The SPINK1 N34S variant is associated with acute pancreatitis.

OBJECTIVE: Acute pancreatitis (AP) is a disease whose pathogenesis remains largely obscure. Genetic research has focussed attention upon the role of the pancreatic protease/protease inhibitor system. The aim of this study was to investigate the prevalence of genetic variants of the trypsin inhibitor, SPINK1, in acute pancreatitis. METHODS: We genotyped 468 patients with AP and 1117 healthy controls for SPINK1 alterations by single-strand conformation polymorphism analysis and by melting curve analysis using fluorescence resonance energy transfer probes. RESULTS: The c.101A>G (p.N34S) variant was detected in 24/936 alleles of patients and in 18/2234 alleles of healthy controls (odds ratio=3.240; 95% confidence interval: 1.766-5.945; P<0.001). In the UK patients, the mean age of patients with N34S was 11.9 years younger compared with N34S negative patients (P=0.023), but this was not apparent in the German patients. Allele frequencies for the c.163C>T (p.P55S) variant did not differ between patients and controls. CONCLUSION: The SPINK1 N34S variant is associated with acute pancreatitis. This supports the importance of premature protease activation in the pathogenesis of AP and suggests that mutated SPINK1 may predispose certain individuals to develop this disease.

A defunctioning stoma significantly prolongs the length of stay in laparoscopic colorectal resection.

BACKGROUND: Reduction in length of stay has several advantages, including healthcare costs, patient choice, and minimizing hospital acquired infections. Additionally, length of stay is a surrogate marker of rate of recovery from the physiological insult of anaesthesia and surgery and complications thereof. A well-documented short-term benefit of laparoscopic compared to open colorectal resection is reduced length of stay. METHODS: This was a review of prospectively collected data on all laparoscopic colorectal resections performed in our unit. We analyzed patients having primary colorectal anastomosis, to assess the effect of conversion compared to completion laparoscopically. Furthermore we compared those with or without diverting stoma, for the effect of stoma formation on postoperative length of stay (LOS). RESULTS: Two hundred and thirteen patients had a colorectal resection. Of these 133 (62%) were left-sided or rectal resections. Resection with primary colorectal anastomosis was undertaken in 112 patients. A defunctioning stoma was performed in 13/112 (12%), and 32/112 (29%) were converted as the procedure could not be completed laparoscopically. Conversion was not significantly associated with increased LOS with weighted median of 6.5 and 6 days for conversion and no conversion, respectively. However, stoma formation significantly increased LOS to a median of 10 days compared with a median of 6 days in patients without a stoma (p = 0.001, Mann-Whitney U). CONCLUSIONS: The need for conversion, if performed in a timely and appropriate manner, has little impact on patient outcome compared to those completed laparoscopically, with no significant increase in LOS in our experience. In contrast, a diverting stoma does prolong LOS and some of the benefits of laparoscopic surgery may be lost unless patients requiring a stoma are identified preoperatively and have intensive pre- and postoperative stoma training.

Heat shock factor-1 and nuclear factor-kappaB are systemically activated in human acute pancreatitis.

CONTEXT: Nuclear factor-kappa B (NF-kappaB) is a transcription factor for a wide range of proinflammatory mediators while heat shock factor-1 (HSF-1) transcribes stress proteins that protect against cellular damage. Both are attractive therapeutic targets, undergoing investigation in other acute inflammatory conditions, such as sepsis. OBJECTIVE: To evaluate the role of the transcription factors NF-kappaB and HSF-1 in human acute pancreatitis and their relationship to cytokine/chemokine production, disease severity and outcome. PATIENTS: Twenty-four patients with acute pancreatitis and 12 healthy controls. MAIN OUTCOME MEASURES: Peripheral blood mononuclear cells were isolated. NF-kappaB and HSF-1 were measured by electrophoretic mobility shift assay. Soluble tumor necrosis factor (TNF) receptor II and interleukin-8 were measured by ELISA. Acute physiology scores (APS), APACHE II scores and final Atlanta designations of severity were also determined. RESULTS: Systemic NF-kappaB activation occurs in acute pancreatitis compared to healthy controls (P=0.004). However, there was no significant difference between those with mild and severe disease (P=0.685). Systemic activation of HSF-1 was observed in acute pancreatitis compared to healthy controls although this did not reach statistical significance (P=0.053). Activation, however, was greatest in those who had a final Atlanta designation of mild pancreatitis compared to those who had a severe attack of acute pancreatitis (P=0.036). Furthermore, HSF-1 was inversely correlated with acute physiology score (APS; r=-0.49, P=0.019) and APACHE II score (r=-0.47, P=0.026). CONCLUSIONS: Both NF-kappaB and HSF-1 are systemically activated in human acute pancreatitis. HSF-1 activation may protect against severity of pancreatitis.

