NO donor KMUP-1 improves hepatic ischemia-reperfusion and hypoxic cell injury by inhibiting oxidative stress and pro-inflammatory signaling.

This study investigates whether KMUP-1 improves hepatic ischemia-reperfusion (I/R) and hypoxic cell injury via inhibiting Nox2- and reactive oxygen species (ROS)-mediated pro-inflammation. Rats underwent ischemia by occlusion of the portal vein and hepatic artery for 45 minutes. Reperfusion was allowed for 4 h. Serum was used for analysis of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). DNA extracted from liver homogenate was analyzed by electrophoresis to observe the fragmentation. Lipid peroxidation (LPO) was evaluated by measuring thiobarbituric acid-reactive substances (TBARS). NO and ROS contents were measured using Griess reagent and 2'-7'-dichlorofluorescein, respectively. Proteins levels were visualized by Western blotting. Liver damage was observed under a microscope. Intravenous KMUP-1 (0.25, 0.5 and 1 mg/kg) reduced I/R-induced ALT and AST levels, DNA fragmentation, ROS and malondialdehyde (MDA) and restored the NO levels of I/R rats. KMUP-1 protected the liver architecture from worsening of damage and focal sinusoid congestion, increased endothelium NO synthase (eNOS), guanosine 3', 5'cyclic monophosphate (cGMP), protein kinase G (PKG) and the B-cell lymphoma 2/Bcl-2-associated X protein (Bcl-2/Bax) ratio, attenuated phosphodiesterase 5A (PDE-5A) and cleaved caspase-3 expression in I/R-liver. In hypoxic HepG2 cells, KMUP-1 increased cGMP/PKG, restored peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and decreased matrix metalloproteinases-9 (MMP-9), Rho kinase II (ROCK II), hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelium growth factor (VEGF). KMUP-1 protects liver from I/R-injury and hypoxic hepatocytes from apoptosis-associated free radical generation and pro-inflammation by restoring/increasing NO/cGMP/PPAR-gamma, reducing ROS/Nox2 and inhibiting ROCKII/MMP-9.

Significant association of ABCG5 604Q and ABCG8 D19H polymorphisms with gallstone disease.

BACKGROUND: Adenosine triphosphate-binding cassette (ABC) transporters ABCG5 and ABCG8 are sterol export pumps regulating biliary cholesterol excretion. The formation of gallstones, supersaturated with cholesterol in bile, is determined by genetic and environmental factors. The interaction of susceptible gene polymorphisms with age, sex and body mass index in gallstone disease is unclear. METHODS: In a cross-sectional study, 979 subjects (880 men and 99 women, mean(s.d.) age 47.7(10.4) years) were recruited from a hospital-based population. Of these, 74 were diagnosed with gallstone disease by abdominal ultrasonography. Five non-synonymous polymorphisms, E604Q (ABCG5), D19H, C54Y, T400K and A632V (ABCG8), were analysed using the TaqMan genotyping assay. RESULTS: The serum total cholesterol and both low- and high-density lipoprotein cholesterol levels were significantly lower in subjects with gallstones than in those without. 604Q (CC) and D19H (GC) genotypes were significantly associated with gallstone disease, even when adjusted for age, sex and body mass index. The genetic risk of developing gallstone disease was further stratified by age. The risk was greatly increased in subjects younger than 50 years with the D19H genotype and those of 50 years or more with the 604Q genotype. CONCLUSION: Carriers of ABCG5 604Q or ABCG8 D19H polymorphisms have an increased risk of gallstone disease independent of age, sex and body mass index.

Potential prognostic value of leptin receptor in hepatocellular carcinoma.

