RESUMO
ABSTRACT: The risk factors associated with 72-hours mortality in patients with extremely high levels of random plasma glucose (RPG) remain unclear.To explore the risk factors predictive of 72-hours mortality in patients with extremely high RPG under heterogenos pathophysiological conditions.Retrospective, single-center, case-controlled cross-sectional study.University teaching hospital.Adults over age 18 were selected from the medical records of patients at the Saitama Medical Center, Japan, from 2004 to 2013.Extremely high RPG (≥500âmg/dl).Mortality at 72âhours following the RPG test, regardless of hospitalization or in an outpatient setting. Multivariate logistic regression analysis was performed with adjustment for age, sex, body mass index (BMI), and RPG level. The final prediction model was built using the logistic regression model with a higher C-statistic, specificity, and sensitivity.A total of 351 patients with RPG ≥500âmg/dl were identified within the 10-year period. The 72-hours mortality rate was 16/351 (4.6%). The C-statistics of the 72-hours mortality prediction model with serum albumin (ALB) and creatine kinase (CK) was 0.856. The probability of 72-hours mortality was calculated as follows: 1/[1â+âexp (-5.142â+â0.901log (CK) -1.087 (ALB)â+â0.293 (presence (1) or absence (0) of metastatic solid tumor)]. The sensitivity and specificity of this model was 75.5%.The independent risk factors associated with 72-hours mortality in patients with RPG ≥500âmg/dl are hypoalbuminemia, elevated CK, and presence of a metastatic solid tumour. Further research is needed to understand the mechanisms and possible interventions to prevent mortality associated with extremely high RPG.
Assuntos
Glicemia/análise , Creatina Quinase/sangue , Hiperglicemia/mortalidade , Hipoalbuminemia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Comorbidade , Estudos Transversais , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
Fanconi anemia (FA) is a chromosome instability syndrome characterized by increased cancer predisposition. Specifically, the FA pathway functions to protect genome stability during DNA replication. The central FA pathway protein, FANCD2, locates to stalled replication forks and recruits homologous recombination (HR) factors such as CtBP interacting protein (CtIP) to promote replication fork restart while suppressing new origin firing. Here, we identify alpha-thalassemia retardation syndrome X-linked (ATRX) as a novel physical and functional interaction partner of FANCD2. ATRX is a chromatin remodeler that forms a complex with Death domain-associated protein 6 (DAXX) to deposit the histone variant H3.3 into specific genomic regions. Intriguingly, ATRX was recently implicated in replication fork recovery; however, the underlying mechanism(s) remained incompletely understood. Our findings demonstrate that ATRX forms a constitutive protein complex with FANCD2 and protects FANCD2 from proteasomal degradation. ATRX and FANCD2 localize to stalled replication forks where they cooperate to recruit CtIP and promote MRE11 exonuclease-dependent fork restart while suppressing the firing of new replication origins. Remarkably, replication restart requires the concerted histone H3 chaperone activities of ATRX/DAXX and FANCD2, demonstrating that coordinated histone H3 variant deposition is a crucial event during the reinitiation of replicative DNA synthesis. Lastly, ATRX also cooperates with FANCD2 to promote the HR-dependent repair of directly induced DNA double-stranded breaks. We propose that ATRX is a novel functional partner of FANCD2 to promote histone deposition-dependent HR mechanisms in S-phase.