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The original version of this article were unfortunately published with an error in "Methods" section. This has been corrected by publishing this correction article.
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The tendency to interpret nonverbal social signals as hostile in intention is associated with aggressive responding, poor social functioning and mental illness, and can already be observed in childhood. To investigate the neural correlates of such hostile attributions of social intention, we performed a functional magnetic imaging study in 10-18 year old children and adolescents. Fifty healthy participants rated videos of laughter, which they were told to imagine as being directed towards them, as friendly versus hostile in social intention. Hostile intention ratings were associated with neural response in the right temporal voice area (TVA). Moreover, self-reported trait physical aggression modulated this relationship in both the right TVA and bilateral lingual gyrus, with stronger associations between hostile intention ratings and neural activation in children with higher trait physical aggression scores. Functional connectivity results showed decreased connectivity between the right TVA and left dorsolateral prefrontal cortex with increasing trait physical aggression for making hostile social intention attributions. We conclude that children's social intention attributions are more strongly related to activation of early face and voice-processing regions with increasing trait physical aggression.
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Agressão/fisiologia , Encéfalo/fisiologia , Hostilidade , Riso/psicologia , Percepção Social , Adolescente , Mapeamento Encefálico , Criança , Sinais (Psicologia) , Feminino , Humanos , Intenção , Relações Interpessoais , Imageamento por Ressonância Magnética , MasculinoRESUMO
Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. The presence of a genetic link between ASD and ADHD symptoms is supported by twin studies, but the genetic overlap between clinically ascertained ASD and ADHD remains largely unclear. We therefore investigated how ASD and ADHD co-aggregate in individuals and in families to test for the presence of a shared genetic liability and examined potential differences between low- and high-functioning ASD in the link with ADHD. We studied 1 899 654 individuals born in Sweden between 1987 and 2006. Logistic regression was used to estimate the association between clinically ascertained ASD and ADHD in individuals and in families. Stratified estimates were obtained for ASD with (low-functioning) and without (high-functioning) intellectual disability. Individuals with ASD were at higher risk of having ADHD compared with individuals who did not have ASD (odds ratio (OR)=22.33, 95% confidence interval (CI): 21.77-22.92). The association was stronger for high-functioning than for low-functioning ASD. Relatives of individuals with ASD were at higher risk of ADHD compared with relatives of individuals without ASD. The association was stronger in monozygotic twins (OR=17.77, 95% CI: 9.80-32.22) than in dizygotic twins (OR=4.33, 95% CI: 3.21-5.85) and full siblings (OR=4.59, 95% CI: 4.39-4.80). Individuals with ASD and their relatives are at increased risk of ADHD. The pattern of association across different types of relatives supports the existence of genetic overlap between clinically ascertained ASD and ADHD, suggesting that genomic studies might have underestimated this overlap.
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Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno Autístico/complicações , Transtorno Autístico/genética , Criança , Pré-Escolar , Estudos de Coortes , Família , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Sistema de Registros , Fatores de Risco , Irmãos , Suécia , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genéticaRESUMO
Despite sizeable short-term effects of neurofeedback (NF) therapy on attention-deficit and hyperactivity disorder (ADHD), longer-term clinical, comorbidity and self-regulation outcomes are less systematically studied. The aim of this largest NF follow-up to date was to evaluate these outcomes 6 months after NF compared to a semi-active control to disentangle specific from unspecific sustained effects. We performed a multicenter, randomized, parallel, controlled, clinical, superiority trial in five German university outpatient departments. Participants were eligible if they fulfilled DSM-IV-TR criteria for ADHD and were aged from 7 to 9 years. Participants were randomly assigned (1:1-ratio) to 25 sessions of slow cortical potential (SCP)-NF or electromyogram biofeedback (EMG-BF). Participants were not blinded, since they received instructions according to each treatment setting. Primary outcomes were parent ratings of ADHD. The trial was registered, number ISRCTN761871859. Both groups showed improvement of ADHD symptoms compared to baseline at 6-months follow-up with large effect sizes for SCP-NF (d = 1.04) and EMG-BF (d = 0.85), but without group differences. When analyzing all assessments (pre-test, post-test-1, post-test-2 and follow-up), a group-by-time interaction emerged (p = 0.0062), with SCP-NF showing stable improvement following treatment but EMG-BF showing a relapse from post-test-1 to post-test-2, and subsequent remission at follow-up. Six months after the end of treatment, improvement after SCP-NF remained large and stable. However, the lack of group differences at follow-up suggests shared specific and unspecific effects contributing to this clinical outcome. Our correlational results indicate specificity of SCP-NF for selected subscales after training, but not at follow-up.
