Randomised controlled trial of transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND Study).

OBJECTIVE: Non-randomised studies suggest that endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM), but EMR might be more cost-effective and safer. This trial compares the clinical outcome and cost-effectiveness of TEM and EMR for large rectal adenomas. DESIGN: Patients with rectal adenomas ≥3 cm, without malignant features, were randomised (1:1) to EMR or TEM, allowing endoscopic removal of residual adenoma at 3 months. Unexpected malignancies were excluded postrandomisation. Primary outcomes were recurrence within 24 months (aiming to demonstrate non-inferiority of EMR, upper limit 10%) and the number of recurrence-free days alive and out of hospital. RESULTS: Two hundred and four patients were treated in 18 university and community hospitals. Twenty-seven (13%) had unexpected cancer and were excluded from further analysis. Overall recurrence rates were 15% after EMR and 11% after TEM; statistical non-inferiority was not reached. The numbers of recurrence-free days alive and out of hospital were similar (EMR 609±209, TEM 652±188, p=0.16). Complications occurred in 18% (EMR) versus 26% (TEM) (p=0.23), with major complications occurring in 1% (EMR) versus 8% (TEM) (p=0.064). Quality-adjusted life years were equal in both groups. EMR was approximately €3000 cheaper and therefore more cost-effective. CONCLUSION: Under the statistical assumptions of this study, non-inferiority of EMR could not be demonstrated. However, EMR may have potential as the primary method of choice due to a tendency of lower complication rates and a better cost-effectiveness ratio. The high rate of unexpected cancers should be dealt with in further studies.

A fully covered self-expandable metal stent with antimigration features for benign biliary strictures: a prospective, multicenter cohort study.

BACKGROUND: Self-expandable metal stents (SEMSs) are increasingly used for the treatment of benign biliary strictures (BBSs). A new fully covered SEMS (FCSEMS) with flared ends and high conformability was designed to prevent migration of the stent. OBJECTIVE: To evaluate the efficacy of a novel FCSEMS with antimigration features. DESIGN: Prospective cohort study. SETTING: Five hospitals in the Netherlands and Belgium. PATIENTS: Consecutive patients with BBS. INTERVENTION: FCSEMS placement for 3 months. MAIN OUTCOME MEASUREMENTS: Initial and long term clinical success, stent migration rate and safety. RESULTS: Thirty-eight patients (24 men; mean age, 53 ± 16 years) were included. Stent placement was technically successful in 37 patients (97%). Two patients died of an unrelated cause before stent removal, and no data on these patients were available on stricture resolution. Initial clinical success was achieved in 28 of 35 patients (80%). During follow-up after stent removal, a symptomatic recurrent stricture developed in 6 of 28 patients (21%). Overall, the long-term clinical success rate was 63% (22 of 35 patients). Stent migration occurred in 11 of 35 patients (31%), including 5 symptomatic (14%) and 6 asymptomatic (17%) migrations. In total, 11 serious adverse events occurred in 10 patients (29%), with cholangitis (n = 5) being most common. LIMITATIONS: Nonrandomized study design. CONCLUSIONS: Good initial clinical success was achieved after placement of this novel FCSEMS, but stricture recurrence was in the upper range compared with other FCSEMSs. The antimigration design could not prevent migration in a significant number of patients with a persisting stricture.

Laparoscopic ileocolic resection versus infliximab treatment of distal ileitis in Crohn's disease: a randomized multicenter trial (LIR!C-trial).

BACKGROUND: With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction. The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs. METHODS/DESIGN: The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007. DISCUSSION: The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease. TRIAL REGISTRATION: Nederlands Trial Register NTR1150.

In-one-continuity rectal excision and anal mucosectomy of a giant villous adenoma: an alternative surgical approach.

