NK-1 receptor desensitization and neutral endopeptidase terminate SP-induced pancreatic plasma extravasation.

Substance P (SP) induces plasma extravasation and neutrophil infiltration by activating the neurokinin-1 receptor (NK1-R). We characterized the mechanisms regulating this response in the rat pancreas. Anesthetized rats were continuously infused with SP, and plasma extravasation was quantified using Evans blue (EB) dye. Continuous infusion of SP (8 nmol. kg(-1). h(-1)) resulted in a threshold increase in EB at 15 min, a peak effect at 30 min (150% increase), and a return to baseline by 60 min. The NK1-R antagonist CP-96,345 blocked SP-induced plasma extravasation. After 60 min, the NK1-R was desensitized to agonist challenge. Resensitization was first detected at 20 min and increased until full recovery was seen at 30 min. Inhibition of the cell-surface protease neutral endopeptidase (NEP) by phosphoramidon potentiated the effect of exogenous SP; therefore endogenous NEP attenuates SP-induced plasma extravasation. Thus the continuous infusion of SP stimulates plasma extravasation in the rat pancreas via activation of the NK1-R, and these effects are terminated by both desensitization of the NK1-R and the cell-surface protease NEP.

The spectrum and cost of complicated gallstone disease in California.

HYPOTHESIS: We hypothesized that complications of gallstone disease are more common than previously recognized and are related to treatment delay. DESIGN: Retrospective review. PATIENTS: Data for 248 consecutive patients from a university hospital in 1995-1996 and 40,571 patients identified through the 1996 California Office of Statewide Health Planning and Development database who underwent cholecystectomy for gallstone disease were reviewed. MAIN OUTCOME MEASURES: Diagnosis, length of hospital stay, hospital mortality, type of admission, type of surgical procedure, hospital cost, and interval of delay between onset of initial symptoms, ultrasound diagnosis, and cholecystectomy. RESULTS: The spectrum of gallstone disease included biliary colic in 56%, acute cholecystitis in 36%, acute pancreatitis in 4%, choledocholithiasis in 3%, gallbladder cancer in 0.3%, and cholangitis in 0.2%. Community hospitals, public or county hospitals, and academic health centers had a similar distribution of diagnoses. Patients undergoing cholecystectomy for biliary colic had a significantly shorter length of hospital stay, lower operative mortality rate, were more likely to have their operations completed laparoscopically, and had lower hospital charges than patients undergoing cholecystectomy for complications such as acute cholecystitis. Over half of the patients requiring cholecystectomy for complications of gallstones initially presented with biliary colic. Patients with gallstone complications had an average delay from ultrasound confirmation to surgery of 6 months. CONCLUSION: Complications of gallstone disease are (1) common, (2) costly, and (3) potentially preventable.

Substance P is a determinant of lethality in diet-induced hemorrhagic pancreatitis in mice.

BACKGROUND: The neuropeptide substance P (SP) induces plasma extravasation and neutrophil infiltration by activating the neurokinin 1-receptor (NK1-R). SP-induced neurogenic inflammation is terminated by the cell surface enzyme neutral endopeptidase (NEP), which degrades SP. We determined whether genetic deletion of the NK1-R reduces mortality and, conversely, whether genetic deletion of NEP increases mortality in a lethal model of hemorrhagic pancreatitis. METHODS: Necrotizing pancreatitis was induced by feeding mice a diet deficient in choline and supplemented with ethionine. We determined the length of survival, the severity of pancreatitis (by measuring the neutrophil enzyme myeloperoxidase [MPO] and by histologic evaluation), and the severity of pancreatitis-associated lung injury (lung MPO and histology) in NK1-R (+/+)/(-/-) and NEP (+/+)/(-/-) mice. RESULTS: Genetic deletion of the NK1-R significantly improved survival (100% vs 8% at 120 hours, P <.001) and reduced pancreatic MPO and acinar cell necrosis. Conversely, genetic deletion of NEP significantly worsened survival (0% vs 90% at 120 hours, P <.001) and exacerbated pancreatic MPO and pancreatitis-associated lung injury. CONCLUSIONS: Substance P is an important determinant of lethality in this model of necrotizing pancreatitis. Defects in NEP expression could lead to uncontrolled inflammation.

Does the participation of a surgical trainee adversely impact patient outcomes? A study of major pancreatic resections in California.

BACKGROUND: Some patients have concerns regarding the impact of surgical trainees on the quality of care that they receive in teaching hospitals. No population-based data exist that describe outcomes of surgical procedures in teaching and nonteaching hospitals; however, institutional data suggest that teaching hospitals provide high-quality care. We hypothesized that the presence of a general surgery residency program (GSRP) is associated with superior outcomes for pancreatic resection, a complex surgical procedure. METHODS: A retrospective, population-based, risk-adjusted analysis of 5696 patients who underwent major pancreatic resection compares the outcomes of patients treated at hospitals with a GSRP (GSRP+) and those hospitals without a GSRP (GSRP-). RESULTS: GSRP+ hospitals had a lower operative mortality rate (8.3% vs 11.0%; P <. 001), a lower percentage of patients discharged to another acute care hospital or skilled nursing facility (6.5% vs 13.0%; P <.001), and a longer length of stay compared with GSRP- hospitals (22.1 +/- 0.4 days vs 19.6 +/- 0.3 days; P <.001). The observed difference in hospital mortality rates was not significant after an adjustment was made for patient mix and hospital volume (9.7% vs 10.0%). However, superior outcomes were found in the university teaching hospitals, as compared with the affiliated teaching and the nonteaching hospitals (5.3% [P <.001] vs 11.4% vs 11.0%; risk adjusted, 8.0% [P <.05] vs 10.9% vs 10.0%). CONCLUSIONS: The presence of surgical trainees does not have an adverse impact on the quality of care for One complex procedure, pancreatectomy, and is associated with superior operative mortality rate in university teaching hospitals.

Heat-shock protein induction in rat hearts. A direct correlation between the amount of heat-shock protein induced and the degree of myocardial protection.

BACKGROUND: Previous studies have demonstrated that heat-shock treatment results in the induction of 72-kD heat-shock protein (HSP72) and a reduction of infarct size after subsequent ischemia and reperfusion. METHODS AND RESULTS: To test the hypothesis that the degree of protection from ischemic injury in heat-shocked rats correlates with the degree of prior HSP72 induction, rats pretreated with 40 degrees C, 41 degrees C, or 42 degrees C of whole-body hyperthermia followed by 24 hours of recovery and control rats (n = 6 in each group) were quantitatively assessed for the presence of myocardial HPS72 by optical densitometry of Western blots and a primary antibody that is specific for HSP72 and a tertiary antibody labeled with 125I. Although rats heat-shocked to 40 degrees C had no significant induction of myocardial HSP72, rats heat-shocked to 41 degrees C and 42 degrees C demonstrated progressively increased amounts of myocardial HSP72 compared with controls. Separate groups of rats heat-shocked to 40 degrees C (n = 16), 41 degrees C (n = 37), and 42 degrees C (n = 36) with 24 hours of recovery and controls (n = 26) were subjected to 35 minutes of left coronary artery occlusion and 120 minutes of reperfusion. Compared with control and 40 degrees C rats, there was progressive infarct size reduction, assessed by triphenyltetrazolium chloride staining, in rats that were heat-shocked to 41 degrees C and 42 degrees C. Furthermore, there was a direct correlation between the amount of HSP72 induced and the reduction in infarct size (r = .97, P = .037). CONCLUSIONS: These results suggest that the improved salvage after heat-shock pretreatment may be related to the amount of HSP72 induced before prolonged ischemia and reperfusion.