Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner.

Ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality after liver surgery. The role of Sirtuin 1 (SIRT1) in hepatic I/R injury remains elusive. Using human and mouse livers, we investigated the effects of I/R on hepatocellular SIRT1. SIRT1 expression was significantly decreased after I/R. Genetic overexpression or pharmacological activation of SIRT1 markedly suppressed defective autophagy, onset of the mitochondrial permeability transition, and hepatocyte death after I/R, whereas SIRT1-null hepatocytes exhibited increased sensitivity to I/R injury. Biochemical approaches revealed that SIRT1 interacts with mitofusin-2 (MFN2). Furthermore, MFN2, but not MFN1, was deacetylated by SIRT1. Moreover, SIRT1 overexpression substantially increased autophagy in wild-type cells, but not in MFN2-deficient cells. Thus, our results demonstrate that the loss of SIRT1 causes a sequential chain of defective autophagy, mitochondrial dysfunction, and hepatocyte death after I/R.

Laparoscopic intussuscepting pancreaticojejunostomy.

Perhaps the greatest barrier to adoption of laparoscopic pancreaticoduodenectomy by experienced pancreatic surgeons is the technical challenge of constructing the pancreaticojejunostomy (PJ). The authors present a less demanding PJ technique they have developed that creates an end-to-end intussuscepting anastomosis using a running monofilament suture. This method reduces technical complexity and operative time while producing acceptably comparable outcomes.

Pancreatic pseudocysts complicated by splenic parenchymal involvement: results of operative and percutaneous management.

UNLABELLED: Pancreatic pseudocysts are a common finding in acute and chronic pancreatitis, but most are small and uncomplicated, and do not require treatment. Pseudocysts with splenic parenchymal involvement are uncommon but have the potential for massive hemorrhage. Data on the clinical presentation and optimal treatment of this unusual complication of pseudocysts are lacking. The purpose of this review was to identify the clinical features of pancreatic pseudocysts complicated by splenic parenchymal involvement and to determine the outcome with nonoperative and operative therapy. METHODS: A retrospective review of the medical records of all patients with pancreatic pseudocysts from December 1984 to January 1999 revealed 238 patients, of whom 14 (6%) had splenic parenchymal involvement. These medical records were reviewed in detail and all pertinent radiographs were reviewed by the authors to confirm splenic parenchymal involvement by a pancreatic pseudocyst. RESULTS: Initial treatment included observation (n = 2), percutaneous drainage (n = 8), and surgery (n = 4). Of the eight patients treated by percutaneous drainage, one died, three required repeated percutaneous drainage, and three required surgical intervention. None of the patients treated primarily by surgery required additional therapy for the pseudocyst. Overall, 11 patients had complications of the primary therapy, and 25% of patients treated by surgery had significant hemorrhage. Complications included infection (n = 5), pseudocyst persistence (n = 4), bleeding (n = 2), multisystem organ failure (n = 2), gastric outlet obstruction (n = 1), and splenic rupture (n = 2). CONCLUSIONS: Pancreatic pseudocysts complicated by splenic parenchymal involvement may have life-threatening clinical presentations and respond poorly to percutaneous drainage. Distal pancreatectomy and splenectomy are effective, but the complication rate is high.

Complete fundoplication is not associated with increased dysphagia in patients with abnormal esophageal motility.