BACKGROUND: The authors present a woman suffering from McKittrick-Wheelock syndrome (MKWS) with a giant rectal villous adenoma. MKWS is a rare disorder caused by fluid and electrolyte hypersecretion from a rectal tumor. The most frequently reported tumors are villous adenomas. Symptoms of dehydration with severe hyponatremia, hypokalemia, metabolic acidosis and acute renal failure are typical in MKWS. Several options for operation have been reported, such as a transsacral approach (according to Kraske), transanal endoscopic microsurgery (TEM) or total mesorectal excision (TME). In this case we report an alternative surgical approach: in-one-continuity transanal mucosectomy and transabdominal TME with a handsewn colonic-anal anastomosis. CASE: A 54-year-old woman had a history of hospital admissions because of repeated bouts of dehydration with electrolyte disorders since 2004. At admission she presented with prerenal azotemia, hyponatremia and severe hypokalemia in combination with watery stools. At colonoscopy an 8-cm villous adenoma was seen in the rectum. Dehydration and electrolyte disturbances were treated by appropriate intravenous fluid administration. An in-one-continuity anal mucosectomy and complete rectal excision were performed and restored by a handmade colonic-anal anastomosis. Postoperative recovery was uneventful. CONCLUSION: MKWS can be a difficult problem to assess in both gastroenterological and nephrological ways. Patients may develop severe complications which require surgical intervention in some cases. In-one-continuity transanal mucosectomy and rectum excision with a handmade colonic-anal anastomosis seemed to be a new and solid surgical therapeutic option in this case.

Endoscopic resection of a large Brunner's gland adenoma.

Brunner's gland adenoma is a rare benign tumour of the duodenum. Less than 150 cases have been reported in English literature. We report a 73-year-old woman presenting with upper gastrointestinal obstructive symptoms and melena. Duodenoscopy revealed a large pedunculated tumour in the bulbus duodeni. Endoscopic snare polypectomy was successfully performed. Histological examination revealed a Brunner's gland adenoma. The literature on Brunner's gland adenoma is reviewed.

A double-blind, randomized comparison of omeprazole Multiple Unit Pellet System (MUPS) 20 mg, lansoprazole 30 mg and pantoprazole 40 mg in symptomatic reflux oesophagitis followed by 3 months of omeprazole MUPS maintenance treatment: a Dutch multicentre trial.

BACKGROUND: Proton pump inhibitors (PPIs) have proved to be effective in treating reflux oesophagitis. Until now, no study had compared the PPIs omeprazole Multiple Unit Pellet System (MUPS), lansoprazole and pantoprazole in patients with reflux oesophagitis. AIM: To compare omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg for treatment effect in symptomatic reflux oesophagitis. METHOD: Patients with grade I-IV symptomatic reflux oesophagitis were randomized to double-blind omeprazole 20 mg once morning, lansoprazole 30 mg o.m. or pantoprazole 40 mg o.m. Patient satisfaction and symptoms were evaluated after 4 and 8 weeks. Patients not satisfied after 8 weeks were treated for another 4 weeks with omeprazole 40 mg MUPS (open). Successful treatment was followed by 3 months' maintenance treatment with omeprazole MUPS 20 mg (patients satisfied after 4 or 8 weeks) or omeprazole MUPS 40 mg (patients satisfied after 12 weeks). RESULTS: On intention-to-treat (ITT) analysis (n = 461) at 4 and 8 weeks, respectively, 84% and 87% (omeprazole MUPS), 78% and 81% (lansoprazole), and 84% and 89% (pantoprazole) were free of heartburn. Equivalence was found between omeprazole MUPS and pantoprazole (heartburn relief), but not with lansoprazole. Patient satisfaction after 4 and 8 weeks, respectively, was 79% and 89% (omeprazole MUPS), 76% and 86% (lansoprazole), and 79% and 91% (pantoprazole). Patient satisfaction was similar in all treatment groups. During maintenance, 87% in the omeprazole MUPS 20 mg group and 81% in the omeprazole MUPS 40 mg group were satisfied after 3 months. CONCLUSIONS: Omeprazole MUPS 20 mg and pantoprazole 40 mg have equivalent efficacy in the treatment of reflux oesophagitis. Based on patient satisfaction, omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg are equally effective.

Four years experience with short term stenting in primary sclerosing cholangitis.

