RESUMO Objetivo: Entre 100 crianças, não selecionadas, com diagnóstico de autismo, pelo menos 20 apresentam anomalias morfológicas, quase sempre associadas a síndromes. Não há no Brasil instrumento de exame físico morfológico padronizado e validado. O objetivo foi traduzir para o português do Brasil e adaptar culturalmente os sinais clínicos descritos no Autism Dysmorphology Measure, assim como procurar evidências de validade quando aplicado a uma amostra de crianças com autismo. Métodos: Foram feitas a tradução e a adaptação cultural do instrumento original, publicado na íntegra. Foram adotados os procedimentos tradicionais de tradução, retrotradução e adaptação da terminologia segundo a Nomina Anatomica. Foram incluídas na amostra 62 crianças com quociente de inteligência entre 50 e 69, de ambos os sexos, com idade cronológica entre três e seis anos, provenientes de estudo multicêntrico com os procedimentos metodológicos já publicados. O exame físico morfológico foi realizado por dois médicos geneticistas e consistiu na pesquisa de 82 características que avaliam 12 áreas corporais. Para avaliar a concordância entre os dois observadores foi utilizado o coeficiente Kappa de Cohen. Resultados: A versão final do instrumento traduzido e adaptado culturalmente ao português do Brasil mostrou alta concordância entre os dois observadores. Conclusões: O instrumento traduzido preenche todos os critérios propostos internacionalmente e o reconhecimento das anomalias menores e sua descrição clínica estão padronizados e são de fácil reconhecimento aos médicos não especialistas em genética.

ABSTRACT Objective: For every 100 random children diagnosed with autism, at least 20 have morphological abnormalities, often associated with syndromes. Brazil does not have a standardized and validated instrument for morphological physical examination. This study aimed to translate into Brazilian Portuguese and culturally adapt the clinical signs described in the Autism Dysmorphology Measure, as well as validate the instrument in a sample of children with autism. Methods: The original instrument was translated, culturally adapted, and published in full, following traditional procedures for translation, back-translation, and terminology adaptation according to the Nomina Anatomica. The sample included 62 children from a published multicenter study, with intelligence quotient between 50–69, of both genders, with chronological age between 3–6 years. Two clinical geneticists performed the morphological physical examination, which consisted of investigating 82 characteristics assessing 12 body areas. We used Cohen’s Kappa coefficient to evaluate the agreement between the two observers. Results: The final version of the instrument – translated into Brazilian Portuguese and culturally adapted – showed high agreement between the two observers. Conclusions: The translated instrument meets all international criteria, and minor anomalies and their clinical descriptions were standardized and are recognizable for physicians not specialized in genetics.

Objective: Cocaine use disorders (CUDs) represent a major public health problem in many countries. To better understand the interaction between the environmental modulations and phenotype, the aim of the present study was to investigate the DNA methylation pattern of CUD patients, who had concomitant cocaine and crack dependence, and healthy controls. Methods: We studied DNA methylation profiles in the peripheral blood of 23 CUD patients and 24 healthy control subjects using the Illumina Infinium HumanMethylation450 BeadChip arrays. Results: Comparison between CUD patients and controls revealed 186 differentially methylated positions (DMPs; adjusted p-value [adjP] < 10-5) related to 152 genes, with a subset of CpGs confirmed by pyrosequencing. DNA methylation patterns discriminated CUD patients and control groups. A gene network approach showed that the EHMT1, EHMT2, MAPK1, MAPK3, MAP2K1, and HDAC5 genes, which are involved in transcription and chromatin regulation cellular signaling pathways, were also associated with cocaine dependence. Conclusion: The investigation of DNA methylation patterns may contribute to a better understanding of the biological mechanisms involved in CUD.

Objective: Theta-burst stimulation (TBS) modulates synaptic plasticity more efficiently than standard repetitive transcranial magnetic stimulation delivery and may be a promising modality for neuropsychiatric disorders such as autism spectrum disorder (ASD). At present there are few effective interventions for prefrontal cortex dysfunction in ASD. We report on an open-label, pilot study of intermittent TBS (iTBS) to target executive function deficits and restricted, repetitive behaviors in male children and adolescents with ASD. Methods: Ten right-handed, male participants, aged 9-17 years with ASD were enrolled in an open-label trial of iTBS treatment. Fifteen sessions of neuronavigated iTBS at 100% motor threshold targeting the right dorsolateral prefrontal cortex were delivered over 3 weeks. Results: Parent report scores on the Repetitive Behavior Scale Revised and the Yale-Brown Obsessive Compulsive Scale demonstrated improvements with iTBS treatment. Participants demonstrated improvements in perseverative errors on the Wisconsin Card Sorting Test and total time for the Stroop test. The iTBS treatments were well tolerated with no serious adverse effects. Conclusion: These preliminary results suggest that further controlled interventional studies of iTBS for ASD are warranted.

