Three-dimensional structures reveal multiple ADP/ATP binding modes for a synthetic class of artificial proteins.

The creation of synthetic enzymes with predefined functions represents a major challenge in future synthetic biology applications. Here, we describe six structures of de novo proteins that have been determined using protein crystallography to address how simple enzymes perform catalysis. Three structures are of a protein, DX, selected for its stability and ability to tightly bind ATP. Despite the addition of ATP to the crystallization conditions, the presence of a bound but distorted ATP was found only under excess ATP conditions, with ADP being present under equimolar conditions or when crystallized for a prolonged period of time. A bound ADP cofactor was evident when Asp was substituted for Val at residue 65, but ATP in a linear configuration is present when Phe was substituted for Tyr at residue 43. These new structures complement previously determined structures of DX and the protein with the Phe 43 to Tyr substitution [Simmons, C. R., et al. (2009) ACS Chem. Biol. 4, 649-658] and together demonstrate the multiple ADP/ATP binding modes from which a model emerges in which the DX protein binds ATP in a configuration that represents a transitional state for the catalysis of ATP to ADP through a slow, metal-free reaction capable of multiple turnovers. This unusual observation suggests that design-free methods can be used to generate novel protein scaffolds that are tailor-made for catalysis.

Beyond guanine quartets: cation-induced formation of homogenous and chimeric DNA tetraplexes incorporating iso-guanine and guanine.

BACKGROUND: iso-Guanine (iso-G) is the purine component of an isomeric Watson-Crick base pair that may have existed prebiotically. By comparing the abiotic molecular recognition properties of iso-G and its complement, iso-cytosine (iso-C), with those of genomic nucleotide bases, it may be possible to explain the exclusion of the iso-G-iso-C base pair from modern genomes. Whether a nucleobase forms quartets may have a key role in determining its functionality. Biotically, nucleic acid tetraplexes have been implicated in cellular functions; prebiotically, tetraplexes would probably interfere with replication. Recently, in vitro selection has yielded receptors and catalysts that incorporate G quartets. The versatility of these structures could be enhanced by expanding the range of bases that can form the quartet motif. RESULTS: Native polyacrylamide gel electrophoresis of oligonucleotides bearing runs of iso-G provides strong support for tetraplex formation via cation-promoted DNA strand association. In particular, when strands of different lengths bearing the same iso-G tetrad recognition element were combined, five bands were observed after electrophoresis, corresponding to all possible heterotetraplexes with parallel strand alignment. An analogous experiment with a mixture of strands bearing iso-G or G tetrad recognition domains supports the existence of mixed iso-G/G tetraplexes with antiparallel strand alignment at chimeric junctions. iso-G tetraplex and quartet structure has also been probed by a photo-crosslinking experiment, ultra-violet spectroscopy and theoretical calculations. CONCLUSIONS: As iso-G and G both have a marked tendency to form tetraplexes, their tandem inclusion in genetic material may be problematic, leading to double-stranded DNA half composed of bases that have a tendency to auto-associate. The resulting density of 'selfish' bases could undermine Watson-Crick pair formation, especially in a prebiotic context devoid of enzymes. Nevertheless, the ability of iso-G to form mixed quartets with G may provide a basis for altering the properties of tetraplexes in the domain of artificial receptors or catalysts from in vitro selections.

Pharmacokinetics of zidovudine in patients with liver cirrhosis.