OBJECTIVE: Symptomatic dominant strictures in primary sclerosing cholangitis are often treated with endoscopic stent therapy, but the optimal treatment duration is not well established. After a promising pilot study, we now report our 4 yr experience with short term endoscopic stent therapy for relief of dominant strictures. METHODS: Between January 1994 and October 1997, 32 patients with symptomatic primary sclerosing cholangitis with a dominant stricture at endoscopic retrograde cholangiopancreatography were treated with insertion of a 7- or 10-Fr polyethylene endoprosthesis, which was extracted after a mean of 11 days (range 1-23 days). Primary end points were changes in complaints and cholestasis after 2 months, and time interval until a repeat endoscopic treatment was deemed necessary. A secondary end point was the occurrence of treatment-related complications. RESULTS: Cholestatic complaints improved after 2 months in 83% of patients. Mean scores for pruritus, fatigue, and right upper quadrant pain decreased from 0.94, 1.0, and 0.87 to 0.26, 0.39, and 0.26, respectively. All improvements were significant. Of 14 patients presenting with jaundice, 12 regained normal serum bilirubin levels 2 months after short term endoscopic stenting. The mean levels of conjugated bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase dropped significantly from 36 micromol/L, 309 U/L, and 426 U/L to 7 micromol/L, 205 U/L, and 258 U/L, respectively. The reintervention-free proportions after 1 and 3 yr were 80% and 60%. Seven transient procedure-related complications occurred in 45 therapeutic endoscopic retrograde cholangiopancreatographies. CONCLUSIONS: Short term endoscopic stenting for symptomatic dominant strictures in primary sclerosing cholangitis is effective and safe, and the beneficial effect is sustained for several years.

Value of brush cytology for dominant strictures in primary sclerosing cholangitis.

BACKGROUND AND STUDY AIMS: Around 10% of patients with primary sclerosing cholangitis (PSC) develop cholangiocarcinoma, which is cholangiographically often indistinguishable from a benign dominant stricture. The aim of the present study was to assess the value of brush cytology in discriminating between benign and malignant dominant strictures in primary sclerosing cholangitis. PATIENTS AND METHODS: The results of all brush cytology specimens from dominant strictures from patients with established primary sclerosing cholangitis, taken at endoscopic retrograde cholangiopancreatography between 1987 and 1996, were compared with the histological diagnosis or clinical status of the patients at least 2 years later. RESULTS: A total of 47 brush cytology samples, taken between 1987 and 1996, from 43 PSC patients could be included. Between 1993 and 1996, p53 immunocytochemical examination was done in 27 brush cytology specimens and K-ras mutation analysis in 25 patients. The sensitivity, specificity, positive predictive value, and negative predictive value of brush cytology for detection of malignancy were 60%, 89%, 59%, and 89%, respectively. These figures were not improved by adding the results of p53 and K-ras analysis. Logistic regression analysis did not reveal any additional benefit of p53 or K-ras analysis either. Prior stenting did not adversely affect specificity. CONCLUSIONS: The sensitivity and positive predictive value of brush cytology for dominant strictures in PSC are rather poor. The specificity and negative predictive value are reasonably good. There was no additional value from p53 immunocytochemistry and K-ras mutation analysis. Prior stenting did not affect the results.

Does ursodeoxycholic acid mediate immunomodulatory and anti-inflammatory effects in patients with primary sclerosing cholangitis?

BACKGROUND AND OBJECTIVES: Therapy with ursodeoxycholic acid (UDCA) has been reported to be associated with improvements in abnormal serum biochemical liver tests in patients with primary sclerosing cholangitis (PSC). To evaluate further the effects of UDCA on this disease, we evaluated immunological markers and indices of inflammation during a one-year, prospective, open-label trial of UDCA therapy in patients with PSC. PATIENTS AND METHODS: Seventeen PSC patients were enrolled for one year of treatment with UDCA 12-15 mg/kg/day. Serum biochemical variables, immunological markers and indices of inflammation were compared before and at the end of therapy and 4 months after treatment had been withdrawn. Liver histology and immunohistochemistry for human leucocyte antigen (HLA) class I/II and intercellular adhesion molecule 1 (ICAM-1) expression were compared before and at the end of therapy. RESULTS: UDCA treatment was associated with significant improvements in serum biochemical liver tests, immunoglobulin levels and blood coagulation factors. Tumour necrosis factor alpha (TNF-alpha) production after in vitro whole-blood phytohaemagglutinin (PHA) stimulation was increased, but unaltered by UDCA therapy. Baseline serum levels of interleukin-6 (IL-6) and soluble IL-2 receptor were normal, and serum IL-8 levels were increased, but none of these variables was significantly affected by UDCA therapy. Liver histological stage/grade and HLA class I/II and ICAM-1 expression on biliary epithelial cells and hepatocytes were not markedly altered by UDCA therapy. CONCLUSIONS: UDCA therapy in PSC patients was associated with a decrease in cholestasis, but no consistent improvement in hepatic inflammation, fibrosis or histological stage of the disease. Immunomodulatory effects of UDCA in PSC do not appear to be HLA-restricted.

Antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis: defined specificities may be associated with distinct clinical features.

PURPOSE: The clinical significance of antineutrophil cytoplasmic autoantibodies (ANCA) in primary sclerosing cholangitis has not been established. We investigated whether analysis of the antigenic specificities of ANCA is useful for delineating clinical subsets of the disease. METHODS: Sixty-nine patients with primary sclerosing cholangitis were studied. The presence of ANCA was analyzed by indirect immunofluorescence. Antibodies directed against specific antigens--proteinase 3, myeloperoxidase, elastase, bactericidal/permeability-increasing protein, cathepsin G, and lactoferrin--were identified by enzyme-linked immunosorbent assay. RESULTS: ANCA were detected by indirect immunofluorescence in 46 (67%) patients. In antigen-specific enzyme-linked immunosorbent assays, 37 (55%) of the 69 patients had antibodies to one or more antigens: 32 (46%) had antibodies to bactericidal/permeability-increasing protein, 16 (23%) had antibodies to cathepsin G, and 15 (22%) had antibodies to lactoferrin. Only 3 patients had antibodies to proteinase 3. Antibodies to myeloperoxidase or elastase were not detected. Twenty (29%) patients had antibodies to different antigens simultaneously. ANCA as detected by indirect immunofluorescence were not significantly associated with the presence of cirrhosis nor with the coexistence of inflammatory bowel disease. However, antibodies to bactericidal/permeability-increasing protein and cathepsin G were both associated with the presence of cirrhosis, and antibodies to lactoferrin were more frequently detected in patients with primary sclerosing cholangitis in conjunction with ulcerative colitis than in those without inflammatory bowel disease. CONCLUSION: Defined specificities of ANCA in primary sclerosing cholangitis may be related to particular clinical features of the disease.

Prevalence and clinical significance of anti-lactoferrin autoantibodies in inflammatory bowel diseases and primary sclerosing cholangitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against cytoplasmic constituents of neutrophil granulocytes. Antibodies with specificity for proteinase 3 and myeloperoxidase are seromarkers for systemic vasculitides. ANCA with specificity for lactoferrin were described in patients with several idiopathic inflammatory diseases, such as the inflammatory bowel diseases and rheumatoid arthritis. However, the clinical significance of anti-lactoferrin autoantibodies is still unclear. In this study, we determined the clinical significance of anti-lactoferrin autoantibodies in sera from large groups of patients with ulcerative colitis (UC), Crohn's disease (CD), and primary sclerosing cholangitis (PSC). Antibodies to human lactoferrin were detected by ELISA and by immunoblotting, using an extract of sonicated neutrophils as antigen source. Autoantibodies to lactoferrin were found in 29% of patients with UC, 13% of patients with CD, and 22% of patients with PSC. In inflammatory bowel diseases, the presence of anti-lactoferrin antibodies was not related to treatment, disease activity, duration of disease, or disease extent. In PSC, the presence of autoantibodies to lactoferrin did not correlate with duration of disease or the presence of cirrhosis. However, patients with PSC and coexistent UC had significantly more frequently antibodies to lactoferrin than PSC patients without IBD. In conclusion, autoantibodies to lactoferrin are a common feature of inflammatory bowel diseases and PSC. However, the clinical significance of those autoantibodies is limited as they lack sensitivity and specificity for those disorders. Future research should address the pathophysiological role of anti-lactoferrin ANCA and the influence of anti-lactoferrin ANCA binding on the functional properties of the lactoferrin molecule.

Lack of complications following short-term stent therapy for extrahepatic bile duct strictures in primary sclerosing cholangitis.

