RESUMO
Crohn's disease (CD) is a polygenic immune-mediated disease characterized by gastrointestinal inflammation. Mice deficient in the hematopoietic-restricted SH2 domain-containing inositolpolyphosphate 5'-phosphatase (SHIP) develop spontaneous CD-like ileal inflammation. Intriguingly, SHIP mRNA is not upregulated in biopsies from patients with ileal CD despite immune cell infiltration, but SHIP's role in human CD remains unknown. We analyzed SHIP mRNA expression and activity in biopsies and peripheral blood mononuclear cells (PBMCs) from control and treatment-naive subjects with ileal CD, and demonstrated that SHIP mRNA and activity were lower in hematopoietic cells in ileal biopsies and PBMCs from subjects with CD. In all tissues from our patient cohort and in PBMCs from a second healthy control cohort, subjects homozygous for the autophagy-related 16-like protein (ATG16L1) CD-associated gene variant (rs2241880), had low SHIP mRNA expression and activity. SHIP protein expression increased during autophagy and SHIP upregulation was dependent on ATG16L1 and/or autophagy, as well as the ATG16L1 CD-associated gene variant. Finally, homozygosity for the ATG16L1 risk variant and low SHIP mRNA expression is inversely related to increased (LPS+ATP)-induced IL-1ß production by PBMCs in our cohorts and was regulated by increased transcription of ILIB. These data suggest a novel mechanism by which the ATG16L1 CD-associated gene variant may predispose people to develop intestinal inflammation.
Assuntos
Proteínas de Transporte/genética , Doença de Crohn/genética , Monoéster Fosfórico Hidrolases/genética , Adulto , Animais , Proteínas Relacionadas à Autofagia , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Doença de Crohn/enzimologia , Doença de Crohn/metabolismo , Feminino , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Inositol Polifosfato 5-Fosfatases , Masculino , Camundongos , Monoéster Fosfórico Hidrolases/sangue , Monoéster Fosfórico Hidrolases/metabolismo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Domínios de Homologia de srcRESUMO
The increasing concern about the high cost of health care led the authors to conduct a pilot study on the overall cost and cost variability for patients who underwent coronary artery bypass grafting. They reviewed the charts of 50 randomly selected patients to determine actual costs of catheterization and bypass grafting. Four patients had single-vessel disease, 12 double- and 34 triple-vessel disease and 13 had moderate to severe impairment of ventricular function. The length of hospital stay ranged from 8 to 43 days (mean 16.5 days). The duration of stay in the recovery room and intensive care unit ranged from 21 to 356 hours (mean 91.6 hours). Operative time ranged from 2 to 6.5 hours (mean 3.95 hours). Using several accepted cost-allocation methods, the authors developed a valid, complete breakdown of clinical and nonclinical costs. Total cost was directly related to the length of hospital stay, left ventricular function, secondary diagnosis and number of diseased vessels. Further studies will address clinical factors related to cost and cost effectiveness of coronary artery bypass grafting as opposed to other forms of treatment for coronary artery disease.
