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Concanavalin A is known to activate T cells and to cause liver injury and hepatitis, mediated in part by secretion of TNFα from macrophages. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been shown to prevent tissue damage in various animal models of inflammation. The objectives of this study were to evaluate the efficacy and mechanism of the PARP-1 inhibitor 3-aminobenzamide (3-AB) in preventing concanavalin A-induced liver damage. We tested the in vivo effects of 3-AB on concanavalin A-treated mice, its effects on lipopolysaccharide (LPS)-stimulated macrophages in culture, and its ability to act as a scavenger in in vitro assays. 3-AB markedly reduced inflammation, oxidative stress, and liver tissue damage in concanavalin A-treated mice. In LPS-stimulated RAW264.7 macrophages, 3-AB inhibited NFκB transcriptional activity and subsequent expression of TNFα and iNOS and blocked NO production. In vitro, 3-AB acted as a hydrogen peroxide scavenger. The ROS scavenger N-acetylcysteine (NAC) and the ROS formation inhibitor diphenyleneiodonium (DPI) also inhibited TNFα expression in stimulated macrophages, but unlike 3-AB, NAC and DPI were unable to abolish NFκB activity. PARP-1 knockout failed to affect NFκB and TNFα suppression by 3-AB in stimulated macrophages. Our results suggest that 3-AB has a therapeutic effect on concanavalin A-induced liver injury by inhibiting expression of the key pro-inflammatory cytokine TNFα, via PARP-1-independent NFκB suppression and via an NFκB-independent anti-oxidative mechanism.

Background/Aims To evaluate associations between delayed gastric emptying (GE) assessed by the octanoic acid breath test and upper gastrointestinal (GI) symptoms. Methods A historical, prospective study included 111 consecutive symptomatic adults referred for a GE breath test because of upper abdominal symptoms suggestive of delayed GE. Exclusion criteria included underlying organic disease associated with delayed GE. Patients completed a symptom questionnaire and underwent a GE octanoic breath test. Patients with delayed GE were compared with those with normal results, for upper GI symptoms. Results Early satiety was the only symptom significantly associated with delayed GE. It was observed in 52% of subjects with delayed GE compared to 33% patients with no evidence of delayed GE (P = 0.005). This association was seen for all degrees of severity of delayed GE. Patients with early satiety had a t1/2 of 153.9 ± 84.6 minutes compared to 110.9 ± 47.6 minutes in subjects without it (P = 0.002). In a logistic regression model, early satiety was significantly associated with delayed GE (OR, 2.29; 95% CI, 1.01-5.18; P = 0.048). Conclusions Early satiety is the only patient-reported GI symptom associated with delayed GE. The utility of GE tests as a clinical diagnostic tool in the work-up of dyspeptic symptoms may be overrated.

Background and aim Methacetin is thought to be a good substrate for the evaluation of different cytochrome P450 enzymatic systems of liver microsomes because of its rapid metabolism and lack of toxicity in small doses. Recent studies indicate that a methacetin breath test may be a non-invasive alternative for the evaluation of liver function since it correlates well with the severity of liver damage. It may also discriminate between different stages of liver cirrhosis and correlates with the Child-Pugh score. The application of this test in experimental liver damage in animal models has not yet been examined. This study aimed to evaluate the efficacy of the (13)C-methacetin breath test in assessing the extent of hepatic injury in models of acute liver failure, liver cirrhosis, and fatty liver in rats. Methods Absorption of methacetin given per os or intraperitoneally in normal rats was evaluated. The association between liver mass and (13)C-methacetin breath test results was assessed in a 70% hepatectomy rat model. Fulminant hepatic failure was induced by three consecutive intraperitoneal injections of thioacetamide, 300 mg/kg, at 24 h intervals. For induction of liver cirrhosis, rats were given intraperitoneal injections of thioacetamide, 200 mg/kg, twice a week for 12 weeks. A methionine-choline deficient diet was used for the induction of fatty liver. Rats were analyzed for (13)C-methacetin by BreathID (MBID) using molecular correlation spectrometry. BreathID continuously sampled the animal's breath for 60 min and displayed the results on the BreathID screen in real-time. Results Methacetin was absorbed well irrespective of the administration method in normal rats. Liver mass was associated with peak amplitude, complete percent dose recovery (CPDR) at 30 and 60 min and MBID peak time. A high degree of association was also demonstrated with MBID results in acute hepatitis (peak amplitude, 19.6 +/- 3.4 vs 6.3 +/- 1.63.4; CPDR30, 6.0 +/- 3.3 vs 1.2 +/- 0.5; CPDR60, 13.3 +/- 4.5 vs 3.2 +/- 1.4; and peak time, 31.0 +/- 14.9 vs 46.9 +/- 10.8 min) and liver cirrhosis (peak amplitude, 24.4 +/- 2.3 vs 15.6 +/- 6.4; CPDR30, 7.9 +/- 1.2 vs 2.7 +/- 1.0; CPDR60, 17.8 +/- 2.6 vs 8.8 +/- 2.1; and peak time, 30.2 +/- 1.5 vs 59.6 +/- 14.5 min), but not with grade of liver steatosis. Conclusions Methacetin is well absorbed and exclusively metabolized in the liver. MBID is a sensitive test and may be a useful tool for the evaluation of functional liver mass in animal models of acute liver failure and cirrhosis. However, MBID could not distinguish between fatty liver and normal liver in rats.

Background: Tumor size and mitotic activity are characteristically associated with the malignant potential and prognosis of gastrointestinal stromal tumors (GIST). However, since neither small tumor size nor low mitotic activity can rule out malignancy, additional factors that may predict malignant behavior have been suggested. Aim: To evaluate the correlation between the cyclin-dependent kinase inhibitor (CDI), p27kip1, expression and the malignant potential of GIST. Methods: Serial sections were evaluated by immunohistochemistry after staining with antibodies against p27/Kip1 and Ki-67 in surgical material obtained from 36 patients with GIST. p27kip1 staining intensity and the percentage of positive cells were investigated for association with the malignancy risk, pathological features, overall survival, and disease-free survival. Histologic grade was assigned by spindle vs. epithelioid cell histology, mucosal invasion, tumor cell necrosis or atypia and the number of mitoses. Results: In the multivariate model, p27kip1 expression was not significantly associated with any of the variables examined except Kit protein-CD117 (r = 0.37, p = 0.03). Comparative evaluation of p27kip1 expression in GIST cells revealed higher levels of p27kip1 in patients who died compared to those who survived (2.04 ± 0.54 vs. 1.3 ± 0.99, p = 0.1). Conclusion: The CDI p27kip1 was not associated with malignancy of GISTs and did not serve as a predictor of survival.

Acquired tracheoesophageal fistula (TEF) is a challenging, life threatening condition. It most commonly appears in critically ill patients requiring prolonged mechanical ventilation, who cannot withstand open neck or chest surgery. An endoscopic technique could be better tolerated by these patients. We present our experience using a cardiac Amplatzer ASD septal occluder for an endoscopic TEF repair in ventilation-dependent patients. Two high risk patients underwent the procedure under general anesthesia and close respiratory monitoring. In one patient the device was inserted through the trachea and in the other through the esophagus. In both cases fistula closure was achieved for different periods of time allowing the patients a temporary relief of symptoms. The procedure was well tolerated by the patients, and no significant adverse effect documented. The technique was successful as a temporary solution for unstable patients with TEFs and should be considered as a treatment modality for similar patients.

