TL1A as a Potential Local Inducer of IL17A Expression in Colon Mucosa of Inflammatory Bowel Disease Patients.

Interaction between TL1A and death receptor 3 (DR3) co-stimulates T cells, induces production of several pro-inflammatory cytokines and has been linked to pathogenesis of inflammatory bowel disease (IBD). This study aimed to establish a link between expression of TL1A and selected TL1A-induced pro-inflammatory cytokines involved in IBD pathogenesis (IL-4, IL-13, IL-17A and IFN-γ) and to investigate a connection between serum concentration of TL1A in patients with IBD and activation of peripheral blood T cells. Elevated levels of IL-4 (2.91-fold) and IL-13 (4.05-fold) mRNA were detected in the inflamed colon mucosa of patients with ulcerative colitis (UC), IFN-γ mRNA was upregulated (3.23-fold) in the inflamed colon mucosa of patients with Crohn's disease (CD), whereas upregulation of IL-17A and TL1A mRNA was present in the inflamed colon mucosa of patients with both CD and UC (IL-17A: 4.48-fold and 2.74-fold, TL1A: 3.19-fold and 3.22-fold, respectively) vs. control subjects. We did not detect any changes in DR3 mRNA expression in the investigated groups of patients. TL1A mRNA level in colon mucosa of patients with IBD correlated only with the level of IL-17A mRNA but no other investigated cytokines. In colon mucosa, expression of TL1A and DR3 was localized to enterocytes and lamina propria mononuclear cells. We did not find any correlation between serum concentrations of TL1A and IL-17A or changes of CD4(+) or CD8(+) lymphocytes phenotype in patients with IBD. Therefore, our data indicate that TL1A may contribute to pathogenesis of IBD via local but not systemic induction of IL-17A but not IL-4, IL-13 or IFN-γ.

Role of melatonin in mucosal gastroprotection against aspirin-induced gastric lesions in humans.

Melatonin and its precursor, l-tryptophan, have been shown to exert gastroprotective effects in animals, but their influence on the gastric damage by aspirin (ASA) in humans has been sparingly investigated. In this study, we designed to determine the effects of melatonin and l-tryptophan on ASA-induced gastric mucosal damage, gastric microbleeding, mucosal generation of prostaglandin E(2), and plasma melatonin, and gastrin levels. Three groups of healthy male volunteers (n = 30) with intact gastric mucosa received daily for 11 days either ASA alone or that combined with melatonin or tryptophan. Gastric blood loss and mucosal damage were evaluated at 3rd, 7th, and 11th days of ASA administration by endoscopy using Lanza score. ASA alone caused a marked rise of gastric damage and gastric blood loss, mainly at day 3rd and 7th, but they were significantly reduced at 11th day. Pretreatment with melatonin or tryptophan remarkably reduced ASA induced gastric lesions and microbleeding. Gastric mucosal generation of PGE(2) was suppressed by about 90% in all subjects treated with ASA alone without or with addition of melatonin or tryptophan. Plasma melatonin was markedly increased after treatment with melatonin or tryptophan plus ASA, but it was also raised significantly after application of ASA alone. Plasma gastrin levels were raised in subjects given melatonin or tryptophan plus ASA, but not in those with ASA alone. We conclude that melatonin and its precursor tryptophan given orally significantly reduce gastric lesions induced by ASA possibly due to (a) direct gastroprotective action of exogenous melatonin or that generated from tryptophan and (b) gastrin released from the gastric mucosa by melatonin or tryptophan.

Altered basal and postprandial plasma melatonin, gastrin, ghrelin, leptin and insulin in patients with liver cirrhosis and portal hypertension without and with oral administration of melatonin or tryptophan.

