Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology

Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa−/− and Csb−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa−/− and Xpc−/− XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa−/−, Csb−/−) or highly sporadic (Xpa−/−, Xpc−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa−/− and Csb−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival

Prevalência e fatores associados ao Transtorno de Estresse Pós-Traumático (TEPT) em profissionais de emergência: uma revisão sistemática da literatura Prevalence and factors associated with Posttraumatic Stress Disorder (PTSD) in emergency workers: a systematic literature review

OBJETIVO: Identificar as prevalências de Transtorno de Estresse Pós-Traumático (TEPT) em profissionais dos serviços de emergências e conhecer os fatores associados ao desfecho. MÉTODOS: Foram consultadas sete bases de dados (MEDLINE via Pubmed, PsycINFO, LILACS, SciELO, BDENF, DISASTRES e MEDCARIB) entre os dias 10 e 25 de setembro de 2009, restringindo-se a pesquisa a artigos em português, inglês ou espanhol publicados no período de 2004 a 2009. Os descritores utilizados abarcaram termos relacionados a profissionais/serviços de emergência, transtorno de estresse pós-traumático e condições de trabalho e saúde ocupacional. Foram incluídos estudos observacionais quantitativos que investigaram a prevalência de TEPT e fatores determinantes ou associados à doença em amostras de bombeiros, profissionais de ambulância, profissionais da Cruz Vermelha e profissionais de emergência em hospitais. Foram excluídos estudos com base em amostras inadequadas para os objetivos da revisão (policiais, voluntários e filhos de profissionais de emergência) ou que não incluíram sintomas de TEPT como variável dependente em pelo menos um dos objetivos. RESULTADOS: A leitura dos títulos e resumos resultou em 30 artigos. A revisão das publicações completas permitiu a inclusão e análise de 17 artigos. Os estudos selecionados adotaram diferentes delineamentos, instrumentos, critérios diagnósticos e técnicas estatísticas de análise. A prevalência da doença variou da ausência de registro de casos à taxa de 38,5%. Características sociodemográficas, biológicas e psicológicas, morbidade, exposição a eventos traumáticos ocupacionais e não-ocupacionais, e características do trabalho e do emprego associaram-se ao TEPT em profissionais de emergência. CONCLUSÃO: Variáveis individuais e de contexto são consideradas fatores associados ou de risco para o TEPT e explicitam o caráter mutidimensional do desfecho em foco.<br>OBJECTIVE: To identify the prevalence of Posttraumatic Stress Disorder (PTSD) in emergency workers and determine the factors associated with outcomes. METHODS: Seven databases were consulted (Medline via Pubmed, PsycINFO, LILACS, SciELO, BDENF, DISASTERS, and MEDCARIB) between September 10 and 25, 2009. The search only included articles published in Portuguese, English or Spanish between 2004 and 2009. The key-words involved terms related to emergency services/workers, Posttraumatic stress disorder, working conditions, and occupational health. Quantitative observational studies on PTSD prevalence and determinant or associated factors regarding the health of firefighters, emergency ambulance personnel, Red Cross workers, and medical emergency workers were included. Studies using samples unrelated to the purposes of this review (police officers, volunteers and emergency workers' children) or that did not include PTSD symptoms as the dependent variable in at least one of the objectives of the study were excluded. RESULTS: 30 articles were selected by reading the titles and abstracts. 17 complete articles were reviewed and analyzed. Studies adopted different research designs, instruments and diagnostic criteria for statistical analysis. The prevalence of the disease ranged from absence of reported cases to a rate of 38.5%. Socio-demographic, biological and psychological characteristics, morbidity, exposure to occupational and non-occupational traumatic events, and work and job features were associated with the prevalence of PTSD in emergency workers. CONCLUSION: Individual and contextual variables are considered as factors associated with PTSD, which explains the multidimensional nature of the outcome studied