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Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Neurorretroalimentação/métodos , Criança , Comorbidade , Feminino , Humanos , Masculino , Fatores de Tempo , Resultado do TratamentoRESUMO
Autism spectrum disorders (ASD) are pervasive developmental disorders comprising problems in social interaction, communication, and stereotyped behavior and interests. They show a prevalence of around 0.8% in children, adolescents, and adults, and a skewed sex distribution (about 4:1 = male:female). ASD are predominantly genetically determined disorders. Heritability estimates from twin studies range between 64 and 91%. Recurrence risk in siblings is 20-fold elevated. De novo and inherited monogenetic disorders, mutations, sex chromosomal abnormalities, cytogenetic and imprinting disorders as well as common variants are associated with ASD. Genetic disorders implicating a specific additional intervention are of specific clinical relevance. Genetic testing and counselling should be provided for all families and individuals with ASD. This article gives an overview on current basic genetic research in ASD, its clinical relevance and genetic counselling in ASD.
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Transtorno do Espectro Autista/genética , Adolescente , Adulto , Transtorno do Espectro Autista/diagnóstico , Criança , Feminino , Aconselhamento Genético , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Fenótipo , Fatores Sexuais , Estudos em Gêmeos como AssuntoRESUMO
Contactin-associated protein-like 2 gene (CNTNAP2), a member of the Neurexin gene superfamily, is one of the best-replicated risk genes for autism spectrum disorders (ASD). ASD are predominately genetically determined neurodevelopmental disorders characterized by impairments of language development, social interaction and communication, as well as stereotyped behavior and interests. Although CNTNAP2 expression levels were proposed to alter ASD risk, no study to date has focused on its 5' promoter. Here, we directly sequenced the CNTNAP2 5' promoter region of 236 German families with one child with ASD and detected four novel variants. Furthermore, we genotyped the three most frequent variants (rs150447075, rs34712024, rs71781329) in an additional sample of 356 families and found nominal association of rs34712024G with ASD and rs71781329GCG[7] with language development. The four novel and the three known minor alleles of the identified variants were predicted to alter transcription factor binding sites (TFBS). At the functional level, the respective sequences spanning these seven variants were bound by nuclear factors. In a luciferase promoter assay, the respective minor alleles showed cell line-specific and differentiation stage-dependent effects at the level of promoter activation. The novel potential rare risk-variant M2, a G>A mutation -215 base pairs 5' of the transcriptional start site, significantly reduced promoter efficiency in HEK293T and in undifferentiated and differentiated neuroblastoid SH-SY5Y cells. This variant was transmitted to a patient with autistic disorder. The under-transmitted, protective minor G allele of the common variant rs34712024, in contrast, increased transcriptional activity. These results lead to the conclusion that the pathomechanism of CNTNAP2 promoter variants on ASD risk is mediated by their effect on TFBSs, and thus confirm the hypothesis that a reduced CNTNAP2 level during neuronal development increases liability for ASD.
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Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Transtorno do Espectro Autista/psicologia , Linhagem Celular Tumoral , Criança , Estudos de Coortes , Feminino , Alemanha , Células HEK293 , Humanos , Desenvolvimento da Linguagem , Masculino , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/fisiologia , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , População Branca/genéticaRESUMO
Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
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Transtorno do Deficit de Atenção com Hiperatividade/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Criança , Planejamento em Saúde Comunitária , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Incarcerated adolescents are a high-risk group for suicidal behaviour, but data on completed suicide are scarce in this population. The present study aimed at calculating relative risks (RR) of suicide in detention and identifying age-related risk factors. We compared data of a German national total survey of completed suicide of young detainees (14 to <21 years, N = 79) during the years 2000-2010 with age- and gender-adjusted suicide deaths in non-incarcerated adolescents (N = 3,484) and incarcerated adults (N = 781). Prison suicide accounted for 2.3% of all suicide deaths in adolescents, but only 0.1% of this age group was detained. The RR = 23.0 for adolescent suicide in detention exceeded the RR = 7.7 of adults by far. In adults, suicide rates in pre-trial detention was fivefold higher than in criminal detention; suicide rates were more balanced in adolescent detainees. Our results underline the need for age-specific suicide prevention strategies in detention.