This investigation was designed to assess the effects of oral administration of melatonin (10 mg) and tryptophan (Trp) (500 mg) on fasting and postprandial plasma levels of melatonin, gastrin, ghrelin, leptin and insulin in 10 healthy controls and in age-matched patients with liver cirrhosis (LC) and portal hypertension. Fasting plasma melatonin levels in LC patients were about five times higher (102 +/- 15 pg/mL) than in healthy controls (22 +/- 3 pg/mL). These levels significantly increased postprandially in LC patients, but significantly less so in controls. Treatment with melatonin or L-Trp resulted in a further significant rise in plasma melatonin, both under fasting and postprandial conditions, particularly in LC patients. Moreover, plasma gastrin, ghrelin, leptin and insulin levels under fasting and postprandial conditions were significantly higher in LC subjects than in healthy controls and they further rose significantly after oral application of melatonin or Trp. This study shows that: (a) patients with LC and portal hypertension exhibit significantly higher fasting and postprandial plasma melatonin levels than healthy subjects; (b) plasma ghrelin, both in LC and healthy controls reach the highest values under fasting conditions, but decline postprandially, especially after oral application of melatonin or Trp; and (c) plasma melatonin, gastrin, ghrelin and insulin levels are altered significantly in LC patients with portal hypertension compared with that in healthy controls possibly due to their portal systemic shunting and decreased liver degradation.

Therapeutic endoscopy in gastroenterology.

The role of therapeutic endoscopy in current gastroenterology is very important. Therapuetic endoscopy is useful in treatment of gastrointestinal bleeding. Endoscopic control of gastrointestinal bleeding includes the following procedures of haemostasis techniques: photocoagulation, electrocoagulation, thermocoagulation and injection method. Owing to these procedures mortality has significantly decreased. Endoscopic hemostasis eliminates the risk of surgery, is less expensive and better tolerated by patients. Colonoscopic polypectomy is a widely used technique. By removal of polyps the incidence of colon cancer can be decreased. The "hot biopsy" forceps can be used to excise polyps of up to 6 mm. Larger polyps can be removed safely by snare electrocautery and retrieved for histologic study. Endoscopic retrograde cholangiopancreatography has a therapeutic application designed to cut the sphincter of Oddi fibers of the distal common bile duct, what is indicated currently in choledocholithiasis and papillary stenosis with ascending cholangitis, acute gallstone pancreatitis. Endoscopic sphincterotomy in now an established procedure that is indicated in patients with common bile duct calculi. Endoscopic decompression of the biliary tree - dilatation benign structures of the biliary tree with baloon catheters and placement an internal endoprothesis allows the nonoperative decompression and significant palliation for patients with obstructing tumors.

Genetic polymorphism of alcohol dehydrogenase 3 in digestive tract alcohol damage.

BACKGROUND/AIMS: Genetic polymorphism of enzymes involved in alcohol metabolism plays a relevant role in etiopathogenesis of alcohol disease. The aim of the present study was to find in the Polish population the ADH3 genotypes, which are likely to be responsible for higher susceptibility to alcohol disease of the liver and chronic alcohol pancreatitis. METHODOLOGY: The ADH3 genotype and ADH3*1 and ADH3*2 alleles frequency were examined in 266 patients. Genotyping of the ADH3 was performed using polymerase chain reaction-restriction fragment length polymorphism methods on white cell DNA. RESULTS: The genotype ADH3*1/ADH3*1 was found to be significantly more frequent in alcohol abusers compared to non-drinkers. The examinations of the group of alcohol abusers showed that the genotype ADH3*2/ADH3*2 occurred statistically significantly less frequently in patients with chronic pancreatitis than those without alimentary lesions and patients with cirrhosis. Thus it is likely to be the protective factor of chronic pancreatitis. CONCLUSIONS: The alleles ADH3*1 and genotype ADH3*1/ADH3*1 were significantly more frequent in men than in women, while alleles ADH3*2 and genotype ADH3*2/ADH3*2 were more common in women. This may account for rarer alcohol addiction observed in Polish women.

The effect of the angiotensin II receptor, type 1 receptor antagonists, losartan and telmisartan, on thioacetamide-induced liver fibrosis in rats.