Laryngopharyngeal sensation is important in the normal process of swallowing, it is often impaired after neurological events and it has been common practice in such an occurrence to order non-oral tube feeding to prevent aspiration. This study assesses a novel approach to the evaluation of the laryngopharyngeal sensation that allows for improved triage of aspiration risk and more lenience towards oral feeding. This is a case series with follow-up period ranging from 6 to 24 months. Forty patients with neurological deficiencies were tested by a modified laryngopharyngeal sensation study that included evaluation of both supra and infra-glottis. All patients had impaired supra glottic sensation but had good infra glottic sensation that enabled cough protection. All had received oral feeding. Main outcome measure is incident aspiration pneumonia. Twenty-two patients maintained oral feeding without any evidence of aspiration. Eighteen patients had some aspirations associated with cough, and were maintained on modified oral feeding. Out of these 18 patients, four patients (10% of the entire group) developed aspiration pneumonia. The presented procedure identified patients with impaired supraglottic sensation but preserved good infra glottic sensation. This observation enables safe oral feeding in most patients and therefore offers a better quality of life for these individuals.

Background: Confirmation of Helicobacter pylori eradication by urea breath test (UBT) is currently performed 4–6 weeks after completion of therapy because of unacceptable false-negative results in UBTs performed earlier. Use of a high-dose citric acid test meal appears to enable accurate detection of H. pylori even during short term therapy with proton pump inhibitors. Aim: To evaluate if use of a high dose citric acid (4.0 g) test meal can decrease the interval required for confirmation of eradication after triple therapy. Methods: 233 patients positive for H. pylori were randomized to undergo UBT at 7 days or 14 days after triple therapy, and again at 6 weeks. The latter test was considered the gold standard test. Results: The UBT performed 6 weeks after the end of treatment found that 79.9% were cured. The same test 7 days after therapy found false-negative detection of H. pylori in 7.3% patients compared to 3.2% patients examined after 14 days. The sensitivity, specificity, positive and negative predictive values and accuracy for evaluation on day 14 were 80, 100, 100, 96.3 and 96.7%, respectively. Conclusions: High-dose citric acid-based UBT is a valid test for the assessment of H. pylori status 14 days after triple therapy. This may obviate the delay in instituting second-line eradication therapy, or further evaluation of the symptomatic patient unresponsive to therapy despite eradication.

Background: Decreased or lost expression of the cyclin-dependent kinase inhibitor p27kip1 protein has been found to be a poor prognostic factor in many cancers, including gastric cancer. Aim: To evaluate p27kip1 expression in gastric mucosa-associated lymphoid tissue (MALT) and gastric B-cell lymphoma. Methods: Fifty-two cases of gastric lymphoma, mean age 68.7 yr (range 23–90 yr), 11 of chronic Helicobacter pylori-associated gastritis, and 5 of normal gastric mucosa were studied. Patients were classified into two groups. Stage IE gastric lymphomas were defined as local gastric lymphoma of MALT and more advanced stages as advanced gastric lymphoma. Twenty-three patients diagnosed as stage IE, 13 of these were low-grade and 10 diffuse large B-cell lymphoma (DLBL). Twenty-nine patients were at stage IIE or above, 18 with low-grade and 11 with DLBL. Serial sections were evaluated by immunohistochemistry after staining with antibodies against p27/Kip1 and Ki-67. Results: The proliferative index was higher in gastric DLBL than in low-grade MALT lymphomas, 57.1±31.2 vs 17.3±20.6 (p=0.0001). The mean p27kip1 expression score for high-grade patients was significantly lower compared with that of low-grade patients, 0.5 ± 0.4 and 1.6±0.8, respectively (p=0.001). Comparative evaluation of p27kip1 expression in malignant lymphoid cells revealed that B cells of the localized gastric DLBL patients expressed the least p27kip1, 0.36±0.32. This value was lower than that of malignant lymphoid cells of patients with advanced DLBL, 0.64±0.53, advanced low-grade MALT lymphoma, 1.59±0.79, and localized low-grade MALT lymphoma, 1.59±0.84. In the multivariate model in which all p27kip1 variables were entered, the expression of p27kip1 in malignant lymphoid cells was inversely correlated with the grade of the lymphoma irrespective of the stage of the disease (p=0.0001), and significantly predicted grade: OR:0.07, 95% CI 0.07–0.31, p=0.0001. Conclusion: p27kip1 may be a putative distinct molecular marker to differentiate between low-grade and high-grade gastric lymphoma.

Objective. Conflicting reports have noted a possible association linking eradication of Helicobacter pylori with aggravation of gastroesophageal reflux (GER) disease. We prospectively evaluated the effect of eradication of H pylori on GER symptoms and epigastric pain and the association among these 3 parameters in a pediatric cohort. Methods. Patients who were referred for gastroscopy were evaluated for frequency, severity, and nocturnal presence of symptoms related to GER as well as epigastric pain. Patients who were positive for H pylori received triple antibiotic therapy. The patients were followed for at least 6 months after therapy. Patients with successful eradication had symptoms compared with their pre-eradication state and were compared with a cohort of patients without H pylori or those with persistent H pylori. Results. Of 119 children and adolescents who were recruited, 95 patients completed the study, with a mean follow-up of 11.2 months. The distribution of outcomes for each GER symptom (better, worse, unchanged) was similar before and after eradication and did not depend on prior H pylori status. Among patients with GER and epigastric pain, improvement in epigastric pain was significantly correlated with the improvement in GER symptoms but not with eradication of H pylori. Conclusions. Eradication of H pylori is not associated with increased symptoms of GER in children and adolescents. Improvement in epigastric pain in children is significantly correlated with the improvement in GER symptoms but not with eradication of H pylori.

BACKGROUND AND AIM There is substantial experimental evidence that the amino acid glycine may have a role in protecting tissues against insults such as ischemia, hypoxia and reperfusion. Our aim was to investigate the ability of the amino acid glycine to prevent hepatic damage induced by injection of lipopolysaccharide and d-galactosamine (d-Gal), to modulate pro- and anti-inflammatory cytokine levels, and to improve survival. METHODS Mice were challenged with an intraperitoneal injection of d-Gal (16 mg/mouse) and lipopolysaccharide (LPS, 1 microg/mouse). The intervention group also received an intraperitoneal injection of glycine (150 mg/kg) in two doses: 24 h before and just after LPS challenge. Serum cytokine levels were measured 2 h after challenge, and liver enzymes and histology were determined 16 h after LPS. Separate groups of mice received the same treatment and the survival rate was determined 24 h and ten days after endotoxin administration. In in vitro experiments, cultured mononuclear cells were stimulated by LPS, and TNF-alpha and IL-10 secretion were measured, in the presence or absence of glycine. RESULTS In the glycine-treated mice, the serum levels of liver enzymes and TNF-alpha, the histologic necroinflammation score and the mortality rate were significantly reduced compared to control mice (P