Abnormal esophageal motility is a relative contraindication to complete (360-degree) fundoplication because of a purported risk of postoperative dysphagia. Partial fundoplication, however, may be associated with increased postoperative esophageal acid exposure. Our aim was to determine if complete fundoplication is associated with increased postoperative dysphagia in patients with abnormal esophageal motor function. Medical records of 140 patients (79 females; mean age 48 +/- 1.1 years) who underwent fundoplication for gastroesophageal reflux disease (GERD) were reviewed retrospectively to document demographic data, symptoms, and diagnostic test results. Of the 126 patients who underwent complete fundoplication, 25 met manometric criteria for abnormal esophageal motility (#30 mm Hg mean distal esophageal body pressure or #80% peristalsis), 68 had normal esophageal function, and 33 had incomplete manometric data and were therefore excluded from analysis. Of the 11 patients who underwent partial fundoplication, eight met criteria for abnormal esophageal motility, two had normal esophageal function, and one had incomplete data and was therefore excluded. After a median follow-up of 2 years (range 0.5 to 5 years), patients were asked to report heartburn, difficulty swallowing, and overall satisfaction using a standardized scoring scale. Complete responses were obtained in 72%. Sixty-five patients who underwent complete fundoplication and had manometric data available responded (46 normal manometry; 19 abnormal manometry). Outcomes were compared using the Mann-Whitney U test. After complete fundoplication, similar postoperative heartburn, swallowing, and overall satisfaction were reported by patients with normal and abnormal esophageal motility. Likewise, similar outcomes were reported after partial fundoplication. This retrospective study found equally low dysphagia rates regardless of baseline esophageal motility; therefore a randomized trial comparing complete versus partial fundoplication in patients with abnormal esophageal motility is warranted.

Autocrine expression of activated transforming growth factor-beta(1) induces apoptosis in normal rat liver.

The aim of this study was to determine the differential effects of latent and activated transforming growth factor (TGF)-beta(1) in growth control of normal and proliferating hepatocytes in vivo. Rats were injected with adenoviruses expressing control transgenes (Ctrl), latent TGF-beta(1) [TGF-beta(L)], or activated TGF-beta(1) [TGF-beta(A)]. Additional animals underwent two-thirds partial hepatectomy (PH) 24 h after injection. Increased hepatocyte apoptosis was observed in TGF-beta(A)-injected but not TGF-beta(L)-injected animals 24 h postinjection (10.5%) compared with Ctrl animals (0.37%). The percent of apoptotic cells increased to 32.1% in TGF-beta(A)-injected animals 48 h after injection. Furthermore, TGF-beta(A)-injected rats did not survive 24 h after PH. Four hours after PH, 0.25 and 14.1% apoptotic hepatocytes were seen in Ctrl- and TGF-beta(A)-injected rats, respectively. TGF-beta(A)-induced apoptosis in primary rat hepatocytes was blocked with a pancaspase inhibitor. Thus autocrine expression of TGF-beta(A) but not TGF-beta(L) induces hepatocyte apoptosis in the normal rat liver. Rats overexpressing TGF-beta(A) do not survive two-thirds PH due to hepatic apoptosis. Thus activation of TGF-beta(1) may be a critical step in the growth control of normal and proliferating rat hepatocytes.

Secondary causes of intestinal obstruction: rigorous preoperative evaluation is required.

The clinical presentation, management and outcome of patients with small intestinal and large bowel obstruction unrelated to adhesive or primary colonic neoplastic disease is not well described. The aim of this study was to determine the clinical presentation, evaluation, operative management, and outcome in patients with secondary causes of intestinal obstruction. The medical records of 200 patients who underwent an operation for intestinal obstruction from January 1995 through December 1997 were reviewed. Seventy-three patients (37%) had secondary causes of intestinal obstruction, and these records were reviewed in detail. The cohort included 37 men and 36 women with a mean age of 52 +/- 2 years. The etiology of intestinal obstruction was metastatic neoplastic obstruction (19%), colonic volvulus (18%), Crohn's disease (14%), herniae (11%), diverticular disease (7%), and miscellaneous causes (31%). Six patients (8%) had intestinal motor disorders and a misdiagnosis of intestinal obstruction. The clinical presentation of patients with secondary causes of obstruction was similar to typical patients with adhesive small bowel obstruction. Preoperative evaluation included frequent use of CT (42%), but intestinal contrast studies were used in 13 (18%) patients only. Two-thirds of the patients required an intestinal resection, and 50 per cent of the patients with a misdiagnosis had a nontherapeutic celiotomy. Operative mortality and morbidity were 3 per cent and 48 per cent, respectively, and 15 per cent of patients required reoperation. Suspected intestinal obstruction from secondary causes requires rigorous preoperative evaluation with liberal use of intestinal contrast examinations to avoid misdiagnosis, operative complications, and reoperations.