Cytochrome P450 2E1 high activity polymorphism in alcohol abuse and end-organ disease.

AIM: To investigate a possible role for a recently identified polymorphism in the gene of cytochrome P450 2E1, the presence of which is associated with high activity of the enzyme. METHODS: Two hundred and thirty-nine alcohol consumers, ICD 10.1/.2 (ALC), and 208 normal controls were studied. PCR amplification of the CYP2E1 gene region was performed to assess polymorphic variation. Fisher's exact test was used to assess the data. RESULTS: Twelve normal controls (5.8%) possessed the insertion. Five ALC (2.1%) had the insertion; of these 2 of 144 with alcohol induced chronic pancreatitis, none of 28 with alcoholic liver disease and 3 of 67 without end-organ disease had the polymorphism. A significantly Lower frequency of subjects possessed the insertion than normal controls [P=0.049 (genotype analysis P=0.03)]. To further assess, if there was a relationship to alcohol problems per se or end-organ disease, we compared patients with alcohol induced end-organ disease vs alcoholic controls without end-organ disease vs normal controls which again showed a significant difference [P=0.045 (genotype analysis, P=0.011)], further sub-group analysis did not identify which group(s) accounted for these differences. CONCLUSION: We have shown the frequencies of this high-activity polymorphism in alcohol related patient groups for the first time. The frequency is significantly less in alcoholics than normal controls, as with high activity polymorphisms of alcohol dehydrogenase. The biological significance, and whether the relevance is solely for alcoholism or is there a relationship to end-organ disease, would benefit from the assessment in the populations with a greater frequency of this polymorphism.

A double-blind placebo-controlled trial of a leukotriene receptor antagonist in chronic pancreatitis in humans.

BACKGROUND/PURPOSE: Chronic pancreatitis is a debilitating condition of which pain is a predominant feature, and, at present, only putative treatments, beyond analgesics, exist. Evidence suggests that leukotrienes may play a role in both acute and chronic pancreatitis and that cells involved in their signalling are implicated in both conditions and pain production in chronic pancreatitis. We thus performed a study of a cysteinyl leukotriene receptor antagonist of proven benefit in chronic asthma (montelukast sodium) in patients with chronic pancreatitis. METHODS: A double-blind, placebo-controlled crossover trial of daily montelukast sodium (10 mg), of 8 months' duration, was performed in those suffering from painful chronic pancreatitis. Daily visual analogue pain scores and analgesic diaries were completed throughout the trial, as were monthly quality-of-life questionnaires and blood taken for inflammatory markers. Visual analogue pain scores were the primary outcome measure. RESULTS: In crossover analysis of mean visual analogue pain scores there was no significant difference between the groups (t = 1.51; P = 0.156). All baseline C-reactive protein results were 13 mg/l or less. Soluble tumor necrosis factor receptor results showed no significant difference pre- and post-treatment. CONCLUSIONS: In both primary and secondary outcome measures there was no significant effect for the cysteinyl leukotriene receptor antagonist, montelukast sodium in chronic pancreatitis in humans.

Use of the Internet and information technology for surgeons and surgical research.

The recent, and extensive, expansion in the use of computers and the Internet offers great potential for benefit in surgical research and, increasingly, surgical practice. However, in addition to the usefulness of information technology, much time can be spent achieving little and the potential missed because of the complexity and excess of information available. In this article, we examine some useful areas relevant to surgeons and surgical research, such as Internet service provision and E-mail, databases, medical Websites, and potential future directions.