The aim of this study was to evaluate the accuracy of a new, continuous real time (13)C-urea breath test, BreathID, for the diagnosis of Helicobacter pylori in patients taking proton pump inhibitors (PPIs).Fifty-two consecutive patients, positive for H. pylori by BreathID, were prospectively evaluated. Patients were randomized to receive either omeprazole 20 mg/day or pantoprazole 40 mg/day for 14 days. A repeat breath test was performed on day 14 while patients received their last PPI pill. Patients were given a test drink containing 75 mg (13)C-urea and 4.0 g citric acid. Real time, continuously sampled expired (13)CO(2), obtained within 6-20 min, was compared with measurement of expired (13)CO(2) by isotope ratio mass spectrometry (IRMS).A full set of test data was available for 43 patients. After 14 days of treatment with PPIs, false negative detection of H. pylori occurred in only 1/43 (2.3%) patients examined by continuous real time (13)C-urea breath test compared with 2/43 (4.6%) patients examined by IRMS. With the exception of one case, complete agreement was observed between BreathID and the IRMS breath tests at both baseline and after PPI treatment. PPI treatment was associated with three different types of responses on UBT: 1) one third of the patients developed a significant decrease in the (13)CO(2)/(12)CO(2) excretion, 2) roughly one third developed a significant increase in the post-PPI breath test results, and 3) results did not change significantly in the remaining patients. Linear regression analysis of 43 H. pylori-positive subjects indicated a significant positive association between baseline and post-PPI Delta (13)CO(2)/(12)CO(2) excretion.The use of a single test drink containing 4.0 g citric acid in BreathID, resulted in a low number of false negative results associated with sustained PPI treatment. Although there were some differences between BreathID versus IRMS, the type of PPI and the sampling method used do not appear to play a critical role in the detection of H. pylori by BreathID. According to these results, BreathID is a reliable tool for testing H. pylori in patients taking PPIs.

There have been several reports implying a benefit for heparin therapy in patients with refractory ulcerative colitis. Although this effect has been attributed to the anti-inflammatory properties of heparin, other mechanisms have not been excluded. Heparin is a potent modulator of receptor binding of growth factors such as fibroblast growth factor (FGF), vascular endothelial growth factor, and heparin-binding epidermal growth factor (HB-EGF), that play a role in wound repair. We examined the effect of heparin on the functional levels of FGF and HB-EGF in a model of experimental colitis. Fifty-six Wistar rats were divided into four groups: group 1 was the control group, group 2 received s.c. heparin 50 units/kg/d, group 3 underwent induction of 3% iodoacetamide colitis, and group 4 underwent induction of colitis and heparin treatment. Rats were killed and evaluated for severity of colitis by macroscopic and microscopic colitis scores, area of inflammation, and myeloperoxidase levels. FGF and HB-EGF levels were functionally assessed in colonic tissue in each group. Heparin therapy resulted in significant improvement in macroscopic and microscopic features of colitis (p < 0.05), accompanied by a partial reduction in myeloperoxidase levels. FGF receptor binding activity was identical in groups 1 and 2 but increased more than 3-fold after colitis induction in group 3 (p < 0.05). Treatment with heparin caused a significant decrease in FGF concentration. Levels of HB-EGF binding activity were similar in groups 1 and 2 and decreased in group 3 (p < 0.01). Heparin caused a significant increase in HB-EGF content in group 4 (p < 0.05). Levels of growth factors are altered differently in experimental colitis. Colonic FGF binding activity increases with colitis, whereas HB-EGF binding decreases with colitis. These trends were reversed by heparin, concomitant with a clinical and pathologic improvement in colitis. We suggest that one mechanism of heparin-mediated improvement in colitis may involve tissue healing associated with changes in functional levels of colonic growth factors.

Now that the laparoscopic treatment of symptomatic liver cystic disease has proven feasible and safe, it is gaining wide acceptance. However, due to diagnostic pitfalls and a relatively high recurrence rate, further improvements and refinement of the procedure are still needed. We have evaluated the contribution of laparoscopic ultrasound in the diagnosis and management of patients with symptomatic liver cysts. Twelve patients with single or multiple cysts of the liver and two patients with polycystic liver disease were managed laparoscopically. Laparoscopic ultrasound served as an integral part of the procedure in all patients. Patients underwent either complete cyst excision (two cases) or resection of the extrahepatic cystic component (eight cases). Additionally, in two patients, deep cysts not demonstrated by preoperative imaging studies were detected and treated with a combination of laparoscopy and laparoscopic ultrasound. In one patient with a cystobiliary fistula, conversion to an open cystjejunostomy was necessary. Patients with polycystic liver disease underwent a combination of excision and unroofing of both superficial and deeper cysts using laparoscopic contact ultrasound throughout the procedure. Laparoscopic ultrasonography was found to have a significant impact on the operative strategy in five patients (36%) with multiple cysts or polycystic disease. The postoperative course was uneventful in all cases. Thirteen patients remained asymptomatic throughout the follow-up period of 30 months; one patient with polycystic liver disease developed recurrent symptoms after 5 months and was treated with left hepatectomy. Additional use of laparoscopic ultrasound enables the detection, differentiation, and treatment of deep, nonvisualized cystic lesions (two patients, 16.6%) and validation of the adequacy of the laparoscopic procedure.

Aim: To evaluate the sensitivity and specificity of a new 13C urea breath test, Oridion BreathID, for the diagnosis of Helicobacter pylori. Methods: A total of 97 consecutive symptomatic patients referred for upper endoscopy were included in the ‘pre-therapy’ part of the study. After endoscopy the patients were analysed for H. pylori by Oridion BreathID. BreathID continuously sampled the subject’s breath for 20 min, and displayed the results on the BreathID screen in real time. Results of the BreathID were compared with the ‘gold standard’ (rapid urease test and histology). We also prospectively tested the validity of BreathID in comparison to isotope ratio mass spectrometry, in 40 patients referred to monitor the efficacy of H. pylori eradication treatment. Results: Complete agreement was observed between the ‘gold standard’ and the Breath ID test in 96.9% (94 out of 97) of the patients. The sensitivity and specificity of BreathID were 97.8% and 96.1%, respectively. The correlation between BreathID and isotope ratio mass spectrometry breath test was 100%. Conclusions: The Oridion BreathID has comparable sensitivity and specificity to the claims of the currently available urea breath tests. Furthermore, BreathID has the potential advantages of ease of use with minimal medical staff requirement, and real time rapid results (20 min maximum) which may make the BreathID preferable to other urea breath test assays.

Hepatic fibrosis is associated with activation of hepatic stellate cells (HSC), the major source of the extracellular matrix (ECM) proteins. The predominant ECM protein synthesized by the HSC is collagen type I. We evaluated the effect of halofuginone-an inhibitor of collagen synthesis-on thioacetamide (TAA)-induced liver fibrosis in rats. In the control rats the HSC did not express smooth muscle actin, collagen type I gene, or tissue inhibitor of metalloproteinases-2 (TIMP-2), suggesting that they were in their quiescent state. When treated with TAA, the livers displayed large fibrous septa, which were populated by smooth muscle actin-positive cells expressing high levels of the collagen alpha1(I) gene and containing high levels of TIMP-2, all of which are characteristic of advanced fibrosis. Halofuginone given orally before fibrosis induction prevented the activation of most of the stellate cells and the remaining cells expressed low levels of collagen alpha1(I) gene, resulting in low levels of collagen. The level of TIMP-2 was almost the same as in the control livers. When given to rats with established fibrosis, halofuginone caused almost complete resolution of the fibrotic condition. The levels of collagen, collagen alpha1(I) gene expression, TIMP-2 content, and smooth muscle actin-positive cells were as in the control rats. Halofuginone inhibited the proliferation of other cell types of the fibrotic liver in vivo and inhibited collagen production and collagen alpha1(I) gene expression in the SV40-immortalized rat HSC-T6 cells in vitro. These results suggest that halofuginone may become an effective and novel mode of therapy in the treatment of liver fibrosis.

