Occurrence of diffuse, poorly differentiated hepatocellular carcinoma during pegylated interferon plus ribavirin combination therapy for chronic hepatitis C.

Interferon therapy is indicated for the treatment of chronic hepatitis C and prevention of hepatocellular carcinoma. We describe the case of a 66-year-old Italian woman who received pegylated interferon alpha-2a plus ribavirin combined therapy for HCV-related chronic liver disease. Preliminary hematochemical, ultrasound and bioptic investigations did not show liver cirrhosis or hepatocarcinoma. After 24 weeks of treatment transaminase serum levels were in the normal range and circulating HCVRNA was undetectable by PCR qualitative assay. On week 46 a serious adverse event occurred, with rapid transaminase increase, severe hyperpyrexia, and abdominal pain, leading to interruption of interferon and ribavirin. Liver biopsy was repeated and it revealed poorly differentiated hepatocellular carcinoma. Only palliative care could be performed and the patient died of liver failure within 2 months. The present case underlines that hepatocellular carcinoma can be misdiagnosed in spite of laboratory and instrumental follow-up. More sensitive tools are needed for tumor detection, to avoid IFN impairment of the liver, even though it eradicates HCV.

Leisure time but not occupational physical activity significantly affects cardiovascular risk factors in an adult population.

BACKGROUND: A large number of studies have demonstrated that regular physical activity during leisure time (LTPA) accounts for a significant protection against cardiovascular diseases (CVD). On the other hand, conflicting findings on the beneficial effects of occupational physical activity (OPA) have been reported. The aim of this study is to evaluate the possible influence of different amounts of LTPA and OPA on circulating levels of several parameters associated with an increased risk of CVD. MATERIALS AND METHODS: We studied 932 individuals (365 M; 567 F, with a mean age of 54 years) living in Florence, Italy, who were enrolled in a population study conducted between 2002 and 2004. Subjects were divided into three classes of LTPA and OPA according to a score derived from a questionnaire that assessed the amount of physical activity performed. RESULTS: LTPA was inversely related to body mass index (BMI), hip circumference, diastolic blood pressure and triglycerides, as well as directly correlated with high-density lipoprotein (HDL) cholesterol. Likewise, a higher OPA was found to be associated with higher HDL cholesterol levels. Moreover, a multivariate logistical regression analysis, adjusted for possible confounders, showed that a moderate-to-high intensity of LTPA was able to confer a significant protection against having abnormal levels of BMI, waist circumference and triglycerides, main features of the metabolic syndrome, whereas no associations between these parameters and OPA were observed. CONCLUSIONS: A moderate-to-high LTPA was found to be significantly associated with a more favourable cardiovascular risk profile in terms of anthropometric, metabolic and lipid parameters among an Italian population. In addition, a relationship between OPA and HDL-cholesterol was reported.

Human gastric epithelium produces IL-4 and IL-4delta2 isoform only upon Helicobacter pylori infection.

Recent evidence suggests that interleukin-4 (IL-4) is related to mucosal tolerance by which an injurious immune response is prevented, suppressed or shifted to a non-injurious response. We investigated the expression of IL-4 and its splice variant isoform IL-4delta2 in gastric epithelial cells of healthy subjects and gastritis patients infected with Helicobacter pylori (H. pylori) with or without the cag pathogenicity island (cag-PAI). IL-4 and IL-4delta2 mRNAs were evaluated in microdissected gastric epithelium and in AGS cell lines co-cultured with H. pylori B128 or SS1 strains. IL-4 mRNA was consistently detected in microdissected gastric epithelial cells from healthy subjects. The IL-4 mRNA expression was low in H. pylori?infected patients, and markedly reduced in cag-PAI-positive ones. IL-4delta2 mRNA was expressed on gastric epithelium of H. pylori-infected patients, but not in healthy subjects. The IL-4delta2 expression was lower in cag-PAI-positive than in cag-PAI-negative H. pylori infected patients. AGS cells also produced IL-4 mRNA upon SS1 strain stimulation, whereas IL-4delta2 mRNA expression was detected in AGS co-cultured with either SS1 or B128 strains. An inverse correlation was documented between IL-4 and IL-4delta2 mRNA expression by microdissected gastric epithelial cells and the score of gastritis. IL-4, but not IL-4delta2, is expressed by gastric epithelium of healthy subjects, whereas IL-4delta2 and lesser IL-4 mRNA are detectable in the gastric epithelium of H. pylori-infected patients. Data suggest that gastric epithelial cells might regulate the balance between tolerance and immune response by the fine tuning of IL-4 and IL-4delta2 expression.

Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study.

BACKGROUND: Recent studies suggest a role of n-3 long-chain polyunsaturated fatty acids (n-3 PUFA) as peroxisome proliferator-activated receptor-alpha ligands in improving non-alcoholic fatty liver disease (NAFLD) in rodents. However, data in humans are still lacking. AIM: To evaluate the efficacy of prolonged PUFA supplementation in patients with NAFLD. METHODS: Fifty-six patients with NAFLD were enrolled. Among the overall eligible patients, 42 assumed n-3 PUFA 1-g capsule daily for 12 months, whereas 14 refused the treatment and were analysed as controls. All patients underwent haematochemical and ultrasound follow-up. RESULTS: Polyunsaturated fatty acid supplementation significantly decreased serum aspartate transaminase (P = 0.003), alanine transaminase (P = 0.002), gamma-glutamyl transpeptidase (P = 0.03), triglycerides (P = 0.02) and fasting glucose (P = 0.02) in comparison with controls. Circulating arachidonate and n-6/n-3 fatty acid ratio was reduced (P = 0.0002, and P = 0.0001 respectively) in treated patients. Moreover, ultrasonography demonstrated improvement of liver echotexture after PUFA (P = 0.0001), and increase of Doppler perfusion index (P = 0.001), whereas no significant changes occurred in controls. CONCLUSIONS: Supplementation with n-3 PUFA improves biochemical, ultrasonographic and haemodynamic features of liver steatosis. Our study supports the efficacy of n-3 PUFA as a new therapeutic approach in the treatment of NAFLD.

Dietary habits, lifestyle and cardiovascular risk factors in a clinically healthy Italian population: the 'Florence' diet is not Mediterranean.

OBJECTIVE: To evaluate dietary habits and lifestyle of Italian subjects, to provide current data on adequacy of the nutritional guidelines and recommendations especially in relation to primary prevention of cardiovascular diseases and to assess the influence of dietary habits on lipid profile and homocysteine levels. DESIGN: Cross-sectional. SETTING: Population-based study. SUBJECTS: A sample of 520 clinically healthy subjects (211 males, 309 females) with a mean age of 46 y, living in Florence area, Italy. INTERVENTIONS: Dietary pattern was assessed by trained dietitians through a semiquantitative food questionnaire. Fasting blood samples were drawn for assessment of lipid profile, homocysteine and circulating vitamins. RESULTS: Contribution from total fats was over 30% in about 70% of subjects and intake of saturated fatty acids (SFA) was above the recommended values in at least 40% of the study population. Furthermore, almost the whole (99.6%) population reported low intake of polyunsaturated fatty acids (PUFA). High levels of total cholesterol were present in over 40% of the study population, whereas abnormal values of LDL-cholesterol were observed in about 30%. High levels of homocysteine were found in 11.7% of the study population. An extremely high percentage of subjects reported low intake of vitamins, especially with regard to folic acid (89%), vitamin B(6) (70.1%) and vitamin E (99.6%). In a multiple linear regression model, circulating levels of vitamin B(12) and folic acid, and intake of alcohol and vitamin C resulted in being independently associated with homocysteine plasma levels. CONCLUSIONS: In a typical Mediterranean country, general outlines of Mediterranean diet are not completely followed, especially concerning total fats, SFA, PUFA and vitamins' intake. SPONSORSHIP: Ministero della Salute (Italy) - 'Progetto per la Salute e la Prevenzione di Malattia' 2001-2003.

Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms.

BACKGROUND/AIMS: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of some epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferators activated receptor gamma (PPARgamma) the mechanism by which TZD exert their anticancer effect is currently unclear. Furthermore, the effect of TZD on local motility and metastatic potential of cancer cells is unknown. The authors analysed the effects of two TZD, rosiglitazone and pioglitazone, on invasiveness of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: Expression of PPARgamma in human pancreatic adenocarcinomas and pancreatic carcinoma cell lines was measured by reverse transcription polymerase chain reaction and confirmed by western blot analysis. PPARgamma activity was evaluated by transient reporter gene assay. Invasion assay was performed in modified Boyden chambers. Gelatinolytic and fibrinolytic activity were evaluated by gel zymography. RESULTS: TZD inhibited pancreatic cancer cells' invasiveness, affecting gelatinolytic and fibrinolytic activity with a mechanism independent of PPARgamma activation and involving MMP-2 and PAI-1 expression. CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth and invasiveness suggesting that these drugs may have application for prevention and treatment of pancreatic cancer in humans.