It has been reported previously that the density of angiotensin II receptors is increased in the rat liver in experimentally-induced fibrosis. We hypothesized that pharmacological blockade of angiotensin receptors may produce beneficial effects in models of liver fibrosis. In this study, we used the widely used thioacetamide (TAA)-induced model of liver fibrosis (300 mg/L TAA ad libitum for 12 weeks). Rats received daily injections (i.p), lasting 4 weeks of the angiotensin II type 1 receptor antagonists, losartan 30 mg/kg (TAA + L) or telmisartan 10 mg/kg (TAA + T) and were compared to rat that received TAA alone. Chronic treatment with losartan and telmisartan was associated with a significant reduction in the activity of alkaline phosphatase, and decreased concentrations of tumor necrosis factor-alpha and transforming growth factor beta-1 compared to controls. We also found a significant reduction interleukin-6 in rats receiving telmisartan (P < 0.05) but not losartan. Both treatments increased the concentration of liver glutathione along with a concomitant decrease of GSSG compared to controls. In addition, increased paraoxonase 1 activity was observed in the serum of rats receiving telmisartan group compared to the TAA alone controls. Finally, histological evaluation of liver sections revealed losartan and telmisartan treatment was associated with reduced inflammation and liver fibrosis. Taken together, these results indicate that both telmisartan and losartan have anti-inflammatory and anti-oxidative properties in the TAA model of liver fibrosis. These finding add support to a growing body of literature indicating a potentially important role for the angiotensin system in liver fibrosis and indicate angiotensin antagonists may be useful agents for fibrosis treatment.

Effects of renin-angiotensin system inhibitors on fibrosis in patients with alcoholic chronic pancreatitis.

Chronic pancreatitis (CP) results in impairment of exocrine as well as endocrine functions and progressive fibrosis. Previous studies, have demonstrated the presence of renin-angiotensin system receptors within different pancreatic cells. The aim of the present study was to assess the effects of renin-angiotensin system (RAS) inhibitors on serum levels of fibrosis biomarkers (matrix metalloproteinase 2 and 9 (MMP-2, MMP-9), tissue inhibitor of MMP (TIMP- 1, TIMP-2), hyaluronic acid (HA)) and fasting glucose levels in patients with alcoholic CP. Seventy seven outpatients (mean age 43 years, 62 males) with diagnosed alcoholic CP were randomly enrolled into 5 study groups depending on the RAS inhibitors administered and their doses (2.5 or 5 mg and 12.5 or 25 mg for ramipril or losartan, respectively). Venous blood was sampled monthly for a period of one year to monitor serum drug levels. MMP-2, -9, TIMP-1, TIMP-2 and HA were measured with ELISA method on the onset and at the end of the study. Only forty five patients regularly participated in follow-up visits and completed the study. The fluctuations in serum HA levels observed among patients from the remaining groups also did not reach statistical significance. Serum MMP-2 levels (P = 0.06) and MMP-2/TIMP-1 ratio (P = 0.06) showed increasing tendency in the losartan 25 mg group. High doses of ramipril and losartan statistically significantly reduced fasting glucose levels. High doses of losartan can increase the MMP-2 activity in serum of alcoholic CP patients, which potentially is likely to affect turnover of extracellular matrix proteins within the pancreas. Moreover, high doses of both RAS inhibitors decrease the fasting glucose level.

Protective effects of melatonin against thioacetamide-induced liver fibrosis in rats.

The aim of this study was to determine the effect of melatonin on thioacetamide (TAA) induced liver fibrosis in rats. The antifibrotic effects of melatonin were assessed by determining activity indirect markers of fibrosis: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), and proinflammatory cytokines: interleukin 6 (IL-6), interleukin-1beta (IL-1ß), tumour necrosis factor alpha (TNF-α), transforming growth factor-beta (TGF-ß) and platelet-derived growth factor (PDGF). Parameters of oxidative stress: oxidised glutathione (GSSG), reduced glutathione (GSH) and presaged activity of paraoxonase 1 (PON-1), an antioxidative enzyme were determined. Inflammatory changes and fibrosis extent were evaluated histologically. Experiments were carried out in Wistar rats. Animals were divided into 4 groups: I - controls, water ad libitum for 12 weeks, group II - TAA, 300 mg/L ad libitum for 12 weeks, III - melatonin, 10 mg/kg b.w. intraperitoneally (i.p.) daily for 4 weeks, IV - TAA, 300 mg/L ad libitum for 12 weeks followed by melatonin, 10 mg/kg/b.w. i.p. daily for 4 weeks. Results of serum determinations demonstrated significantly lower activity of AST, ALT and AP in the group receiving TAA followed by melatonin compared to the group receiving only TAA. Immunoenzymatic findings on effect of melatonin on concentration of proinflammatory cytokines confirmed these data. Biochemical examinations in liver homogenates revealed statistically significant improvement (concentration of GSH increases and concentration of GSSG decreases) in animals with TAA-induced liver damage receiving melatonin. Moreover, the activity of PON-1 toward phenyl acetate and paraoxon was increased in liver homogenates and serum in the group receiving TAA followed by melatonin compared to the TAA group without melatonin treatment. Microscopic evaluation disclosed inhibitory effects of melatonin on inflammatory changes and extent of liver fibrosis.

