Under-prescription of statins in patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is a common disease associated with high cardiovascular risk. Management of dyslipidaemia plays a pivotal role in the prevention of CV events and statins have proved to be safe in these patients. However, in everyday clinical practice statin prescription is sometimes limited because of the concern of physicians about side-effects. The aim of the study was to investigate if the presence of NAFLD affects the prescription of lipid-lowering treatment in a large series of patients with cardio-metabolic disorders. METHODS AND RESULTS: Cardiovascular risk and LDL-C targets were defined according to ESC/EAS Guidelines in 605 consecutive adult subjects referred for screening of suspected metabolic diseases. Liver steatosis was assessed by ultrasound Hamaguchi criteria. In the whole cohort, 442 patients had indication for cholesterol-lowering treatment. Lack of statin prescription was present in 230 (52.0%) patients. Of these, 77 (33.5%) were very high-risk, 48 (20.8%) high-risk, and 105 (45.6%) moderate risk patients. Only 44% of the NAFLD patients with indication for statin treatment were on therapy. NAFLD patients on statin treatment had significantly lower ALT values as compared to those not on treatment (p < 0.05). CONCLUSIONS: Our findings show that about 50% of patients with indication to statin treatment do not receive any cholesterol-lowering medication. Statin under-use was particularly high in subjects with NAFLD. Use of statin treatment should be encouraged in the context of NAFLD, as it may improve lipid profile and reduce the cardiovascular risk in this setting.

Effects of dark chocolate on endothelial function in patients with non-alcoholic steatohepatitis.

BACKGROUND AND AIM: Oxidative stress plays a pivotal role in inducing endothelial dysfunction and progression from simple fatty liver steatosis (FLD) to non-alcoholic steatohepatitis (NASH). Polyphenols could reduce oxidative stress and restore endothelial function by inhibiting the nicotinamide-adenine-dinucleotide-phosphate (NADPH) oxidase isoform Nox2. The aim of this study was to assess endothelial function and oxidative stress in a population affected by simple FLD and NASH. Furthermore, we analysed the effect of high vs low content of cocoa polyphenols on endothelial function and oxidative stress in patients with NASH. METHODS: In a cross-sectional study we analysed endothelial function, as assessed by flow-mediated dilation (FMD), and oxidative stress, as assessed by Nox2 activation, serum isoprostanes and nitric oxide bioavailability (NOx), in patients with NASH (n = 19), FLD (n = 19) and controls (n = 19). Then, we performed a randomized, cross-over study in 19 subjects with NASH comparing the effect of 14-days administration of 40 g of chocolate at high (dark chocolate, cocoa >85%) versus low content (milk chocolate, cocoa <35%) of polyphenols on FMD and oxidative stress. Compared to controls, NASH and FLD patients had higher Nox2 activity and isoprostanes levels and lower FMD and NOx, with a significant gradient between FLD and NASH. The interventional study showed that, compared to baseline, FMD and NOx increased (from 2.9 ± 2.4 to 7.2 ± 3.0% p < 0.001 and from 15.9 ± 3.6 to 20.6 ± 4.9 µM, p < 0.001, respectively) in subjects given dark but not in those given milk chocolate. A simple linear regression analysis showed that Δ (expressed by difference of values between before and after 14 days of chocolate assumption) of FMD was associated with Δ of Nox2 activity (Rs = -0.323; p = 0.04), serum isoprostanes (Rs: -0.553; p < 0.001) and NOx (Rs: 0.557; p < 0.001). CONCLUSIONS: Cocoa polyphenols improve endothelial function via Nox2 down-regulation in NASH patients.

Low-grade endotoxemia, gut permeability and platelet activation in patients with impaired fasting glucose.

