RESUMO
The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RASERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 µM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RASERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.
Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Piperidinas/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Nus , Modelos Moleculares , Neoplasias/patologia , Proteína Oncogênica p21(ras)/metabolismo , Piperidinas/química , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Estabilidade Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Pirimidinas/química , Pirimidinas/uso terapêutico , Reprodutibilidade dos Testes , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.
Assuntos
Amidas/farmacologia , Ciclopropanos/farmacologia , Citocinas/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Adenosina/análogos & derivados , Amidas/síntese química , Amidas/química , Cristalografia por Raios X , Ciclopropanos/síntese química , Ciclopropanos/química , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Nicotinamida Fosforribosiltransferase/metabolismo , Fenótipo , Relação Estrutura-AtividadeRESUMO
Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals the presence of mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11. One of the key downstream targets of the constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway. Herein, we describe the discovery of darovasertib (NVP-LXS196), a potent pan-PKC inhibitor with high whole kinome selectivity. The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM).
Assuntos
Melanoma , Neoplasias Uveais , Adulto , Humanos , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , MutaçãoRESUMO
Can criminology thrive on quantitative studies alone? Can evil be operationalized? Quantitative work may have, for the time being, supplanted common sense, personal experience and resulting in an improbable "Periodic Table of humanity". Has the construction of the psychopathic concept surpassed positivist "constitutional" formulations and translated into effective (re)habilitation of individuals lacking affiliative ethical behaviors? Or has it simply fueled a deterministic neo-Lombrosian truism: moral development has a brain. Has it helped so far? Has letting go of fundamental moral concepts, implicit in organized religion - but pervasive in most cultures irrespective of religious affiliation and devotion - in favor of causal explanations based solely on neuroimaging, personality inventories or structured emotional decoding tasks, made a difference in the life - or in the defense for that matter - of wrongdoers diagnosed as intrinsically evil?
Assuntos
Cérebro , Princípios Morais , Humanos , MasculinoRESUMO
SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Antineoplásicos/uso terapêutico , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Macaca fascicularis , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ratos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Small molecules that inhibit the metabolic enzyme NAMPT have emerged as potential therapeutics in oncology. As part of our effort in this area, we took a scaffold morphing approach and identified 3-pyridyl azetidine ureas as a potent NAMPT inhibiting motif. We explored the SAR of this series, including 5 and 6 amino pyridines, using a convergent synthetic strategy. This lead optimization campaign yielded multiple compounds with excellent in vitro potency and good ADME properties that culminated in compound 27.
RESUMO
Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma, and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1R132H. This Letter describes SAR exploration focused on improving both the in vitro and in vivo metabolic stability of the compounds, leading to the identification of 19 as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents. In a preclinical patient-derived IDH1 mutant xenograft tumor model study, 19 efficiently inhibited the production of the biomarker 2-HG.
RESUMO
Predictability of dangerousness in association with mental disorders remains elusive, outside of a few relatively well-established risk factors for the prognostication of violence, such as male sex, the presence of a psychotic disorder, and comorbid substance abuse. In clinical practice, inquiry into the presence of aggressive or violent ideation, in the form of ideas of homicide or suicide, is part of a standard mental status examination. Nonetheless, fantasy life, when it concerns harm toward others, may not be as reliable an indicator of imminent danger as it may be in the case of self-harm. Five cases of young Italian men with Asperger syndrome and recurrent and extremely violent femicide fantasies are presented. While there is no direct correlation between autism spectrum conditions and violence, as other humans, persons with an autistic condition are capable of committing crimes, including homicide. All five had in common a number of characteristics and behaviors felt to be pathoplastic: All had been bullied, all had been romantically rejected, all were long-standing First Person Shooter (FPS) game players, and all were avid violent pornography consumers. The potential for an actual neurocognitive impact of violent video games, well documented in the literature, and its combination with personal life history and chronic habituation following long-standing violent pornography use is discussed in the context of social and emotional vulnerabilities. While aggressive fantasies cannot and should not be underestimated, in countries where duty to protect legislation does not exist, a clinical approach is imperative, as, incidentally, should be anywhere.
