Effects of red wine, tannic acid, or ethanol on glucose tolerance in non-insulin-dependent diabetic patients and on starch digestibility in vitro.

This study examines the effect of moderate intake of red wine, tannic acid, or ethanol during a meal in type 2 diabetic patients and the influence of tannic acid on the digestibility of starch by alpha-amylase. Thirty non-insulin-dependent diabetes mellitus (NIDDM) patients aged 53 +/- 6 years were studied (in vivo study) 10 of whom received red wine (200 mL), 10 tannic acid (150 mg), and 10 ethanol (16 g) with their midday meal (600 calories, 65 g carbohydrate, 20 g lipid, and 34 g protein). All patients were tested on two occasions (water or placebo v wine, alcohol, or tannic acid). The influence of tannic acid (0.25, 0.5, and 1 mg) on the digestibility of starch (100 mg) by alpha-amylase (100 U) was tested in vitro by sequential incubation at 37 degrees C (in vitro study). The maximum glucose excursion after lunch was 2.6 +/- 0.8 mmol/L at 90 minutes (T90) for water and 1.8 +/- 0.9 mmol/L at T90 for red wine taken with the meal. The values at T60 and T90 were significant (P < .01). Comparable results were obtained with tannic acid alone (nonalcoholic component of wine): the maximum glucose excursion after lunch was 2.76 +/- 0.9 mmol/L at T120 for placebo and 1.97 +/- 0.9 mmol/L at T90 for tannic acid (P < .01); no difference in glucose and insulin excursion was observed between water and ethanol. No interaction between tannic acid and starch was observed in the in vitro experiments, although after preincubation of alpha-amylase with tannic acid, digestion was slowed in a dose-dependent manner (6.1 +/- 1.1 minutes for 0.25 mg tannic acid and 13.1 +/- 1.59 minutes for 1 mg tannic acid). Drinking red wine with a meal did not increase blood glucose in NIDDM patients, and led to a slight decrease in some instances. The effect appeared to be mediated by the nonalcoholic compounds in wine such as tannic acid. Ethanol itself had no effect on plasma glucose or insulin levels.

Intention-to-treat vs. on-treatment analyses of clinical trial data: experience from a study of pyrimethamine in the primary prophylaxis of toxoplasmosis in HIV-infected patients. ANRS 005/ACTG 154 Trial Group.

Randomized clinical trials analyzed by the intent-to-treat approach provide unbiased comparisons among treatment groups. To avoid dilution of treatment effect, many people also perform an analysis by treatment actually received, although this method may introduce bias into the results. This paper presents several approaches used for analyzing data of a recent trial and the difficulties encountered in interpreting the results of each approach. The ANRS 005/ACTG 154 Study was a double-blind, placebo-controlled, randomized, international (French, U.S., and Spanish) multicenter trial designed to assess the effectiveness of pyrimethamine for the primary prophylaxis of cerebral toxoplasmosis (CT) in HIV-infected patients with advanced immunodeficiency. In the intention-to-treat analysis, the cumulative probability of CT at 1 year did not differ significantly between the pyrimethamine arm (11.9%) and the placebo arm (13.1%), Hazard Ratio (HR) = 0.94 (95% Confidence Interval (CI) = 0.62-1.42), whereas an on-treatment analysis resulted in a significant difference: 4.2% in the pyrimethamine arm and 12.4% in the placebo arm, HR = 0.44 (95% CI = 0.24-0.80). The data showed a significant interaction between compliance and treatment outcome; and side effects were more frequently cited as reasons for compliance violations in the pyrimethamine group. Several different analytic approaches (censoring data at the time patients discontinued the study medication only for selected reasons) failed to explain the disparity between the estimation of effect of pyrimethamine by the intention-to-treat and on-treatment analyses. This experience led us to believe that comparing the results of both analyses was the best method to convince clinicians that intention-to-treat was the only interpretable analysis. We were concerned that even if pyrimethamine had a beneficial effect, it was very difficult (1) to quantify and (2) to apply to clinical practice unless one could predict the occurrence of study drug discontinuation for each patient at the time of treatment assignment. Although exploratory analyses may yield clinically relevant information and useful clarifications in the evaluation of treatments, intention-to-treat remains the only interpretable analysis of clinical trials.

A low-protein diet improves insulin sensitivity of endogenous glucose production in predialytic uremic patients.

