Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: Effects of environmental enrichment

Mental retardation in individuals with Down syndrome (DS) is thought to result from anomalous development and function of the brain; however, the underlying neuropathological processes have yet to be determined. Early implementation of special care programs result in limited, and temporary, cognitive improvements in DS individuals. In the present study, we investigated the possible neural correlates of these limited improvements. More specifically, we studied cortical pyramidal cells in the frontal cortex of Ts65Dn mice, a partial trisomy of murine chromosome 16 (MMU16) model characterized by cognitive deficits, hyperactivity, behavioral disruption and reduced attention levels similar to those observed in DS, and their control littermates. Animals were raised either in a standard or in an enriched environment. Environmental enrichment had a marked effect on pyramidal cell structure in control animals. Pyramidal cells in environmentally enriched control animals were significantly more branched and more spinous than non-enriched controls. However, environmental enrichment had little effect on pyramidal cell structure in Ts65Dn mice. As each dendritic spine receives at least one excitatory input, differences in the number of spines found in the dendritic arbors of pyramidal cells in the two groups reflect differences in the number of excitatory inputs they receive and, consequently, complexity in cortical circuitry. The present results suggest that behavioral deficits demonstrated in the Ts65Dn model could be attributed to abnormal circuit development.

Cytomegalovirus seroepidemiology in an urban community of São Paulo, Brazil

INTRODUCTION: After the era of rubella vaccine, cytomegalovirus (CMV) infection is one of the most frequently causes of mental retardation and congenital deafness. Seroepidemiological studies are necessary to understand the transmission dynamics of the disease. The purpose of the study was to quantify the transmission rate of CMV disease in a community in the state of São Paulo, Brazil. METHODS: Using ELISA test (IgG), a retrospective serological survey looking for CMV antibodies was performed in an non-immunized community. Frozen sera from 443 individuals, randomly selected by cluster sampling technique in the town of Caieiras, São Paulo, were collected from November 1990 to January 1991. Seroprevalence was stratified by age (0-40 years). Mathematical techniques were applied to determine the age-dependent decay function of maternal antibodies during the first year of life, the age-dependent seroprevalence function and the force of infection for CMV in this community. RESULTS: It was observed a descending phase of seropositivity in the first 9 months, but changes in antibody titration were observed between 8 months old and one year of age. The average age of the first infection was 5.02 months of age and 19.84 years, when the age-dependent seroprevalence and the force of infection were analyzed between 10 months of age and 10 years of age and from 10 to 40 years old, respectively. CONCLUSION: CMV infection is highly prevalent among the population studied and infection occurs in the first year of life. This study shows that most women at reproductive age are vulnerable to the first infection, increasing the risk for congenital infection.

Auto-determinação e inclusão social das pessoas com deficiência mental - uma intervenção centrada no sujeito

Dotar as pessoas com deficiência mental com competências para se autodeterminarem e terem a oportunidade de concretizar a sua plena inclusão social, é um desafio colocado à sociedade actual. Torna-se importante colocar em prática o que diferentes autores e organizações como a American Association of Mental Retardation defendem, criando condições para que os profissionais, famílias e comunidade possam ser os facilitadores deste processo. Neste sentido foi implementado no Centro de Reabilitação de Ponte de Lima um modelo de intervenção específico baseado na promoção e desenvolvimento da autonomia pessoal, social e de realização da pessoa com deficiência mental e criado um instrumento de observação e registo que reflecte essa forma de intervenção designado por Protocolo de Registo e Avaliação de Competências - PRAC. Neste estudo realizou-se uma análise ao instrumento em causa, pretendendo dar um contributo para a sua posterior validação. Nesse sentido, utilizou-se uma metodologia qualitativa e quantitativa para analisar se o instrumento pode ou não ser considerado representativo da capacidade de autodeterminação; se é estável quando utilizado por mais que um utilizador; se descrimina os indivíduos com maior ou menor autonomia e se os itens quando sujeitos à análise factorial, evidenciam os constructos teóricos previamente traçados. Muito embora o PRAC tenha sido pensado e estruturado para pessoas com deficiência mental, neste estudo foi utilizado por um grupo diversificado de profissionais oriundos de áreas distintas o que veio comprovar que o instrumento pode ser utilizado em diferentes contextos e com público-alvo mais alargado. Os resultados evidenciados são consistentes, permitindo respostas positivas às questões elaboradas, é de referir contudo que necessitam de um maior aprofundamento de forma a estabelecer outro tipo de generalizações.

