FoxP3 overexpression and CD1a+ and CD3+ depletion in anal tissue as possible mechanisms for increased risk of human papillomavirus-related anal carcinoma in HIV infection.

AIM: We analysed local cellular and humoral immunity factors in the anal mucosa in an attempt to explain how HIV infection increases the risk of anal cancer in HPV-infected patients. METHOD: HIV-positive cases and matched HIV-negative controls with more than one recurrence of condylomas were included in a prospective study following treatment of the initial lesions. Patients were followed every 3 to 6 months for the development of anal intraepithelial neoplasia (AIN3) and cancer for up to 60 months. Tissue CD1a(+), CD3(+), CD4(+), CD8(+) cells and mRNAs of selected cytokines and chemokines were quantified and compared in patients with or without AIN3 or cancer using morphometric or immunohistochemistry analysis and qRT-PCR. RESULTS: Sixty-six individuals (22 patients and 44 controls) were included. In the case group, CD1a(+) and CD3(+) cell counts were significantly lower in biopsies from AIN3 and cancer specimens compared with those from AIN 1-2 or normal biopsies (P < 0.0001). A CD1a(+) count of < 10/mm was predictive of AIN3 and cancer (Odds ratio = 9.4, 95% CI: 5.4-18.3, P < 0.0001). IL-8 and IL23 levels were significantly higher in cancer than in non-cancer tissues regardless of HIV status (P = 0.02). FoxP3 expression was significantly higher in HIV-infected cases than in controls with AIN3/cancer (P < 0.04). CONCLUSION: Depletion of CD1a(+) and CD3(+) cells and overexpression of FoxP3 in the anal mucosa appear likely to contribute to the risk of HPV-related anal cancer in HIV-infected patients. Furthermore, overexpression of IL-8 and IL-23 in the anal mucosa might be responsible for the development of this cancer regardless of HIV status.

Does lansoprazole influence postprandial digestive function?

The effects of a potent proton pump inhibitor on postprandial digestive functions were compared with those of a placebo in a double-blind randomized crossover study. Six healthy male volunteers received 30 mg/day of lansoprazole or placebo for 7 days, with a wash-out period of 14 days. As compared to placebo, lansoprazole induced a marked decrease of mean +/- S.E.M. 3-h gastric acid secretion from 46.8 +/- 10.8 mmol to 10.9 +/- 2.5 mmol (P < 0.05), and a decrease of the volume of gastric contents emptying into the duodenum from 1043 +/- 139 ml to 660 +/- 87 ml (P < 0.05). However, gastric emptying remained unchanged with meal gastric emptying half times of 66 +/- 5 min and 67 +/- 13 min, respectively. During the 3-h postprandial period, duodenal lipase and chymotrypsin outputs were 366 +/- 123 KIU and 56 +/- 11 KIU with lansoprazole and 436 +/- 119 KIU and 49 +/- 8 KIU with placebo (N.S.). Bile acid outputs were 5.3 +/- 0.7 mmol and 6.0 +/- 1.0 mmol, respectively (N.S.) There was no change in kinetic profiles of biliary-pancreatic secretion. We conclude that potent inhibition of gastric secretion by chronic administration of a proton pump inhibitor at usual therapeutic dose alters neither meal gastric emptying nor postprandial biliary-pancreatic secretion.

[Sensitivity of gastric parietal cells to histamine after administration of enprostil and ranitidine during 4 weeks in healthy subjects]. / Sensibilité des cellules pariétales gastriques à l'histamine après administration pendant 4 semaines d'enprostil et de ranitidine chez le sujet sain.

Parietal cell sensitivity is increased in patients with active duodenal ulcer. It has been shown to increase in healthy volunteers after a 4-week treatment with H2-receptor blockers. Metaanalyses of therapeutic trials have indicated that time to first relapse was longer after ulcer healing with prostaglandins (PG) than after healing with H2-receptor blockers, which might be due to a different effect of the two treatments on parietal cell sensitivity. OBJECTIVES--To study, in healthy volunteers, basal gastric acid secretion, acid secretory responses and parietal cell sensitivity to histamine before and after a 4-week treatment with enprostil (E) and ranitidine (R). METHODS--This was a randomized double-blind double-dummy crossover study. Twelve male healthy volunteers (22-44 years) were randomly assigned to receive a 4-week treatment with either E (35 micrograms bid) or R (150 mg bid). After a 2-month washout period, they were crossed to the alternate treatment. Basal acid output (BAO), acid secretory responses to low-dose histamine infusion (histamine dihydrochloride 2.5 micrograms/kg/h) (LDAO), to a high-dose histamine infusion (25 micrograms/kg/h) (HDAO) and parietal cell sensitivity (PCS = LDAO/HDAO x 100) were measured 24 hours before the first administration and 72 hours after the last administration of each medication. RESULTS--All secretory parameters were similar before treatment with E and R. As compared to pretreatment values: a) HDAO tended to increase after both treatments (NS); b) LDAO (m +/- sem) slightly increased after R (18.4 +/- 2.6 vs 13.9 +/- 3.3 mEq) (NS) but not after E (12.5 +/- 1.8 vs 13.2 +/- 1.9 mEq); c) PCS (m +/- sem) was unchanged after R (36 +/- 4 vs 33 +/- 6) but decreased after R (30 +/- 6 vs 36 +/- 0.5; P < 0.02). When secretory parameters after treatment with R and treatment with E were compared, the difference was significant for LDAO (P < 0.02) and PCS (P < 0.05). CONCLUSIONS--If also found in patients with duodenal ulcer disease, these results might, at least partly, explain the lesser propensity of the ulcers to relapse early after healing with PG than after healing with H2-receptor blockers. However enprostil has been with-drawn from the market and it is now well established that one factor influencing the relapse rate is the efficiency of the treatment given to achieve ulcer healing in eradicating Helicobacter pylori. Consequently, the interest of our results is presently mostly physiological.

[Pathogenesis of cholelithiasis in chronic pancreatitis]. / Pathogénie de la lithiase biliaire au cours de la pancréatite chronique.

The prevalence and the pathogenesis of gallstones in patients with chronic pancreatitis have never been studied prospectively. The aim of this study was to evaluate prospectively the prevalence of gallstones with ultrasonography and to look for markers of pigment or cholesterol stone formation in gallbladder bile. Ultrasonography was performed in 39 patients and detected gallstones in 7 patients and sludge in 3. Common bile duct and intrahepatic bile duct dilatation were observed in 16 and 13 patients, respectively. Liver biopsies were obtained in 31 patients and cirrhosis was found in 4. There were calcium bilirubinate granules in 7 of the 27 bile samples examined. Cholesterol crystals were not found in any case. The nucleation time (median: 21 days) was higher in patients with chronic pancreatitis than in patients with cholesterol stones (median: 2 days) (P < 0.001) but was not different from nucleation time in patients either free of stones (median: 21 days) or with pigment stones (median: 21 days). The cholesterol saturation index was similar in patients with chronic pancreatitis and in controls. The 2 patients with chronic pancreatitis who underwent cholecystectomy had pigment stones. Calcium bilirubinate granules were more frequent in patients with intrahepatic bile ducts dilatation (P < 0.02). In conclusion, this study demonstrates a high prevalence of cholelithiasis in chronic pancreatitis patients. Pigment stone formation could be favored by cholestasis.

Measurement of gastric intramucosal pH in patients with cirrhosis and portal hypertensive gastropathy.

OBJECTIVES: Patients with cirrhosis often have gastric mucosal lesions associated with portal hypertension. Microvascular changes due to portal hypertension may cause mucosal ischaemia. The decrease in intramucosal pH is used as an index of this condition. In this study we compared the gastric intramucosal pH in patients with cirrhosis and portal hypertension and in control group. METHODS: Estimates of pH were calculated using the Henderson-Hasselbalch equation, assuming that measured concentrations of CO2 in the gastric lumen (pCO2) and of HCO3- in arterial blood represented intramucosal CO2 and intramucosal HCO3- concentrations, respectively. Tonometer measurements of intragastric CO2, validated in vitro, were made in patients treated by famotidine (10 mg.h-1 continuous infusion) to suppress gastric acid secretion and minimize CO2 production from luminal gastric bicarbonate. Intramucosal pH was determined in 19 control patients (mean age: 50.2 years) and in 25 patients with cirrhosis and portal hypertensive gastropathy (mean age: 54.2 years). In the patients with cirrhosis the severity of mucosal and parietal abnormalities induced by portal hypertension were graded according to endoscopic score from 0 to 9 and endoscopic ultrasonography score from 0 to 3. RESULTS: The mean endoscopic and ultrasonographic scores were 5.0 and 1.8 respectively. The median gastric intramucosal pH of patients with cirrhosis (7.42; range: 7.36 to 7.53) was similar to that of the controls (7.42; range: 7.33-7.51). A positive correlation was found between intramucosal pH and severity of portal hypertensive gastropathy, in the antrum, but not in the fundus. CONCLUSION: These findings do not support the hypothesis that gastric mucosal lesions are the consequence of ischaemia in patients with cirrhosis.