The pharmacokinetics of zidovudine (azidothymidine, AZT) was investigated after oral administration (200 mg) in 14 human immunodeficiency virus seronegative patients with liver cirrhosis. They were divided in three groups according to the severity of the liver disease quantitated by the Child-Pugh score. Plasma and urine concentrations of zidovudine and its glucuronidated metabolite (GAZT) were measured simultaneously by HPLC assay. Findings were compared with those previously measured in six healthy volunteers. As a consequence of a marked drop in oral clearance (10 +/- 4 versus 38 +/- 15 ml/min/kg), zidovudine concentrations, half-life, and mean residence time were increased in patients with cirrhosis. No difference could be established between the three groups. The reason for such a decrease in oral clearance of zidovudine was the reduction in the GAZT formation clearance (236 +/- 73 versus 1540 +/- 540 ml/min); this led to a decrease in the AUC ratio of GAZT and zidovudine (1.3 +/- 0.6 versus 4.6 +/- 0.7), which was directly related to the severity of the cirrhosis. In patients, as in volunteers, formation of GAZT rate limits its elimination. To avoid important cumulation of zidovudine after repeated dosing in patients with acquired immunodeficiency syndrome who have hepatic impairment, a dosage adjustment could be proposed.

Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome.

AIM: To assess the efficacy of smooth muscle relaxants in the treatment of patients with irritable bowel syndrome, a meta-analysis of 26 selected double-blind randomized trials vs. placebo was performed. METHODS: Five end-points were assessed: global assessment, abdominal pain, constipation, abdominal distension and the absence of adverse reactions. Analyses were performed according to the intention-to-treat method. For each end-point, the drug efficacy was assessed by the Der Simonian and Peto methods. When a significant difference was observed, sensitivity analyses were performed by successive stratifications according to the type of drug, the treatment duration, the prevalence of constipated patients, the trial design and the methodological quality. RESULTS: All myorelaxants analysed were significantly better than placebo for the improvement of global assessment (62% improvement rate vs. 35% on placebo, that is 27% improvement rate, P < 0.01) and for pain improvement (64% improvement rate vs. 45% on placebo, that is 19% improvement rate, P < 0.01). No significant differences were observed for constipation and abdominal distension. The percentage of patients with adverse reactions was significantly higher in patients receiving myorelaxants than placebo (6% mean difference, P < 0.01). CONCLUSION: According to this overview five drugs have proved their clinical efficacy in patients with irritable bowel syndrome, without significant adverse reactions: cimetropium bromide, pinaverium bromide, trimebutine, octilium bromide and mebeverine.

Meta-analysis: evaluation of adjuvant therapy after curative liver resection for hepatocellular carcinoma.

AIM: To evaluate adjuvant modalities after curative resection for hepatocellular carcinoma using a meta-analysis of randomized and non-randomized controlled trials. METHODS: In a first step, a meta-analysis of randomized controlled trials was carried out. Sensitivity analyses after inclusion of non-randomized controlled trials were performed. Four therapeutic modalities were evaluated: pre-operative transarterial chemotherapy, post-operative transarterial chemotherapy, systemic chemotherapy and a combination of systemic and transarterial chemotherapy. RESULTS: Only post-operative transarterial chemotherapy improved survival significantly at 2 years [difference, 22.8%; confidence interval (CI), 8.6-36.9%; P = 0.002] and 3 years (difference, 27.6%; CI, 8.2-47.1%; P = 0.005), and decreased the probability of no recurrence at 1 year (difference, 28.8%; CI, 16.7-40.8%; P < 0.001), 2 years (difference, 27.6%; CI, 8.2-47.1%; P = 0.005) and 3 years (difference, 28%; CI, 8.2-47.9%; P = 0.006). In a sensitivity analysis after inclusion of non-randomized controlled trials, post-operative transarterial chemotherapy still improved survival at 1 year (difference, 9.6%; CI, 0.8-18.3%; P = 0.03), 2 years (difference, 13.5%; CI, 0.9-26%, P = 0.04) and 3 years (difference, 18%; CI, 7-28.9%; P < 0.001), and decreased the probability of no recurrence at 1 year (difference, 20.3%; CI, 7.7-33%; P = 0.002), 2 years (difference, 35%; CI, 21.4-46.3%; P < 0.001) and 3 years (difference, 34.5%; CI, 18.7-50.3%; P < 0.001). CONCLUSION: Post-operative transarterial chemotherapy improved survival and decreased the cumulative probability of no recurrence. New randomized controlled trials evaluating this modality are required.