BACKGROUND AND AIM: Impaired fasting glucose (IFG) is associated with an increased risk of cardiovascular disease but the underlying mechanisms are still unclear. Aim of the study was to investigate the interplay between platelet activation, lipopolysaccharides (LPS) and markers of oxidative stress in patients with IFG and control subjects. METHODS AND RESULTS: We performed a cross-sectional study including 35 patients with IFG and 35 control subjects who were well comparable for age, sex, body mass index and smoking history. Serum levels of LPS, zonulin (a marker of gut permeability), oxidized LDL and plasma levels of soluble P-selectin, were measured. Patients with IFG had significantly higher levels of sP-selectin, LPS, zonulin and oxLDL compared to control subjects. The IFG status (beta coefficient: 0.518, p < 0.001), higher LPS (beta coefficient: 0.352, p = 0.001) and female sex (beta coefficient: 0.179, p = 0.042) were independently associated with higher sP-selectin; in addition, oxLDL was positively associated with sP-selectin (r = 0.530, p < 0.001) and LPS (r = 0.529, p = 0.001). In IFG patients, we found a significant association between LPS and zonulin (r = 0.521, p = 0.001); this association was confirmed at multivariable analysis (beta coefficient: 0.512, p = 0.007). CONCLUSION: Our study provides evidence that patients with IFG have increased platelet activation, and suggests LPS as a potential trigger for in vivo platelet activation in this patient population.

The vitamin D receptor (VDR) gene rs11568820 variant is associated with type 2 diabetes and impaired insulin secretion in Italian adult subjects, and associates with increased cardio-metabolic risk in children.

BACKGROUND AND AIMS: 1α,25-dihydroxyvitamin-D3, the biologically active vitamin D, plays a central role in several metabolic pathways through the binding to the vitamin D receptor (VDR). VDR has been shown to be involved in cardiovascular diseases, cancer, autoimmunity and type 2 diabetes mellitus (T2DM). Several polymorphisms in the VDR gene have been described. Among these, the rs11568820 G-to-A nucleotide substitution was found to be functional, modulating the transcription of the VDR gene. Objective of this study was to perform an association study between rs11568820 polymorphism and T2DM in a cohort of Italian adults with T2DM and in non-diabetic controls. To add further insight into the role of VDR gene we explored whether this association begins early in life in overweight/obese children, or becomes manifest only in adulthood. METHODS AND RESULTS: As many as 1788 adults and 878 children were genotyped for the rs11568820 polymorphism. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose and insulin levels. Indices of insulin-resistance and secretion were also calculated. The AA genotype was significantly more frequent in adults with T2DM compared to controls (7.5% vs. 4.6%, P = 0.037), and conferred a higher risk of T2DM (ORHom = 1.69C.I. = [1.13-2.53], P = 0.011). In the adult cohort, rs11568820 was also associated with reduced indices of ß-cell insulin secretion. In children, the AA genotype was associated with 2 h high-normal glucose, a marker of cardio-metabolic risk. CONCLUSIONS: Our study demonstrates for the first time that VDR gene AA carriers have higher risk of T2DM and impaired insulin secretion. In children, the association between AA homozygous and high-normal 2h glucose suggests that mild alterations associated with this genotype may appear early in life.

Adipose tissue fatty acid composition and colon cancer: a case-control study.

PURPOSE: An increased dietary intake of fat, particularly polyunsaturated fatty acids (PUFAs), has been related to an increased risk of breast, prostate and colon cancers. Patients with and without colon cancer were tested for differences in their fatty stores composition. METHODS: The fatty acid levels were determined by gas-liquid chromatography in adipose tissue samples, subcutaneous and visceral, obtained intra-operatively from 52 colon cancer and 50 nonneoplastic abdominal disease patients. Statistical analysis was performed using one-way ANOVA, SNK test and Dunnet test. Differences in the composition of saturated, monounsaturated and polyunsaturated fatty acids, in visceral and in subcutaneous samples of colon cancer and nonneoplastic patients, were assessed. RESULTS: The sum of saturated and monounsaturated fatty acids, respectively, in visceral and in subcutaneous samples, was higher in neoplastic patients (p < 0.001). The sum of some n-6 polyunsaturated fatty acids (PUFAs), the dietary precursor linoleic acid (LA-18:2n-6), and their metabolites, gammalinolenic acid (GLA-18:3n-6) + dihomogammalinolenic acid (DGLA-20:3n-6) + arachidonic acid (AA-22:4n-6), was higher in subcutaneous fat of controls (p < 0.05). The samples from these patients had a fatty acid composition, both subcutaneous and visceral, with a higher content of alphalinolenic acid (ALA-18:3n-3) and stearidonic acid (SDA-18:4n-3) compared to neoplastic patients (p < 0.001). These had subcutaneous and visceral fat stores statistically higher in GLA, DGLA and AA (p < 0.001). Colon cancer patients had subcutaneous adipose stores higher in ALA and LA than visceral sites (p < 0.001). CONCLUSIONS: Fatty acids may be involved in colon carcinogenesis and there is a depot-specific impact on this process by visceral fat.