BACKGROUND: Obesity is associated with several human malignancies, including hepatocellular carcinoma (HCC). This association may result from the deregulated expression of adipokines. AIMS: To explore the potential role and the prognostic value of leptin receptor (Ob-R) in HCC. METHODS: 66 patients with pathologically confirmed HCC were included in this study. Immunohistochemistry was used to evaluate the expression of Ob-R, microvessel density (MVD) and Ki-67 index in these patients. Eventually, the profiles of Ob-R expression, obtained by a semiquantitative scoring system, were further correlated with Ki-67 expression, intratumour MVD, clinicopathological characteristics and overall survival. RESULTS: High Ob-R expression was seen in 53% of patients with HCC and was significantly correlated with intratumour MVD (high v low; 59.4 (3.2) v 44.7 (3.7); p = 0.004), but not with Ki-67 expression. In addition, Ob-R expression was inversely correlated with vascular invasion (p = 0.037), but not with other known clinicopathological characteristics. The Kaplan-Meier survival curve showed that high Ob-R expression was associated with a better overall survival (p = 0.027). Meanwhile, multivariate analysis showed that Ob-R expression was a significant determinant for HCC (odds ratio 0.02, 95% confidence interval 0.01 to 0.85; p = 0.041). CONCLUSION: Ob-R expression may have a potential role in the carcinogenesis of HCC. The positive association of Ob-R expression in the cancerous lesions of HCC with the survival outcome can be explained by its inverse correlation with vascular invasion, and may have prognostic value in HCC.

APC haploinsufficiency coupled with p53 loss sufficiently induces mucinous cystic neoplasms and invasive pancreatic carcinoma in mice.

Adenomatous polyposis coli (APC), a tumor-suppressor gene critically involved in familial adenomatous polyposis, is integral in Wnt/ß-catenin signaling and is implicated in the development of sporadic tumors of the distal gastrointestinal tract including pancreatic cancer (PC). Here we report for the first time that functional APC is required for the growth and maintenance of pancreatic islets and maturation. Subsequently, a non-Kras mutation-induced premalignancy mouse model was developed; in this model, APC haploinsufficiency coupled with p53 deletion resulted in the development of a distinct type of pancreatic premalignant precursors, mucinous cystic neoplasms (MCNs), exhibiting pathomechanisms identical to those observed in human MCNs, including accumulation of cystic fluid secreted by neoplastic and ovarian-like stromal cells, with 100% penetrance and the presence of hepatic and gastric metastases in >30% of the mice. The major clinical implications of this study suggest targeting the Wnt signaling pathway as a novel strategy for managing MCN.

Morphology of intrahepatic duct in surgical treatment of hepatolithiasis.

BACKGROUND/AIMS: Surgery is the usual treatment for hepatolithiasis. However, the method of choice is based on intrahepatic duct morphology. MATERIAL AND METHODS: Six hundred sixty-two patients with hepatolithiasis were operated on in the period between 1980-1994. Hepatolithiasis was clinically classified into primary (75.8%) and secondary (24.2%) types. RESULTS: Patients treated between 1990-1994 (35.9%), liver resection was performed in 71 patients (69 of left and 2 of the right liver). However, liver resection was chosen only in 6.7% (11/163) during the 1970s. Candidacy for liver resection increased recently due to the increase in primary type. According to the morphology of intrahepatic ducts, the location of stricture was classified into: Central type (n = 59, 30%), Segmental type (n = 101, 51%), and Subsegmental type (n = 21, 10.6%), and unclassified (n = 17, 8.4%). Liver resection was recommended for patients of segmental or subsegmental type. Choledocho-lithotomy with T-tube drainage was indicated in two third of the patients with hepatolithiasis. However, the incidence of post-operative retained stones was very high, and post-operative choledochoscopic lithotripsy was used to treat these post-operative problems easily. The mortality of this disease was 1% (2/198) in the 1990s compared with that of 4.1% (19/464) in 1980s and 10.1% (15/148) in 1970s. CONCLUSION: We strongly recommend that liver resection for patients with adequate indications will have good results. In addition, one should pay attention to the abnormal pattern of intrahepatic ducts that are commonly found in patients with hepatolithiasis during liver resection. Liver resection is an ideal surgical method for the eradication of diseased lesions and to prevent malignant changes from bile duct with stones. Concise information concerning the anatomic structure was found to be important in determining post-operative results in the management of hepatolithiasis.