Assuntos
Síndrome de Asperger/psicologia , Fantasia , Violência/psicologia , Adolescente , Comportamento Perigoso , Responsabilidade pela Informação , Humanos , Masculino , Adulto JovemRESUMO
Performance on an emotional labeling task in response to schematic facial patterns representing five basic emotions without the concurrent presentation of a verbal category was investigated in 40 parents of children with autism and 40 matched controls. 'Autism fathers' performed worse than 'autism mothers', who performed worse than controls in decoding displays representing sadness or disgust. This indicates the need to include facial expression decoding tasks in genetic research of autism. In addition, emotional expression interactions between parents and their children with autism, particularly through play, where affect and prosody are 'physiologically' exaggerated, may stimulate development of social competence. Future studies could benefit from a combination of stimuli including photographs and schematic drawings, with and without associated verbal categories. This may allow the subdivision of patients and relatives on the basis of the amount of information needed to understand and process social-emotionally relevant information.
Assuntos
Afeto , Transtorno Autístico/psicologia , Crianças com Deficiência , Expressão Facial , Pais/psicologia , Reconhecimento Psicológico , Percepção Visual , Adulto , Idoso , Criança , Pai/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mães/estatística & dados numéricosRESUMO
Childhood disruptive behaviors can be precursors to later deviance. To verify the efficacy of karate, a complex psychomotor activity that enhances self-regulation and executive skills, as an intervention for externalizing behaviors, 16 children, ranging in age from 8 to 10 years, and meeting diagnostic criteria for oppositional defiant disorder were studied. Eight were randomly assigned to a 10-month Wa Do Ryu karate program, whereas 8 children received no intervention. The children were assigned to a larger karate class, composed of typically developing youngsters. Three domains of temperament--intensity, adaptability, and mood regulation--were measured at the beginning and the end of the training period in all 16 participants. A significant improvement in temperament scale scores was measured in the karate group for all tested items compared to controls. Karate, when properly taught, can be a useful adjunct in multimodal programs aimed at externalizing behavior reduction.
Assuntos
Transtornos de Deficit da Atenção e do Comportamento Disruptivo/prevenção & controle , Crime/prevenção & controle , Artes Marciais , Comportamento Social , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/epidemiologia , Criança , Crime/estatística & dados numéricos , Feminino , Humanos , Masculino , Projetos Piloto , TemperamentoRESUMO
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
Assuntos
Antineoplásicos/química , Piperidinas/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirazinas/química , Pirimidinas/química , Administração Oral , Regulação Alostérica , Sítio Alostérico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Feminino , Xenoenxertos , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Piperidinas/síntese química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirazinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene. The analysis was performed in two genetically and diagnostically distinct groups of sporadic AD from Italy and the USA. In the Italian group a significant association between the IL-1alpha-889 T/T genotype and AD (OR=3.022, 95% CI: 1.001-9.119) was found, whereas no difference was found in the group from the USA. Results were also compared with previously published studies that analyzed the same IL-1 polymorphisms in AD. In both groups, the analysis of the estimated haplotypes shows that AD patients and controls who carry the IL-1beta-511 C allele, were also more frequently carriers of the IL-1Ra 1 allele (haplotypes -C-1). The total frequency of the two -C-1 haplotypes (C-C-1 plus T-C-1) was about one half of the total frequency of the eight estimated haplotypes. This was confirmed by significant linkage disequilibrium between these two loci in both the Italian and USA groups. In the Italian group a weak association of the T-C-2 haplotype with the disease (OR=1.648, 95% CI: 1.519-1.788) was also found, whereas in the USA group no difference was found. Although ours and other published data on different samples of Caucasian and non-Caucasian AD show a great heterogeneity in the frequencies of the IL-1alpha-889, the IL-1beta-511 and the IL-1Ra VNTR gene polymorphisms, we confirm the role of the IL-1alpha-889 T/T genotype as a risk factor for sporadic AD, and show the presence of an allelic association between IL-1beta C and IL-1Ra 1 alleles in both the Italian and the USA groups, confirmed by the presence of significant levels of linkage disequilibrium between these two loci.