Molecular mechanisms of alcohol-induced liver injury. An Update.

Alcoholic liver disease has a known etiology but a complex pathogenesis. The understanding of how alcohol damages the liver has expanded substantially over the last decade. In particular the genesis of fatty liver, the effect of the metabolites of ethanol oxidation, the interaction between endotoxin and kupffer cells, and the genetic predisposition to develop severe liver disease have been the focus of a great deal of research. Recent studies have demonstrated that in addition to the altered redox state ethanol induced lipid accumulation by altering the expression and transcriptional regulation of nuclear receptors such as peroxisome proliferator-activated receptor a and sterol regulatory element binding protein 1 which are involved in the expression of enzymes regulating lipid metabolism. Aldehydes generated by ethanol oxidizing pathways are involved in several toxic effects of alcohol by forming protein adducts which are responsible for activation of specific intracellular signaling pathways which modulate collagen synthesis and inflammatory response. This latter effect was also coordinated by kupffer cells, which are activated by portal vein endotoxin to release cytokines and chemokines. These actions appear to be in part dependent on genetic factors including polymorphism of genes belonging to ethanol metabolizing enzymes and to inflammatory/immune response. These complex pathways leading to liver injury offer many targets for potential therapeutic approaches.

Regression of duodenal gastric metaplasia in Helicobacter pylori positive patients with duodenal ulcer disease.

BACKGROUND: It is unclear whether the extent of duodenal gastric metaplasia is due to Helicobacter pylori and/or acid. AIMS: To investigate the role of Helicobacter pylori eradication in the regression of duodenal gastric metaplasia in patients with duodenal ulcer maintained in acid suppression conditions. METHODS: . Duodenal (anterior, superior inferior walls of first part of duodenum) and gastric antrum biopsies were obtained from 44 Helicobacter pylori positive duodenal ulcer patients. Helicobacter pylori infection was diagnosed by rapid urease test, histology and 13C-Urea Breath Test. Patients were treated with 20 mg omeprazole tid associated with 250 mg clarithromycin and 500 mg amoxycillin four times daily for 10 days and maintained with 20 mg omeprazole daily for 18 weeks. Control endoscopies were performed at 6 and 18 weeks after beginning treatment. RESULTS: Duodenal gastric metaplasia regression was observed in all (32/32) patients in whom Helicobacter pylori was eradicated, but in only 3 out of 6 patients in whom eradication was not achieved (p<0. 001). CONCLUSIONS: . The present results suggest that Helicobacter pylori eradication associated with prolonged acid suppression may represent a good therapeutic strategy to achieve duodenal gastric metaplasia regression and highlight the combined role of acid and Helicobacter pylori in the pathogenesis of duodenal gastric metaplasia.

Autonomic nerve dysfunction in pathologically obese patients.

BACKGROUND: Obese patients frequently present clinical symptoms related to gastrointestinal motility alterations and autonomic nervous system dysfunction. AIM: To evaluate the possible correlation between cardiovascular autonomic nervous dysfunction and oesophageal motility in pathologically obese patients. PATIENTS AND METHODS: Enrolled in the study were 22 patients with a body mass index of 45.72 +/- 7.48 and 10 control subjects, all within 20% of their ideal weight. Oesophageal motility was measured by stationary manometry and scintigraphic transit. Tests for the evaluation of autonomic nervous system were: Valsalva ratio, deep breathing, sustained handgrip, sudormotor axon reflex test and spectral analysis of the variability of R-R interval. RESULTS: The mean pressure of oesophageal peristaltic waves in patients and controls was 39.36 +/- 14 mmHg and 73 +/- 12 mmHg, respectively The scintigraphic mean transit time was 22.96 +/- 16.26 seconds in patients and 10.23 +/- 16.26 seconds in controls (p < 0.001). Spectral analysis of the variability of the R-R interval showed an increase in the parasympathetic component both in the lying and standing position compared to controls. The other autonomic nervous system function tests showed no significant difference between obese patients and controls. CONCLUSIONS: These results suggest that obese patients present a reduction of oesophageal transit and autonomic nervous system dysfunction albeit no direct correlation was found between these phenomena.