Expression of histocompatibility antigens and characterization of the lymphocyte infiltrate in hyperplastic polyps of the large bowel.

HLA-DR expression, lymphocyte subsets, and the distribution of proliferating cells were studied in hyperplastic polyps from the colorectum. The density of T-cells (CD5+) (mean of cells/mm2 of tissue +/- SEM) was higher in the lamina propria of hyperplastic polyps (64.2 +/- 4.2) than in normal colonic mucosa (36.7 +/- 2.6, P less than .001). The CD4/CD8 ratio was higher in hyperplastic polyps (6.3 +/- 0.9, P less than .0001) and in colonic adenomas (5.9 +/- 0.9, P less than .001) compared with normal mucosa (2.3 +/- 0.2). Lymphocytes of the lamina propria were never Ki-67 positive either in normal mucosa or in hyperplastic polyps or adenomas. The epithelial layer of hyperplastic polyps and of normal mucosa did not express the HLA-DR antigen, whereas pericryptal fibroblasts and most of the leukocytes of the lamina propria were strongly positive for this antigen. In the epithelial layer proliferating cells were localized exclusively in the lower part of epithelial crypts, as was the case in normal mucosa, whereas in adenomas Ki-67-positive cells were present throughout the entire height of the mucosa. Thus, in hyperplastic polyps lymphocytes are increased in the lamina propria, with a predominance of the CD4 subset in close contact with HLA-DR positive pericryptal fibroblasts.

Diaphragm function is not impaired by pneumoperitoneum after laparoscopy.

Open cholecystectomy is known to induce a major restrictive respiratory syndrome. These respiratory disturbances, although of reduced magnitude, still persist after laparoscopic cholecystectomy. To determine the role of pneumoperitoneum per se in the respiratory dysfunction observed after this procedure, seven patients were studied before and 2 hours after laparoscopy. This diagnostic procedure avoids the upper midline incision and the surgical injury of cholecystectomy. Ventilatory performance and diaphragm function were assessed as follows: (1) during quiet tidal breathing by obtaining measurements of esophageal, gastric, and transdiaphragmatic pressures; determining the ratio of gastric pressures to esophageal pressures; and abdomen-rib cage partitioning of tidal volume obtained from two differential linear transformers and (2) during maximal respiratory efforts by obtaining measurements of vital capacity and maximal transdiaphragmatic pressure during Müller's maneuver and a sniff test. Although a large residual pneumoperitoneum (assessed as the maximal height of the suprahepatic space: Hmax = 30.3 +/- 7.8 mm) was observed after laparoscopy, we did not find any change suggestive of diaphragm dysfunction. We thus conclude that postoperative residual pneumoperitoneum per se is unable to explain the diaphragm dysfunction observed after open or laparoscopic cholecystectomy.

Serum apolipoprotein A-I in alcoholic patients with chronic calcifying pancreatitis.

Serum apolipoprotein A-I measurement was compared in alcoholic patients according to presence or absence of chronic pancreatitis and liver fibrosis. Among alcoholic patients without liver disease, apolipoprotein A-I was significantly lower in patients with chronic pancreatitis (157 +/- 70 mg/dl) than in patients without pancreatitis (209 +/- 74 mg/dl, p less than 0.001). In cirrhotic patients, apolipoprotein A-I was lower in patients with chronic pancreatitis (82 +/- 35 mg/dl) than in patients without pancreatitis (102 +/- 45 mg/dl), but this difference was not significant. The decrease of serum apolipoprotein A-I was independent of nutritional parameters whether or not there was cirrhosis. Immunohistochemical study of pancreatic samples with chronic pancreatitis showed that apolipoprotein A-I was located in the pancreatic fibrosis whereas lobules were unstained. This study suggests that apolipoprotein A-I is trapped by the pancreatic extracellular matrix and that this sequestration might explain, in part, the decrease of the serum apolipoprotein A-I.