The effect of caerulein-induced acute pancreatitis on the levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in various rat tissues.

The effects of caerulein-induced acute pancreatitis (AP) on the levels of 5-HT and 5-HIAA in pancreas, liver, brain, kidney and different parts of the digestive tract in rats have been studied. The acute pancreatitis was induced by the continuous intravenous infusion of caerulein in the doses of 5 x 10(-6) g/kg/h and 7.5 x 10(-6) g/kg/h for 12 hours, and the 5-HT and 5-HIAA concentrations were determined by the method of Curzon and Green. The changes evoked by caerulein varied qualitatively and quantitatively between organs. The significant decrease of both 5-HT and 5-HIAA was observed in pancreas, liver, brain and kidney while in the stomach there was a significant fall of 5-HT level accompanied by the relevant increase of 5-HIAA level. In the duodenum, an opposite effect was noticed, the level of 5-HT was higher than normal whereas the 5-HIAA level was reduced. The significant decrease of the 5-HT and 5-HIAA levels in pancreas observed in the present study suggests the importance of 5-HT in the development of acute pancreatitis.

Enkephalinase activity in the intestinal epithelial cells of the fetus of 19 days and their immortalized and transformed counterparts the SLC-cell lines.

Enkephalinase (EC 3.4.24.11), an enzyme widely distributed in brain and peripheral tissues of human and various animal species, was measured in the intestinal fetal cells and in the intestinal epithelial cells of adult rat, where its activity was respectively 96,1 +/- 10,18 fmol/mg protein and 52,27 +/- 8,43 fmol/mg protein. The immortalized cell lines: SLC-11 (after transfection with the plasmid containing oncogene from the human adenovirus type 2-E1A), SLC-21 (plasmid containing oncogene from polyoma virus) and SLC-41 (plasmid containing oncogene from simian virus 40 large tumor antigen) presented relatively strong enkephalinase activity; it was respectively 28,3 +/- 1,7, 37,9 +/- 3,6 and 49,3 +/- 3,1 fmol/mg protein. The cells of SLC-12T and SLC-44T lines, obtained after transfection with the mutant Ha-ras-1-gene and possessing tumorigene potency have the enkephalinase activity very decreased: 1,6 +/- 0,9 and 8,7 +/- 3,2 fmol/mg protein (p < 0,001). This interesting properties of the tumorigene cells may constitute a new subject of investigations in the carcinomas therapy.

Ultrastructural studies of daunorubicin hepatotoxicity in rats including protective effects of tocopherol and ascorbic acid.

The Wistar rats were treated with daunorubicin in the doses corresponding to average doses administered in humans. Analysis under TEM concerned changes in hepatocytes induced by the drug. The changes were compared with those observed in the liver when daunorubicin administration followed protective administration of tocopherol (vitamin E) and ascorbic acid (vitamin C) and when daunorubicin was given simultaneously with tocopherol and ascorbic acid. The results showed nucleus heterochromatin scattering, segregation of nucleolus granular and fibrillar components, swelling of mitochondria and myelin structures in them, segmental degranulation of rough endoplasmic reticulum and decreased number of glycogen granules. The studies led to the conclusion that daunorubicin hepatotoxicity was blunted in animals receiving simultaneously vitamin E and C, which indicates to assume that those antioxidants exert some protective effect on hepatocytes. Normalization of the changes 3 weeks after administration of the last dose suggests that most of the changes are reversible and do not result in chronic liver damage.

[Activity of enkephalinase (EC.3.4.24.11). Neutral endopeptidase (NEP)in human digestive tract epithelial cells]. / Aktywnosc enkefalinazy (EC. 3.4. 24. 11). Neutralnej endopeptydazy (NEP) w komórkach nablonka przewodu pokarmowego czlowieka.