Substance P (neurokinin-1) and neurokinin A (neurokinin-2) receptor gene and protein expression in the healthy and inflamed human intestine.

Increasing evidence suggests that tachykinins are involved in the control of pathophysiological states, such as inflammation. The precise localization of tachykinin receptors is of paramount importance in the search for their possible physiological and pathological role; in this study, therefore, we attempted to define cellular sites of substance P (NK-1R) and neurokinin A (NK-2R) receptor expression in the healthy and the inflamed human intestine by in situ hybridization and immunohistochemistry. In the normal ileum and colon, NK-1R and NK-2R were localized to smooth muscle cells of the muscularis mucosae and propria and a few inflammatory cells of the lamina propria; NK-1R expression was also found in the muscular wall of submucosal blood vessels, enteric neurons and, to a lesser degree, in surface epithelial cells. Patients with Crohn's disease and ulcerative colitis showed a dramatic increase in NK-1R density relative to controls, in both the inflamed and the uninvolved mucosa. Up-regulation of NK-1R was particularly evident on epithelial cells lining the mucosal surface and crypts, as well as on endothelial cells of capillaries and venules. Also, a marked increase in NK-2R expression was found in both groups of patients on inflammatory cells of the lamina propria, especially eosinophils. Our findings demonstrate that in the normal human intestine NK-1R and NK-2R are expressed in multiple cell types, which are endowed with different physiological functions; in addition, they demonstrate that both NK-1R and NK-2R are up-regulated in patients with Crohn's disease and ulcerative colitis. Taken together, these observations may have important physiological and pathophysiological implications, and provide the rationale for the use of NK-1R and NK-2R antagonists in the treatment of inflammatory bowel disease.

Helicobacter pylori cag pathogenicity island is associated with enhanced interleukin-8 expression in human gastric mucosa.

BACKGROUND: In vitro studies showed that Helicobacter pylori strains carrying the cag pathogenicity island are able to induce epithelial secretion of Interleukin-8. AIMS: To evaluate the assessment of cag pathogenicity island and the expression of Interleukin-8 in the gastric mucosa of Helicobacter pylori-infected patients and correlate these data with the activity of gastritis and Helicobacter pylori density. METHODS: cag status was determined by polymerase chain reaction directly on gastric biopsies from 13 Helicobacter pylori+ patients with non-ulcer dyspepsia and 13 Helicobacter pylori+ with duodenal ulcer. Interleukin-8 gene transcription and protein expression were analysed by in situ hybridization and immunofluorescence, respectively. Gastritis activity and Helicobacter pylori density were also investigated. RESULTS: cag was present in 20/26 of Helicobacter pylori+ patients: in 7/13 non-ulcer dyspepsia (53.8%] and in 13/13 duodenal ulcer patients (100%), (p<0.05). Interleukin-8 mRNA and protein expression in epithelial and inflammatory cells was higher in cag+ than in cag- patients (p<0.005). Gastritis activity significantly correlated with cag (p<0.05) and Interleukin-8 expression (p<0.005]. Helicobacter pylori density was enhanced in cag+ [p<0.005] and correlated with Interleukin-8 expression (p<0.0051. CONCLUSIONS: The present study demonstrates that in Helicobacter pylori-infected human gastric mucosa, cag+ infection is associated with enhanced Interleukin-8 expression, higher levels of active gastritis and bacterial density, and presence of duodenal ulcer.

Collagen type I synthesized by pancreatic periacinar stellate cells (PSC) co-localizes with lipid peroxidation-derived aldehydes in chronic alcoholic pancreatitis.