Deficiência Mental: Casuística da Unidade de Desenvolvimento do Hospital de Dona Estefânia

Segundo a DSM IV a Deficiência Mental (DM) define-se como o funcionamento intelectual global inferior à média (QI < 70) associado a perturbações do comportamento adaptativo com início antes dos 18 anos. Procurou-se caracterizar retrospectivamente a população de crianças com DM observadas no Centro de Desenvolvimento do Hospital de Dona Estefânia (CDHDE), entre Janeiro 2005 e Junho 2007. Foram avaliados os dados epidemiológicos, gravidade, etiologia, co-morbilidade e intervenção proposta. Do total de 232 processos clínicos observados, 185 apresentavam DM. Classificaram-se em DM ligeira 112 (61%), DM moderada 54 (29%), DM grave 17 (9%) e profunda 2 (1%). Foram definidas etiologias em 86 crianças (46%) sendo a taxa de diagnóstico mais elevada na DM de maior gravidade. Observou-se uma elevada variabilidade de etiologias: as mais frequentemente encontradas foram as doenças genéticas, prematuridade e patologia associada. Foi detectada co-morbilidade em 123 crianças (66%), sendo a mais frequente as do foro oftalmológico (57 crianças, 46%). Foram propostas e sinalizadas para apoio a totalidade das crianças com DM, 47% em intervenção precoce e 58% em educação especial, das quais 5% usufruiram, por curto período, do apoio simultaneo de educadora de Intervenção Precoce e de docente do Ensino Especial, durante o período inicial de integração em jardim de infância. Observou-se um predomínio do sexo masculino. Foi efectuada caracterização clínica e funcional das crianças seguidas no CDHDE com o diagnóstico de DM e encontraram-se semelhanças entre os dados presentes e os descritos na literatura. Contudo alguns dados diferem de outras casuísticas decorrente, muito provavelmente decorrente da heterogeneidade da população estudada, quer do ponto de vista etiológico, quer no referente aos grupos etários, provavelmente condicionada, pela política assistencial.

Miopatia Miotubular Ligada ao Cromossoma X - Caso Clínico

Introdução:A miopatia miotubular ligada ao cromossoma X e uma miopatia congénita grave neonatal que afecta o sexo masculino, com prognóstico reservado. Relato de Caso: Lactente com hipotonia generalizada grave detectada após o nascimento, atrofia muscular generalizada e abolição dos reflexos osteotendinosos, cujo estudo etiológico específico (biópsia muscular e estudo de genética molecular) revelo tratar-se de miopatia miotubular ligada ao cromossoma X. Internado em Unidade de Cuidados Intensivos até aos oito meses, foi submetido a traqueostomia e gastrotomia, tendo alta para domicílio. Faleceu aos dez meses, subitamente, de causa indeterminada. Discussão: Este caso mostra que, apesar da terapêutica actual ser apenas paliativa, a importância do conhecimento do mecanismo genético é enorme, abrindo novos horizontes para uma terapia génica no futuro.

Encefalite Crónica a Enterovírus num Doente com Agamaglobulinémia Congénita Ligada ao Cromossoma X

Os autores apresentam um caso clínico de encefalite crónica a enterovírus num rapaz de 9 anos com agamaglobulinémia congénita ligada ao cromossoma X (doença de Bruton). Apesar da terapêutica intraventricular com doses elevadas de gamaglobulina, registou-se uma progressão da doença com deterioração neurológica maciça e morte. Discutem-se os aspectos diagnósticos e terapêuticos desta situação.

Prevalence of mental disorders among sexual offenders and non-sexual offenders

OBJECTIVE: To evaluate the prevalence of mental disorders in convicted sex offenders admitted to the Psychiatric Custody and Treatment Hospital (Forensic Psychiatric Facility). METHOD: 89 patient records of males admitted from March 2005 to August 2006 were analyzed. The analysis included evaluation of two study groups: Group I comprised subjects who had committed sex offenses (sexual offenders) while Group II contained subjects convicted for other crimes (non-sexual offenders). Variables studied were: age bracket, years of schooling, marital status, skin color, place of birth, previous psychiatric admissions and psychiatric diagnosis. RESULTS: Mental retardation and personality disorders were the mainly diagnoses in Group I (sexual offenders) (61,76% and 29,41% respectively). In the other hand, schizophrenic subjects predominated in Group II (non-sexual offenders) (82,93%). CONCLUSION: Different from international data, we have found low prevalence of personality disorders among Brazilian forensic population and we believe that it's due to a distinguishing characteristic of the Brazilian legal system, which does not consider personality disorder a mental disease, thus, not prompting these patients to civil commitment.

