O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis

Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases

An analysis of near misses identified by anesthesia providers in the intensive care unit

© 2015 Lipshutz et al. Background: Learning from adverse events and near misses may reduce the incidence of preventable errors. Current literature on adverse events and near misses in the ICU focuses on errors reported by nurses and intensivists. ICU nea

Predicting mortality in the intensive care unit: a comparison of the University Health Consortium expected probability of mortality and the Mortality Prediction Model III.

BackgroundQuality benchmarks are increasingly being used to compare the delivery of healthcare, and may affect reimbursement in the future. The University Health Consortium (UHC) expected probability of mortality (EPM) is one such quality benchmark. Although the UHC EPM is used to compare quality across UHC members, it has not been prospectively validated in the critically ill. We aimed to define the performance characteristics of the UHC EPM in the critically ill and compare its ability to predict mortality with the Mortality Prediction Model III (MPM-III).MethodsThe first 100 consecutive adult patients discharged from the hospital (including deaths) each quarter from January 1, 2009 until September 30, 2011 that had an intensive care unit (ICU) stay were included. We assessed model discrimination, calibration, and overall performance, and compared the two models using Bland-Altman plots.ResultsEight hundred ninety-one patients were included. Both the UHC EPM and the MPM-III had excellent performance (Brier score 0.05 and 0.06, respectively). The area under the curve was good for both models (UHC 0.90, MPM-III 0.87, p = 0.28). Goodness of fit was statistically significant for both models (UHC p = 0.002, MPM-III p = 0.0003), but improved with logit transformation (UHC p = 0.41; MPM-III p = 0.07). The Bland-Altman plot showed good agreement at extremes of mortality, but agreement diverged as mortality approached 50 %.ConclusionsThe UHC EPM exhibited excellent overall performance, calibration, and discrimination, and performed similarly to the MPM-III. Correlation between the two models was poor due to divergence when mortality was maximally uncertain

Mesangial sclerosis in a patient with type 1 diabetes following simultaneous pancreas-kidney transplantation despite maintenance of normoglycemia: a case report.

BackgroundSimultaneous pancreas-kidney transplantation is considered a curative treatment for type 1 diabetes complicated by end-stage kidney disease. We report herein a case of mesangial sclerosis in a patient who underwent successful kidney-pancreas transplantation despite well-controlled glucose and excellent pancreatic allograft function.Case presentationA 76-year-old type 1 diabetic man who underwent a simultaneous pancreas-kidney transplantation 19 years prior presented with persistent nephrotic range proteinuria although creatinine was at his baseline (normal) level. Hemoglobin A1c and fasting glucose were well controlled without the use of insulin or oral antihyperglycemic agents. Serum lipase and amylase were within the reference range and there was no evidence of donor-specific antibodies. Kidney allograft biopsy was performed to evaluate proteinuria and showed diffuse capillary loop thickening and diffuse moderate to severe mesangial sclerosis resembling diabetic nephropathy.ConclusionsThis case demonstrates a case of mesangial sclerosis resembling diabetic nephropathy in a patient with good glucose control after simultaneous pancreas-kidney transplantation with excellent pancreatic allograft function

O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis

Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases