Second study shows that octreotide may prevent early rebleeding in cirrhosis.
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Adrenergic beta-Antagonists↗
Biomedical subjects
L Pagliaro
Publications and source records attributed to L Pagliaro.
Long-term course of interferon-treated chronic hepatitis C.
BACKGROUND/AIMS: To evaluate whether sustained response to a-interferon improves clinical outcome in patients with chronic hepatitis C. METHODS: A cohort of 410 consecutive patients (65% with chronic hepatitis, 35% with cirrhosis) were treated with a-interferon in two trials (mean follow-up 62.1 months, range 7-109 months). All were serum HCV RNA positive before therapy and received first 10 then 5 million units of a-2b or a-nl interferon three times weekly for 6 to 12 months. Sustained response was defined as normal aminotransferases 12 months after stopping interferon. RESULTS: Sixty-two patients (15.1%: 54 with chronic hepatitis, eight with cirrhosis) were sustained responders. At the end of follow-up, 56 out of 62 sustained responders (90.3%) were serum HCV RNA negative. No biochemical relapse after 12 months was seen in sustained responders, regardless of initial histology, HCV genotype or persistence of HCV RNA. Although three died of non-hepatic causes, no liver-related events were observed among sustained responders. Complications of liver disease occurred in 34 relapsers/non-responders: nine hepatocellular carcinomas, 21 ascites and four portal hypertensive bleedings. Eleven relapsers/nonresponders died: eight of hepatic and three of non-hepatic causes. Event-free survival was significantly longer in sustained responders than in all the remaining patients. In a regression analysis, sustained response to interferon, low age and absence of cirrhosis were independent predictors of event-free survival. CONCLUSIONS: Hepatitis C virus is probably eradicated and progression of liver disease is prevented in most patients who remain HCV RNA negative with normal transaminases for more than 1 year after stopping treatment.
Adult↗
[Evidence-based medicine].
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Evidence-Based Medicine↗
Metabolic compartmentation in living cells: structural association of aldolase.
The glycolytic enzyme aldolase is concentrated in a domain around stress fibers in living Swiss 3T3 cells, but the mechanism by which aldolase is localized has not been revealed. We have recently identified a molecular binding site for F-actin on aldolase, and we hypothesized that this specific binding interaction, rather than a nonspecific mechanism, is responsible for localizing aldolase in vivo. In this report, we have used fluorescent analog cytochemistry of a site-directed mutant of aldolase to demonstrate that actin-binding activity localizes this molecule along stress fibers in quiescent cells and behind active ruffles in the leading edge of motile cells. The specific cytoskeletal association of aldolase could play a structural role in cytoplasm, and it may contribute to metabolic regulation, metabolic compartmentation, and/or cell motility. Functional duality may be a widespread feature among cytosolic enzymes.
3T3 Cells↗
A randomized controlled trial of high-dose maintenance interferon therapy in chronic hepatitis C.
In chronic hepatitis C virus (HCV) infection, the rate of sustained response to interferon is low. We evaluated, in patients responding to a 26-week course of interferon, the effect of high-dose maintenance therapy in preventing relapse. Three hundred and ten patients with chronic HCV infection (38.3% with cirrhosis, 80.6% with HCV type 1) received interferon alfa-2b for 26 weeks (10 MU tiw for 8 weeks, then 5 MU tiw for 18 weeks). One hundred and twenty-four subjects (40%) normalized aminotransferases, and were allocated randomly either to continue on 5 MU tiw for a further 26 weeks (prolonged therapy group: 60 patients) or to stop interferon (brief therapy group: 64 patients). Fifty-two weeks after stopping interferon the overall sustained biochemical response rate was 13.2% (41/310). The number of patients with normal aminotransferases was comparable between the prolonged and brief therapy groups (30% vs. 35.9%, P = n.s.), and the rate of HCV-RNA clearance was similar (48.8% vs. 42.4%, P = n.s.). The timing of posttreatment relapse was not influenced by the duration of therapy. Fifty-nine patients (19%) did not complete therapy due to adverse effects. Multivariate analysis identified four features predicting sustained biochemical response in subjects normalizing aminotransferases under therapy: negative HCV-RNA at end of therapy, normal aminotransferases at 4 weeks of therapy, high baseline aminotransferases, and high baseline platelets. Infection with HCV type 1 was not a significant predictor of response, due to its high prevalence in our population (80.6%). It is concluded that in patients with chronic hepatitis C mostly infected by HCV type 1, a prolonged high-dose interferon course (900 MU over 52 weeks) did not increase the rate of sustained biochemical response and of HCV-RNA clearance in comparison to a brief course (510 MU over 26 weeks).