Anorexia nervosa e retardo mental

OBJETIVO: Revisar a literatura pertinente, observando a prevalência, etiopatogenia, aspectos nutricionais, diagnóstico e tratamento da anorexia nervosa (AN) em pacientes com retardo mental (RM). MÉTODO: Revisão bibliográfica realizada nos sistemas Medline, SciELO e PubMed usando os descritores "transtornos alimentares", "anorexia nervosa" e "retardo mental". RESULTADOS: A AN pode se manifestar de formas atípicas em indivíduos com RM, exigindo critérios diagnósticos específicos. O mais utilizado atualmente é o Diagnostic Criteria for Psychiatric Disorders for Use with Adults with Learning Disabilities/Mental Retardation, conhecido por DC-LC. A prevalência é incerta e o tratamento ainda não está estabelecido, apesar de exigir treinamento específico da equipe. A alimentação costuma ser "pobre" e alimentos que engordam normalmente são evitados. Na maioria das vezes, é difícil acessar a complexa psicopatologia da AN nesses pacientes, em virtude das dificuldades de obter o relato de insatisfação e/ou distorção da imagem corporal, baixa autoestima e crenças alimentares. CONCLUSÃO: Muitos fatores indicam a necessidade de maiores estudos de AN no RM, entre eles a falta de critérios diagnósticos próprios validados e diretrizes para tratamento. Paralelamente, o debate da forma de acesso à conceitualização e ao tratamento dos distúrbios da imagem corporal nessa população deve ser intensificado.

Paper de RIP140 en la fisiopatogenia de la adrenoleucodistròfia lligada a l'X.

La adrenoleucodistrofia ligada al X (X-ALD) es un enfermedad neurometabólica fatal caracterizada por una desmielinización cerebral progresiva infantil (CCALD) o por una neurodegeneración de la médula espinal (adrenomieloneuropatía, AMN), insuficiencia adrenal y acumulación de ácidos grasos de cadena muy larga (AGCML) como el ácido hexacosanoico (C26:0) en tejidos. La enfermedad está causada por mutaciones en el gen ABCD1 el cual codifica para un transportador peroxisomoal que importa AGCML. El ratón knockout para Abcd1 (Abcd1-) desarrolla alteraciones en la médula espinal que mimetizan el modelo de enfermedad AMN con inicio de los síntomas a los 20 meses. Previamente, nuestro grupo evidenció mediante análisis de transcriptómica, una desregulación mitocondrial en el modelo murino Abcd1- . En este trabajo demostramos que tanto en el ratón Abcd1- como en la sustancia blanca afectada de pacientes X-ALD hay una depleción mitocondrial. Para poder explicar esta depleción, estudiamos los niveles de un repressor de la biogenesis mitocondrial, RIP140. En cultivo organotípico de cortes de médula espinal observamos un aumento de los niveles proteicos de RIP140 en el ratón Abcd1- y también un aumento mediado por C26:0. Estos resultados indican que la sobreexpresión de RIP140 puede ser la responsable de la depleción mitocondrial presente en el ratón Abcd1- y una posible nueva diana terapèutica para la X-ALD.

The frequency of Toxocara infection in mental retarded children

Human toxocariasis is commonly seen in places where stray and Toxocara canis-infected dog population is high. There is a strong correlation between frequency of Toxocara infection, life style, and infection risk. Institutionalization of mental retarded patients increases to risk of toxocariasis. In this study, we aimed at investigating the frequency of Toxocara infection among children with mental retardation not requiring institutionalization. The study included 96 cases, who had educatable mental retardation and 85 healthy subjects who comprised the control group. Anti-Toxocara IgG or IgM antibodies were investigated in all serum samples, using ELISA method. The frequency of Toxocara infection was found significantly higher in mental retarded cases than in those in the control group (18.8% and 7.1% respectively) (p < 0.05). There was no significant difference between mental retarded children and the control group in terms of mean age, age groups, gender, owning dogs and cats and duration of their ownership, socio-economic level and behavioural factors, and personal hygiene (p > 0.05). We did not find any significant difference between Toxocara seropositive and seronegative mental retarded children in terms of demographic factors and epidemiological factors that could increase the risk of Toxocara infection (p > 0.05). The present study is the first seroprevalence study carried out with a mental retarded group not requiring institutionalization. Determination of high frequency of Toxocara infection suggests that these subjects constitute a risk factor for Toxocara infection, which may be attributed to their behavioural patterns.