Evaluation of choledochojejunostomy with subcutaneous jejunostomy for treatment of intrahepatic stones.

Twenty-nine patients, 16 males and 13 females, with intrahepatic stones were treated by choledochojejunostomy with subcutaneous jejunostomy after choledocholithotomy in cases where the common bile duct was dilated more than 2 cm in diameter. This surgical technique consists of putting a segment of jejunum in the subcutaneous area with a jejunostomy after finishing the choledochojejunostomy. If the stone recurs years later, this loop of jejunum will offer a route for inserting the scope while producing the fistulotomy under local anesthesia. These patients became symptomless soon after removal of the residual stone by postoperative choledochoscope. After more than five years of follow-up study, seven cases (24.1%) had reflux cholangitis and among them, four patients had recurrent stones. Reopening of the fistulotomy was carried out under local anesthesia, and the choledochoscope was inserted into the bile duct through the jejunum for removal of those recurrent stones. We believe that this surgical technique is very effective for the treatment of patients with recurrent intrahepatic stones without the necessity of major laparotomy.

Hepatic Schistosomiasis japonica in a patient with gallstones and bile duct stones--a case report.

Schistosomiasis, a common parasitic disease in many countries, is found as imported cases in Taiwan. Responsible for human infections are five species, one of which, Schistosoma japonicum, is currently endemic in China and South-east Asia. Chronic infection with S. japonicum may lead to the development of liver fibrosis, calcification and portal hypertension. Under investigation by sonography and computed tomography (CT) scan, a peculiar "turtle-back" appearance of liver fibrosis and calcification may be found. Herein, we report a case referred to our department due to jaundice. The sonography of liver showed typical "turtle-back" appearance. Gallstones and bile duct stones were also found in this case. Surgical interventions with percutaneous transhepatic biliary drainage (PTBD), cholecystectomy and choledocholithotomy were performed to relieve the obstructive jaundice and remove the stones. There were no parasitic eggs in the extracted stones or in drained bile juice. However, deposits of calcified S. japonicum eggs in liver parenchyma and portal tracts were identified in liver biopsy. No special treatment was given for the schistosomiasis japonica because the calcified parasitic eggs were the sequelae of past infection.

Pancreatic pseudocyst involving the spleen.

The pseudocyst of the pancreas is a frequent complication of acute pancreatitis. The splenic involvement from the pancreatic pseudocyst is an uncommon entity. A 40-year-old man, who had a five-year history of alcohol consumption, was referred to our hospital for treatment of throbbing pain over left upper quadrant (LUQ) of the abdomen. Except for LUQ tenderness, physical examination was essentially normal. MRI showed two cystic lesions in splenic hilum and pancreatic tail, and prominent vessels in left infrasplenic area and gastrosplenic ligament. Angiography revealed splenic vein thrombosis. Because of persistent LUQ pain, he underwent laparotomy. During the operation, we found the cysts in pancreatic tail and splenic hilum. The cystic content was aspirated to check amylase, which showed the level of amylase being as high as 20,000 IU/L. The diagnosis of a pancreatic pseudocyst involving the spleen was established. Splenectomy and distal pancreatectomy were performed to remove both cysts. The pathologic examination of the resected spleen showed splenic infarction with cyst formation and pancreatic pseudocyst. The patient recovered uneventfully after operation.

Ultrasound-guided percutaneous transhepatic drainage of gallbladder followed by cholecystectomy for acute cholecystitis--10 years' experience.