Adolescent↗
The effect of interferon on the liver in chronic hepatitis C: a quantitative evaluation of histology by meta-analysis.
BACKGROUND/AIMS: Several randomized clinical trials of interferon in chronic hepatitis C have examined the histological changes in paired biopsy specimens. We have attempted a quantitative evaluation by meta-analysis. METHODS: Randomized Clinical Trials found by MEDLINE search were included if: a) they compared different IFN regimens with non-active treatment or with each other, b) they obtained biopsies before starting and at the time of stopping IFN in a sizable proportion of the treated and control patients, and c) they assessed the biopsy-specimens semi-quantitatively according to Scheuer's numerical scoring system or Knodell's Histological Activity Index, with quantitation of fibrosis and of lobular, portal and periportal necroinflammation. RESULTS: Seventeen trials were identified, in which 1223 adult patients had been studied. All trials homogeneously pointed towards a favorable interferon effect. The pooled data show a statistically significant histological improvement in treated patients as compared with controls for each of the four Histological Activity Index components and for the total Histological Activity Index score (overall improvement was -0.82 in favor of interferon, p<0.0001, 95% Confidence Interval -1.25 to -0.40). In the ten trials reporting histological changes separately in biochemical responders (primary and sustained responders) and non-responders, histological improvement was confined to the subset of biochemical responders. No change or very little change occurred in non-responders. CONCLUSIONS: Interferon treatment in chronic hepatitis C significantly improves liver histology. The effect of interferon is closely related to biochemical response. Studies assessing histological outcome 1 year or more after interferon treatment in long-term responders and comparatively in non-responders or relapsers would be important to confirm the regression of the necroinflammatory process in the former, as suggested by the normal serum alanine aminotransferase levels.
Adult↗
Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials.
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Many treatments have been proposed but considerable uncertainty still remains about their effectiveness. In this review we evaluated the quality, clinical coherence, consistency and results of Randomized Controlled Trials (RCT) of non-surgical treatments for HCC. METHODS: Thirty-seven RCTs examining the effect of different treatments were retrieved using MEDLINE (November 1978 to December 1995) and a review of reference lists. Selected aspects of the quality of design, conduct and reporting were examined. The odds ratio for the probability of surviving up to one year was calculated according to the Mantel Haenszel Peto method and displayed using l'Abbe plots. RESULTS: The 37 RCTs overall included 2803 patients (median 56, range 20-289). Patients prognosis varied widely across studies which also failed to report on important information about their characteristics. Only 10 RCTs had an untreated control group; the remaining 27 compared different regimens of intravenous or intraarterial chemotherapy with or without embolization of hepatic artery, hormono- and immunotherapy regimens. Some evidence of a moderate benefit emerged only from RCTs using tamoxifen and transcatheter arterial embolization vs. no treatment in unresectable patients: pooled odds ratio for 1-year survival were, respectively, 2.0 (95% confidence intervals (CI) 1.1-3.6) and 2.0 (95% CI 1.1-3.6). At 2 years, however, pooled odds ratio were no longer statistically significant for tamoxifen 1.2 (95% CI 0.6-2.6) but was significant for embolization 2.3 (95% CI 1.2-4.6). No evidence of efficacy was detected for embolization as adjuvant therapy in resected or transplanted patients nor for chemotherapy added to intraarterial embolization. CONCLUSIONS: This systematic review of RCTs on HCC, mostly in non resectable patients, indicate that the non-surgical current treatments are ineffective or minimally and uncertainly effective. The three treatment modalities minimally and uncertainly effective (i.e., embolization, tamoxifen and IFN) can deserve further assessment by larger and methodologically more sound randomized trials.
Antineoplastic Combined Chemotherapy Protocols↗
Does regulatory protein play a role in glucokinase localization?