Polymorphism at a sex-linked transcription cofactor in European tree frogs (Hyla arborea): Sex-antagonistic selection or neutral processes?

Nascent sex chromosomes offer a unique opportunity to investigate the evolutionary fate of genesrecently trapped in non-recombining segments. A housekeeping gene (MED15) was recently shown to lie on the nascent sex-chromosomes of the European tree frog (Hyla arborea), with different alleles fixed on the X and the Y chromosomes. Here we document a polymorphism (glutamine deletion) in the X copy of the gene, and use population surveys and experimental crosses to test whether this polymorphism is neutral or maintained by sex-antagonistic selection. Tadpoles from parents of known genotypes revealed significant discrepancies from Mendelian inheritance, suggesting possible sex-antagonistic effects under laboratory conditions. Quantitatively, however, these effects did not meet the conditions for polymorphism maintenance. Furthermore, field estimates of female genotypic frequencies did not differ from Hardy-Weinberg equilibrium and allelic frequencies on the X chromosome did not differ between sexes. In conclusion, although sex antagonistic effects cannot be excluded given the laboratory conditions, the X-linked polymorphism under study appears neutral in the wild. Alternatively, sex-antagonistic selection might still account for the fixation of a male specific allele on the Y chromosome.

The size and burden of mental disorders and other disorders of the brain in Europe 2010.

Aims: To provide 12-month prevalence and disability burden estimates of a broad range of mental and neurological disorders in the European Union (EU) and to compare these findings to previous estimates. Referring to our previous 2005 review, improved up-to-date data for the enlarged EU on a broader range of disorders than previously covered are needed for basic, clinical and public health research and policy decisions and to inform about the estimated number of persons affected in the EU. Method: Stepwise multi-method approach, consisting of systematic literature reviews, reanalyses of existing data sets, national surveys and expert consultations. Studies and data from all member states of the European Union (EU-27) plus Switzerland, Iceland and Norway were included. Supplementary information about neurological disorders is provided, although methodological constraints prohibited the derivation of overall prevalence estimates for mental and neurological disorders. Disease burden was measured by disability adjusted life years (DALY). Results: Prevalence: It is estimated that each year 38.2% of the EU population suffers from a mental disorder. Adjusted for age and comorbidity, this corresponds to 164.8 million persons affected. Compared to 2005 (27.4%) this higher estimate is entirely due to the inclusion of 14 new disorders also covering childhood/adolescence as well as the elderly. The estimated higher number of persons affected (2011: 165 m vs. 2005: 82 m) is due to coverage of childhood and old age populations, new disorders and of new EU membership states. The most frequent disorders are anxiety disorders (14.0%), insomnia (7.0%), major depression (6.9%), somatoform (6.3%), alcohol and drug dependence (>4%), ADHD (5%) in the young, and dementia (1-30%, depending on age). Except for substance use disorders and mental retardation, there were no substantial cultural or country variations. Although many sources, including national health insurance programs, reveal increases in sick leave, early retirement and treatment rates due to mental disorders, rates in the community have not increased with a few exceptions (i.e. dementia). There were also no consistent indications of improvements with regard to low treatment rates, delayed treatment provision and grossly inadequate treatment. Disability: Disorders of the brain and mental disorders in particular, contribute 26.6% of the total all cause burden, thus a greater proportion as compared to other regions of the world. The rank order of the most disabling diseases differs markedly by gender and age group; overall, the four most disabling single conditions were: depression, dementias, alcohol use disorders and stroke. Conclusion: In every year over a third of the total EU population suffers from mental disorders. The true size of "disorders of the brain" including neurological disorders is even considerably larger. Disorders of the brain are the largest contributor to the all cause morbidity burden as measured by DALY in the EU. No indications for increasing overall rates of mental disorders were found nor of improved care and treatment since 2005; less than one third of all cases receive any treatment, suggesting a considerable level of unmet needs. We conclude that the true size and burden of disorders of the brain in the EU was significantly underestimated in the past.Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research in order to identify better strategies for improved prevention and treatment for isorders of the brain as the core health challenge of the 21st century. (C) 2011 Published by Elsevier B.V.

