RESUMEN
Background and study aims Prognostic and risk factors for upper gastrointestinal bleeding (UGIB) might have changed overtime because of the increased use of direct oral anticoagulants and improved gastroenterological care. This study was undertaken to assess the outcomes of UGIB in light of these new determinants by establishing a new national, multicenter cohort 10 years after the first. Methods Consecutive outpatients and inpatients with UGIB symptoms consulting at 46 French general hospitals were prospectively included between November 2017 and October 2018. They were followed for at least for 6 weeks to assess 6-week rebleeding and mortality rates and factors associated with each event. Results Among the 2498 enrolled patients (mean age 68.5 [16.3] years, 67.1â% men), 74.5â% were outpatients and 21â% had cirrhosis. Median Charlson score was 2 (IQR 1-4) and Rockall score was 5 (IQR 3-6). Within 24 hours, 83.4â% of the patients underwent endoscopy. The main causes of bleeding were peptic ulcers (44.9â%) and portal hypertension (18.9â%). The early in-hospital rebleeding rate was 10.5â%. The 6-week mortality rate was 12.5â%. Predictors significantly associated with 6-week mortality were initial transfusion (OR 1.54; 95â%CI 1.04-2.28), Charlson score >â4 (OR 1.80; 95â%CI 1.31-2.48), Rockall score >â5 (OR 1.98; 95â%CI 1.39-2.80), being an inpatient (OR 2.45; 95â%CI 1.76-3.41) and rebleeding (OR 2.6; 95â%CI 1.85-3.64). Anticoagulant therapy was not associated with dreaded outcomes. Conclusions The 6-week mortality rate remained high after UGIB, especially for inpatients. Predictors of mortality underlined the weight of comorbidities on outcomes.
RESUMEN
The activation peptide of mammalian trypsinogens contains a highly conserved tetra-aspartate sequence (D19-D20-D21-D22) preceding the K23-I24 scissile peptide bond, which is hydrolyzed as the first step in the activation process. Here, we examined the evolution and function of trypsinogen activation peptides through integrating functional characterization of disease-associated mutations with comparative genomic analysis. Activation properties of three chronic pancreatitis-associated activation peptide mutants (the novel D19A and the previously reported D22G and K23R) were simultaneously analyzed, for the first time, in the context of recombinant human cationic trypsinogen. A dramatic increase in autoactivation of cationic trypsinogen was observed in all three mutants, with D22G and K23R exhibiting the most marked increases. The physiological activator enteropeptidase activated the D19A mutant normally, activated the D22G mutant very poorly, and stimulated activation of the K23R mutant. The biochemical and structural data, taken together with a comprehensive sequence comparison, indicates that the tetra-aspartate sequence in mammalian trypsinogen activation peptides has evolved not only for optimal enteropeptidase recognition in the duodenum but also for efficient inhibition of trypsinogen autoactivation within the pancreas. Moreover, the use of lysine instead of arginine at the P1 position of activation peptides also has an advantageous effect against trypsinogen autoactivation. Finally, fixed substitutions in the key residues of the trypsinogen activation peptide may suggest the evolution of new functions unrelated to digestion, as found in the group III trypsinogens of cold-adapted fishes.
Asunto(s)
Oligopéptidos/química , Oligopéptidos/genética , Secuencia de Aminoácidos , Animales , Arginina/química , Cationes/química , Enteropeptidasa/química , Activación Enzimática , Evolución Molecular , Peces , Hidrólisis , Lisina/química , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Mutación , Péptidos/química , Plásmidos/metabolismo , Proteínas Recombinantes/química , Factores de Tiempo , Tripsinógeno/químicaRESUMEN
We report the case of a 33-year-old man who presented with a large B-cell non Hodgkin's lymphoma presenting as acute pancreatitis. Abdominal CT showed diffuse swelling of the pancreas, with two distinct masses in the corpus and the tail. Thoracic CT showed a markedly enlarged mediastinum, with a voluminous mass in the middle mediastinum. Direct biopsy of this mass revealed a large B-cell lymphoma. Chemotherapy followed by peripheral blood cell autotransplantation led to complete disappearance of the pancreatic and mediastinal masses. Fatty diarrhea occurred after chemotherapy, probably owing to gland destruction by lymphomatous infiltration. Twenty-six months later, the patient is disease-free but continues to require pancreatic enzyme supplements.