Prospective randomized trial of early initiation and hospital discharge on a liquid diet following elective intestinal surgery.

Length of hospital stay after elective intestinal surgery may be related to patient tolerance of a diet. We hypothesized that early initiation and discharge home on a clear liquid diet would decrease the length of hospital stay without increasing morbidity. The aim of this study was to determine if early initiation and discharge on a clear liquid diet decreases the length of hospital stay and is safe. Forty-four patients were randomly assigned to either a standard diet or a clear liquid diet. A standard diet (n = 17) was begun after the passage of flatus or stool, and consisted of clear liquids to a volume of approximately 750 ml, then three solid meals, and discharge thereafter. Patients randomized to a clear liquid diet (n = 27) received 30 ml/hr of clear liquids on postoperative day 2, unlimited clear liquids on postoperative day 3, and were dismissed on a clear liquid diet on postoperative day 4. All patients were followed by a daily telephone call and clinic visit. The primary outcome variable was length of hospital stay. The incidence of postoperative intestinal-related sequelae, complications, and readmission rates did not differ between groups. Postdischarge intestinal symptoms were common in both groups but tended to resolve faster in the patients on a standard diet. The length of hospital stay was decreased in the patients on a clear liquid diet compared to those on a standard diet (6.1 +/- 1.1 days vs. 4.4 +/- 0.2 days; P = 0.09), but total hospital costs did not differ. Early initiation and hospital discharge on a clear liquid diet after elective intestinal surgery decreases the length of hospital stay and is safe.

c-Jun does not mediate hepatocyte apoptosis following NFkappaB inhibition and partial hepatectomy.

Inhibition of the transcription factor nuclear factor kappa B (NFkappaB) induces marked hepatocyte apoptosis and liver dysfunction after partial hepatectomy (PH) in rats. Hepatocyte apoptosis may be due to direct inhibition of NFkappaB-induced hepatocyte survival genes or due to indirect increased signaling through the stress-activated protein kinase pathway (SAPK), resulting in increased c-Jun. c-Jun, an AP-1 transcription factor, induces apoptosis in fibroblasts. Our aim was to determine if hepatocyte apoptosis following inhibition of NFkappaB and partial hepatectomy in rats is due to increased c-Jun. Adult male Sprague-Dawley rats (200 g) were injected intraportally with 6 x 10(9) PFU adenoviral vector containing luciferase (Ad5Luc) or superrepressor IkappaB (Ad5IkappaB) transgene that inhibits NFkappaB translocation into the nucleus. Two-thirds PH was performed 24 h after vector administration, and the remnant liver was harvested 30 min or 24 h after PH. Northern and Western blots were performed to examine the presence of IkappaB and c-Jun. A GST c-Jun kinase assay was used to examine Jun-N-terminal kinase (JNK) activity. AP-1 DNA binding activity was assessed by electrophoretic mobility shift assay. TUNEL assay was performed to assess apoptosis. All rats receiving adenoviral vectors expressed the luciferase or superrepressor IkappaB transgenes. c-Jun mRNA, protein levels, and DNA binding activity were not increased in rats treated with Ad5IkappaB at 30 min after PH compared to rats injected with Ad5Luc. Jun kinase activity increased following partial hepatectomy, but activity was similar in Ad5Luc- and Ad5IkappaB-treated animals. AP-1 DNA binding activity was not altered substantially in rats treated with Ad5IkappaB. The percentage of apoptotic hepatocytes was similar between Ad5Luc- and Ad5IkappaB-injected animals at 0 h, but livers from Ad5IkappaB-treated rats had increased apoptosis at 24 h compared to Ad5Luc rats (24% vs. 4%) after PH. Hepatocyte apoptosis after NFkappaB inhibition and PH is not mediated by increased JNK activity or c-Jun.