The enzyme glucokinase has recently been found to be largely responsible for glucose homeostatic responses of both the liver and pancreas. The mechanism(s) of these responses remains unknown but recent studies suggest that the intracellular localization of glucokinase, controlled by glucokinase regulatory protein, may be important. This protein is known to bind to and inhibit glucokinase in a phosphofructose-sensitive manner, and we present evidence for the interaction of these proteins with F-actin. Glucokinase regulatory protein gelled F-actin, and gelation was specifically inhibited by glucokinase and the regulatory protein effectors fructose-1-phosphate (F1P) and fructose-6-phosphate (F6P). These results suggest that glucokinase regulatory protein may play a role in metabolism-sensitive glucokinase localization in vivo.
Actins↗
Glossitis, stomatitis, and black tongue with lansoprazole plus clarithromycin and other antibiotics.
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2-Pyridinylmethylsulfinylbenzimidazoles↗
Treatment of small hepatocellular carcinoma associated with cirrhosis by percutaneous ethanol injection. A trial with a comparison group.
BACKGROUND: Ethanol injection has been reported to be effective in the treatment of hepatocellular carcinoma, but no controlled randomized trials have been performed. We therefore performed a trial comparing ethanol injection with an untreated, matched historical comparison group in the treatment of hepatocellular carcinoma. METHODS: From 1992 to 1993, 35 patients (14 Child's A and 21 Child's B cirrhosis) with small (< 4 cm) hepatocellular carcinoma associated with cirrhosis were treated by ethanol injection. Each patient was matched with an untreated case (followed up during the period 1984-89) for variables known to have independent prognostic value (age, Child's classification, number of lesions, alpha-fetoprotein, and modality of diagnosis). RESULTS: The 1-, 2-, and 3-year survival rates of ethanol-treated patients were 86% (95% confidence interval (CI), 69-94), 53% (95% CI, 34-68), and 33% (95% CI, 15-52), whereas the survival rates of the comparison group were 75% (95% CI, 56-85), 26% (95% CI, 13-41), and 14% (95% CI, 5-27) (P = 0.01). The 1-, 2-, and 3-year survival rates of Child's A were 100%. 87% (95% CI, 30-97), 71% (95 CI, 33-90), 71% (95% CI, 33-90) in the ethanol-treated patients and 92 (95% CI, 59-99), 43% (95% CI, 23-73), and 21% (95% CI, 23-72) in untreated patients. The 1-, 2-, and 3-year survival of Child's B patients were 76% (95% CI, 59-97), 32% (95% CI, 13-53), and 9% (95% CI, 0.8-33) in the treated group and 61% (95% CI, 40-83), 14% (95% CI, 3-32), and 9% (95% CI, 1-26) in the treated group. CONCLUSIONS: These data suggest that ethanol injection prolongs the life of patients with hepatocellular carcinoma associated with Child's A cirrhosis but seems not to influence the survival of Child's B patients.
Carcinoma, Hepatocellular↗
Enalapril-associated acute pancreatitis: recurrence after rechallenge.
Three patients with acute pancreatitis diagnosed while they were taking enalapril are described. In two of these patients, enalapril was the only drug taken immediately before the symptoms began, and other etiologies were accurately excluded. In the third patient, the relationship between enalapril and acute pancreatitis was shown by a rechallenge with the drug that resulted in severe acute pancreatitis. This report is a definite demonstration of the relationship between enalapril and acute pancreatitis. We suggest stopping treatment with enalapril in patients suspected of having acute pancreatitis. We also recommend not rechallenging patients with the drug because of the risk of inducing severe acute pancreatitis.
Acute Disease↗
Preparing and interpreting meta-analysis in clinical research.
