Expression of human cationic trypsinogen (PRSS1) in murine acinar cells promotes pancreatitis and apoptotic cell death.

Hereditary pancreatitis (HP) is an autosomal dominant disease that displays the features of both acute and chronic pancreatitis. Mutations in human cationic trypsinogen (PRSS1) are associated with HP and have provided some insight into the pathogenesis of pancreatitis, but mechanisms responsible for the initiation of pancreatitis have not been elucidated and the role of apoptosis and necrosis has been much debated. However, it has been generally accepted that trypsinogen, prematurely activated within the pancreatic acinar cell, has a major role in the initiation process. Functional studies of HP have been limited by the absence of an experimental system that authentically mimics disease development. We therefore developed a novel transgenic murine model system using wild-type (WT) human PRSS1 or two HP-associated mutants (R122H and N29I) to determine whether expression of human cationic trypsinogen in murine acinar cells promotes pancreatitis. The rat elastase promoter was used to target transgene expression to pancreatic acinar cells in three transgenic strains that were generated: Tg(Ela-PRSS1)NV, Tg(Ela-PRSS1*R122H)NV and Tg(Ela-PRSS1*N29I)NV. Mice were analysed histologically, immunohistochemically and biochemically. We found that transgene expression is restricted to pancreatic acinar cells and transgenic PRSS1 proteins are targeted to the pancreatic secretory pathway. Animals from all transgenic strains developed pancreatitis characterised by acinar cell vacuolisation, inflammatory infiltrates and fibrosis. Transgenic animals also developed more severe pancreatitis upon treatment with low-dose cerulein than controls, displaying significantly higher scores for oedema, inflammation and overall histopathology. Expression of PRSS1, WT or mutant, in acinar cells increased apoptosis in pancreatic tissues and isolated acinar cells. Moreover, studies of isolated acinar cells demonstrated that transgene expression promotes apoptosis rather than necrosis. We therefore conclude that expression of WT or mutant human PRSS1 in murine acinar cells induces apoptosis and is sufficient to promote spontaneous pancreatitis, which is enhanced in response to cellular insult.

FDG-PET-CT is effective in selecting patients with poor long term survivals for colorectal liver metastases.

AIMS: Having incorporated PET-CT as part of the staging process for colorectal liver metastases (CRLM) in our unit since 2008, this study aims to evaluate the survival outcomes of all patients managed by our specialist multi-disciplinary team (MDT). METHODS: All patients with colorectal liver metastases referred to a single liver MDT between 2008 and 2011 were examined. Overall survival (OS) for palliative groups due to occult extrahepatic disease detected by PET-CT (A) and those upfront palliative patients with extensive multi-site disease as identified on baseline CT or disease progression during chemotherapy (B), and resected (C) groups were evaluated and compared. Different extents of occult extrahepatic disease as characterised by PET-CT were also compared. RESULTS: 532 patients were included in the study. Median OS for group A (n = 80), B (n = 161) and C (n = 291) were 10.9, 12.0 and 46.7 months, with a 5-year OS approaching 6.5%, 6.1% and 43.0% respectively. There were significant differences in OS of C vs. A & B (p < 0.001). Single compartment metastases had a significant better survival outcomes than non-torso metastases (p = 0.04). CONCLUSION: This is the first report of OS of patients with CRLM excluded from surgery on the basis of PET-CT. We have confirmed that PET-CT is effective in selecting patients with occult extrahepatic disease, which has poor survival outcomes. However, a subgroup with single compartment extrahepatic disease has a better than expected outcome.

Real-time patient weight monitoring system for chair based renal dialysis.

A system is described for monitoring weight changes in patients undergoing renal dialysis. Relatively fit patients dialyse in easy chairs rather than in bed but no commercial system is currently available to monitor weight changes under these conditions. The authors have considered basic requirements and have developed a cost effective system based on a Single Point Off-Centre load cell, all components being mounted under a platform on which the easy chair is located. There is an electrical output signal which may be used to drive a display or be sampled by a computer system.