A low-protein, low-phosphorus diet (LPD) has been shown to improve insulin sensitivity in uremic patients; however, this improvement has not been studied at low physiologic concentrations of plasma insulin, and the metabolic pathways concerned with this improvement have not been located. We used the glucose clamp technique at a low (0.25 mU.kg-1.min-1) level of hyperinsulinemia associated with the infusion of D[6,6-2H2] glucose to assess the insulin sensitivity of endogenous glucose production (EGP). Eight nondialyzed uremic patients were studied before and after 3 mo on an LPD providing 0.3 g/kg protein, 5-7 mg P/kg, and 146 kJ/kg (67% of energy as carbohydrates and 30% as lipids) per day, supplemented with ketoanalog amino acids. Postabsorptive plasma glucose and insulin declined after 3 mo of the diet (plasma glucose: 5.0 +/- 0.1 mmol/L before compared with 4.7 +/- 0.1 mmol/L after the LPD, P < 0.05; plasma insulin: 82.4 +/- 20.7 pmol/L before compared with 48.8 +/- 6.0 pmol/L after, P < 0.05). Postabsorptive glucose turnover rates did not change with the diet (2.06 +/- 0.14 mg.kg-1.min-1 before compared with 2.11 +/- 0.17 mg.kg-1.min-1 after LPD; NS). The insulin metabolic clearance rate was enhanced after the diet, so a lower level of hyperinsulinemia was obtained during the clamp (168.8 +/- 28.1 pmol/L before compared with 115.2 +/- 14.7 pmol/L after; P < 0.05). However, EGP was more easily inhibited after the diet (0.90 +/- 0.31 mg.kg-1.min-1 before compared with 0.30 +/- 0.17 mg.kg-1.min-1 after; P < 0.05), providing evidence of an improved insulin sensitivity of this parameter. This beneficial influence takes place at a physiologic level of hyperinsulinemia, and it probably plays an important role in the better glucose tolerance that has been reported in uremic patients on an LPD. An abnormal insulin sensitivity of EGP may participate in the disturbances of glucose metabolism in chronic renal failure.

Survival after AIDS-defining events in patients with < 200 lymphocytes CD4+ x 10(6)/L who are toxoplasmosis antibody positive. ANRS 005/ACTG 154 Trial Group.

The objective of this study was to assess whether patients with CD4+ cell counts <200 x 10(6)/L have a decreased survival after the occurrence of any AIDS-defining event; 187 patients from the placebo arm of a clinical trial of toxoplasmosis prophylaxis (ANRS005-ACTG154) were included. For this analysis, patients were HIV infected without any AIDS-defining event, had a CD4+ lymphocyte count < 200 x 10(6)/L, had a positive serology for Toxoplasma gondii, and had no severe liver, renal, or hematologic abnormalities. We used proportional hazards regression to study the relationships between baseline variables. AIDS-defining events as time-dependent variables, and survival. The risk of dying was increased by 1.9 for a 10-year increase in age and by 1.3 when CD4+ decreased by 50 x 10(6)/L; after the occurrence of a pneumocystosis, a cytomegalovirus infection, or a toxoplasmosis, the risk of dying was multiplied, respectively, by 10.9 (3.0-40.2), 10.0 (2.8-35.4), and 10.0 (4.5-22.2). None of the other AIDS-defining events was associated with an increased risk of dying, but the power to detect such an association was limited. We conclude that the occurrence of pneumocystosis, cytomegalovirus infection, or toxoplasmosis; age; and CD4+ cell count are important determinants of survival for HIV1-infected patients with CD4+ counts < 200 x 10(6)/L who are toxoplasmosis antibody positive.

Low protein diet in uremia: effects on glucose metabolism and energy production rate.

Low-protein diets (LPD) increase insulin-mediated glucose disposal in chronic renal failure (CRF), but the fate of the better utilized glucose and the effect on energy production rate are unknown. Using a two-step (1 and 5 mU x kg(-1) x min(-1)) euglycemic hyperinsulinemic clamp combined with indirect calorimetry, we studied the effects of a LPD (0.3 g x kg(-1) x day(-1), supplemented with essential amino acids and ketoanalogs) in six patients suffering from chronic renal failure. After three months of diet, no significant change was observed concerning glomerular filtration rate, body wt, or arterial pH. In the postabsorptive state, plasma glucose and insulin levels were significantly lower, and energy production rose from 15.72 +/- 0.48 to 17.16 +/- 0.67 Cal x kg(-1) x min(-1) (P < 0.05). Insulin-stimulated glucose oxidation (2.36 +/- 0.29 vs. 3.37 +/- 0.35 mg x kg(-1) x min(-1); P < 0.05 at first clamp step) and nonoxidative disposal (P < 0.05 at both clamp steps) increased after LPD. This confirms that LPD ameliorates insulin sensitivity in CRF, even for low plasma insulin concentrations. Since energy production rate is increased by LPD, the caloric intake should be increased when protein intake is restricted.

Increased risk of toxoplasmic encephalitis in human immunodeficiency virus-infected patients with pyrimethamine-related rash. ANRS 005-ACTG 154 Trial Group. Agence Nationale de Recherche sur le SIDA (ANRS-INSERM) and the NIAID-AIDS Clinical Trials Group.

Although drug-induced rash is frequent in human immunodeficiency virus (HIV)-infected patients, rash due to pyrimethamine has not been described previously. In a randomized, double-blind, placebo-controlled study of pyrimethamine as primary prophylaxis for toxoplasmic encephalitis, the incidence of rash (per hundred patient-years) was 8.1 in the pyrimethamine group versus 1.5 in the placebo group (P < .0002). The 1-year incidence of toxoplasmic encephalitis after occurrence of rash was 37%, as compared with 9.6% in the pyrimethamine group without rash, with a 3.7 times higher risk for patients with pyrimethamine-induced rash (P = .001); the incidence was 13% in the placebo group. At the time of toxoplasmic encephalitis, pyrimethamine was successfully readministered to 80% of patients who discontinued it because of rash. Thus, pyrimethamine, when used for prophylaxis, does induce rash in HIV-infected patients. These patients are at higher risk for toxoplasmic encephalitis and should be carefully monitored for it.

[Prevalence of clinical manifestations of allergic reactions in HIV infection. Cross sectional study of 115 subjects]. / Prévalence des manifestations cliniques évocatrices d'allergie au cours de l'infection par le VIH. Etude transversale de 115 sujets.

A cross sectional survey was set up to study the relation between the prevalence of allergic-type reactions during HIV infection course. For each patient, a standardized interview about recent allergic-type manifestations (RATM), skin prick-tests to six common airborne allergens, IgE serum level were done. Among the 115 included patients, the mean CD4 lymphocyte count (CD4) was 214.7/mm3 (range: 0-1328/mm3). RATM were found in 8.8% of patients with CD4 < 50, in 30% of patients with CD4 between 51 and 200, in 36% of patients with CD4 between 201 and 350 and in 11.5% of patients with CD4 < 350 (p = 0.03). The risk of presenting RATM was 4.8 times (95% confidence interval = 1.7-13.5) higher in patients with CD4 between 51 and 350 than in other patients (p = 0.003). The proportion of positive prick-tests did not significantly vary according to the level of CD4. The increased frequency of RATM in patients with CD4 between 51 and 350/mm3 could be due to an allergic predisposition acquired during the course of HIV infection. The mechanisms explaining the reduced frequency of allergic manifestations when immunodeficiency is profound (CD4 < 50/mm3) remain to be explained.

Lipid-carbohydrate interactions in post-absorptive non-insulin-dependent diabetic patients.

Substrate competition is an important mechanism of insulin resistance, although its role in the post-absorptive hyperglycemia of NIDDM is not clear: lipid infusion does not raise plasma glucose levels in normal subjects, and total lipid oxidation, the elevation of which is a hallmark of disrupted carbohydrate metabolism, is normal in non-insulin-dependent diabetes mellitus (NIDDM). To examine further these two arguments against the involvement of lipid-carbohydrate interactions in the hyperglycemia of NIDDM, we compared the effect of a 3-hour lipid infusion ('Ivélip') on post-absorptive blood glucose levels, plasma lipids and respiratory exchanges in 15 patients with NIDDM, with that of an infusion of saline in 15 other patients with similar metabolic profiles. The lipid infusion significantly slowed the natural post-absorptive decline in blood glucose levels (saline -0.47 +/- 0.14 and Ivélip -0.10 +/- 0.12 mmol.l-1.h-1, p < 0.05), with marked interindividual differences. Substrate oxidation rates were unchanged during saline infusion, and were immediately (within 30 min) and reciprocally modified by the lipid infusion (lipid oxidation enhanced: 0.90 +/- 0.14 to 1.06 +/- 0.13 mg.kg-1.min-1 at time 30 min, p < 0.05; glucose oxidation inhibited: 1.27 +/- 0.19 to 0.87 +/- 0.18, p < 0.05), but this was not correlated with the alteration in blood glucose levels. In contrast, the increase in plasma lipids was continuous, and positively correlated with the change in blood glucose levels (r = 0.58, p < 0.05 for change of plasma free fatty acids; r = 0.55, p < 0.05 for change of plasma triglycerides, TGs). In line with the Randle mechanism, the lipid infusion affected oxidation rates, but another mechanism, depending on intravascular lipolysis of the infused TGs, was thought to occur in certain individuals whose blood glucose levels rose during the infusion.