Meta-analysis is a procedure to systematically research and collect published and (ideally) unpublished randomized clinical trials (RCTs) of treatments and quantitatively summarise their results, in order to obtain an objective assessment of efficacy. Collaboration between statisticians and clinical experts in the field of pathology addressed by the treatment is needed for performing reliable meta-analyses. "Typical" meta-analysis can be refined as "cumulative" meta-analysis, where the pooled assessment of treatment effect is repeated every time a new trial is added to a set of trials, and by meta-analysis "on individual patient data", i.e. using information on each patient included in every trial. Due to the emergence of Evidence-Based Medicine (EBM), the role of meta-analysis is expanding. EBM is a way of practising medicine by integrating individual clinical expertise with the most reliable evidence from the medical literature. Meta-analysis is suggested as the most convenient and reliable source of data for practising EBM. EBM is taking advantage from the Cochrane Collaboration, an international network of experts performing, updating and disseminating meta-analyses of important treatments, according to a common model and established procedures.
Evidence-Based Medicine↗
Health services: an Italian market.
One of the glories of Italy is its capacity to surprise. In out-of-the-way places extraordinary things are suddenly encountered; and this is hardly less true of science than of architecture or music or painting. Italian medicine can boast excellence in many quiet spots. Yet Italy's record in medical science and practice is perceived to be below par, and one reason may be a lack of central coordination--forgivable in a country that had fifty governments in half a century. The latest administration offers a rare chance of political stability and the prospect of reforms. In this profile of Italian medicine The Lancet's guide was Dr Giuseppe Remuzzi, whose central coordination was exemplary.
Acquired Immunodeficiency Syndrome↗
The molecular nature of the F-actin binding activity of aldolase revealed with site-directed mutants.
We used site-directed mutagenesis of rabbit muscle aldolase, falling ball viscometry, co-sedimentation binding assays, and negative stain electron microscopy, to identify specific residues involved in the aldolase-actin interaction. Three mutants, R42A (Arg --> Ala), K107A (Lys --> Ala), and R148A (Arg --> Ala), had minimal actin binding activity relative to wild type (wt) aldolase, and one mutant, K229A (Lys --> Ala), had intermediate actin binding activity. A mutant with approximately 4,000-fold reduced catalytic activity, D33S (Asp --> Ser), had normal actin binding activity. The aldolase substrates and product, fructose 1,6-bisphosphate, fructose 1-phosphate, and dihydroxyacetone phosphate, reversed the gelling of wt aldolase and F-actin, consistent with at least partial overlap of catalytic and actin-binding sites on aldolase. Molecular modeling reveals that the actin-binding residues we have identified are clustered in or around the catalytic pocket of the molecule. These data confirm that the aldolase-actin interaction is due to specific binding, and they suggest that electrostatic interactions between specific residues, rather than net charge, mediate this interaction. Low concentration of wt and D33S aldolase caused formation of high viscosity actin gel networks, while high concentrations of wt and D33S aldolase resulted in solation of the gel by bundling actin filaments, consistent with a potential role for this enzyme in the regulation of cytoplasmic structure.
Actins↗
Ascites, pleural, and pericardial effusions in acute pancreatitis. A prospective study of incidence, natural history, and prognostic role.
Ascites and pleural and pericardial effusions can be observed during acute pancreatitis. The aims of this study were to evaluate their incidence, natural history, and prognostic role in patients with acute pancreatitis. One hundred patients consecutively admitted with a diagnosis of acute pancreatitis were prospectively submitted to abdominal, pleural, and cardiac ultrasonography at admission and during follow-up. Ascites was found in 18 patients, pleural effusion in 20, and pericardial effusion in 17. Twenty-four patients of this series had severe pancreatitis; three of them died. All effusions disappeared spontaneously in patients who survived pancreatitis up to two months after dismissal. At multivariate analysis ascites and pleural effusion were demonstrated to be accurate independent predictors of severity. The respective odds ratios were 5.9 [95% confidence interval (CI), 1.5-23.0%) and 8.6 (95% CI, 2.3-32.5%). Furthermore the presence of pleural effusion, ascites, and pericardial effusion were associated with an increased incidence of pseudocyst during follow-up. Ascites and pleural and pericardial effusions are frequent during acute pancreatitis. Pleural effusion and ascites are accurate predictors of severity in these patients.
Acute Disease↗
Transfusion-associated chronic hepatitis C: alpha-n1 interferon for 6 vs. 12 months.