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Prisioneiros/psicologia , Prisioneiros/estatística & dados numéricos , Suicídio/estatística & dados numéricos , Adolescente , Fatores Etários , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Transtornos Mentais/epidemiologia , Distribuição por Sexo , Fatores Sexuais , Ideação Suicida , Suicídio/psicologiaAssuntos
Hemorragia Cerebral Traumática/etiologia , Traumatismos Craniocerebrais/complicações , Sistema Glinfático/patologia , Adulto , Hemorragia Cerebral Traumática/diagnóstico , Traumatismos Craniocerebrais/diagnóstico , Dilatação Patológica/complicações , Dilatação Patológica/diagnóstico , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/lesões , Lobo Frontal/patologia , Sistema Glinfático/lesões , Humanos , Imageamento por Ressonância Magnética , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/lesões , Córtex Pré-Frontal/patologia , Futebol/lesõesAssuntos
Tecido Adiposo/transplante , Embolia Gordurosa/etiologia , Embolia Intracraniana/etiologia , Procedimentos Cirúrgicos Oftalmológicos/efeitos adversos , Órbita/cirurgia , Procedimentos de Cirurgia Plástica/efeitos adversos , Embolia Gordurosa/diagnóstico , Humanos , Embolia Intracraniana/diagnóstico , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Oftalmológicos/métodos , Complicações Pós-Operatórias/diagnóstico , Procedimentos de Cirurgia Plástica/métodos , Transplante AutólogoRESUMO
Mesenchymal stem cells have become extremely interesting for regenerative medicine and tissue engineering in the horse. Stem cell therapy has been proven to be a powerful and successful instrument, in particular for the healing of tendon lesions. We pre-differentiated equine adipose-tissue-derived stem cells (ASCs) in a collagen I gel scaffold by applying tensile strain, growth differentiation factors (GDFs) and various oxygen tensions in order to determine the optimal conditions for in vitro differentiation toward the tenogenic lineage. We compared the influence of 3% versus 21% oxygen tension, the use of GDF 5, GDF 6 and GDF 7 and the application of uniaxial tensile strain versus no mechanical stimulation on differentiation results as evaluated by cell morphology and by the expression of the tendon-relevant genes collagen I, collagen III, cartilage oligomeric matrix protein and scleraxis. The best results were obtained with an oxygen tension of 21%, tensile stimulation and supplementation with GDF 5 or GDF 7. This approach raises the hope that the in vivo application of pre-differentiated stem cells will improve healing and recovery time in comparison with treatment involving undifferentiated stem cells.
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Tecido Adiposo/citologia , Diferenciação Celular/efeitos dos fármacos , Fatores de Diferenciação de Crescimento/farmacologia , Oxigênio/farmacologia , Células-Tronco/citologia , Tendões/citologia , Resistência à Tração/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Reatores Biológicos , Comunicação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Colágeno Tipo I/farmacologia , Géis , Regulação da Expressão Gênica/efeitos dos fármacos , Cavalos , Imuno-Histoquímica , Junções Intercelulares/efeitos dos fármacos , Junções Intercelulares/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Células-Tronco/efeitos dos fármacos , Células-Tronco/ultraestrutura , Alicerces TeciduaisRESUMO
In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.
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Transtorno do Deficit de Atenção com Hiperatividade/genética , Cromossomos Humanos Par 11/genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Encéfalo/metabolismo , Estudos de Casos e Controles , Colina/metabolismo , Glutamina/metabolismo , Humanos , Inositol/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Metilfenidato/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , PrótonsRESUMO
A behaviorally inhibited temperament in early childhood has been identified as a potential risk factor for anxiety disorders in children and adolescents. The purpose of our investigation was the development and evaluation of the factor structure, reliability and validity of the first retrospective parent report measure to assess behavioral inhibition in infants and toddlers. Principal Component Analysis of the Retrospective Infant Behavioral Inhibition Scale (RIBI) supported a three factor solution of the core features of BI in two unselected samples. Internal consistency and inter-rater agreement of both parent judgments were >.90 and >.70. Scores of the RIBI were positively correlated with the parent report temperament questionnaire IBQ and a laboratory-based test at age 14 months with the child.