The activity was studied of enkephalinase (endopeptidase 24.11, neutral endopeptidase)--a membrane enzyme of epithelial cells within human digestive tract (in the stomach, duodenum, small intestine, ascending, descending and sigmoid colon, and rectum). The enzyme activity was determined by column method using the labelled substrate (H-D-AlaLeu)--enkephalin and the selective enkephalin inhibitor--thiorfan in the presence of bestatin and captopril--inhibitors of aminopeptidases and angiotensin converting enzyme respectively. The highest enkephalinase activity was found in the duodenal epithelium (77.3 8.0 fmol of the substrate/min/mg of protein) and in the small intestine (23.4 0.9 fmol/min/mg of protein) with its gradual decrease when progressing down the gastrointestinal tract. This result confirms the hypothesis of enkephalinase participation in protein hydrolysis processes.

Influence of receptor activator of nuclear factor kappa B ligand, osteoprotegerin and interleukin-33 on bone metabolism in patients with long-standing ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic disease with periods of remission and recurrences. Dysfunction of the local immune response leads to chronic inflammation within the large intestine which triggers morphological changes in the intestinal wall as well as induces the synthesis of numerous factors that have an adverse impact on the bone metabolism. The aim of the study was to determine the expression of RANKL, OPG and IL-33 in mucosal biopsies of UC patients with long disease duration as well as serum level of these cytokines in the context of bone density and bone metabolism. MATERIALS AND METHODS: The UC group consisted of 56 patients with average disease duration of 16y. The control group comprised 37 healthy individuals. Local expression of cytokines was assessed in the biopsies of colonic mucosa by the real-time PCR and immunohistochemistry (IHC), and their serum concentration was measured by ELISA. RESULTS: The increased bone resorption observed in patients with UC was reflected by low bone density and high serum level of C-terminal telopeptide (CTX). Mucosal RANKL expression and serum concentration were similar in UC group and healthy subjects, however, UC patients had higher local expression of OPG and serum OPG concentration. Increased IL-33 gene expression was observed only in UC at the mRNA level. We propose that bone resorption in UC patients despite OPG up-regulation could be caused by IL-33-induced mucosal synthesis of a potent proinflammatory cytokine, such as TNF-α, known as a possible inducer of osteoclastogenesis in the way independent of RANKL.

Effects of treatment with melatonin and tryptophan on liver enzymes, parameters of fat metabolism and plasma levels of cytokines in patients with non-alcoholic fatty liver disease--14 months follow up.

Non-alcoholic fatty liver disease (NAFLD), most common chronic hepatic pathology, that occurs in the developed countries is estimated at 1/3 of the population. Amongst the numerous pathogenetic factors, oxidative stress and apoptosis of hepatocytes initiate many inflammatory processes and are involved in the progression of disease, particularly in transformation of non-alcoholic steatohepatitis (NASH) to cirrhosis. The aim of our study was to determine the effects of tryptophan and melatonin on the selected biochemical parameters in patients with NAFLD, and additionally, to evaluate the effects of tryptophan and melatonin in improvement of liver tissue in selected NAFLD patients. Seventy four patients with NAFLD confirmed by histopathological examination of liver biopsy samples, were admitted to the study. They were randomly assigned to three groups. Group I received the preparation Essentiale forte in the dose of 3 x 1 tablet per day and tryptophan 2 x 500 mg/day over the period of 14 months, group II received Essentiale forte and melatonin 2 x 5 mg/day over 14 months and group III received only Essentiale over the period of 14 months. In nine patients of groups I, II, and III, the liver biopsy was performed after 14-months of treatment period. Out of nine patients whom biopsy was performed, three of them were from group I, four from group II and two of them were from group III, respectively. After the 14-month treatment period, gamma-glutamyl transferase (GGPT) activity and levels of triglycerides and LDL-cholesterol were found to be significantly reduced in group I and II. The level of melatonin after the therapy was significantly elevated in group I and II and did not change in group III. Statistically significantly lower levels of IL-1, IL-6 and TNF-α were observed in patients receiving melatonin and tryptophan, comparing with group III treated with Essentiale forte only. These study findings demonstrate that melatonin and tryptophan substantially reduce the levels of pro-inflammatory cytokines and improve some parameters of fat metabolism in patients with NAFLD. In few patients with NASH melatonin and tryptophan reduced the inflammation in liver. We conclude that melatonin is worth considering for the therapy of NAFLD, particularly in patients with impaired fat metabolism accompanied by hypertriglyceridemia and hyper-LDL cholesterolemia.