Chronic alcoholic pancreatitis (CAP) is characterized by progressive pancreatic fibrosis and loss of the acinar cell mass, but the pathogenesis of pancreatic fibrosis in the human is poorly understood. It has been recently suggested that lipid peroxidation-derived aldehydes such as 4-hydroxynonenal (HNE) are involved in tissue damage and fibrosis in other organs. The aim of this study was to evaluate the role of oxidative stress in the development of alcohol-induced pancreatic fibrosis in humans, and to assess the contribution of pancreatic periacinar stellate cells (PSC) in the in vivo synthesis of extracellular matrix components during CAP. Lipid peroxidation was evaluated in tissue specimens obtained from patients with CAP who underwent surgical procedures, by immunohistochemistry using a monoclonal antibody directed against HNE-protein adducts. Immunohistochemical determination of collagen type I, alpha-smooth muscle actin (alpha-SMA), and the beta subunit of human platelet-derived growth factor (PDGF-Rbeta) was also performed. In addition, the tissue mRNA expression of procollagen I, PDGF-Rbeta, and transforming growth factor-beta1 (TGF-beta1) was evaluated by in situ hybridization. In CAP, increased formation of HNE-protein adducts was evident in acinar cells adjacent to the interlobular connective tissue that stained positively for collagen type I. HNE staining was absent in normal pancreas. Several non-parenchymal periacinar cells (PSC) underlay the HNE-stained acinar cells. Those PSC stained positively for alpha-SMA and PDGF-Rbeta and showed active synthesis of procollagen type I by in situ expression of the specific mRNAs. The pattern of expression of PDGF-Rbeta mRNA reflected that observed in immunostaining, showing increased amounts of transcripts in PSC. TGF-beta1 mRNA expression was increased in CAP, but transcripts were found in several cell types including PSC, acinar, and ductal cells. These results indicate that significant lipid peroxidation phenomena occur in CAP and that they are associated with active synthesis of collagen by PSC.

Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells.

During liver injury, hepatic stellate cells (HSC) acquire a myofibroblast-like phenotype associated with reduction of lipid droplets, increased collagen synthesis, and proliferation. Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates adipocyte differentiation and controls gene transcription in response to various activators including prostanoids and antidiabetic thiazolidinediones. We explored whether the presence of PPARgamma and its transcriptional activity were involved in control of HSC proliferation in vitro. PPARgamma ligands, 15-deoxy-triangle up(1214) prostaglandin J(2) (15d-PGJ(2)) and ciglitizone, significantly decrease platelet-derived growth factor (PDGF)-induced proliferation in activated human HSC and inhibit alpha smooth muscle actin (alpha-SMA) expression during HSC transdifferentiation. Treatment with 9-cis retinoic acid (9-cisRA) and LG268, ligands of the heterodimerization partner retinoic X receptor (RXR), had a negligible effect in PDGF-treated cells but caused a further reduction of proliferation when used in combination with ciglitizone. Transfection experiments with a reporter gene consisting of 3 copies of a PPAR response element (peroxisome proliferator response element [PPRE](3)-tk-luciferase) showed a progressive reduction of PPAR transcriptional activity during plastic-induced HSC transdifferentiation. Cotransfection with human PPARgamma expression vector restored the PPRE(3)-tk-luciferase reporter expression and the increased level of the receptor in activated HSC-inhibited cell proliferation in a dose-dependent manner. Incubation of human PPARgamma-cotransfected HSC with PDGF strongly inhibited luciferase activity and this effect was blocked by the inhibition of the mitogen-activated protein (MAP) kinase signal cascade. Our results indicate that depression of PPARgamma expression and activity is involved in HSC proliferation and that the PPARgamma ligand-mediated activation exerts a previously unrecognized inhibition of PDGF-induced mitogenesis in activated human HSC.

Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis.

The pharmacokinetics of dirithromycin were determined over a 72-h period following oral administration of a single 500-mg dose to 8 healthy volunteers and to 16 cirrhotic patients (8 patients with class A cirrhosis and 8 patients with class B cirrhosis according to Pugh's & Child's classification). Drug levels in plasma and urine were determined by microbiological assay. The mean maximum concentrations of drug in serum obtained 3 to 4 h after administration were 0.29 +/- 0.22 mg/liter in volunteers and 0.48 +/- 0.21 and 0.52 +/- 0.38 mg/liter in patients with class A and class B cirrhosis, respectively. The elimination half-life (t1/2beta) was 23.3 +/- 7.6 h in healthy subjects and 35.2 +/- 11.8 h and 39.5 +/- 11.0 h in patients with class A and class B cirrhosis, respectively. The mean area under the concentration-time curve (AUC) and t1/2beta were significantly higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced (P < 0.01). The time to the maximum concentration of drug in serum and the volume of distribution values appeared to be similar in all groups, and the mean recovery in urine at 72 h ranged from 3.7 to 5.7%, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, an increase in the t1/2beta or AUC, which is also observed with other semisynthetic macrolides (e.g., azithromycin), does seem to be not clinically relevant if one takes into account both the high therapeutic indices of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.