Increased gastric bicarbonate secretion in portal hypertensive anesthetized rats: role of prostaglandins and nitric oxide.

Gastric bicarbonate secretion might be modified in portal hypertension as a consequence of the intramucosal increase in prostaglandins and nitric oxide content. Therefore, we studied gastric bicarbonate secretion in control and portal hypertensive rats and investigated the role of prostaglandins and nitric oxide. Basal gastric bicarbonate secretion was studied in rats, using a gastric pH back-titration technique, two weeks after partial portal vein ligation or a sham operation. The effects of the following drugs were investigated: the prostaglandin synthase inhibitor indomethacin (5 mg/kg intravenously), prostaglandin (PGE2) (1 mg/kg intravenously), the nitric oxide synthase inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME, 5 mg/kg intravenously) and N(G)-monomethyl-L-arginine (L-NMMA, 50 mg/kg intravenously), and the nitric oxide donor nitroprusside (5 mmol/liter in the gastric perfusate). Plasma leakage in the gastric wall was also measured after Evans blue dye injection in portal hypertensive and sham-operated rats pretreated by indomethacin (5 mg/kg, intravenously) and L-NAME (5 mg/kg, intravenously). Basal bicarbonate secretion was significantly increased in portal hypertensive rats as compared to controls. After indomethacin, the bicarbonate secretion was significantly reduced to a similar level in both groups. PGE2 increased bicarbonate secretion significantly more in portal hypertensive rats than in sham-operated rats. The NO synthase inhibitor L-NMMA significantly increased bicarbonate secretion in portal hypertensive rats only, while the other inhibitor, L-NAME, increased it significantly more in portal hypertensive than in the sham-operated rats. Plasma leakage in portal hypertensive rats, which was increased in the basal condition as compared to control, was further enhanced by indomethacin but not by L-NAME pretreatment. The nitric oxide donor significantly reduced bicarbonate secretion in portal hypertensive rats to reach a similar level as in sham-operated rats. Basal gastric bicarbonate secretion is increased in portal hypertensive rats. This could be due to an enhanced prostaglandin mucosal level. Nitric oxide, which reduces bicarbonate secretion, may contribute to limiting prostaglandin-induced bicarbonate overproduction.

Comparative study of availability of prednisolone after intestinal infusion of prednisolone metasulfobenzoate and prednisone.

The role of intestinal absorption in the differential availability of prednisone (PN) and prednisolone metasulfobenzoate (PO-MS), which might account for clinical resistance to PO-MS, has been studied by an infusion technique. In a randomized cross-over design trial, a solution in isotonic saline of PN or PO-MS (115 mg.l-1 was infused at 5 ml.min-1 for 2 h, into a 25 cm segment of jejunum in 8 healthy fasting subjects. The intestinal content was partly collected and the flow rate at the end of the test segment was determined by using a water movement marker (PEG 4000). Plasma, intestinal and urine concentrations of PN and PO were determined by liquid chromatography. From the data on PO, the active molecule, the systemic availability of PO-MS was significantly smaller than of PN, with the respective mean AUCs being 1.71 and 3.60 mg.h-1. The difference was associated with smaller mean Cmax, 0.20 vs 0.64 mg.l-1, higher mean tmax, 2.94 vs 2.06 h and lower mean ka, 0.98 vs 2.18 l/h after PO-MS. No significant difference was found in the half-life or renal clearance of the formulations tested. The mean MRT was significantly increased after PO-MS, 6.82 vs 5.30 h. The observed difference probably reflected a difference in intestinal absorption. The mean absorption in the test segment of PO-MS was significantly smaller at 17.4 vs 85.5% for PN. The ester form may be a limiting factor in the intestinal absorption of PO.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of gastric alcohol dehydrogenase activity by histamine H2-receptor antagonists has no influence on the pharmacokinetics of ethanol after a moderate dose.

Ethanol undergoes gastric first pass metabolism by alcohol dehydrogenase (ADH). We have shown that cimetidine and famotidine both cause competitive inhibition of human gastric ADH in vitro. However, in a randomized 4-way cross-over study in 12 healthy subjects a 7-day course of treatment with cimetidine (800 mg day-1), ranitidine (300 mg day-1) or famotidine (40 mg day-1), did not modify the pharmacokinetics of ethanol given as a post-prandial 0.3 g kg-1 dose. We conclude that gastric mucosal concentrations of histamine H2-receptor blockers achieved after oral dosing are probably too low to cause significant inhibition of gastric ADH in vivo.