Assuntos
Doença de Alzheimer/genética , Genótipo , Interleucina-1/genética , Repetições Minissatélites/genética , Polimorfismo Genético/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Análise de Variância , Distribuição de Qui-Quadrado , Análise por Conglomerados , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Interleucina-1/classificação , Itália/epidemiologia , Desequilíbrio de Ligação , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de Risco , Estatísticas não Paramétricas , Estados Unidos/epidemiologia , População Branca/genéticaRESUMO
Posthumous diagnoses are not uncommonly given to notorious public and historical figures by applying retrospectively, and typically in the absence of the individual being diagnosed, contemporary diagnostic criteria. Although this may be relatively easy and free of consequences when it concerns clear-cut medical conditions, it may have unintended repercussions in the case of psychiatric disorders by creating myths and perpetuating stigma. The case of serial killer Jeffrey Dahmer is a typical example where a somewhat facile and almost syllogistic application of perhaps over-inclusive criteria may have contributed to the legend of solitary murderers as possibly suffering from an autism spectrum condition. Although there may be an understandable human need to explain abominable and heinous behaviors, the lack of the possibility to verify a diagnostic theory and the ill-advised attempt to make a diagnosis fit may de facto be the basis of prejudice and profiling that do not correspond to clinical reality. Although there is no doubt that the brain is the organ of behavior, the authors caution against a budding neo-Lombrosian approach to crime and criminality and against the all too common use of widely differing terms in the study of deviance, such as crime, delinquency, and aggression, the operational use of which, often used interchangeably even in association studies, often erroneously leads to further confusion.
Assuntos
Transtorno da Personalidade Antissocial/história , Transtorno da Personalidade Antissocial/psicologia , Síndrome de Asperger/diagnóstico , Síndrome de Asperger/história , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/história , Canibalismo/história , Canibalismo/psicologia , Homossexualidade Masculina/história , Homossexualidade Masculina/psicologia , Estigma Social , Adulto , Síndrome de Asperger/psicologia , Transtorno do Espectro Autista/psicologia , Diagnóstico Tardio , Manual Diagnóstico e Estatístico de Transtornos Mentais , História do Século XX , História do Século XXI , Humanos , MMPI/estatística & dados numéricos , Masculino , Psicometria , Estados UnidosRESUMO
BACKGROUND: Patients with autism show clinical features suggestive of abnormal processing of auditory and other sensory information. We hypothesized that low-functioning autistic subjects present abnormalities in discriminating simple auditory stimuli at sensory system preconscious stages of cortical processing. METHODS: To verify our hypothesis, we used magnetoencephalographic measurements of mismatch field (MMF), which reflects the detection of a change in the physical characteristics of a repetitive sound. Fourteen patients (aged 8-32 years) who met DSM-IV diagnostic criteria for autistic disorder participated in an auditory oddball experiment. Ten healthy participants matched for age and gender acted as control subjects. RESULTS: Significant differences in cerebral responses between patients and control subjects were recorded. Whereas control subjects showed a clearly identifiable MMF, with distinct generators in the M100 brain wave with regard to latency, position, and strength, no identifiable MMF was present in the autistic group. CONCLUSIONS: Our findings suggest that low-functioning autistic subjects present a dysfunction at preconscious stages of cortical auditory discrimination, playing a role in the abnormal processing of auditory sensory afferences. The attention independence of the MMF allows for exclusion of an effect related to impaired attention or task-related responses.