Acute cholecystitis is a common disease which may carry the risk of complications, including empyema, perforation, abscess, peritonitis and sepsis. Percutaneous transhepatic drainage of the gallbladder (PTGBD) with antibiotics can provide prompt decompression of gallbladder in acute cholecystitis and interrupt the natural history of the disease effectively. From July 1986 to June 1996, 154 patients with acute cholecystitis were reviewed retrospectively in Kaohsiung Medical College Hospital. The chief symptoms and signs were pain (98.1%), fever (57.1%) and jaundice (37.7%). WBC count more than 10,000 was noted in 116 (75.3%) patients. Associated diseases included empyema: 42 (27.3%), septic shock: 14 (9.1%), diabetes mellitus: 13 (8.4%), pancreatitis: 10 (6.5%), perforation: 7 (4.5%), liver cirrhosis: 6 (3.9%) and respiratory failure: 1 (0.6%). All of them underwent ultrasound-guided PTGBD immediately after the diagnosis was established. The symptoms and signs disappeared soon after this procedure. Bacterial culture was found positive in 104 (67.5%) of 154 patients in which Escherichia coli (51.9%) was the most common organism, followed by Klebsiella pneumonia (20.2%). After acute stage, 138 patients obtained the cholangiography via PTGBD tube. Gallbladder stones were only noted in 56 (40.6%) patients, gallbladder stone concomitant with common bile duct stone in 26 (18.8%), cystic duct obstruction in 25 (18.1%), acalculous cholecystitis in 21 (15.2%), gallbladder perforation in 1 (0.7%), choledochocyst in 1 (0.7%), and cholecystocolonic fistula in 1 (0.7%). There were 135 patients to undergo surgery after the clinical condition was stable. The operative findings included gallbladder stones only in 88 (65.2%), gallbladder stone concomitant with common bile duct stone in 34 (25.2%), acalculous cholecystitis in 13 (9.6%), choledochocyst in 1 (0.7%), and cholecysto-colonic fistula in 1 (0.7%). The postoperative complications included wound infection 8 (5.9%), UGI bleeding 3 (2.2%), acute renal failure 1 (0.7%) and acute respiratory failure 1 (0.7%). The postoperative mortality rate was 0.7% (1/135), which was much lower than those of previous reports, which not undergoing PTGBD initially. It led us to conclude that PTGBD, as an initial preoperative modality to treat acute cholecystitis, is effective in decreasing postoperative morbidity and mortality.

Spontaneous multiple cholecystoenteric fistulas--a case report.

Spontaneous multiple cholecystoenteric fistulas are relatively rare complications of chronic cholecystitis. One cholecystoduodenal and two cholecystocolonic fistulas were observed in a 65-year-old woman whose symptoms included fever, chills, jaundice, diarrhea, and prolonged right upper quadrant pain. Pneumobilia, which is a pathognomonic sign of bilioenteric fistula, was also detected by her plain abdomen X-ray on admission. Both types of fistulas were correctly diagnosed preoperatively by barium enema, upper GI series and endoscopic retrograde cholangiopancreaticography. The patient was referred for surgery and fistulas were identified during laparotomy. Cholecystectomy, division of these fistulas, and primary repair of these bowel defects were successfully performed. The postoperative course was unremarkable. We report this unusual case and briefly review the hypothesized pathogenesis, typical symptomatology, radiographic diagnosis, complications and therapeutic modalities of this condition.

Liver Surgery for Hepatocellular Carcinoma: Laparoscopic versus Open Approach.

In this study, we try to compare the benefit of laparoscopic versus open operative procedures. Patients and Methods. One hundred and sixteen patients underwent laparoscopic liver resection (LR) and another 208 patients went for open liver resection (OR) for hepatocellular carcinoma (HCC). Patients' selection for open or laparoscopic approach was not randomized. Results. The CLIP score for LR and OR was 0.59 ± 0.75 and 0.86 ± 1.04, respectively, (P = .016). The operation time was 156.3 ± 308.2 and 190.9 ± 79.2 min for LR and OR groups, respectively. The necessity for blood transfusion was found in 8 patients (6.9%) and 106 patients (50.9%) for LR and OR groups. Patients resumed full diet on the 2nd and 3rd postoperative day, and the average length of hospital stay was 6 days and 12 days for LR and OR groups. The complication rate and mortality rate were 0% and 6.0%, 2.9% and 30.2% for LR and OR groups, respectively. The 1-yr, 3-yr, and 5-yr survival rate was 87.0%, 70.4%, 62.2% and 83.2%, 76.0%, 71.8% for LR and OR group, respectively, of non-significant difference. From these results, HCC patients accepted laparoscopic or open approach were of no significant differences between their survival rates.