Measuring quality of life in dyspeptic patients: development and validation of a new specific health status questionnaire: final report from the Italian QPD project involving 4000 patients.

OBJECTIVE: Despite the fact that gastrointestinal disorders represent one of the most common reasons for medical consultations, formal assessment of patients' health-related quality of life (HRQOL) has been carried out only in a few studies, and in most cases generic questionnaires have been adopted. Because the specific issue of living with dyspeptic problems has been addressed in very few cases and no questionnaire has been shown to be appropriate for the Italian setting, a prospective project was launched to develop a specific HRQOL questionnaire for dyspepsia sufferers tailored to Italian patients but also appropriate in other cultural settings. METHODS: The project consisted in a 3-yr, three-phase survey, in which different versions of the quality of life in peptic disease questionnaire (QPD) were developed through expert and patient focus groups and empiric field studies and then administered to patients recruited in five multicenter studies. Standard psychometric techniques were used to evaluate the validity, reliability, responsiveness, and patient acceptability of the QPD. RESULTS: Three different versions of the QPD questionnaire were self-administered to more than 4000 patients. The final 30-item version, measuring three health concepts related to dyspeptic disease (anxiety induced by pain, social restriction, symptom perception), fulfilled the recommended psychometric criteria in terms of reliability and validity, correlated with health concepts measured with a well-known independent generic HRQOL instrument (the SF-36 Health Survey questionnaire) and was relatively invariant to diagnosis and sociodemographic variables; it also correlated with a measure of gastric pain frequency and was able to detect meaningful differences over time. CONCLUSIONS: Although further validation studies in different cultural and linguistic settings are mandatory before any firm conclusions can be drawn regarding the cross-cultural validity of the QPD, the data obtained provide evidence of the psychometric validity and robustness of the questionnaire when used in a fairly large, well-characterized population of Italian dyspeptic patients.

Ethanol-induced alterations of matrix network in the duodenal mucosa of chronic alcohol abusers.

Excessive consumption of alcoholic beverages may be associated with gastrointestinal symptoms, including dyspepsia and diarrhoea. It is not clear whether or not chronic alcohol ingestion damages the mucosa of the small intestine. We investigated the effect of chronic alcohol abuse on the duodenal mucosa, and particularly on its extracellular matrix (ECM) network. Duodenal biopsy specimens were obtained during upper gastrointestinal endoscopy from 50 chronic alcoholics without cirrhosis and 10 healthy subjects. Morphological studies were performed by routine histology, immunohistochemistry and electron microscopy. Morphometry of duodenal tissues was performed with a computerized image analyser. No significant duodenal epithelial changes were found in alcoholics, despite an evident reduction in the enterocyte turnover. Myofibroblast-like cells were significantly increased in the villus stroma of alcoholics in comparison to controls. These cells stained positively for desmin, alpha-smooth muscle actin and for several ECM components. In alcohol abusers the thickness of the mucosal basement membrane was greater and the staining for collagen I and III was enhanced both in the basement membrane and in the villus stroma. A higher expression of tenascin was also seen at the base of villi of alcoholics. Chronic alcohol abuse may induce fibrosis of duodenal villi which is associated with a transformation of villus juxta-parenchymal cells into active subepithelial myofibroblast-like cells able to produce different ECM components.

Eradication of Helicobacter pylori reduces the rate of duodenal ulcer rebleeding: a long-term follow-up study.

OBJECTIVES: The long-term efficacy of Helicobacter pylori eradication to reduce the rate of recurrence of peptic ulcer bleeding is still uncertain. We evaluated the rate of duodenal ulcer rebleeding for 48 months after H. pylori eradication. METHODS: Thirty-two male patients with H. pylori infection and duodenal ulcer bleeding were treated with omeprazole (40 mg/day for 4 wk), colloidal bismuth (480 mg/day for 2 wk), amoxicillin (2 g/day for 1 wk), and metronidazole (750 mg/day for 1 wk), and followed up for 48 months. Endoscopy and tests for H. pylori infection were repeated every year. RESULTS: Ulcer healed in all patients, but H. pylori infection persisted or recurred in 11 patients. Within 48 months, rebleeding occurred in nine (81.8%) of these patients, whereas the 21 patients who were persistently negative for H. pylori infection remained asymptomatic without rebleeding (0/ 21 = 0%, p < 0.002) during the whole follow-up. CONCLUSIONS: Eradication of H. pylori can reduce the rate of duodenal ulcer rebleeding for at least 4 yr, thus potentially modifying the natural history of the disease.