Comparison of anti-inflammatory properties of peroxisome proliferator-activated receptor gamma agonists rosiglitazone and troglitazone in prophylactic treatment of experimental colitis.

Non-specific inflammatory bowel disease (IBD), including ulcerative colitis and Crohn`s disease, is a chronic noninfectious inflammatory disease whose incidence is increasingly high, especially in the developed countries. Effective methods of its treatment and prevention of recurrences are still under investigation. Amongst the options to control effectively the inflammatory processes of the gastrointestinal tract are thiazolidinediones - peroxisome proliferator-activated receptors gamma (PPAR-γ) agonists, whose beneficial effects on macroscopic and histopathological features of colitis have been confirmed in numerous studies. In the present study, possible effects of PPAR-γ agonists rosiglitazone and troglitazone enhancing the resistance of colonic tissues to the damaging factor were examined and compared. Rats received the food with 0.01% rosiglitazone or troglitazone for 4 weeks; during the final 2 weeks, colitis-inducing 1.5% DSS (dextran sodium sulfate) was additionally administered in the drinking water. The large intestine specimens were microscopically evaluated and the levels of Th1- (IL-2, INF) and Th2-dependent (IL-4, IL-10) cytokines were determined in the serum and intestinal homogenates. Prophylactic treatment with rosiglitazone and troglitazone ameliorated colitis substantially down-regulating the microscopic inflammatory parameters. Rosiglitazone and troglitazone administered before the induction of colitis exerted comparable effects on colitis. Both substances significantly reduced the levels of pro-inflammatory cytokines and increased the levels of inflammation-limiting cytokines. We conclude that thiazolidinedione drugs are likely to be successfully used for therapy and prevention of non-specific bowel diseases.

Comparison of the anti-inflammatory and therapeutic actions of PPAR-gamma agonists rosiglitazone and troglitazone in experimental colitis.

Non-specific inflammatory bowel diseases, including ulcerative colitis and Crohn`s disease, are chronic non-infectious diseases that showed an increase in prevalence in recent years, particularly in the developed countries. The effective methods of their treatment and prevention of recurrences are currently under investigation. One type of therapy that can prevent the inflammatory recurrence in the gastrointestinal tract is the PPAR-γ agonists thiazolidinediones. Numerous studies available in literature have confirmed the beneficial effects of thiazolidinediones (glitazones), namely rosiglitazone and troglitazone in the gut. The objective of the present study was to compare the possible effects of rosiglitazone 10 mg/kg b.w. or 30 mg/kg b.w. and troglitazone 30 mg/kg b.w. on experimental colitis induced by administration of 1.5% dextran sodium sulphate (DSS) administered in drinking water to rats. Specimens collected from the large intestine were microscopically evaluated, and concentrations of Th1- dependent (IL-2, INF) and Th2-dependent (IL-4, IL-10) cytokines were determined in the serum and intestinal homogenates. Both rosiglitazone and troglitazone have demonstrated significant anti-inflammatory properties. This observation was confirmed by histopathological and immunoenzymatic tests. The therapeutic efficacy of rosiglitazone was dose-dependent. Troglitazone resulted in significantly stronger enhancement of anti-inflammatory cytokine expression than rosiglitazone and comparable downregulation of pro-inflammatory cytokine expression compared to rosiglitazone used in a higher dose.

Can we expect progress in the treatment of fibrosis in the course of chronic pancreatitis?

Chronic pancreatitis (CP) is a necroinflammatory process characterized by loss of both exocrine and endocrine function. To date, the disease has been treated symptomatically. Real advances in CP management can be expected once the pathophysiology of the disease is elucidated and individual stages of its development are properly managed. A key role in the CP pathogenesis is played by activation of pancreatic stellate cells (PSCs) that cooperate with the remaining pancreatic cells. All these cells produce cytokines, growth factors, angiotensin and other substances, which paracrinally or autocrinally induce further, persistent activation of PSCs. The activated PSCs are capable of producing and modifying the extracellular matrix. An optimal therapeutic preparation should exert beneficial effects on all the above-mentioned phenomena observed in CP. The most promising treatment modalities include blocking of the renin-angiotensin system (RAS), activation of peroxisome proliferator-activated receptors gamma (PPAR-γ), influence on the remaining PSC signaling pathways, blocking of substances produced by activated PSCs, and antioxidants. The findings of many recent experimental studies are highly encouraging; however, their efficacy should be confirmed in well-designed clinical trials.