Percutaneous drainage of pancreatic pseudocysts is associated with a higher failure rate than surgical treatment in unselected patients.

OBJECTIVE: The primary aim was to compare directly the effectiveness of percutaneous drainage versus surgical treatment of pancreatic pseudocysts in unselected patients. The authors also wished to identify factors that may predict a successful outcome with percutaneous drainage. SUMMARY BACKGROUND DATA: Pancreatic pseudocysts are a common complication of pancreatitis, and recent data suggest that many pseudocysts may be observed or treated successfully by percutaneous drainage. Failures with percutaneous drainage have been recognized increasingly, and a direct comparison of percutaneous and surgical treatment was initiated to identify factors that may affect outcome with these approaches. METHODS: A computerized index search of the medical records of patients with a diagnosis of pancreatic pseudocyst was performed from 1984 to 1995. One hundred seventy-three patients were identified retrospectively and assigned to treatment groups: observation (n = 41), percutaneous drainage (n = 66), or surgical treatment (n = 66). Data on demographics, clinical presentation, pseudocyst etiology and characteristics, diagnostic evaluation, management, and outcome were obtained. Treatment failure was defined as persistence of a symptomatic pseudocyst or the need for additional intervention other than the original treatment. RESULTS: The etiology of pancreatitis, clinical presentation, and diagnostic evaluation did not differ between groups. Twenty-seven percent had documented chronic pancreatitis, and the etiology of pancreatitis was alcohol in 61% of patients. Mean pseudocyst size was 4.2 +/- 1 cm, 8.2 +/- 1.1 cm, and 7.4 +/- 1.3 cm in the observed, percutaneously treated, and surgically treated groups, respectively. Expectant treatment was successful in 93% of patients. Percutaneous drainage was successful in 42% of patients, whereas surgical treatment resulted in a success rate of 88%. Patients treated by percutaneous drainage had a higher mortality rate (16% vs. 0%), a higher incidence of complications (64% vs. 27%), and a longer hospital stay (45 +/- 5 days vs. 18 +/- 2 days) than patients treated by surgery. Eighty-seven percent of patients in whom percutaneous drainage failed required surgical salvage therapy. Multiple logistic regression analysis failed to reveal any factors significantly associated with a successful outcome after percutaneous drainage. CONCLUSIONS: Percutaneous drainage results in higher mortality and morbidity rates and a longer hospital stay than surgical treatment of pancreatic pseudocysts. The clinical benefit of percutaneous drainage of pancreatic pseudocysts in unselected patients has not been realized, and the role of this treatment should be established in a clinical trial.

Molecular and cellular biology of the small intestine.

The crypt-villus axis is composed of a dynamic cell population in perpetual change from a crypt proliferative and undifferentiated stage to a mature villus stage. The migration of crypt cells is accompanied by cellular differentiation that leads to morphological and functional changes. In addition to this intrinsic gene program, intestinal epithelial cells respond to extrinsic signals by producing various molecules. Using different experimental approaches, recent studies have further characterized intestinal epithelial-cell biology and provided evidence of their polyvalent and important role in gut homeostasis.

Hepatic steatosis as a potential risk factor for major hepatic resection.

Hepatic steatosis is a recognized risk factor for primary nonfunction of hepatic allografts, but the effect of steatosis on postoperative recovery after major liver resection is unknown. Our aim was to determine if hepatic steatosis is associated with increased perioperative morbidity and mortality in patients undergoing major resection. A retrospective review of medical records of 135 patients who had undergone major hepatic resection from 1990 to 1993 was performed. Histopathology of the hepatic parenchyma at the resection margin was reviewed for the presence of macro- or microvesicular steatosis. The extent of steatosis was graded as none (group 1), mild with less than 30% hepatocytes involved (group 2), or moderate-to-severe with 30% or more hepatocytes involved (group 3). Outcome of patients was correlated with extent of steatosis. Patients with moderate-to-severe steatosis were obese (body mass index = 25.8 +/- 0.5 vs. 26.5 +/- 1.0 vs. 33.4 +/- 2.9; P< 0.05 groups 1, 2, and 3, respectively) and had an increased serum bilirubin concentration preoperatively. Hepatectomy required a longer operative time for group 3 (290 +/- 9 minutes vs. 287 +/- 13 minutes vs. 355 +/- 24 minutes; P

Type I choledochal cyst in association with familial adenomatous polyposis.