In vitro inhibition of human colonic motility with SR 59119A and SR 59104A: evidence of a beta3-adrenoceptor-mediated effect.

The new beta3-adrenoceptor is present in the gastrointestinal tract of various species. This study aimed to show that this receptor modulates human colonic motility in vitro. We used circular muscle strips from the human colon suspended in single organ baths containing Krebs solution and subjected to an initial 1.5-2 g tension. We measured the effects of different beta3-adrenoceptor agonists, including SR 59104A (N-[(6-hydroxy-1,2,3,4-tetrahydronaphthalen-(2R)-2-yl)methyl]-(2 R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride), SR 59119A (N-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-(2R)-2-yl)methyl]-(2R) -2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride), BRL 37344 (R,R + S,S) [4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl] phenoxy] acetic acid), and of isoprenaline and salbutamol in the absence or in the presence of propranolol alone or in combination with the beta3-adrenoceptor antagonist SR 59230A (3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydro-naphthalen-1- ylamino]-(2S)-2-propanol oxalate) on amplitude of spontaneous contractions. To evaluate a possible beta2-adrenoceptor-mediated effect, we studied the action of these compounds on human isolated bronchi. On the human isolated colon, SR 59119A, SR 59104A and isoprenaline reduced the initial amplitude of spontaneous contractions by 60%. The curves obtained in the presence of antagonists suggested an action mediated by beta3-adrenoceptor stimulation, since propranolol did not antagonize the action of SR 59119A and SR 59104A, whereas the combination of propranolol and SR 59230A significantly displaced the concentration-response curve of these agonists to the right. This study provides pharmacological evidence of modulation of human colonic motility, and especially of the amplitude of spontaneous contractions, by the atypical beta-adrenoceptor, the beta3-adrenoceptor.

Pretreatment expression of the perforin gene by circulating CD8(+) T lymphocytes predicts biochemical response to interferon-alpha in patients with chronic hepatitis C.

It would be of great value to be able to predict, before the initiation of treatment, which patients with hepatitis C virus-induced chronic hepatitis will be cured by interferon-alpha (IFN-alpha). Competitive RT-PCR was used to evaluate spontaneous expression of the perforin gene, a marker of cytotoxic cell activation, by circulating mononuclear cells in 17 patients undergoing IFN-alpha treatment. IFN-alpha increased perforin gene expression (p < 0.003), but this was not correlated with outcome. In contrast, pretreatment perforin gene expression levels were higher in the 8 patients with a sustained biochemical response after treatment than in the 9 non-responsive patients (p = 0.01). This factor predicted favorable clinical outcome with a sensitivity of 75% and a specificity of 89%. Thus, pretreatment immunological status has a major influence on the ability of IFN-alpha to cure chronic hepatitis C, and the evaluation of perforin gene expression may help to select patients that will benefit from IFN-alpha treatment.

A particularly aggressive combined glucagonoma and gastrinoma syndrome.

Duodeno-pancreatic biochemically polyfunctional endocrine tumour is a well known entity. Usually, only one hormone is responsible for the clinical features. We report a case of aggressive combined glucagonoma and gastrinoma tumour without metastases, causing respectively diabetic ketoacidosis and fulminant peptic ulcer, and death. Occasional patients can present with clinical features of both glucagonoma and gastrinoma. Diabetic patients exhibiting migratory skin lesions should be suspected of glucagonoma. In addition, a multidisciplinary approach to such patients including dermatologists, surgeons, radiologists and endoscopists is mandatory.

Relations between effectiveness of a diagnostic test, prevalence of the disease, and percentages of uninterpretable results. An example in the diagnosis of jaundice.