Background/Aims: Protooncogenes may play an important role, not only in carcinogenesis, but also in the regulation of normal cellular proliferation and differentiation. Several studies have indicated increased expression of the Ras protooncogenes in the liver in animal models and in patients with liver cirrhosis. The aim of the present study was to examine whether a synthetic Ras antagonist, S-farnesylthiosalicylic acid (FTS), which specifically dislodges Ras from the membrane of Ras-transformed fibroblasts (EJ cells), can prevent experimentally-induced liver cirrhosis in rats. Methods: Cirrhosis was induced in male Wistar rats by intraperitoneal administration of thioacetamide (200 mg/kg twice weekly for 12 weeks). The Ras antagonist, farnesylthiosalicylic acid (FTS, 5 mg/kg), was administered during the study period 3 times a week. Ras expression in the liver was determined by Western blot analysis with pan anti-Ras antibodies and by immunohistochemistry. Results: Rats treated with thioacetamide and the Ras antagonist, farnesylthiosalicylic acid (FTS), for 12 weeks had lower histopathologic scores of fibrosis and inflammation ( p -values of 0.003 and 0.008, respectively) than those treated with thioacetamide only. There were no differences between the histopathologic scores in vehicle (control) and in Ras-antagonist (FTS) only treatments. Analysis of hepatic hydroxyproline levels from the two thioacetamide-treated groups and controls confirmed the histopathologic scores (7.7±0.9 mg/g protein in the TAA-treated vs . 3.8±0.5 mg/g protein in the TAA+FTS treated group, p =0.007). Ras levels, determined by Western blot analysis, were markedly increased in the livers treated with TAA (17-fold over control) and significantly decreased (by about 70%) in the livers of rats treated with TAA and FTS. Studies in isolated human hepatic stellate cells demonstrated that FTS inhibited both DNA synthesis and migration of those cells ( p Conclusion: These results indicate that inhibition of Ras expression in the liver during fibrogenesis, prevents the development of experimentally-induced hepatic cirrhosis.

Recent data from animal studies suggest thatinduced hypothyroidism inhibits the development of liverinjury in several animal models, including livercirrhosis and fulminant hepatic failure in rats, and immune-mediated acute liver injury in mice. Theaim of the present study was to determine whetherhypothyroidism would likewise preventacetaminophen-induced hepatic damage in rats. Liverdamage was induced by acetaminophen (2 g/kg) administered bygavage to fasting rats as a single dose. Hypothyroidismwas induced by methimazole, propylthiouracil, orsurgical thyroidectomy and confirmed by elevated serum levels of TSH. Hypothyroidism significantlyinhibited acetaminophen-induced liver damage asmanifested by the decreased serum levels of liverenzymes, malondialdehyde and blood ammonia, as well asby the higher hepatic glutathione content, in allthree groups of hypothyroid rats compared to euthyroidcontrols (P < 0.01). Histopathologic analysis showedsignificantly less liver necrosis and inflammation in the acetaminophen-treated hypothyroid rats.Oxygen extraction, measured in isolated perfused ratliver preparation, was also reduced in the hypothyroidlivers to 42 ± 8% compared to 81 ± 14% ofcontrols (P < 0.01). However, the expression ofCYP2E1 in the livers of hypothyroid rats, as measured bywestern blot analysis, was not decreased compared tocontrol rats. These results suggest that inducedhypothyroidism, regardless of the mode of induction, protectsrat liver from acetaminophen hepatotoxicity. This effectmay be related to hypometabolism of liver cells, but theexact mechanism needs further clarification.

Backgroun/Aims: Concanavalin A activates T lymphocytes and causes T cell-mediated hepatic injury in mice. Tumor necrosis factor α is a critical mediator in this experimental model. T-cell-mediated liver injury involves the migration of immune cells, notably CD4 + T lymphocytes, into liver tissue. Pentoxifylline is a strong suppresser of tumor necrosis factor α release and prevents leukocyte adherence to vascular endothelium and down-regulates the expression of intercellular adhesion molecule-1 in monocytes. In this study, we examined the efficacy of pentoxifylline as a potential therapeutic compound for the treatment of concanavalin A hepatitis. Methods: Balb/c mice were injected with 12 mg/kg concanavalin A with or without a single injection of pentoxifylline (5–300 mg/kg), 2 h prior to concanavalin A administration. Liver damage was evaluated by determining serum levels of liver enzymes and tumor necrosis factor α, and hepatic histopathology compared to mice treated with concanavalin A only. We also assessed the effects of pentoxifylline on the adhesive properties of T lymphocytes to fibronectin, as a paradigm for immune cell-extracellular matrix interactions required for migration. Results: Pretreatment with pentoxifylline significantly reduced serum levels of liver enzymes (3800±650 vs 150±28 IU/I) and tumor necrosis factor α (710±105 vs 113±15 pg/ml) with no evidence of inflammation in histopathologic examination compared to control mice treated with concanavalin A. Pentoxifylline also inhibited the binding of murine T cells to fibronectin. All the effects of pentoxifylline were dose-dependent. Conclusions: These results indicate that high doses of pentoxifylline can prevent concanavalin A hepatitis by suppression of tumor necrosis factor α release and inhibition of T cells adhesion to extracellular matrix.

Recent data from animal studies suggest that induced hypothyroidism prevents the hyperdynamic circulation in portal vein ligated rats, liver cirrhosis in rats chronically treated with thioacetamide (TAA), and immune-mediated acute liver injury induced in mice by concanavalin A. Therefore, the aim of this present study is to determine whether hypothyroidism would likewise prevent fulminant hepatic failure (FHF) in rats. FHF was induced by 3 consecutive ip injections of TAA (400 mg/kg) at 24-hour intervals. Hypothyroidism was induced in rats by either methimazole (MMI) or propylthiouracil (PTU) and surgical thyroidectomy and was confirmed by elevated serum thyroid stimulating hormone levels. Serum levels of liver enzymes, blood ammonia, and prothrombin time were significantly lower in all 3 groups of hypothyroid rats. The stage of hepatic encephalopathy (HE) and the survival rates were significantly improved in the hypothyroid rats (P < .01); the histologic examination of their livers showed less necrosis and inflammation (P < .01). In the hypothyroid rats, the serum levels of malondialdehyde 48 hours after thioacetamide (TAA) administration were lower than in control rats (P < .01). Exogenous supplementation of hypothyroid rats with L-thyroxine started 48 hours before TAA administration abrogated the protective effects of hypothyroidism. The serum levels of tumor necrosis factor alfa (TNF-alpha), interleukin (IL) 2 and IL-6 after 24 hours were slightly lower in the hypothyroid rats, but the administration of soluble receptor of TNF (10-1,000 microg/rat) did not prevent the induction of fulminant liver failure by TAA. Oxygen extraction, studied in isolated perfused liver preparation, was significantly lower in livers of hypothyroid rats (P < .01). These results suggest that induced hypothyroidism decreases the development of liver injury in a rat model of FHF. The mechanism may involve diminished oxidative cell injury caused by decreased oxygen utilization and hypometabolism associated with hypothyroidism.

The success rate of pneumatic dilation of the esophagus in patients with achalasia is variable. We aim to assess whether levels of muscle enzymes in the serum are useful for predicting the efficacy of this procedure. Consecutive adults with symptomatic achalasia treated with pneumatic dilation were included. Blood samples were taken immediately before the procedure and after 12, 24 and 32 h. Clinical efficacy of the pneumatic dilation was evaluated on the basis of a symptom score defined prior to, and 2 months after the procedure. Eleven patients underwent 13 pneumatic dilations. In nine patients this was the first dilation attempt. Ten dilations were clinically effective. The study was discontinued after enzyme levels did not show a trend of increase in any of our patients. Moreover, a statistically significant unexpected decrease in creatine phosphokinase values was found 12 h after the procedure, among the 10 successful dilations. We believe that levels of muscle enzymes in the serum cannot predict the efficacy of pneumatic dilation in patients with achalasia.