Open heart surgery in a patient with an implanted pacemaker: case report.

When a patient has a pacemaker and requires operation, surgeons have to consider some possible intraoperative pacemaker complications induced by electrocautery. Electrocautery is commonly used during surgery to achieve hemostasis. However, this very effective tool may introduce innumerable problems in the paced patient, including irreversible damage to the pulse generator, pacemaker reprogramming, induction of a rise in the capture threshold, and ventricular fibrillation. Although electrocautery may be avoided in some surgical procedures, open heart surgery cannot be performed without it. One case is presented to illustrate how to achieve hemostasis while decreasing electric interference and how to protect the permanent pacemaker while avoiding those possible complications during the defibrillation. The purpose of this article is to call attention to potential problems induced by electrocautery and in an effect to facilitate the perioperative management of the paced patient undergoing open heart surgery.

Sphincter of Oddi motility in patients with hepatolithiasis and common bile duct stones.

The purpose of this study was to explore a difference in sphincter of Oddi (SO) motor activity among patients with intrahepatic (I, N = 5), intra- and extrahepatic (IE, N = 15), and common bile duct (CBD, N = 6) stones. Interdigestive motility of the SO and duodenum was studied by pneumohydraulic infusion manometry via the percutaneous route. SO phasic contractions showed a cyclic change in concert with the duodenal migrating motor complex (MMC) in all these patients. There was no significant difference in the cycle length, frequency, or amplitude of the SO phasic waves among the three groups throughout the whole cycle. The SO basal pressure during duodenal phases I and II of the duodenal MMC was significantly lower in patients with the IE type of hepatolithiasis than in those with the I type (P = 0.04), but there was no significant difference during phase III between the two groups. The SO basal pressure during phases I and II of the CBD group was also significantly lower than that of the I group (P = 0.02). The significance became even more prominent (P = 0.001) when a subgroup of patients with a dilated CBD (diameter > 1 cm) was examined. Lower basal pressure in the IE group or CBD group than in the I group suggested that stones in the common duct might injure or irritate the SO and cause SO dysfunction. In the subgroup with dilated CBD, which may have resulted from repeated and severe SO injury, the statistics became more prominent.

Centrosome abnormalities in human carcinomas of the gallbladder and intrahepatic and extrahepatic bile ducts.

During mitosis, 2 centrosomes ensure accurate assembly of bipolar spindles and fidelity of the chromosomal segregation. The presence of more than 2 copies of centrosomes during mitosis can result in the formation of multipolar spindles, unbalanced chromosome segregation, and aneuploidy. Recent studies have provided evidence that centrosome hyperamplification plays a pivotal role in carcinogenesis. Using immunofluorescence analysis with gamma-tubulin and pericentrin antibodies, paraffin-embedded sections from 40 malignant biliary diseases including gallbladder cancers (GC; n = 13), intrahepatic cholangiocellular carcinoma (CCC; n = 19), and extrahepatic bile duct cancers (BDC; n = 8) were examined. Thirty-seven benign biliary diseases including chronic cholecystitis, gallbladder adenoma, hepatolithiasis, and choledochal cyst were included as benign controls. The frequencies of the centrosome abnormalities were 70% for GC, 58% for CCC, and 50% for BDC, respectively. The frequencies of centrosome abnormalities in malignant biliary diseases were significantly higher than in their benign counterparts (GC, CCC, BDC; P =.001,.002, and.001, respectively). The results of current study also indicated that biliary malignancy in the advanced stage (III-IV) displayed a higher frequency of centrosome abnormalities than in the early stage (I-II) (P <.001). We conclude that abnormalities in size, number, and shape of the centrosome are frequently observed in biliary tract malignancy. Centrosome abnormalities started to occur in the early stage of biliary malignancy and became very frequent in the advanced stage. This implies that centrosome abnormality might relate to the transition from early to advanced malignancy in biliary malignancy.