AIMS: To compare the long-term effects of brief and prolonged therapy with alpha-n1 interferon for transfusion-associated chronic hepatitis C. METHODS: One hundred and sixteen subjects (male/female 48/68, mean age 46.9 years) were studied. Sixty patients were randomised to brief treatment (group 1: interferon 5 Mu/msq. t.i.w. for 2 months, then 3 Mu/msq. t.i.w. for 4 months), and 56 to prolonged treatment (group 2: interferon 5 Mu/msq. t.i.w. for 2 months, then 3 Mu/msq. t.i.w. for 10 months). All were followed for 12 months after stopping interferon. RESULTS: The early response rate was 47.4% (Group 1 [45%], Group 2[50%]. No "breakthrough" reactivations were observed. The early response rate was 19% in patients with and 63% in patients without cirrhosis. Twenty-three (19.8%) subjects stopped therapy. Among 54 evaluable early responders, 21 had a sustained response. The rate of sustained response was comparable in group 1 (18.3%) and group 2 (18.2%). All sustained response subjects and some non-responders were HCV-RNA negative at the end of follow-up. Histological improvement was seen only after sustained response. Cirrhosis developed in 20% of non-responders. Overall, interferon induced a long-lasting remission of chronic hepatitis C in about one of every five patients. CONCLUSIONS: In a population predominantly infected by hepatitis C virus type 1, 12 months of therapy with high doses of interferon does not confer any additional benefit on the early response or sustained response rates as compared to a 6-month course.
Adolescent↗
HCV viraemia is more important than genotype as a predictor of response to interferon in Sicily (southern Italy).
BACKGROUND/AIMS: To investigate host- and virus-related factors predictive of early and sustained alanine aminotransferase normalization after interferon therapy for HCV-related chronic liver disease, in an area where genotype 1 is highly prevalent. METHODS: We studied 100 patients with HCV-RNA positive chronic liver disease (73 chronic hepatitis and 27 cirrhosis) undergoing alpha-interferon treatment. Thirty-four patients had an early response but relapsed, 15 patients remained into sustained response for at least 12 months after therapy, and 51 patients did not respond. Serum HCV-RNA levels were assessed by bDNA (Chiron), and genotype by LiPA (Innogenetics) and by sequencing of the 5' non-coding region. RESULTS: Mean pre-treatment HCV-RNA level (x 10(3) genome equivalents/ml +/- SD) was lower in sustained responders (3854 +/- 7142) than in relapsers (9587 +/- 10163) or in non-responders (5709 +/- 6618). HCV subtype 1b was highly prevalent (82%), while types 1a, 2a, 3 and 4 were rare (about 5% each). However, the prevalence of 1b was much lower (31%) under 40 years of age. The prevalence of subtype 1b among sustained responders (74%) was similar to that observed among relapsers (82%) or non-responders (84%), but some nucleotide substitutions in the putative RNA loop of the 5' non-coding region were seen only among relapsers or non-responders. Multiple logistic regression model showed that early response to interferon was predicted by absence of cirrhosis and a pre-treatment HCV-RNA level below 350. Sustained response to interferon was predicted by pre-treatment HCV-RNA level below 350 and a low fibrosis score. CONCLUSIONS: Among patients with hepatitis C from an area where subtype 1b is highly prevalent, absence of cirrhosis and low pre-treatment serum HCV-RNA level are the most important predictors of response to IFN. Some nucleotide substitutions found in the 5' non-coding region of subtype 1b are associated with non-response or relapse.
Adult↗
Mortality in patients with Crohn's disease.
BACKGROUND: No data on mortality for Crohn's disease are available from southern Europe. METHODS: Five hundred and thirty-one patients with Crohn's disease were observed in our unit between 1973 and 1993. In 325 patients the first diagnosis was made in our hospital. In this consecutive incidence series, in which the follow-up was 99% complete, the standardized mortality rate (SMR) was calculated. RESULTS: Nine deaths were observed, against 9.25 expected. The SMR was 0.97 (95% confidence interval (CI), 0.4-1.8). The relative risk of dying was significantly higher in the female group in the first 5 years after diagnosis (SMR, 10.3; 95% CI, 2.30-30.2). There was an excess of deaths from tumors of the digestive organs (1 observed, 0.37 expected). CONCLUSIONS: These results show that in our geographic area the mortality from Crohn's disease was not increased as shown in other community studies.
Adolescent↗