Immunomodulator therapy with thiopurine analogues azathioprine or 6-mercaptopurine is commonly prescribed for the treatment of organ transplantation, inflammatory bowel disease, autoimmune diseases and malignancies. Hepatotoxicity due to thiopurine analogues usually presents as an increase in serum transaminase levels. Toxicity is usually not severe, and a dose reduction is effective in most patients. Nodular regenerative hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing therapy. NRH is often asymptomatic, neither biochemical nor molecular markers are indicative for NRH. The suspicion rises when there are clinical symptoms of portal hypertension or increases in transaminases levels orthrombocytopenia. Liver biopsy is essential for definitive diagnosis. This is a case report of a 40-year-old male patient with Crohn's disease who developed increased serum levels of liver enzymes and thrombocytopenia following the administration of thiopurine. Although treatment with thiopurine was discontinued, he has further progressed and presented with acute variceal bleeding due to portal hypertension. The diagnosis of nodular regenerative hyperplasia was proven by a liver biopsy. In conclusion, NRH is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for IBD.

BACKGROUND: We constructed an animal model to examine the possibility that erythrophagocytosis may contribute to decreased hemoglobin (Hgb) levels in acute infection in mice. METHODS: BALB/c mice weighing 20 to 25 g were injected (intraperitoneally) with lipopolysaccharide (LPS) (Escherichia coli serotype) of some concentrations. Control mice were injected intraperitoneally with saline (0.5 mL). Two and 4 hours after LPS administration, mice were bled (0.25 mL) for complete blood count measures and tumor necrosis factor-α and interleukin-6 levels. The mice were then killed, and their spleen, liver, and bone marrow were examined microscopically for erythrophagocytosis. RESULTS: After LPS administration, mouse Hgb and hematocrit levels dropped significantly. At 4 hours after LPS injection, all Hgb and hematocrit concentrations were found to be significantly lower compared with that of controls (P = 0.002 and 0.001, respectively). Significantly increased concentrations of tumor necrosis factor-α and interleukin-6 were evident after LPS injection. Prominent hepatic erythrophagocytosis was observed in the LPS-injected mice compared with controls. A significant across-group difference was observed at 4 hours, driven by significantly higher values in group 500 mcg versus controls (P = 0.005) and 100 mcg (P = 0.025). A significant increase in erythrophagocytes was observed at 2 to 4 hours in the 500 mcg LPS group (P = 0.044). CONCLUSIONS: Erythrophagocytosis may play a role in anemia associated with acute infection in mice.

Before the development of efficient medications for peptic ulcer disease many patients were treated surgically by partial gastrectomy. The pathogenetic role of Helicobacter pylori was also not known yet. Some of these patients may therefore still harbor H. pylori in their remnant stomach as a carcinogenic agent for gastric cancer. This could be even more relevant for patients who were operated for tumors in the stomach. The efficacy of the urea breath test (UBT) is not clear in this population.To study the prevalence of H. pylori and to evaluate the sensitivity and specificity of the continuous UBT (BreathID) in postgastrectomized patients in Israel. In this system, the pH of the stomach is lowered by the addition of citric acid that may be beneficial in the smaller and more alkalic stomach.We compared retrospectively the results of our continous UBT with a rapid urease test (RUT) and the histology in all our patients who underwent gastroscopy for any clinical indication, and had a history of partial gastrectomy during the years 2002 to 2010. Only patients in whom H. pylori was tested by all the 3 methods during the same day were included in the study. We identified 76 such patients older than 18 years and performed a statistical analysis of all possibly related clinical data. The 3 methods were compared with each other.H. pylori was positive in 14/76 (18.4%) patients when histology was considered as the gold standard method. The positive predictive value of the continuous UBT and the RUT was 0.64 and 0.35, respectively. The negative predictive value was high by both the methods, 0.92 and 0.95, respectively. Weight loss was correlated with positivity for H. pylori (P=0.032) and a longer gastric stump was marginally related to H. pylori (P=0.071). There was no difference for H. pylori positivity between patients with Billroth I or Billroth II operations. Prevalence of H. pylori was not lower in patients who had partial gastrectomy several years earlier.The prevalence of H. pylori is considerable even several years after partial gastrectomy. The BreathID is reliable to exclude H. pylori after partial gastrectomy. The positive predictive value of the UBT is not very high but better than the RUT. We suggest that all positive patients found by the breath test should be treated. Our results support the view that alternative noninvasive methods, such as the stool antigen test should be further studied and compared with the BreathID in larger populations.

Octanoate (also known as sodium octanoate), a medium-chain fatty acid metabolized in the liver, is a potential substrate for non-invasive breath testing of hepatic mitochondrial β-oxidation. We evaluated the 13C-octanoate breath test (OBT) for assessing injury in acute hepatitis and two rat models of liver cirrhosis, first testing octanoate absorption (per os or intraperitoneally (i.p.)) in normal rats. We then induced acute hepatitis with thioacetamide (300 mg/kg/i.p., 24-h intervals). Liver injury end points were serum aminotransferase levels and 13C-OBT (24 and 48 h following initial injection). Thioacetamide (200 mg/kg/i.p., twice per week, 12 weeks) was used to induce liver cirrhosis. OBT and liver histological assessment were performed every 4 weeks. Bile duct ligation (BDL) was used to induce cholestatic liver injury. We completed breath tests with 13C-OBT and 13C-methacetin (MBID), liver biochemistry, and liver histology in BDL and sham-operated rats (baseline, 6, 14, 20 days post-BDL). Octanoate absorbs well by either route. Peak amplitudes and cumulative percentage dose recovered at 30 and 60 min (CPDR30/60), but not peak time, correlated with acute hepatitis. Fibrosis stage 3 at week 8 significantly correlated with each OBT parameter. Cholestatic liver injury (serum bilirubin, ALP, gamma-GT, liver histology) was associated with significant suppression of the maximal peak values and CPDR30/60, respectively (P

BACKGROUND:: Nonalcoholic steatohepatitis is most often attributed to the effects of obesity, hyperlipidemia, diabetes mellitus and drugs. It is still unknown whether livers with steatohepatitis are more vulnerable to toxic damage. AIM:: To determine the effect of the hepatotoxicant thioacetamide in a rat nutritional model of hepatic steatohepatitis. METHODS:: Steatohepatitis was induced in rats by placing them on a methionine-choline deficient diet for 1 month. Thioacetamide was administered by three consecutive intraperitoneal injections (300mg/kg) at 24h intervals. RESULTS:: Following treatment with thioacetamide, the elevated serum levels of liver enzymes and blood ammonia, liver necroinflammation and the survival rate after 48h were not different between rats with normal or fatty liver. However, those parameters were significantly worse when steatohepatitis regressed after return to normal diet for 1 month (P0.01). Western blot analysis of hepatic extracts revealed no difference in cytochrome P4502E1 levels between livers with steatohepatitis and steatohepatitis after regression, suggesting that the enhanced hepatotoxicity after regression of steatohepatitis could not be attributed to increased cytochrome P4502E1. CONCLUSIONS:: In a nutritional model of steatohepatitis, rats with fatty liver were not more vulnerable than normal rats to liver damage induced by thioacetamide. However, liver damage was significantly more severe in rats with steatohepatitis after 1 month regression.

