RESUMO
Base excision repair (BER) of an oxidized base within a trinucleotide repeat (TNR) tract can lead to TNR expansions that are associated with over 40 human neurodegenerative diseases. This occurs as a result of DNA secondary structures such as hairpins formed during repair. We have previously shown that BER in a TNR hairpin loop can lead to removal of the hairpin, attenuating or preventing TNR expansions. Here, we further provide the first evidence that AP endonuclease 1 (APE1) prevented TNR expansions via its 3'-5' exonuclease activity and stimulatory effect on DNA ligation during BER in a hairpin loop. Coordinating with flap endonuclease 1, the APE1 3'-5' exonuclease activity cleaves the annealed upstream 3'-flap of a double-flap intermediate resulting from 5'-incision of an abasic site in the hairpin loop. Furthermore, APE1 stimulated DNA ligase I to resolve a long double-flap intermediate, thereby promoting hairpin removal and preventing TNR expansions.
Assuntos
Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Expansão das Repetições de Trinucleotídeos , DNA/química , DNA/metabolismo , DNA Ligase Dependente de ATP , DNA Ligases/metabolismo , Exodesoxirribonucleases/metabolismo , Endonucleases Flap/metabolismo , Conformação de Ácido NucleicoAssuntos
Medicina de Emergência/educação , Hemorragia/prevenção & controle , Incidentes com Feridos em Massa/estatística & dados numéricos , Instituições Acadêmicas , Ferimentos por Arma de Fogo/terapia , Adolescente , Violência com Arma de Fogo , Conhecimentos, Atitudes e Prática em Saúde , Promoção da Saúde , Técnicas Hemostáticas , Humanos , Estudantes , Estados UnidosRESUMO
The effect of timing in patients requiring tracheostomy varies in the literature. The purpose of this study was to evaluate the impact of early tracheostomy on outcomes in trauma patients with and without traumatic brain injury (TBI). This study is a four-year review of trauma patients undergoing tracheostomy. Patients were divided into two groups based on TBI/non-TBI. Each group was divided into three subgroups based on tracheostomy timing: zero to three days, four to seven days, and greater than seven days postadmission. TBI patients were stratified by the Glasgow Coma Scale (GCS), and non-TBI patients were stratified by the Injury Severity Score (ISS). The primary outcome was ventilator-free days (VFDs). Significance was defined as P < 0.05. Two hundred eighty-nine trauma patients met the study criteria: 151 had TBI (55.2%) versus 138 (47.8%) non-TBI. There were no significant differences in demographics within and between groups. In TBI patients, statistically significant increases in VFDs were observed with GCS 13 to 15 for tracheostomies performed in four to seven versus greater than seven days (P = 0.005). For GCS <8 and 8 to 12, there were significant increases in VFDs for tracheostomies performed at days 1 to 3 and 4 to 7 versus greater than seven days (P ⪠0.05 for both). For non-TBI tracheostomies, only ISS ≥ 25 with tracheostomies performed at zero to three days versus greater than seven days was associated with improved VFDs. Early tracheostomies in TBI patients were associated with improved VFDs. In trauma patients with no TBI, early tracheostomy was associated with improved VFDs only in patients with ISS ≥ 25. Future research studies should investigate reasons TBI and non-TBI patients may differ.