The relations between effectiveness, the percentages of uninterpretable results of a test, and the prevalence of the disease are studied in the example of the diagnosis of jaundice. Ten hepatologists and ten hepatobiliary surgeons were interviewed, and nineteen articles were reviewed. Accuracies of ultrasonography, endoscopic retrograde cholangiography, and transhepatic cholangiography, as well as of three strategies combining these tests, were ranked by hepatologists in an order that differed from chance, and by surgeons in an order that did not differ from chance. Analyses of published data, taking into account the percentages of uninterpretable results, showed that for a high prevalence of extrahepatic cholestasis, as in jaundiced patients seen by surgeons, there is no significant difference between the respective effectiveness of each test or strategy. We concluded that effectiveness must take into account the percentages of uninterpretable results and must be expressed as a function of prevalence.

[Radiological and endoscopic study of the esophagus in 33 cases of generalized scleroderma]. / Studio radiologico ed endoscopico dell'esofago in 33 casi di sclerodermia generalizzata

The radiological and endoscopic picture of the oesophagus was investigated in 33 patients with generalised sclerodermia. Signs of involvement were noted in 26 subjects, whereas symptoms of such involvement had been observed in 13 only. Screening for oesophageal sclerodermia sites requires accurate assessment of oesophageal kinetics. Fibroscopic examination gives equally reliable evidence of involvement in the form of two distinctive signs: absence of peristaltic contractions in the lower half of the oesophagus and persistence of a "pool of water" in the organ for over 30 secs following injection of a few cc of water in the lying patient. Endoscopy frequently reveals concomitant peptic oesophagitis (10 cases). This is invisible radiologically. Endoscopy also permits accurate appraisal of the lesions associated with peptic stenosis. Fibroscopic examination of the oesophagus, in fact, could well be made a feature of the evaluation of all patients with actual or suspected generalised sclerodermia, on account of its aid to diagnosis and the early notice it gives of oesophageal complications.

[Palliative treatment of cancers of the esophagus and cardia with YAG neodymium laser. (Preliminary noncontrolled trial)]. / Traitement palliatif des cancers de l'oesophage et du cardia par le laser YAG Néodyme. (Essai préliminaire non contrôlé).

The aim of this study was to report results of endoscopic YAG laser therapy in palliative treatment of esophageal and cardial carcinoma. Twenty-eight patients were treated: 9 with adenocarcinoma and 19 with squamous cell carcinoma. Among these patients, 9 had complete aphagia; radiotherapy was contraindicated in 17; in the remaining 2 patients the aim of laser therapy was to achieve sufficient luminal enlargement to allow the endoscopic insertion of a prothesis. Dysphagia improved in 24 cases; destruction of a major portion of the intraluminal tumor was achieved in 17 patients, and incomplete destruction was possible in 9 patients. In one case, the treatment had no effect. Among 22 subjects in maintenance treatment, 13 good results were obtained. Several complications of laser therapy were observed: 2 cases of minor bleeding, 2 cases of esophagitis and 1 perforation of the upper esophagus. The patient died after surgical operation. It is concluded that endoscopic YAG laser therapy for palliative treatment of esophageal and cardial carcinoma is effective, providing rapid improvement of dysphagia. Maintenance treatment is necessary to sustain the improvement. Randomized studies are now needed to compare endoscopic laser therapy with other palliative treatment of malignant tumors of the upper gastrointestinal tract.

[Endoscopic hemostasis for hemorrhagic gastroduodenal ulcer. Meta-analysis of randomized clinical trials]. / Hémostase endoscopique des hémorragies ulcéreuses gastro-duodénales. Méta-analyse des essais randomisés.