Choledochal cysts and familial adenomatous polyposis are infrequent disorders that are often manifest in childhood or in early adult life. The rarity and early presentation of these diseases suggests a genetic basis, which has been established for familial polyposis but not for choledochal cysts. We report a case of a 26-yr-old woman with both disorders and offer an alternative genetics-based etiology for the formation of choledochal cysts.

Canine small bowel motor patterns and contractions are not neurally regulated during enteric nutrient infusion.

The aims of this study were to determine the effects of duodenal and jejunoileal nutrient infusions on small intestinal motor patterns and intestinal contractions in neurally intact and neurally isolated small bowel. Fifteen dogs were prepared with duodenal and jejunal infusion and manometry catheters and a diverting jejunal cannula. Ten of the dogs underwent in situ neural isolation of the jejunoileum. A mixed nutrient meal (0.5 kcal/ml) was infused into the duodenum or jejunum at 3 ml/min for 5 h. Control experiments involved infusion of a balanced salt solution. Manometric data collected on-line to a microcomputer were analyzed for direction, distance, and velocity of spread of single pressure waves (SPW) and clustered contractions. Isolated duodenal and jejunoileal nutrient infusions inhibited the fasting motor pattern in neurally intact and neurally isolated small bowel. Motor activity (motility index) increased slightly during nutrient infusion within groups, but there were few differences between groups. Neither neural isolation nor nutrient infusion had a consistent effect on spread of SPW or migration of clustered contractions. Isolated duodenal and jejunoileal nutrient infusions in the dog inhibit fasting motor patterns and increase motor activity slightly but have little effect on characteristics of individual and clustered contractions. Extrinsic innervation to the jejunoileum or intrinsic neural continuity of the jejunum with the duodenum had little effect on single or grouped contractions. Although the changes in motor activity demonstrated in this study appear small, alterations in intestinal transit and absorption may still occur and may be of importance physiologically.

NFkappaB prevents apoptosis and liver dysfunction during liver regeneration.

Although NFkappaB binding activity is induced during liver regeneration after partial hepatectomy, the physiological consequence of this induction is unknown. We have assessed the role of NFkappaB during liver regeneration by delivering to the liver a superrepressor of NFkappaB activity using an adenoviral vector expressing a mutated form of IkappaBalpha. This adenovirus (Ad5IkappaB) was almost exclusively expressed in the liver and inhibited NFkappaB DNA binding activity and transcriptional activity in cultured cells as well as in the liver in vivo. After partial hepatectomy, infection with Ad5IkappaB, but not a control adenovirus (Ad5LacZ), resulted in the induction of massive apoptosis and hepatocytes as demonstrated by histological staining and TUNEL analysis. In addition, infection with Ad5IkappaB but not Ad5LacZ decreased the mitotic index after partial hepatectomy. These two phenomena, increased apoptosis and failure to progress through the cell cycle, were associated with liver dysfunction in animals infected with the Ad5IkappaB but not Ad5LacZ, as demonstrated by elevated serum bilirubin and ammonia levels. Thus, the induction of NFkappaB during liver regeneration after partial hepatectomy appears to be a required event to prevent apoptosis and to allow for normal cell cycle progression.

Laparoscopic management of paraesophageal hernia: early results.