Tumor size and mitotic activity are characteristically associated with the malignant potential and prognosis of gastrointestinal stromal tumors (GIST). However, since neither small tumor size nor low mitotic activity can rule out malignancy, additional factors that may predict malignant behavior have been suggested.To evaluate the correlation between the cyclin-dependent kinase inhibitor (CDI), p27kip1, expression and the malignant potential of GIST.Serial sections were evaluated by immunohistochemistry after staining with antibodies against p27/Kip1 and Ki-67 in surgical material obtained from 36 patients with GIST. p27kip1 staining intensity and the percentage of positive cells were investigated for association with the malignancy risk, pathological features, overall survival, and disease-free survival. Histologic grade was assigned by spindle vs. epithelioid cell histology, mucosal invasion, tumor cell necrosis or atypia and the number of mitoses.In the multivariate model, p27kip1 expression was not significantly associated with any of the variables examined except Kit protein-CD117 (r = 0.37, p = 0.03). Comparative evaluation of p27kip1 expression in GIST cells revealed higher levels of p27kip1 in patients who died compared to those who survived (2.04 +/- 0.54 vs. 1.3 +/- 0.99, p = 0.1).The CDI p27kip1 was not associated with malignancy of GISTs and did not serve as a predictor of survival.

Background: The correlation between the width of muscularis propria and esophageal pressure in patients with the nutcracker esophagus is unknown. We examined by endoscopic ultrasonography the width of the muscularis propria in patients with nutcracker esophagus. Methods: The width of muscularis propria was measured at the gastroesophageal junction and at the lower, middle, and upper esophagus in 18 patients and 10 control subjects. Results: Mean muscularis propria diameter in patients was 1.8 ± 1.4, 1.5 ± 1.2, 1.5 ± 0.8, and 1.2 ± 0.4 mm at the gastroesophageal junction, lower, middle, and upper esophagus. In the control group, the mean width was 1.2 ± 0.3, 1.2 ± 0.3, 1.1 ± 0.3, and 0.9 ± 0.1 mm, respectively. The difference was significant at the gastroesophageal junction and upper esophagus. The muscularis propria was wider than 3 mm in 30% of patients. There was no correlation between the site of the wide muscularis propria and the esophageal segment where high pressure was recorded. Length of disease, frequency of symptoms, and length of each symptomatic period did not correlate with the width of muscularis propria. Conclusion: The muscularis propria is thickened in one third of patients with nutcracker esophagus. The extent and magnitude of this thickening do not correspond to the location and the magnitude of the manometric abnormality or clinical presentation.(Gastrointest Endosc 1997;46:223-5.)

Decreased or lost expression of the cyclin-dependent kinase inhibitor p27kip1 protein has been found to be a poor prognostic factor in many cancers, including gastric cancer.To evaluate p27kip1 expression in gastric mucosa-associated lymphoid tissue (MALT) and gastric B-cell lymphoma.Fifty-two cases of gastric lymphoma, mean age 68.7 yr (range 23-90 yr), 11 of chronic Helicobacter pylori-associated gastritis, and 5 of normal gastric mucosa were studied. Patients were classified into two groups. Stage IE gastric lymphomas were defined as local gastric lymphoma of MALT and more advanced stages as advanced gastric lymphoma. Twenty-three patients diagnosed as stage IE, 13 of these were low-grade and 10 diffuse large B-cell lymphoma (DLBL). Twenty-nine patients were at stage IIE or above, 18 with low-grade and 11 with DLBL. Serial sections were evaluated by immunohistochemistry after staining with antibodies against p27/Kip1 and Ki-67.The proliferative index was higher in gastric DLBL than in low-grade MALT lymphomas, 57.1+/-31.2 vs 17.3+/-20.6 (p=0.0001). The mean p27kip1 expression score for high-grade patients was significantly lower compared with that of low-grade patients, 0.5+/-0.4 and 1.6+/-0.8, respectively (p=0.001). Comparative evaluation of p27kip1 expression in malignant lymphoid cells revealed that B cells of the localized gastric DLBL patients expressed the least p27kip1, 0.36+/-0.32. This value was lower than that of malignant lymphoid cells of patients with advanced DLBL, 0.64+/-0.53, advanced low-grade MALT lymphoma, 1.59+/-0.79, and localized low-grade MALT lymphoma, 1.59+/-0.84. In the multivariate model in which all p27kip1 variables were entered, the expression of p27kip1 in malignant lymphoid cells was inversely correlated with the grade of the lymphoma irrespective of the stage of the disease (p=0.0001), and significantly predicted grade: OR:0.07, 95% CI 0.07-0.31, p=0.0001.p27kip1 may be a putative distinct molecular marker to differentiate between low-grade and high-grade gastric lymphoma.

Confirmation of Helicobacter pylori eradication by urea breath test (UBT) is currently performed 4-6 weeks after completion of therapy because of unacceptable false-negative results in UBTs performed earlier. Use of a high-dose citric acid test meal appears to enable accurate detection of H. pylori even during short term therapy with proton pump inhibitors.To evaluate if use of a high dose citric acid (4.0 g) test meal can decrease the interval required for confirmation of eradication after triple therapy.233 patients positive for H. pylori were randomized to undergo UBT at 7 days or 14 days after triple therapy, and again at 6 weeks. The latter test was considered the gold standard test.The UBT performed 6 weeks after the end of treatment found that 79.9% were cured. The same test 7 days after therapy found false-negative detection of H. pylori in 7.3% patients compared to 3.2% patients examined after 14 days. The sensitivity, specificity, positive and negative predictive values and accuracy for evaluation on day 14 were 80, 100, 100, 96.3 and 96.7%, respectively.High-dose citric acid-based UBT is a valid test for the assessment of H. pylori status 14 days after triple therapy. This may obviate the delay in instituting second-line eradication therapy, or further evaluation of the symptomatic patient unresponsive to therapy despite eradication.

We prospectively evaluated a 13 C urea breath test (UBT) that involves passive continuous sampling for diagnosis of Helicobacter pylori in 72 children. Results were obtained within 10 minutes in 96% of patients. The test is rapid, user-friendly, and has 100% concordance with conventional diagnostic methods.

Background The Maastricht 2-2000 guidelines on the current management of Helicobacter pylori infection were recently adopted by the Israeli Gastroenterological Association. Goal To determine the impact of these clinical guidelines on the current knowledge, attitudes, and management of H. pylori among primary care physicians, hospital internists, and gastroenterologists in Israel. Study Self-administered, voluntary, anonymous questionnaires were given personally to 229 physicians, 73 primary care physicians, 71 internists, and 85 gastroenterologists. The questions evaluated 4 main issues in the management of H. pylori: (1). the optimal diagnostic test, (2). indications for eradication, (3). combination and duration of triple therapy, and (4). the need for confirmation following eradication. Results There were significant variations in the adherence of those recommendations among gastroenterologists, internists, and primary care physicians. Specifically, 94.1% of gastroenterologists and 88.9% of internists consider the urea breath test the test of choice for H. pylori diagnosis compared with 60.0% of the primary care physicians. Significant differences in the eradication indications for mucosa-associated lymphoid tissue (MALT) lymphoma, first-degree relatives of gastric cancer patients, atrophic gastritis, functional dyspepsia, and concomitant use of nonsteroidal antiinflammatory drugs were demonstrated among gastroenterologists and the other groups. Conclusions Primary care physicians may not be aware of important indications for diagnosis and eradication of H. pylori related to the risk of gastric malignancy or concomitant use of nonsteroidal antiinflammatory drugs. Public health agencies may need to increase penetration of the Maastricht 2000 recommendations to primary care physicians.