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Transtornos de Ansiedade/psicologia , Ansiedade/psicologia , Comportamento Infantil/psicologia , Inibição Psicológica , Pais , Temperamento , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Psicometria , Estudos Retrospectivos , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
Mismatch repair (MMR) protein-deficient non-neoplastic colonic crypts and endometrial glands (dMMR crypts and glands) have been reported as a unique marker of underlying Lynch syndrome (LS). However, no large studies have directly compared the frequency of detection in cases with double somatic (DS) MMR mutations. We retrospectively analyzed 42 colonic resection specimens (24 LS and 18 DS) and 20 endometrial specimens (9 LS and 11 DS), including 19 hysterectomies and 1 biopsy for dMMR crypts and glands. All specimens were from patients with known primary cancers, including colonic adenocarcinomas and endometrial endometrioid carcinomas (including 2 mixed carcinomas). Four blocks of normal mucosa away from the tumor were selected from most cases, as available. MMR immunohistochemistry specific to the primary tumor mutations was analyzed. dMMR crypts were found in 65% of LS and 0% of DS MMR-mutated colonic adenocarcinomas (P < .001). Most dMMR crypts were detected in the colon (12 of 15) compared to the ileum (3 of 15). dMMR crypts showed single and grouped losses of MMR immunohistochemical expression. dMMR glands were found in 67% of LS and 9% (1 of 11) of DS endometrial cases (P = .017). Most dMMR glands were found in the uterine wall, with 1 LS and 1 DS case exhibiting dMMR glands in the lower uterine segment. Most cases exhibited multifocal and grouped dMMR glands. No morphologic atypia was identified in dMMR crypts or glands. Overall, we demonstrate that dMMR crypts and glands are highly associated with underlying LS, while being rarer in those with DS MMR mutations.
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Adenocarcinoma , Neoplasias do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA , Estudos Retrospectivos , Neoplasias do Colo/genética , Mutação , Proteína 1 Homóloga a MutL/genética , Mucosa Intestinal/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Instabilidade de MicrossatélitesRESUMO
CONTEXT.: Pancreatic adenocarcinoma is the third leading cause of cancer death in the United States. Surgery remains the mainstay of treatment, and frozen section analysis is used to confirm diagnosis and determine resectability and margin status. OBJECTIVE.: To evaluate use and accuracy of frozen section and how diagnosis impacts surgical procedure. DESIGN.: We reviewed patients with planned pancreatic resections between January 2014 and March 2019 with at least 1 frozen section. Pathology reports including frozen sections, preoperative cytology, and operative notes were reviewed. Frozen sections were categorized by margin, primary pancreatic diagnosis, metastasis, or vascular resectability. The deferral and error rates and surgeons' response were noted. RESULTS.: We identified 898 planned pancreatic resections and 221 frozen sections that were performed on 152 cases for 102 margins, 94 metastatic lesions, 20 primary diagnoses, and 5 to confirm vascular resectability. The diagnosis was deferred to permanent sections in 13 of 152 cases (8.6%) on 16 of 221 frozen sections (7.2%): 6 for metastasis, 8 for margins, and 2 for primary diagnosis. Discrepancies/errors were identified in 4 of 152 cases (2.6%) and 4 of 221 frozen sections (1.8%). Surgeons' responses were different than expected in 8 of 221 frozen sections (3.6%), but their actions were explained by other intraoperative findings in 6 of 8. CONCLUSIONS.: Frozen section remains an important diagnostic tool used primarily for evaluation of margins and metastasis during pancreatectomy. In most cases, a definitive diagnosis is rendered, with occasional deferrals and few errors. Intraoperative findings explain most cases where surgeons act differently than expected based on frozen section diagnosis.
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Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirurgia , Erros de Diagnóstico , Secções Congeladas , Humanos , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirurgia , Estudos RetrospectivosRESUMO
Empathy is defined as the ability to vicariously experience others' suffering (vicarious pain) or feeling their joy (vicarious reward). While most neuroimaging studies have focused on vicarious pain and describe similar neural responses during the observed and the personal negative affective involvement, only initial evidence has been reported for the neural responses to others' rewards and positive empathy. Here, we propose a novel approach, based on the simultaneous recording of multi-subject EEG signals and exploiting the wavelet coherence decomposition to measure the temporal alignment between ERPs in a dyad of interacting subjects. We used the Third-Party Punishment (TPP) paradigm to elicit the personal and vicarious experiences. During a positive experience, we observed the simultaneous presence in both agents of the Late Positive Potential (LPP), an ERP component related to emotion processing, as well as the existence of an inter-subject ERPs synchronization in the related time window. Moreover, the amplitude of the LPP synchronization was modulated by the presence of a human-agent. Finally, the localized brain circuits subtending the ERP-synchronization correspond to key-regions of personal and vicarious reward. Our findings suggest that the temporal and spatial ERPs alignment might be a novel and direct proxy measure of empathy.