Assuntos
Percepção Auditiva , Transtorno Autístico/fisiopatologia , Córtex Cerebral/fisiopatologia , Discriminação Psicológica , Magnetoencefalografia , Estimulação Acústica , Adolescente , Adulto , Córtex Auditivo/fisiopatologia , Estudos de Casos e Controles , Criança , Feminino , Humanos , MasculinoRESUMO
The role of methylenetetrahydrofolate reductase (MTHFR) and angiotensin converting enzyme (ACE) gene polymorphisms as risk factors for the occurrence of Alzheimer's disease (AD) is still controversial. In this study, we investigated the common MTHFR C677-->T and ACE insertion/deletion (I/D) gene polymorphisms as risk factors for AD in two genetically and diagnostically distinct cohort of Alzheimer's patients. We analyzed a neuropathologically confirmed American cohort of 124 AD patients and 97 elderly controls, and a clinically diagnosed Italian cohort of 126 probable AD cases, 106 elderly controls, and a community-based sample of 1232 subjects aged under 65 years. No difference was found in polymorphism distribution between cases and controls in both study cohorts. We also tested a possible association between the polymorphisms investigated. No interaction was found between the MTHFR and ACE alleles. Moreover, no association was found for the ACE and MTHFR polymorphisms with age at onset, disease duration and MMSE score at observation. Thus, in our study, MTHFR C677-->T and ACE I/D polymorphisms do not appear to confer an added risk for AD.
Assuntos
Doença de Alzheimer/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Doença de Alzheimer/classificação , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/etnologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Estudos de Coortes , Feminino , Ligação Genética , Predisposição Genética para Doença , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Valores de Referência , Fatores de Risco , Estados Unidos/epidemiologia , População Branca/genéticaRESUMO
Autism is a chronic and lifelong pervasive developmental disorder for which there is yet no effective cure, and medical management remains a major challenge for clinicians. In spite of the possible similarities with conditions that have an established pharmacotherapy, and despite improvements in some associated "problematic behaviors" following the use of available medications, effective medical treatment for the core symptoms involving language and social cognition remains elusive. The purpose of the present article is to review current biologic knowledge about autism in an attempt to correlate clinical trials with known mechanisms of disease. In addition, the need for controlled studies and for the creation of homogeneous subgroups of patients based on clinical and genetic characteristics is emphasized. The application of molecular genetic investigations and pharmacogenetics in the diagnostic work-up of autistic patients can lead to more effective individualized medical care.
Assuntos
Transtorno Autístico/tratamento farmacológico , Psicotrópicos/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Transtorno Autístico/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Criança , Aberrações Cromossômicas , Mapeamento Cromossômico , Ensaios Clínicos como Assunto , Dopaminérgicos/efeitos adversos , Dopaminérgicos/uso terapêutico , Humanos , Farmacogenética , Psicotrópicos/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Scattered reports propose that pervasive developmental disorders (PDDs) are risk factors for criminal behavior, yet the association between PDD and delinquent behavior is untrue for the majority of patients. However, individuals with PDDs may be at risk for legal trouble in the presence of comorbid psychopathology, and not solely on the basis of their developmental disability. This article analyzes theoretically the relationship between complex developmental disorders and delinquency with the hypothesis that the delinquent behaviors reported in it resulted from comorbid psychopathology and not as a direct consequence of a developmental disorder. A small series of patients diagnosed with a PDD and comorbid psychiatric illnesses whose admission to the hospital was precipitated by delinquent behavior is presented.
Assuntos
Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Crime/legislação & jurisprudência , Crime/estatística & dados numéricos , Transtornos Mentais/epidemiologia , Adulto , Criança , Hospitalização , Hospitais Psiquiátricos , Humanos , Masculino , Transtornos Mentais/reabilitação , Estados UnidosRESUMO
Autism is a complex neurodevelopmental disorder that affects social behaviors and parent-child interaction. It has been associated with an increased risk of social victimization, and a recent rise in number of acts of filicide of developmentally disabled children has included several cases of autism. In this article, possible risk factors for filicidal behavior in families with autistic children and prevention strategies are reviewed.