Free radical-mediated oxidative stress has been implicated in the pathogenesis of acute liver injury. The aim of our study was to investigate whether melatonin, a potent free radical scavenger could prevent fulminant hepatic failure in rats.Liver damage was induced by two consecutive injections of thioacetamide (TAA, 300 mg/kg/i.p.) at 24 h intervals. Treatment with melatonin (3 mg/kg/daily, i.p) was initiated 24 h prior to TAA.Twenty-four h after the second TAA injection, serum liver enzymes and blood ammonia were lower in rats treated with TAA+melatonin compared to TAA (P0.001). Liver histology was significantly improved and the mortality in the melatonin-treated rats was decreased (P0.001). The increased nuclear binding of nuclear factor kappa B in the livers of the TAA-treated rats, was inhibited by melatonin. The hepatic levels of thiobarbituric acid reactive substances, protein carbonyls and inducible nitric oxide synthase were lower in the TAA+melatonin-treated group (P0.01), indicating decreased oxidative stress and inflammation.In a rat model of TAA-induced fulminant hepatic failure, melatonin improves survival and reduces liver damage and oxidative stress. The results suggest a causative role of oxidative stress in TAA-induced hepatic damage and suggest that melatonin may be utilized to reduce liver injury associated with oxidative stress.

There is substantial experimental evidence that the amino acid glycine may have a role in protecting tissues against insults such as ischemia, hypoxia and reperfusion. Our aim was to investigate the ability of the amino acid glycine to prevent hepatic damage induced by injection of lipopolysaccharide and d-galactosamine (d-Gal), to modulate pro- and anti-inflammatory cytokine levels, and to improve survival.Mice were challenged with an intraperitoneal injection of d-Gal (16 mg/mouse) and lipopolysaccharide (LPS, 1 microg/mouse). The intervention group also received an intraperitoneal injection of glycine (150 mg/kg) in two doses: 24 h before and just after LPS challenge. Serum cytokine levels were measured 2 h after challenge, and liver enzymes and histology were determined 16 h after LPS. Separate groups of mice received the same treatment and the survival rate was determined 24 h and ten days after endotoxin administration. In in vitro experiments, cultured mononuclear cells were stimulated by LPS, and TNF-alpha and IL-10 secretion were measured, in the presence or absence of glycine.In the glycine-treated mice, the serum levels of liver enzymes and TNF-alpha, the histologic necroinflammation score and the mortality rate were significantly reduced compared to control mice (P0.001). Serum IL-10 levels in the glycine-treated mice were increased (P0.01). In vitro studies in cultured lymphocytes isolated from either normal or glycine pretreated mice, demonstrated a significant and dose-dependent inhibition of LPS-induced TNF-alpha secretion and increase in IL-10 response after treatment with glycine (P0.01). In conclusion, glycine reduces hepatic damage and improves survival rate in this mouse model of endotoxemia. The protective effect of glycine is associated with modulation of TNF-alpha and IL-10 secretion.

A 74-year-old patient who has developed fecal incontinence following continuous ambulatory peritoneal dialysis (CAPD) is presented. Incontinence was caused by elevated intra-abdominal pressure during peritoneal dialysis, which correlated with the volume of dialysate and position of the patient. The lowest pressure was found in the recumbent position. A change of dialysis schedule to continuous cycler peritoneal dialysis (CCPD) with "dry day" resulted in a disappearance of the symptoms.

Clinically significant liver disease is probably a rare condition in Turner’s syndrome and only a few cases of severe liver disease have been described. The natural history of patients with Turner’s syndrome and elevated cholestatic liver enzymes is unclear. We report a case with a long history of intrahepatic cholestasis and without clinical or histopathological progression in 12 years of follow-up. Like some other reports our case suggests, also histologically, that the liver disease in these patients runs a benign course.

Recently, several investigators have suggested that H. pylori may be a contributory factor in hyperemesis gravidarum. The purpose of this study was to evaluate whether seropositivity for IgG antibodies to H. pylori may also be related to nausea, vomiting, heartburn and epigastric pain in pregnancy.One hundred and eighty-five women, at term pregnancy, were included in the study. All women completed a questionnaire regarding information on the number of pregnancies and deliveries, weight gain, smoking and gastrointestinal complaints before and during pregnancy. The presence of H. pylori infection was determined by serology.The overall prevalence rate of H. pylori seropositivity was 45.9%. Women positive for H. pylori IgG were older (28.7+/-4.5 vs. 27.0+/-4.5, p=0.02), had more prior pregnancies (3.2+/-2.1 vs. 2.6+/-1.6, p=0.02) and deliveries (2.6+/-1.6 vs. 2.0+/-1.1, p=0.006) and reported vomiting in the first trimester more frequently than H. pylori negative patients (81.2% vs. 65%, p=0.004). On the other hand vomiting in the second trimester was reported more frequently among smokers during pregnancy compared to non-smokers.H. pylori seropositivity is significantly associated with emesis gravidarum but not with gastro-intestinal symptoms later in pregnancy. First trimester vomiting more than doubles the likelihood that the gravida is H. pylori IgG positive.

Reactive oxygen species and nuclear factor kappa B (NF-kappaB) activation have been implicated in the pathogenesis of cell injury in experimental models of liver damage. The aim of the present study was to examine whether pyrrolidine dithiocarbamate (PDTC), an anti oxidant and inhibitor of NF-kappaB activation, would prevent hepatic damage induced in a rat model of thioacetamide (TAA)-induced liver failure.Fulminant hepatic failure was induced in the control and treatment groups by two intraperitoneal injections of TAA (either 300 or 400 mg/kg) at 24-h intervals. In the treatment groups, rats were treated also with PDTC (60 mg/kg/24 h, i.p.), initiated 24 h prior to TAA.Liver enzymes, blood ammonia, and hepatic levels of thiobarbituric acid reactive substances (P0.001) and protein carbonyls (P0.05) were significantly lower in rats treated with PDTC compared to TAA only. Liver histology and the survival rate in the PDTC-treated rats were also improved (P0.01 compared to TAA only). NF-kappaB activation, 2 and 6 h after TAA administration, was inhibited by PDTC.In a rat model of fulminant hepatic failure, the administration of PDTC attenuated liver damage and improved survival. This effect may be due to decreased oxidative stress and inhibition of NF-kappaB activation.

