous T-cells. Therefore, we investigated bcl-2 expression in a wide variety of cutaneous T-cell infiltrates using one- and two-color immunohistologic techniques, bcl-2 was expressed by the majority of lesional CD3⁺ T-cells in most cases. This included 22Departments of 26 cases of mycosis fungoides (MF), 3/3 cases of non-MF cutaneous T-cell lymphoma, 5/5 cases of lymphomatoid papulosis, 4/4 cases of T-cell rich cutaneous lymphoid hyperplasia, 2/3 cases of bullous pemphigoid, 2/2 cases of discoid lupus erythematosus and 1/1 case of lichen planus. Titration experiments and comparative studies of tonsil section positive controls revealed that, relative to mantle zone B-cells, there was over- expression of bcl-2 by a variable subset of T-cells in most cases. Assessment of multiple biopsies in a subset of MF cases showed stable expression of bcl-2 over intervals of up to two years. In contrast to the widespread expression of bcl-2 in both early and advanced MF skin lesions, abundant expression of the nuclear proliferation antigen, Ki-67, was skewed toward advanced MF skin lesions. Ten percnt or more Ki-67⁺ cells were present in 5% of patients with patches/thin plaques, 38% with moderate plaques, 64% with thick plaques and 100% with tumor nodules. Two-color immunohistologic analysis combined with molecular biologic analysis of clonality in the cases of T-cell rich cutaneous lymphoid hyperplasia indicated that bcl-2 expression was both a polyclonal and multi-lineage phenomenon, suggesting that it occurred by a physiologic rather than mutational mechanism. We conclude that bcl-2 expression is a common feature of cutaneous T-cell infiltrates that has minimal differential diagnostic value for distinguishing lymphomas from reactive T-cell infiltrates. In early MF lesions, abundant expression of bcl-2 and sparse expression of Ki-67 suggested that the accumulation of tumor cells during the initial progression of MF may be facilitated by prolonged clonal survival in conjunction with low-grade clonal proliferation.     

Long term functioning in early onset psychosis: Two years prospective follow-up study

Background

Neuroimaging technology has afforded advances in our understanding of normal and pathological brain function and development in children and adolescents. However, noncompliance involving the inability to remain in the magnetic resonance imaging (MRI) scanner to complete tasks is one common and significant problem. Task noncompliance is an especially significant problem in pediatric functional magnetic resonance imaging (fMRI) research because increases in noncompliance produces a greater risk that a study sample will not be representative of the study population.

Method

In this preliminary investigation, we describe the development and application of an approach for increasing the number of fMRI tasks children complete during neuroimaging. Twenty-eight healthy children ages 9-13 years participated. Generalization of the approach was examined in additional fMRI and event-related potential investigations with children at risk for depression, children with anxiety and children with depression (N = 120). Essential features of the approach include a preference assessment for identifying multiple individualized rewards, increasing reinforcement rates during imaging by pairing tasks with chosen rewards and presenting a visual 'road map' listing tasks, rewards and current progress.

Results

Our results showing a higher percentage of fMRI task completion by healthy children provides proof of concept data for the recommended tactics. Additional support was provided by results showing our approach generalized to several additional fMRI and event-related potential investigations and clinical populations.

Discussion

We proposed that some forms of task noncompliance may emerge from less than optimal reward protocols. While our findings may not directly support the effectiveness of the multiple reward compliance protocol, increased attention to how rewards are selected and delivered may aid cooperation with completing fMRI tasks

Conclusion

The proposed approach contributes to the pediatric neuroimaging literature by providing a useful way to conceptualize and measure task noncompliance and by providing simple cost effective tactics for improving the effectiveness of common reward-based protocols.     

Pervasive refusal syndrome. Three German cases provide further illustration

Pervasive refusal syndrome (PRS) has been proposed as a new diagnostic entity among child and adolescent psychiatric disorders. It is characterized by a cluster of life-threatening symptoms including refusal of hood intake, decreased or complete lack of mobilization, and lack of communication as well as retreat from normal life activities. Active refusal to accept help as well as neglect of personal care have been core features of PRS in the limited number of cases reported in the last decade. There have, however; been cases with predominantly passive resistance, indicating the possibility that there may be a continuum from active refusal to passive resistance within PRS. Postulating this continuum allows for the integration of "depressive devitalization" -- a refusal syndrome mainly characterized by passive resistance -- into the concept of PRS. Here, three case vignettes of adolescent patients with PRS are presented. The patients' symptomatology can be allocated on this continuum of PRS. PRS and dissociative disorders are compared in greater detail and contrasted within this discussion of differential diagnoses at the poles of such a continuum. PRS is a useful diagnosis for cases involving symptoms of predominating refusal and retreat which cannot satisfactorily be classified by existing diagnostic categories, and which can mostly clearly be separated from dissociative disorder.     

Pharmacotherapy in depressed children and adolescents

In children and adolescents, antidepressants are used in the treatment of depressive symptoms and several other psychiatric conditions. In the treatment of mild and moderate depressive symptoms, non-pharmacological approaches such as psychotherapy play a major role, a severe symptomatology may demand a combination with antidepressants. As first-choice medication for the treatment of juvenile depression, the selective serotonin reuptake inhibitor (SSRI) fluoxetine is recommended, due to its efficacy and approval. As second-choice antidepressants the SSRIs sertraline, escitalopram and citalopram might be used. Other antidepressants - such as tricyclic antidepressants, α(2)-adrenoceptor antagonists, selective noradrenalin reuptake inhibitors (SNRI) - may be alternatively used, but not as first- or second-choice medications. In the case of "off-label" use, patients and parents have to be carefully informed prior to the start of medication, after a thorough risk-benefit analysis. In the following overview we address a general framework, therapeutic strategies and the issues of antidepressant pharmacotherapy for the treatment of unipolar depression in childhood and adolescence.     

特质焦虑量表在农村自杀死亡及其对照组中的信度和效度评价

目的 检验特质焦虑量表在农村自杀研究中的信度和效度.方法 应用配对病例对照研究,在山东省疾病监测点上选取3个县(市)自2008年9月1日至2009年8月31日农村自杀死亡病例200例作为病例组,并按照同性别、年龄(±3岁)、当地居住者1:1配比选取正常对照组,用问卷调查和特质焦虑童表进行测评.结果 自杀死亡组和正常对照...