Cancer-associated fibroblasts (CAF) influence tumor development at primary as well as in metastatic sites, but there have been no direct comparisons of the transcriptional profiles of stromal cells from different tumor sites. In this study, we used customized cDNA microarrays to compare the gene expression profile of stromal cells from primary tumor (CAF, n = 4), lymph node metastasis (N+, n = 3) and bone marrow (BM, n = 4) obtained from breast cancer patients. Biological validation was done in another 16 samples by RT-qPCR. Differences between CAF vs N+, CAF vs BM and N+ vs BM were represented by 20, 235 and 245 genes, respectively (SAM test, FDR < 0.01). Functional analysis revealed that genes related to development and morphogenesis were overrepresented. In a biological validation set, NOTCH2 was confirmed to be more expressed in N+ (vs CAF) and ADCY2, HECTD1, HNMT, LOX, MACF1, SLC1A3 and USP16 more expressed in BM (vs CAF). Only small differences were observed in the transcriptional profiles of fibroblasts from the primary tumor and lymph node of breast cancer patients, whereas greater differences were observed between bone marrow stromal cells and the other two sites. These differences may reflect the activities of distinct differentiation programs.

Pervasive developmental disorders are now commonly referred to as autism spectrum disorders (ASDs). ASDs present with a range of severity and impairments, and often are a cause of severe disability, representing a major public health concern. The diagnostic criteria require delays or abnormal functioning in social interaction, language, and/or imaginative play within the first 3 years of life, resulting in a deviation from the developmental pattern expected for the age. Because establishing a diagnosis of ASD is possible as early as 18-24 months of age, clinicians should strive to identify and begin intervention in children with ASD as soon as signs are manifest. Increasing efforts are underway to make ASD screening universal in pediatric healthcare. Given the crucial importance of early identification and multiple modalities of treatment for ASD, this review will summarize the diagnostic criteria, key areas for assessment by clinicians, specific scales and instruments for assessment, and discussion of evidence-based treatment programs and the role of specific drug therapies for symptom management.

O transtorno obsessivo-compulsivo (TOC) é um quadro psiquiátrico de prevalência considerável na população e de etiologia desconhecida. No entanto, há evidências de que o sistema imunológico pode desempenhar um papel importante em sua patogênese. No presente estudo, dois polimorfismos (rs1800795 e rs361525), localizados na região promotora do gene que codifica a citocina conhecida como fator de necrose tumoral alfa (TNFA), foram genotipados em 183 pacientes com TOC e 249 controles saudáveis. Os testes estatísticos foram realizados utilizando-se o software PLINK®. Assim, evidenciou-se que o alelo A do polimorfismo rs361525 apresentava associação estatisticamente significante com o TOC (p=0,007). A presença de marcadores genéticos, tais como genes que codificam citocinas inflamatórias, associados com TOC, confere suporte adicional ao papel do sistema imunológico na patogênese desse transtorno.

Obsessive-compulsive disorder (OCD) is a prevalent psychiatric disorder of unknown etiology. However, there is some evidence that the immune system may play an important role in its pathogenesis. In the present study, two polymorphisms (rs1800795 and rs361525) in the promoter region of the cytokine tumor necrosis factor-alpha (TNFA) gene were genotyped in 183 OCD patients and in 249 healthy controls. The statistical tests were performed using the PLINK® software. We found that the A allele of the TNFA rs361525 polymorphism was significantly associated with OCD subjects, according to the allelic χ² association test (p=0.007). The presence of genetic markers, such as inflammatory cytokines genes linked to OCD, may represent additional evidence supporting the role of the immune system in its pathogenesis.

CONTEXTO: Deficiência de vitaminas do complexo B tem sido associada a deterioração cognitiva e quadros demenciais em idosos. OBJETIVO: Neste trabalho, foi avaliado se pacientes com doença de Alzheimer (DA) e com comprometimento cognitivo leve (CCL) apresentam níveis séricos de ácido fólico e cobalamina (vitamina B12) menores que idosos controles. MÉTODOS: Foram recrutados 146 idosos (40 com DA, 56 com CCL e 49 idosos controles) para este estudo. Os níveis séricos de ácido fólico e vitamina B12 foram avaliados pelo método de eletroquimioluminescência. RESULTADOS: Os pacientes com DA apresentaram redução estatisticamente significativa nos níveis de ácido fólico em relação aos idosos com CCL e controles (p = 0,02). Esses resultados mantiveram-se estatisticamente significativos após controlar por variáveis sociodemográficas e desempenho cognitivo. Não se observaram diferenças estatisticamente significativas nos níveis de vitamina B12 nem em variáveis hematológicas entre os grupos. CONCLUSÃO: Esses resultados reforçam a importância de anormalidades em aspectos nutricionais, em particular do metabolismo de um-carbono, na fisiopatologia da DA.

BACKGROUND: Complex B vitamin deficiency has been associated to cognitive impairment and dementing disorders in the elderly. OBJECTIVE: This work aims to assess whether patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) have lower levels of folic acid and cobalamin (vitamin B12) compared to age and gender-matched controls. METHODS: One hundred and forty six elderly subjects (40 AD, 56 MCI and 49 healthy older adults) were recruited for this study. Serum folic acid and vitamin B12 levels were measured by electrochemoluminescence. RESULTS: Compared to MCI and healthy controls a statistically significant reduction in serum concentrations of folic acid in AD patients was found (p = 0.02). This result remained statistically significant after controlling for socio-demographic and cognitive performance variables (p = 0.01). No significant differences were found in serum concentrations of vitamin B12 in patients with AD, MCI and healthy controls. No significant changes in hematologic parameters were observed across these diagnostic groups. DISCUSSION: The present study provides additional evidence that folic acid is reduced in patients with AD and reinforces the importance of nutritional changes, in particular the one-carbon metabolism, in the physiopathology of AD.