RESUMO
BACKGROUND: Previous literature demonstrates mortality discrepancies at Level II vs. Level I centers in patients with isolated Traumatic Brain Injury (TBI). Our hypothesis is that the implementation of the 2014 version of the resources manual ("the Orange Book") is associated with an elimination of this outcome disparity. METHODS: Utilizing the Trauma Quality Program Participant Use File for 2017, we compared TBI outcomes at ACS Level I vs. Level II centers. RESULTS: 39,764 records met inclusion criteria where 25,382 (63.8%) were admitted to a Level I center. Level I patients were younger (56.4 vs.59.1 years, p < 0.001) and less likely to have been injured in a single level fall (39.5%vs.45.5%, p < 0.001). The incidence of severe TBI (11.3%vs.10.3%, p < 0.001) was more common. Adjusted mortality at a Level II vs. Level I center were similar [7.8% vs. 8.4%, 0.669]. CONCLUSIONS: Implementation of 2014 version of the ACS resources manual is associated with improved TBI associated mortality in ACS Level II centers relative to their Level I counterparts.
Assuntos
Lesões Encefálicas Traumáticas/mortalidade , Lesões Encefálicas Traumáticas/terapia , Indicadores de Qualidade em Assistência à Saúde , Centros de Traumatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Lesões Encefálicas Traumáticas/diagnóstico , Protocolos Clínicos , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos , Adulto JovemRESUMO
Cellular senescence is associated with global chromatin changes, altered gene expression, and activation of chronic DNA damage signaling. These events ultimately lead to morphological and physiological transformations in primary cells. In this study, we show that chronic DNA damage signals caused by genotoxic stress impact the expression of histones H2A family members and lead to their depletion in the nuclei of senescent human fibroblasts. Our data reinforce the hypothesis that progressive chromatin destabilization may lead to the loss of epigenetic information and impaired cellular function associated with chronic DNA damage upon drug-evoked senescence. We propose that changes in the histone biosynthesis and chromatin assembly may directly contribute to cellular aging. In addition, we also outline the method that allows for quantitative and unbiased measurement of these changes.
Assuntos
Senescência Celular/genética , Dano ao DNA/genética , Histonas/genética , Transdução de Sinais/genética , Sequência de Aminoácidos , Antibióticos Antineoplásicos , Bleomicina , Western Blotting , Senescência Celular/efeitos dos fármacos , Cromatina/genética , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Histonas/metabolismo , Humanos , Imuno-Histoquímica , Espectrometria de Massas/métodos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacosRESUMO
Cellular aging is linked to deficiencies in efficient repair of DNA double strand breaks and authentic genome maintenance at the chromatin level. Aging poses a significant threat to adult stem cell function by triggering persistent DNA damage and ultimately cellular senescence. Senescence is often considered to be an irreversible process. Moreover, critical genomic regions engaged in persistent DNA damage accumulation are unknown. Here we report that 65% of naturally occurring repairable DNA damage in self-renewing adult stem cells occurs within transposable elements. Upregulation of Alu retrotransposon transcription upon ex vivo aging causes nuclear cytotoxicity associated with the formation of persistent DNA damage foci and loss of efficient DNA repair in pericentric chromatin. This occurs due to a failure to recruit of condensin I and cohesin complexes. Our results demonstrate that the cytotoxicity of induced Alu repeats is functionally relevant for the human adult stem cell aging. Stable suppression of Alu transcription can reverse the senescent phenotype, reinstating the cells' self-renewing properties and increasing their plasticity by altering so-called "master" pluripotency regulators.