Extensive gene traffic on the mammalian X chromosome.

Mammalian sex chromosomes have undergone profound changes since evolving from ancestral autosomes. By examining retroposed genes in the human and mouse genomes, we demonstrate that, during evolution, the mammalian X chromosome has generated and recruited a disproportionately high number of functional retroposed genes, whereas the autosomes experienced lower gene turnover. Most autosomal copies originating from X-linked genes exhibited testis-biased expression. Such export is incompatible with mutational bias and is likely driven by natural selection to attain male germline function. However, the excess recruitment is consistent with a combination of both natural selection and mutational bias.

Evidence against close linkage of the loci for fraXq of Martin-Bell syndrome and for factor IX.

Linkage between the loci for fraXq of Martin-Bell syndrome and factor IX was studied in nine families exhibiting this syndrome by means of a restriction fragment length polymorphism at the factor IX locus. Computer analysis of the data indicates there to be no evidence for close linkage between the syndrome and the factor IX locus.

Evolution of mRNA expression levels of autosomal and sex-linked genes in amniotes

In addition to differences in protein-coding gene sequences, changes in expression resulting from mutations in regulatory sequences have long been hypothesized to be responsible for phenotypic differences between species. However, unlike comparison of genome sequences, few studies, generally restricted to pairwise comparisons of closely related mammalian species, have assessed between-species differences at the transcriptome level. They reported that gene expression evolves at different rates in various organs and in a pattern that is overall consistent with neutral models of evolution. In the first part of my thesis, I investigated the evolution of gene expression in therian mammals (i.e.7 placental and marsupials), based on microarray data from human, mouse and the gray short-tailed opossum (Monodelphis domestica). In addition to autosomal genes, a special focus was given to the evolution of X-linked genes. The therian X chromosome was recently shown to be younger than previously thought and to harbor a specific gene content (e.g., genes involved in brain or reproductive functions) that is thought to have been shaped by specific sex-related evolutionary forces. Sex chromosomes derive from ordinary autosomes and their differentiation led to the degeneration of the Y chromosome (in mammals) or W chromosome (in birds). Consequently, X- or Z-linked genes differ in gene dose between males and females such that the heterogametic sex has half the X/Z gene dose compared to the ancestral state. To cope with this dosage imbalance, mammals have been reported to have evolved mechanisms of dosage compensation.¦In the first project, I could first show that transcriptomes evolve at different rates in different organs. Out of the five tissues I investigated, the testis is the most rapidly evolving organ at the gene expression level while the brain has the most conserved transcriptome. Second, my analyses revealed that mammalian gene expression evolution is compatible with a neutral model, where the rates of change in gene expression levels is linked to the efficiency of purifying selection in a given lineage, which, in turn, is determined by the long-term effective population size in that lineage. Thus, the rate of DNA sequence evolution, which could be expected to determine the rate of regulatory sequence change, does not seem to be a major determinant of the rate of gene expression evolution. Thus, most gene expression changes seem to be (slightly) deleterious. Finally, X-linked genes seem to have experienced elevated rates of gene expression change during the early stage of X evolution. To further investigate the evolution of mammalian gene expression, we generated an extensive RNA-Seq gene expression dataset for nine mammalian species and a bird. The analyses of this dataset confirmed the patterns previously observed with microarrays and helped to significantly deepen our view on gene expression evolution.¦In a specific project based on these data, I sought to assess in detail patterns of evolution of dosage compensation in amniotes. My analyses revealed the absence of male to female dosage compensation in monotremes and its presence in marsupials and, in addition, confirmed patterns previously described for placental mammals and birds. I then assessed the global level of expression of X/Z chromosomes and contrasted this with its ancestral gene expression levels estimated from orthologous autosomal genes in species with non-homologous sex chromosomes. This analysis revealed a lack of up-regulation for placental mammals, the level of expression of X-linked genes being proportional to gene dose. Interestingly, the ancestral gene expression level was at least partially restored in marsupials as well as in the heterogametic sex of monotremes and birds. Finally, I investigated alternative mechanisms of dosage compensation and found that gene duplication did not seem to be a widespread mechanism to restore the ancestral gene dose. However, I could show that placental mammals have preferentially down-regulated autosomal genes interacting with X-linked genes which underwent gene expression decrease, and thus identified a novel alternative mechanism of dosage compensation.