[Lactic acidosis and hepatic mitochondrial changes during a treatment with zidovudine]. / Acidose lactique et altérations mitochondriales hépatiques au cours d'un traitement par zidovudine.

Adverse effects of zidovudine, which mainly result in myopathies and hematological disorders, could be due to multitissular mitochondrial toxicity of the drug. During zidovudine treatment, most cases of lactic acidosis have been attributed to mitochondrial myopathy. We report a case of hepatocellular failure with lactic acidosis in a 33 year-old patient with the human immunodeficiency virus infection and treated with zidovudine for 8 months. Liver biopsy showed massive macrovacuolar steatosis and ultrastructural mitochondrial abnormalities similar to those previously described in the skeletal muscle. This is the second reported case of lactic acidosis and hepatocellular failure which is probably related to hepatic mitochondrial dysfunction caused by zidovudine.

Extensive spread of a squamous cell carcinoma in situ of the esophagus: an unusual case.

A case of extensive squamous cell carcinoma in situ along the esophageal height in a 58-yr-old female is presented. After subtotal esophagectomy, the course was favorable 11 months later. The pathological study of the specimen showed that the tumor was confined to the epithelium. The lesion was located diffusely along the entire esophageal height and one-third of its circumference. Neither foci of dysplasia or inflammatory erosions nor metastatic nodes were observed. Problems pertaining to the terminology, histopathological interpretation, pathogenesis, and management of such unusual lesion are reviewed. The necessity of large radical resection of the esophagus was validated upon histological confirmation that the resected stump is cancer free.

Predictive value of Toxoplasma gondii antibody titres on the occurrence of toxoplasmic encephalitis in HIV-infected patients. ANRS 005/ACTG 154 Trial Group.

OBJECTIVE: To study the predictive value of anti-Toxoplasma gondii antibody titres for the occurrence of toxoplasmic encephalitis (TE) in HIV-infected patients. METHODS: Data from the placebo arm of a trial of primary prophylaxis for TE (ANRS 005/ACTG 154) were analysed. Patients included had CD4+ cell counts < 200 x 10(6)/l and a positive Toxoplasma serology. Immunoglobulin (Ig) G and IgM Toxoplasma antibody titres at entry were retrospectively determined by enzyme-linked immunosorbent assay and agglutination on serum samples in a single laboratory. Incidence of TE was estimated by Kaplan-Meier method and a Cox model was used to study the predictive value of antibody titres, adjusted for other covariates. RESULTS: All 164 patients studied were positive for IgG antibodies and one had IgM antibodies. After a mean follow-up of 16 months, 31 cases of TE were documented. One-year incidence of TE was significantly higher in patients with IgG titres > or = 150 IU/ml (23.7%) than in patients with titres < 150 IU/ml (7.7%; relative risk, 3.1; P < 0.003). IgG titres remained significantly associated with the occurrence of TE (relative risk, 3.3; P < 0.005) in the Cox model. Predictive value of IgG titres did not differ according to baseline CD4+ cell counts. CONCLUSIONS: In patients with CD4+ cell counts < 200 x 10(6)/l, IgG anti-Toxoplasma antibody titre is a prognostic factor of occurrence of TE, with a higher risk for titres > or = 150 IU/ml. This finding should reinforce the recommendation of specific prophylaxis in these patients.

Evolution of tumor necrosis factor-alpha serum concentrations in HIV infected individuals treated with zidovudine.