The objective was to review our early results with laparoscopic repair of paraesophageal hernias to determine the safety, technical feasibility, and short-term outcome of the operation. Twelve patients with a mean age of 75 +/- 1 years underwent laparoscopic repair of a paraesophageal hernia. Principles of open repair, including sac excision, primary crural repair, and pexy, were accomplished laparoscopically in 83%, 83%, and 100% of patients, respectively. In two patients the diaphragmatic defect was closed with mesh. Fundoplication was also performed in seven patients with symptoms of reflux disease. No laparoscopic procedure was converted to an open repair; however, one patient required a postoperative celiotomy to control hemorrhage. Short-term evaluation of all patients postoperatively detected gastroesophageal reflux disease (GERD) in five patients (42%), four of whom did not undergo fundoplication. Two major complications were esophageal perforation and bleeding. Minor complications included atrial fibrillation in two patients, meat impaction in one patient, and a small asymptomatic recurrence in a single patient. Overall patient satisfaction was high. Laparoscopic repair of paraesophageal hernias was safe and technically feasible and warrants further investigation. The incidence of postoperative esophageal reflux, however, is high if an antireflux procedure is not performed. Extensive preoperative evaluation for reflux should objectively identify patients requiring fundoplication and decrease the incidence of postoperative GERD.

Neural control of canine small intestinal motility during nonnutrient infusion.

Our aim was to determine the effect of in situ neural isolation of the jejunoileum (extrinsic denervation and disruption of enteric neural continuity with the duodenum) on the spread of single pressure waves (SPW) and clustered contractions (CC) in response to increasing rates of isolated duodenal and jejunoileal nonnutrient infusions. Ten dogs were prepared with duodenal and jejunal infusion and manometry catheters and a diverting proximal jejunal cannula. Five of the dogs also underwent in situ neural isolation of the entire jejuno- ileum A noncaloric solution was infused at 0-15 ml/min into proximal duodenum or jejunum while manometric data were collected. Alterations in direction, distance, and velocity of spread of SPW and CC with increasing rates of intestinal infusion were analyzed by linear regression of responses to increasing infusion rates. Neural isolation of the jejunoileum did not markedly alter characteristics of duodenal or jejunal SPW or CC under conditions of no intestinal infusion. After neural isolation of jejunoileum, increasing rates of jejunal infusion decreased both the proportion and distance of antegrade spread of SPW in duodenum. These findings suggest that extrinsic innervation to the jejunoileum and enteric neural continuity with the duodenum do not regulate jejunal SPW or CC. Increasing rates of nonnutrient intestinal infusions do not alter local motor patterns in the innervated or neurally isolated jejunum, but after neural isolation of the jejunoileum, these infusions do alter characteristics of duodenal SPW by mechanisms independent of neural pathways.

Jejunoileal transplantation. Effects on characteristics of canine jejunal motor activity in vivo.

This study was designed to determine if extrinsic innervation and intrinsic neural continuity with the duodenum (neuroenteric physiologic pathways disrupted during intestinal transplantation) modulate the characteristics of interdigestive motor activity in the canine small bowel. Five dogs served as neurally intact controls (group 1) and 10 dogs (group 2) underwent a model of jejunal autotransplantation involving in situ neural isolation of the jejunoileum. Fasting duodenal and jejunal motor activity was recorded on-line to a microcomputer using closely spaced duodenal and jejunal manometry catheters. Characteristics of global motor patterns, the migrating motor complex (MMC), and local motor patterns, including individual contractions and grouped clustered contractions, were determined. Neural isolation of the jejunoileum disrupted coordination of duodenal and jejunal phase III activity, increased the variability of cycling of the MMC, decreased the period of the jejunal MMC, and increased motility indices in the neurally isolated jejunum. In contrast, single pressure waves and clustered contractions in the neurally isolated jejunum were not altered significantly in incidence or direction, distance, or velocity of spread. In situ neural isolation of the jejunoileum leads to temporal dissociation of the MMC between the transplanted segment (jejunum) and the duodenum but does not appear to alter markedly the characteristics of local contractile activity as measured by individual or grouped contractions. The occurrence of interdigestive jejunal motor patterns and the local organization of individual and grouped small intestinal contractions are not controlled by extrinsic innervation or intrinsic neural continuity with the duodenum.