To demonstrate the advantages of various endoscopic hemostatic methods (laser photocoagulation, electrocautery, injection therapy) for bleeding gastroduodenal ulcer in patients at high risk for continued or recurrent bleeding, a critical review of published randomized clinical trials was made with meta-analytic methods. Only the 15 clinical trials dealing either with patients with visible non bleeding vessels or spurting arterial bleeding were included. Regarding visible non bleeding vessels, the meta-analysis of five trials on electrocautery and two trials on sclerotherapy showed a significant reduction in rebleeding rates in the treatment group compared with untreated controls. The odds ratios were 4 (95 percent confidence levels (CL): 2.4-6.9) (P less than 0.001) and 6.8 (95 percent CL: 2.7-17.2) (P less than 0.001), respectively. As well, the meta-analysis of four trials on electrocautery and the two trials on sclerotherapy showed a significant reduction in the number of emergency surgical operations in the treated groups a compared with the untreated groups. The odds ratios were 5.5 (95 percent confidence levels (CL): 2.7-11.3) (P less than 0.001) and 6.1 (95 percent CL: 2.1-17.8) (P less than 0.001), respectively. Meta-analysis did not show any advantage for laser, electrocautery, or sclerotherapy in terms of mortality. Indirect meta-analysis did not reveal any difference between electrocautery and sclerotherapy. Regarding spurting arterial bleeding, meta-analysis of the two YAG laser trials, the two Argon laser trials, and the two electrocautery trials showed a significant reduction of rebleeding or continued bleeding in the treatment groups as compared with the control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

[Double-blind controlled study of the efficacy of nifuroxazide versus placebo in the treatment of acute diarrhea in adults]. / Etude contrôlée en double aveugle de l'efficacité du nifuroxazide versus placebo dans le traitement de la diarrhée aiguë de l'adulte.

In a double-blind, controlled randomized trial, 88 adult patients with acute diarrhea (more than three watery stools per day) received either 400 mg of nifuroxazide twice daily or placebo for 5 days. The mean duration of diarrhea in the nifuroxazide group was 2.09 days versus 3.26 days in the placebo group (p less than 0.004). The number of bowel movements per day diminished and mucus disappeared more quickly in patients treated by nifuroxazide than in patients of the placebo group. Nifuroxazide was well tolerated and no side effects were observed. Nifuroxazide is an effective therapy for acute diarrhea and can be prescribed from the onset of diarrhea without waiting for stool culture results which can be late or negative.

[Sclerotherapy of esophageal varices using ethanol in combination with propranolol: clinical study of 30 patients]. / Sclérothérapie des varices oesophagiennes par l'éthanol associée au propranolol: étude clinique de 30 malades.

A prospective study was conducted in 30 patients to assess the efficacy and safety of endoscopic sclerotherapy with absolute alcohol associated with propranolol for prevention of recurrent variceal bleeding. Patients were included if propranolol alone had failed or if they had at least three factors which increased the risk of rebleeding although the patients were receiving propranolol; two patients were treated by sclerotherapy only because of contraindications to propranolol. Etiology of portal hypertension was cirrhosis in 29 patients and portal vein thrombosis in one patient. Seventeen patients were grade A and 13 were grade B according to Child-Pugh's classification. The cumulative percentage of patients free of rebleeding 12 months after inclusion was 43 +/- 10 p. 100 (m +/- SD). The cause of recurrent bleeding was esophageal varices in nine patients and esophageal ulcers in five patients. The cumulative percentage of variceal rebleeding 12 months after inclusion was 61 +/- 10 p. 100. The cumulative percentages of patients free of rebleeding from varices were not significantly different between the Pugh A (64 +/- 14 p. 100) and Pugh B (56 +/- 15 p. 100) patients. The cumulative percentage of patients surviving 12 months after inclusion was 55 +/- 9 p. 100. The cause of death was not related to sclerotherapy in 11 patients. Two patients died of esophageal wall necrosis associated with mediastinitis. These two patients had received large volumes of sclerosing agent because of important bleeding during the last injection. Our results suggest that in patients without severe cirrhosis who cannot be treated by propranolol alone, the risk of rebleeding and the risk of death are high despite sclerotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

[Chronic alcoholic pancreatitis: relation of pain to withdrawal and pancreatic surgery]. / Pancréatite chronique alcoolique: relations de la douleur avec le sevrage et la chirurgie pancréatique.