BACKGROUND: In 10% to 20% of patients with primary sclerosing cholangitis, a dominant stricture of an extrahepatic bile duct is responsible for symptoms and an exacerbation of cholestasis. The complications of a dominant stricture can usually be relieved by endoscopic placement of a stent through the stricture. The conventional policy of leaving stents in situ for 2 to 3 months is associated with a high incidence (e.g., 50%) of clinical deterioration due to stent occlusion. We have attempted to overcome this problem by substantially reducing the duration of stent placement. METHODS: Sixteen patients with symptomatic primary sclerosing cholangitis and dominant extrahepatic bile duct strictures were treated by stent placement for a median interval of only 9 days. RESULTS: In all patients endoscopic stent therapy was technically successful with a 7% incidence of transient procedure-related complications. During median follow-up of 19 months (range 7 to 27 months) serum biochemical evidence of cholestasis decreased substantially and 13 (81%) of the 16 patients became asymptomatic. No patient had a recurrence or exacerbation of either symptoms or biochemical evidence of cholestasis that could be attributed to stent occlusion. CONCLUSIONS: Short-term endoscopic stent therapy is a safe and effective treatment for symptomatic dominant extrahepatic bile duct strictures in patients with primary sclerosing cholangitis.

Allopurinol dosage and effect on ischemia-reperfusion damage in elective and acute aortic surgery.

To study the effect of a safe dosage of allopurinol on ischemia-reperfusion damage following aortic surgery, 24 patients undergoing either elective or acute aortic reconstruction, were randomized to receive allopurinol or placebo, yielding four groups: elective/placebo (EP), elective/allopurinol (EA), acute/placebo (AP) and acute/allopurinol (AA). Blood concentrations of allopurinol, oxypurinol, uric acid, malondialdehyde, ascorbic acid, and 99mTc-albumin were determined perioperatively. Adequate concentrations and biochemical activity of allopurinol and oxypurinol were obtained, without side-effects. Malondialdehyde did not increase perioperatively, but was significantly higher in acute surgery than in elective surgery intraoperatively. Yet, ascorbic acid levels and 99mTc-albumin disappearance were not different from groups EP and EA. No influence of allopurinol was found on malondialdehyde, ascorbic acid and 99mTc-albumin. An influence of allopurinol may have been obscured, as patients in group AA were more hypotensive than in group AP. In conclusion, adequate allopurinol concentration can be obtained with a safe dosage in abdominal aortic surgery. Signs of ischemia-reperfusion injury were found in acute surgery, not in elective surgery. Therefore, further investigation on the clinical effect of allopurinol is only useful in acute aortic surgery.

Tissue reactions to bacteria-inoculated rat lead samples. I. Effect of local gentamicin release through vicinal sponge or solution-dipping.

The effect of local gentamicin release through a vicinal collagen sponge or through preoperative solution-dipping of rat lead samples was investigated in an early-infection model. The efficacy of these methods and their effect on tissue response were determined. It was demonstrated that both methods of local gentamicin release suppress lead-related infectious complications as compared to the control lead, which showed a high presence of inflamed/infected tissues and bacterial growth at each explantation time point. The first day the vicinal collagen sponge was more effective in suppressing the infection than was the solution-dipped lead, probably because there is a faster and higher dose release of gentamicin from the sponge. However, continued implantation time revealed that gentamicin release from the solution-dipped lead was more effective than the sponge. This supports our hypothesis that the presence of lumina are decisive for bacterial growth and persistence of implant-related infections.

Tissue reactions to bacteria-inoculated rat lead samples. II. Effect of local gentamicin release through surface-modified polyurethane tubing.

A surface modification technique was developed to achieve controlled release of gentamicin from implanted polyurethane (PU) rat lead samples. PU tubing first was provided with an acrylic acid/acrylamide copolymer surface graft and then loaded with gentamicin. This surface modification technique resulted in release of gentamicin base (GB) and was applied either to the inner luminal surface only (PU-GB-1x) or to both the inner and outer surfaces (PU-GB-2x). First we investigated whether the early tissue response was harmfully compromised when surface-modified rat lead samples were implanted without any infectious challenge. Additionally, the efficacy of this type of local gentamicin therapy was investigated by establishing its effect on tissue response and its ability to prevent lead-related infections after inoculation with Staphylococcus aureus. It was demonstrated that the applied surface modification(s) did not induce adverse effects although an increase in the infiltration of granulocytes and macrophages and an increase in the formation of wound fluid and fibrin were observed. This effect was stronger with PU-GB-2x than with PU-GB-1x. With bacterial inoculation the applied surface modification successfully suppressed the infectious challenge, PU-GB-2x more effectively than PU-GB-1x. PU-GB-2x also was more effective when compared to the gentamicin-delivery methods discussed in the first part of this two-part study, i.e., release through a vicinal gentamicin-containing collagen sponge and preoperative gentamicin solution-dipping of rat lead samples.