BACKGROUND Constipation is common in elderly patients with diabetes mellitus (DM); its prevalence is estimated as up to 60% among patients with diabetic neuropathy. Acarbose, an alpha-glucosidase inhibitor, has a beneficial role in controlling DM, although one of its side effects is diarrhea. This study evaluates the efficacy of acarbose in improving constipation using transit time (TT) studies in elderly long-term care (LTC) patients. METHODS Twenty-eight patients with type 2 DM and constipation were recruited for the study. TT was measured by radiopaque markers and was calculated separately for the four segments of the colon (ascending, transverse, descending, and rectosigmoid) and for the total colonic transit time (CTT). Segmental TT and CTT were evaluated in each patient before and after 1 week, and again after 4 weeks of treatment with acarbose. RESULTS The mean baseline CTT measured in patients was 202 plus minus 136 hours. After 1 and 4 weeks of acarbose treatment, the baseline CTT significantly decreased to 149 plus minus 107 hours and 161 plus minus 97 hours, respectively (p

Epidemiologic studies in different parts of the world have revealed controversial results on the association between hepatitis C virus infection and non-Hodgkin's lymphoma. This discrepancy suggests that HCV lymphotropism or its effect on host lymphocytes may be influenced by regional and racial factors, as well as by genomic variations.To determine the prevalence of HCV infection in patients with lymphoproliferative disorders diagnosed and treated in our institute in Israel.A total of 212 consecutive patients (95 males and 117 females) treated in our hematology outpatient clinic between August 1997 and September 1999 was screened for anti-HCV antibodies and hepatitis B surface antigen. HCV infection was confirmed by the presence of HCV RNA in the serum. The prevalence of HCV in patients with lymphoproliferative disorders was compared to that in a control group of patients with myeloproliferative disorders and myelodysplastic syndromes.HCV infection was more prevalent in the group of LPD patients than in the control group, but this finding was not statistically significant. The prevalence of HCV among LPD patients was 7.8%, while that in the group with myeloproliferative and myelodysplastic disorders was 1.19% and in the general population 0.64%. Among the different classes of LPD, a significant association with HCV infection was established only in patients with diffuse large B cell lymphoma. Furthermore, HCV infection was significantly more prevalent than HBV infection in the LPD group, but not in the myeloproliferative and myelodysplastic disorders group.Our finding of a significant association between HCV infection and diffuse large B cell lymphoma leads us to suggest that anti-HCV antibodies be performed routinely in such subjects.

INTRODUCTION: Anismus is a common cause of constipation and outlet obstruction. Standard therapy with laxatives or biofeedback has conflicting results. Surgical treatment gives poor results and has practically been abandoned. PURPOSE: This study was designed to evaluate the efficacy of botulinum toxin type-A (Botox®) injection to the puborectalis muscle in patients with anismus. METHODS: Twenty-five patients (15 females; mean age, 23.2) with history of constipation and symptoms of outlet obstruction underwent anorectal perfusion manometry and video-proctography. All patients were found to have a nonrelaxing puborectalis muscle on both modalities. All have been unable to expel a rectal balloon. Each patient who participated in the study was randomly assigned to undergo local injection of Botox—10 units to each side of the puborectalis or 20 units to the posterior aspect of this muscle. Eight patients underwent further injections1–5 every 3 months in accordance with previous results. Follow-up was conducted 1, 4, 12, and 24 weeks after injection. Straining, anorectal pain, and overall satisfaction were assessed on a visual analog scale. Weekly evacuation, fecal incontinence, and complications were recorded. At the weekly meeting, each patient underwent anorectal manometry with a balloon expulsion test. RESULTS: Manometric relaxation was achieved after the first injection in 18 patients (75 percent). Once relaxation was achieved, it lasted throughout the follow-up. Nine patients (37.5 percent) expelled the rectal balloon after the first injection. Seven of 16 patients who failed the first injection had an additional one. In 2 patients it was successful (28.6 percent). Symptom improvement of 29.2 percent in straining index was recorded during follow-up. In 3 patients (12.5 percent) pain developed after injection. No other complications were observed. Overall satisfaction with Botox injection results was observed in 58.3 percent. CONCLUSIONS: Botox injection to the puborectalis muscle has been found to have a limited therapeutic effect on patients suffering from anismus. Our results justify the need for further double-blind placebo-controlled trials to determine the exact role of botulinum toxin type-A in anismus.

Hypothesis Laparoscopy and laparoscopic ultrasonographic (LAPUS) examinations combined with a biopsy of the pancreatic lesion contribute significantly in the determination of resectability of pancreatic cancer. Design A prospective evaluation of the impact of laparoscopy and LAPUS on surgical decision making in patients with pancreatic cancer. Setting A general community hospital; the department of surgery serves as referral for pancreatic surgery. Patients During a 36-month period, 94 patients with pancreatic lesions were prospectively examined. Twenty-seven patients were found to have advanced disease. The remaining 67 patients were examined by laparoscopy and LAPUS to determine the resectability of the pancreatic tumor. Results Laparoscopy and LAPUS contributed new, additional data in 40 patients (60%). Advanced disease was found in 30 patients, precluding curative resection. The study indicated potentially resectable tumors in 37 patients (55%), including 3 defined by conventional imaging studies as probably unresectable, and these patients were operated on with the intention of curative resection. Thirty-three patients underwent resection, and 4 (6%) were found to have nonresectable disease and form the false-positive group of the study. A summary of the results shows that the study resulted in a change of the decision regarding surgical intervention in 24 patients (36%) and avoided unnecessary laparotomies in 21 (31%). The study had a sensitivity of 100%, a specificity of 88%, and a false-positive rate of 6%. The positive predictive value of the study is 89%, and the negative predictive value is 100%. Conclusions Although rather invasive procedures that require general anesthesia and hospitalization, laparoscopy and LAPUS significantly contribute to the staging of patients with potentially resectable pancreatic cancer, avoiding unnecessary explorative laparotomies. These procedures should be performed in all patients with potentially resectable pancreatic cancer before explorative laparotomy.

Reactive oxygen species, proinflammatory cytokines, glutathione depletion and nitric oxide have all been implicated in the pathogenesis of fulminant hepatic failure. The aim of the present study was to examine the respective roles of these factors in the pathogenesis of thioacetamide-induced fulminant hepatic failure in rats.Fulminant hepatic failure was induced by 3 consecutive intraperitoneal injections of thioacetamide (400 mg/kg) at 24-h intervals. Rats were pretreated with one of the following agents: the free radical scavengers dimethylsulfoxide (4 g/kg every 6 h) or dimethylthiourea (200 mg/kg every 12 h), the glutathione donor, N-acetylcysteine (130 or 200 mg/kg every 6 h), or the anti-tumor necrosis factor-alpha agents pentoxifylline (100 and 200 mg/kg) and soluble tumor necrosis factor receptor (100 or 1000 microg/rat). The nitric oxide synthase inhibitor N-mono-methyl arginine ester (L-NAME, 0.1 mg/ml) was administered in the drinking water, starting 7 days prior to thioacetamide administration.Serum levels of liver enzymes, blood ammonia and prothrombin time and the stage of hepatic encephalopathy were significantly improved in rats treated with dimethylsulfoxide or dimethylthiourea compared to the other treatment groups (p0.001). Liver histology and the survival rate in these rats were not adversely affected by thioacetamide administration (p0.001), while in all the other treatment groups those parameters were similar to control rats with fulminant hepatic failure. Furthermore, dimethylsulfoxide ameliorated liver damage and improved survival even when its administration was initiated 8 and 16 h after the first thioacetamide injection. The hepatic concentration of methanesulfinic acid, which is produced after direct interaction of dimethylsulfoxide with hydroxyl radicals, was increased five-fold in rats treated with thioacetamide+dimethylsulfoxide (p0.001), suggesting a role for hydroxyl radical scavenging in the protection from fulminant hepatic failure in this model. In the group of thioacetamide-treated rats that were pretreated with L-NAME, liver enzymes, blood ammonia levels and the mortality rate were higher than in the control group, treated with thioacetamide only.In thioacetamide-induced fulminant hepatic failure, the hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea prevent liver injury. Neither N-acetylcysteine nor antagonists of tumor necrosis factor-alpha are protective in this rat model. Inhibition of nitric oxide formation aggravates liver damage and reduces the survival of rats with thioacetamide-induced liver damage.