We studied the evolution of Tumor Necrosis Factor-alpha serum concentration (TNF-alpha) and CD4+ lymphocyte counts (CD4+) in a pilot cohort study of HIV-infected patients during the first year of zidovudine therapy. Data on 17 patients remaining asymptomatic during the one-year follow-up period (non progressors) were analysed. Serum samples were obtained at entry and at each follow-up visit (1, 3, 6, 9 and 12 months). TNF-alpha was quantified in pg/ml using a very sensitive radioimmunoassay (Medgenix). All patients had increased TNF-alpha at entry (median: 26.4 pg/ml). TNF-alpha decreased significantly as soon as the first month of therapy (median: 16 pg/ml). A steady state was then observed until Month 6 (median: 17.5 pg/ml), from which a slow increase appeared, without reaching the initial level (median at Month 9: 21.3, at Month 12: 19.8). During the same time, less sustained changes in CD4+ lymphocytes count and beta-2 microglobulin level were observed. The results of this pilot study suggest that, during HIV infection treated course, TNF-alpha could potentially be an additional surrogate marker to CD4+ lymphocyte count.

Endoscopic ultrasonography immediately prior to laparoscopic cholecystectomy: a prospective evaluation.

BACKGROUND AND STUDY AIMS: In patients who are highly likely to have common bile duct (CBD) stones, it seems necessary to image the biliary tract before laparoscopic cholecystectomy, and endoscopic ultrasonography (EUS) is one way of doing this. The aim of this study was to compare immediate preoperative EUS to intraoperative cholangiography for imaging the CBD and for the diagnosis of CBD stones, in a population with a high risk of choledocholithiasis (as assessed by clinical, biochemical, and ultrasound criteria). PATIENTS AND METHODS: From January 1993 to August 1995, EUS was carried out in the operating room in 50 patients (11 men, 39 women; mean age 57 years) before laparoscopic cholecystectomy for symptomatic choledocholithiasis. A diagnosis of CBD stones by EUS or intraoperative cholangiography was always confirmed by instrumental exploration. An absence of stones in the CBD was established by a negative EUS and intraoperative cholangiography, as well as normal findings at clinical monitoring three months after laparoscopic cholecystectomy. RESULTS: EUS visualized the CBD in 100% of cases. Intraoperative cholangiography was successful in 94% of cases (n = 47 of 50), and after conversion to open laparotomy in eight patients. CBD stones were found in 12 patients (24%). The sensitivity, specificity, and positive and negative predictive values for EUS were 100%, 97%, 92%, and 100%, respectively. CONCLUSIONS: Immediate preoperative EUS may make it possible to select the best form of treatment in patients with CBD stones, avoiding inappropriate laparoscopic instrumental CBD exploration.

Dieulafoy's ulcer: combined endoscopic and laparoscopic treatment.

Dieulafoy's disease is a rare, but dangerous cause of upper gastrointestinal hemorrhage. We report here the case of a patient in whom the failure of endoscopic therapy necessitated a surgical approach by combining endoscopy and laparoscopy. The intraoperative endoscopic examination located the site of the lesion precisely, allowing a limited adapted wedge resection to be carried out laparoscopically.

Measurement of post-absorptive glucose kinetics in non-insulin-dependent diabetic patients: methodological aspects.

Post-absorptive glucose metabolism was studied in non-insulin-dependent diabetes mellitus (NIDDM) patients and normal subjects using dideuterated glucose as tracer. From the progressive fall in blood glucose levels and the increase in isotopic enrichment, the post-absorptive situation could not be regarded as a steady state for glucose metabolism, and non-steady-state approximations had therefore to be applied. However, this did not alter significantly the results in the 10 NIDDM patients studied. Significantly higher values of endogenous glucose production (EGP) were obtained (178 center dot 1 +/- 24 center dot 0 mg m-2 min-1 vs. 80 center dot 2 +/- 14 center dot 4; P < 0 center dot 01) if the tracer priming dose was not adapted to the degree of hyperglycaemia. Valid measurements could be made after only 1 h isotopic equilibration time if an appropriately matched priming dose was employed. Methodologically acceptable values for EGP in the 10 NIDDM patients did not differ significantly from those of 10 normal control subjects (80 center dot 2 +/- 14 center dot 4 mg m-2 min-1 vs. 85 center dot 6 +/- 3 center dot 9; not significant). The post-absorptive hyperglycaemia in these patients was assumed to stem essentially from a defect in peripheral glucose uptake.