Substance P and vasoactive intestinal polypeptide but not calcitonin gene-related peptide concentrations are reduced in patients with moderate and severe ulcerative colitis.

BACKGROUND AND AIMS: Ulcerative colitis is a chronic inflammatory condition characterized by an altered intestinal immunoinflammatory response. Since increasing evidence indicates that neuropeptides play a key role in the regulation of gastrointestinal immune function, the aims of this study were: a) to determine tissue and plasma levels of Vasoactive Intestinal Polypeptide, Substance P, and Calcitonin Gene-Related Peptide in patients with ulcerative colitis, and b) to ascertain whether a relationship exists between tissue concentrations of neuropeptides and the histological grading of mucosal inflammation. METHODS: A total of 29 patients with active and 39 with inactive ulcerative colitis, and 16 control subjects took part in the study. Biopsy specimens of colonic mucosa and blood samples were obtained from each subject, and neuropeptide concentrations were measured by sensitive and specific radioimmunoassays. RESULTS: Both Vasoactive Intestinal Polypeptide and Substance P concentrations were found to be significantly reduced in endoscopic biopsy specimens of patients with ulcerative colitis compared to controls (p < 0.01 and p = 0.05, respectively), and the reduction appeared to be related to the degree of mucosal inflammation; in contrast, Calcitonin Gene-Related Peptide tissue levels were unchanged. In addition, there was no significant difference in the neuropeptide plasma levels between ulcerative colitis patients and control subjects. CONCLUSIONS: Taken together, our results suggest that the reduction of Vasoactive Intestinal Polypeptide and Substance P is probably a secondary phenomenon, correlated with the degree of mucosal inflammation; whatever the mechanism, the decreased availability of these neuropeptides in the local microenvironment may play an important role in the pathogenesis of ulcerative colitis, by affecting many components of the normal immune response. Moreover, based on our data, the measurement of neuropeptide plasma concentrations does not appear to be a useful tool to monitor disease activity.

Human hepatic stellate cells express class I alcohol dehydrogenase and aldehyde dehydrogenase but not cytochrome P4502E1.

BACKGROUND/AIMS: Alcohol dehydrogenase, cytochrome P4502E1 (CYP2E1), and aldehyde dehydrogenase are known to play an important role in alcohol metabolism in the liver. Although the ethanol oxidation pathways are mainly localized in hepatocytes, we examine whether human hepatic stellate cells might also metabolize ethanol and acetaldehyde. METHODS: Hepatic stellate cells were isolated from normal human livers and exposed in vitro to 50 mmol/l ethanol or 85 micromol/l acetaldehyde for different periods of time. Alcohol dehydrogenase/aldehyde dehydrogenase activity and CYP2E1 protein expression were measured in hepatic stellate cells. Moreover, alcohol dehydrogenase and aldehyde dehydrogenase mRNA expression were evaluated in hepatic stellate cells. RESULTS: Exposure of hepatic stellate cells to ethanol for 24 h resulted in a 5-fold increase in cell alcohol dehydrogenase activity. The effect of ethanol on alcohol dehydrogenase activity was paralleled by a significant increase in the alcohol dehydrogenase mRNA expression in hepatic stellate cells. Acetaldehyde significantly increased the activity of high affinity aldehyde dehydrogenase in hepatic stellate cells, whereas ethanol was devoid of any effect. Acetaldehyde also induced high affinity aldehyde dehydrogenase mRNA expression in hepatic stellate cells. CYP2E1 was not expressed in hepatic stellate cells either in basal condition or after ethanol/acetaldehyde exposure. CONCLUSIONS: This study shows that human hepatic stellate cells have the capacity to metabolize both ethanol and acetaldehyde through a class I alcohol dehydrogenase- and an aldehyde dehydrogenase-oxidizing pathway. Conversely, no detectable levels of CYP2E1-associated proteins are expressed in these cells.