Effects of melatonin and tryptophan on healing of gastric and duodenal ulcers with Helicobacter pylori infection in humans.

Melatonin (MT) and its precursor L-tryptophan (TRP) are implicated in the protection of gastric mucosa against aspirin-induced lesions and in the acceleration of healing of idiopathic gastro-duodenal ulcers, but no information is available whether these agents are also effective in healing of gastroduodenal ulcers accompanied by Helicobacter pylori (H. pylori) infection. In this study three groups A, B and C, each including 7 H. pylori-positive patients with gastric ulcers and 7 H. pylori-positive patients with duodenal ulcers, aging 28-50 years, were randomly assigned for the treatment with omeprazole 20 mg twice daily combined with placebo (group A), MT administered in a dose of 5 mg twice daily (group B) or TRP applied in a dose of 250 mg twice daily (group C). All patients underwent routine endoscopy at day 0 during which the gastric mucosa was evaluated and gastric biopsies were taken for the presence of H. pylori and histopathological evaluation. The rate of ulcer healing was determined by gastroduodenoscopy at day 0, 7, 14 and 21 after the initiation of the therapy. Plasma MT, gastrin, ghrelin and leptin were measured by specific RIA. At day 21, all ulcers were healed in patients of groups B and C but only 3 out of 7 in group A of gastric ulcers and 3 out of 7 in duodenal ulcers. Initial plasma MT showed similar low levels in all three groups but it increased several folds above initial values in ulcer patients at day 7, 14 and 21. Plasma gastrin and leptin levels showed a significant rise over initial values in patients treated with omeprazole and placebo, MT or TRP while plasma ghrelin levels were not significantly affected by these treatments. We conclude that MT or TRP added to omeprazole treatment, significantly accelerates healing rate of H. pylori infected chronic gastroduodenal ulcers over that obtained with omeprazole alone and this likely depends upon the significant rise in plasma MT and possibly also in leptin levels, both hormones involved in the mechanism of gastroprotection and ulcer healing.

Prevalence of spontaneous bacterial peritonitis in asymptomatic inpatients with decompensated liver cirrhosis - a pilot study.

PURPOSE: To assess the prevalence of spontaneous bacterial peritonitis (SBP) in asymptomatic patients with decompensated liver cirrhosis. MATERIAL AND METHODS: Patients (pts) with symptoms of decompensation of liver cirrhosis, ascites, and no signs indicating SBP were included to our study. Exclusion criteria include: 1/ clinical symptoms of infection, 2/ developing de novo or worsening hepatic encephalopathy, 3/ gastrointestinal bleeding within the last month, 4/ renal failure, 5/ antibiotic treatment or norfloxacin prophylaxis at admission. About 60 ml of ascitic fluid were drawn for lab examination. Pathologic assessment for atypical cells was also performed. RESULTS: 37 patients fulfilled inclusion criteria. Their mean age was 56.2 ± 12.1. The Child-Pugh classification revealed 13 (35.1%) patients of class B and 24 (64.9%) patients of class C. The mean Model for End-Stage Liver Disease score in this group was 16.6 ± 6.8. The mean ascitic protein content was 1.85 ± 1.09 g/dL and mean neutrophil count 144.8 ± 445.1/mm3. Ascitic fluid analysis revealed: signs of bacterascites in 6 of 37 (16.2%) pts; neutrocytic ascites in 1 of 37 (2.7%) pts; and 2 of 37 (5.4%) pts met criteria for SBP. C-reactive protein level was the best predictor of infection [SBP(+) 47.9 ± 40.9 versus SBP(-) 11.7 ± 5.1; p= 0.0005]. CONCLUSIONS: The prevalence of SBP in asymptomatic cirrhotics with ascites is low. We observed the trend towards more frequent occurrence of the infection in patients suffered from severe liver disease (Child-Pugh C group).