A group of 73 patients suffering from painful alcoholic, chronic pancreatitis, hospitalized from 1971 to 1981, has been analyzed retrospectively. The aim was to assess the effects of alcohol withdrawal and pancreatic surgery on the course of pancreatic pain. The mean number of years during which the patients complained of pain was 3.5 +/- 0.5 (m +/- SEM). At the end of follow-up, 70 p. 100 of the patients did no longer suffer, alcohol withdrawal was obtained in 45 p. 100 and surgery had been performed in 41 p. 100. Continued alcohol abuse did not prevent pain relief: 60 p. 100 of patients continuing to drink at the end of follow-up, did not suffer any longer. One year after pancreatic surgery, pain relief was more frequent, if alcohol abstinence had been obtained before surgery (p less than 0.01). Among the 53 patients followed up to 5 years after the start of pain: a) the cumulative actuarial probability of disappearance of pain was 17 p. 100 at 2 years, 52 p. 100 at 5 years, 62 p. 100 at 8 years after the start of pain. Alcohol abstinence and surgery were observed during the first five years of pain; b) the mean number of years of pain was lower among the patients who became abstinent early (less than 4 years after the beginning of pain) than among those who did not (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of long term recombinant interferon-alfa in patients with chronic hepatitis C. A clinical, biological, histological and immunohistological study.

A prospective, non randomized trial was conducted in 22 patients with chronic hepatitis C treated for 6 months with interferon-alfa at the dose of 3 million units three times a week followed by decreasing doses for the following 6 months. Transaminase activity measurements were taken at 2, 6, 12, 18, and 24 months and a liver biopsy was performed at zero and 6 months to assess efficacy. Immunohistochemical study of HLA class I and lymphocyte subsets was performed on the biopsy specimen before and after 6 months of treatment. A complete biological response was observed in 82, 82, 60, 64 and 70 percent of patients at 2, 6, 12, 24 and 36 months, respectively. Four patients relapsed including 2 patients who suddenly stopped taking interferon-alfa. An improvement of histological features was observed in 90 percent of patients for necrosis and in 80 percent of patients for inflammation, with an overall improvement in Knodell's score reaching 85 percent. Immunohistochemical studies showed CD8+ cell infiltration already present in the area of necrosis before treatment. These tests also showed that HLA class I expression by the hepatocyte membranes was increased at 6 months and was identical in patients with or without histological improvement.

[Treatment of gastroesophageal reflux: analysis of randomized double-blind trials]. / Traitement du reflux gastro-oesophagien: analyse des essais randomisés en double aveugle.

The aim of this study was to analyze the results and the quality of methodology of 51 controlled double blind trials in the medical treatment of gastroesophageal reflux. The results of H2 receptor antagonist treatment were evaluated by the pooling method. Evaluation of methodology was carried out by using a special form filled in by two independent observers. The major criticisms in methodology were: small sample size, unblind evaluation of end-points, inappropriate statistical tests for small samples, and inaccurate handling of the withdrawals. There were only two trials concerning antacids versus placebo: one showed that Novaluzid improved symptoms and another that Maalox did not differ from placebo. The effectiveness of alginic acid and domperidone on either symptoms or endoscopic lesions was not demonstrated. Metoclopramide and bethanechol produced significant relief of reflux symptoms. Sucralfate and bethanechol were better than placebo in improvement of esophagitis endoscopic lesions. The H2-inhibitors efficiently relieved symptoms and esophagitis. Pooling analysis showed that H2-inhibitors were superior to placebo in the healing of esophagitis; the odds ratios were 2.5 for cimetidine and 3.3 for ranitidine, without significant difference. Omeprazole was better than ranitidine in relief of symptoms and esophagitis. The comparison of cimetidine alone with cimetidine plus metoclopramide showed that combined therapy was better in one trial out of two. New controlled trials are necessary to compare these different drugs and their association.