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Encéfalo , Empatia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Emoções/fisiologia , Humanos , Dor/psicologia , RecompensaRESUMO
PURPOSE: Attention deficit/hyperactivity disorder is a common comorbid disorder in children with nocturnal enuresis, daytime urinary incontinence and fecal incontinence. We assessed the specific association of these conditions in a population based sample. We hypothesized that children with elimination disorders have a higher rate of attention deficit/hyperactivity disorder, and that children with daytime urinary incontinence are more strongly affected than those with nocturnal enuresis. MATERIALS AND METHODS: All children in a defined geographic area (Saarpfalz Kreis) were examined at school entry. Mean age was 6.22 years in 734 boys and 6.18 years in 645 girls. A questionnaire regarding elimination problems and the attention problems scale of the Child Behavior Checklist were administered as an interview to parents. Participation rate was 99.1% (1,379 parents). RESULTS: Of the children 71 (5.1%) had attention deficit/hyperactivity disorder problems of clinical relevance (7.1% of boys and 2.9% of girls). A total of 185 children (13.4%) were wet (nocturnal enuresis in 9.1% and daytime urinary incontinence in 4.4%) and 19 (1.4%) had fecal incontinence. Attention deficit/hyperactivity disorder symptoms were more common in children with urinary incontinence than nonwetting children (16.8% vs 3.4%). When controlled for confounding variables, only children with daytime urinary incontinence (but not nocturnal enuresis) had a significantly higher risk of attention deficit/hyperactivity disorder symptoms (OR 4.4). CONCLUSIONS: Attention deficit/hyperactivity disorder symptoms were increased in children with urinary incontinence in this population based sample. Children with daytime urinary incontinence were at greater risk for attention deficit/hyperactivity disorder than those with nocturnal enuresis. Screening and referral for specialized treatment of both disorders are recommended.
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Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Enurese Diurna/epidemiologia , Incontinência Fecal/epidemiologia , Enurese Noturna/epidemiologia , Criança , Pré-Escolar , Comorbidade , Constipação Intestinal/epidemiologia , Feminino , Humanos , Masculino , Análise Multivariada , Fatores de RiscoRESUMO
Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.
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Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estimulantes do Sistema Nervoso Central/uso terapêutico , Predisposição Genética para Doença , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Adolescente , Adulto , Encéfalo/metabolismo , Sobrevivência Celular/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Ligação Genética , Genótipo , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Polimorfismo Genético , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/metabolismoRESUMO
Estrogen receptor (ER) alpha, a ligand-dependent nuclear transcription factor encoded by the ESR1 gene, is expressed in 70% of breast carcinomas (BCs) and is used as a target for endocrine-based therapies. However, some patients develop resistance to endocrine-based therapies due to ESR1 mutation, which leads to constitutive activation in the absence of ligand. We retrospectively analyzed 223 clinically advanced BCs using the FoundationOne CDX assay and found 13.9% (31/223) of cases had ESR1 genetic alterations (26 mutations and 5 amplifications). All ESR1 mutations occurred within the ligand binding domain, with the most prevalent being Y537S (42.3%) and D538G (38.5%), and all ESR1-mutated cases had a history of aromatase inhibitor use. No significant difference in clinicopathologic features was identified between ESR1-mutated and ESR1-amplified cases except higher frequency of HER2 positivity and TP53 mutations in ESR1-amplified cases. The prevalence of ESR1 mutations in ER-positive BCs was 19.1% (26/136). In comparison to ESR1-nonmutated ER-positive cases, ESR1-mutated cases demonstrated significantly higher percentage of tumor cells with ER and progesterone receptor expression, an increased tendency for overall distant metastasis and liver metastasis, higher frequency of FGF3/4/19 mutations, lower frequency of TP53 mutation, but no difference in overall survival and metastatic/recurrent intervals. In conclusion, our findings suggest that development of ESR1 mutations are selected for under the influence of estrogen deprivation, and a positive correlation between ESR1 mutations and ER protein expression may exist.