Endoscopic stent therapy for dominant extrahepatic bile duct strictures in primary sclerosing cholangitis.

BACKGROUND: In 15% to 20% of patients with primary sclerosing cholangitis, a dominant stricture of the extrahepatic bile ducts may be responsible for declining results of serum biochemical liver tests and may contribute to symptoms such as jaundice, cholangitis, pruritus, and right upper quadrant pain. METHODS: Retrospectively, over the period 1985 to 1994, we evaluated 25 patients who had been treated by endoscopic stent therapy after declining results of serum biochemical liver tests and symptoms attributable to dominant extrahepatic bile duct strictures. Serum biochemical liver test results and symptoms were compared before and after treatment. RESULTS: Endoscopic therapy was technically successful in 21 patients (84%). In these 21 patients results of all serum biochemical liver tests improved significantly (p < 0.001) within 6 months of stent therapy. During median follow-up of 29 (2 to 120) months after stent removal, 12 patients (57%) remained asymptomatic with stable serum biochemical liver tests and 4 (19%) had clinical and biochemical relapse of disease that responded favourably to additional endoscopic therapy. Early procedure-related complications occurred in 14% of therapeutic endoscopic biliary procedures. CONCLUSIONS: Endoscopic stent therapy is a safe and effective treatment modality for an acute exacerbation of disease caused by dominant extrahepatic bile duct strictures in patients with primary sclerosing cholangitis.

Immunogenetic aspects of primary sclerosing cholangitis: implications for therapeutic strategies.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibro-obliterative inflammation of the intra- and extrahepatic bile ducts; in 70% of cases, it is associated with inflammatory bowel disease. The disease usually runs a progressive course, ultimately leading to biliary cirrhosis, hepatic failure, and sometimes cholangiocarcinoma, with a median survival of 12 yr after diagnosis. As yet, the etiology of primary sclerosing cholangitis remains unknown, although several recent studies have implicated immunogenetic factors as important pathogenic mechanisms. Besides liver transplantation for patients with end-stage cirrhotic liver disease and endoscopic therapy for patients with dominant extrahepatic bile duct strictures, recent studies have also shown promising results of drug therapy with ursodeoxycholic acid in the treatment of PSC. The purpose of this article is to summarize our current knowledge of the immunogenetic factors in the pathogenesis of PSC and to present support for drug therapy with ursodeoxycholic acid in the treatment of PSC. The genetic and immunological factors in the pathogenesis of PSC are outlined first, followed by a rationale of drug therapy with ursodeoxycholic acid in the treatment of PSC.

Influence of low dose allopurinol on ischaemia--reperfusion injury during abdominal aortic surgery.

OBJECTIVES: To ascertain whether surgery causes ischaemia-reperfusion (I-R) related injury, if this injury is augmented by preoperative shock, and reduced with low dose allopurinol. DESIGN: Randomised blind placebo controlled trial. SETTING: Surgical laboratory. MATERIAL AND METHODS: 22 pigs were randomly allocated to four groups; OP = operation/placebo, OA = operation/ allopurinol, SOP = shock + operation/placebo, SOA = shock + operation/allopurinol. An aortic tube prosthesis was inserted in all. In groups SOP and SOA preoperative shock was induced by exsanguination. Allopurinol was administered in group OA on the preoperative day and peroperatively, in group SOA during shock and peroperatively. CHIEF OUTCOME MEASURES: Perioperative blood concentrations of thiobarbituric acid reactive species (TBARS), ascorbic acid (AA), albumin, 99mTc-albumin and creatine phosphokinase (CPK) as indicators of oxidative membrane damage, antioxidant activity, microvascular permeability changes and muscular cell damage respectively. MAIN RESULTS: In the OP and OA groups TBARS gradually increased, while AA, 99mTc-albumin and CPK remained unchanged and albumin decreased. No effect of allopurinol was observed in these groups. In the SOP group TBARS and AA were not significantly different from groups OP and OA. Yet, albumin, 99mTc-albumin and CPK decreased significantly more in the SOP group. Compared with the SOP group, allopurinol treatment (SOA) produced lower TBARS and higher AA levels, and reduced the effect of shock on albumin, 99mTc-albumin and CPK concentrations. CONCLUSIONS: Aortic surgery causes no I-R related damage. Pre-operative shock produces I-R related damage, which is reduced by allopurinol.