Antioxidant supplements for non-alcoholic fatty liver disease and/or steatohepatitis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterised by fatty deposition in the hepatocytes of patients with minimal or no alcohol intake and without other known cause. NAFLD includes a wide spectrum of histologic abnormalities ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH), or even cirrhosis. Antioxidant supplements, therefore, could potentially protect cellular structures against oxidative stress and the resulting lipid peroxidation. OBJECTIVES: To systematically evaluate the beneficial and harmful effects of antioxidant supplements versus no intervention, placebo, or other interventions for patients with NAFLD or NASH. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (June 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 2, 2006), MEDLINE (1966 to June 2006), EMBASE (1980 to June 2006), and the Chinese Biomedical Database (1978 to June 2006). No language restrictions were applied. SELECTION CRITERIA: Randomised clinical trials evaluating any antioxidant supplements versus no intervention, placebo, or other interventions in patients with NAFLD or NASH. Our inclusion criteria for NAFLD or NASH were based on history of minimal or no alcohol intake, imaging techniques showing hepatic steatosis, and/or histological evidence of hepatic damage (including simple steatosis, fatty infiltration plus nonspecific inflammation, steatohepatitis, fibrosis, and cirrhosis), and by exclusion of other causes of hepatic steatosis. DATA COLLECTION AND ANALYSIS: We extracted data from the identified trials and contacted authors. We used a random-effects model and fixed-effect model with the significant level set at P = 0.05. We evaluated the methodological quality of the randomised trials by looking at how the generation of allocation sequence, allocation concealment, blinding, and follow-up were performed. We made our analyses following the intention-to-treat method by imputing missing data. MAIN RESULTS: We identified six trials: two were regarded of high methodological quality and four of low methodological quality. None of the trials reported any deaths. Treatment with antioxidant supplements showed a significant, though not clinically relevant, amelioration of aspartate aminotransferase levels, but not of alanine aminotransferase levels, as compared to placebo or other interventions. Gamma-glutamyl-transpeptidase was decreased, albeit not significantly, in the treatment arm. Radiological and histological data were too limited to draw any definite conclusions on the effectiveness of these agents. Adverse events were non-specific and of no major clinical relevance. AUTHORS' CONCLUSIONS: There is insufficient data to either support or refute the use of antioxidant supplements for patients with NAFLD. It may be advisable to carry out large prospective randomised clinical trials on this topic.

Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. It is suspected in persons with elevated aminotransferase levels and features of insulin resistance (or metabolic) syndrome. The pathogenesis of NAFLD is not clear and there is no universal treatment. OBJECTIVES: To assess beneficial and harmful effects of drugs improving insulin resistance for NAFLD and/or NASH. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and The Chinese Biomedical Database until February 2006. SELECTION CRITERIA: We included randomised clinical trials assessing the effects of drugs improving insulin resistance for patients with NAFLD or NASH. DATA COLLECTION AND ANALYSIS: We evaluated the methodological quality of the randomised clinical trials by the generation of the allocation section, allocation concealment, and follow-up. Two independent observers extracted data from each trial. Dichotomous outcomes were reported as odds ratio (OR) with 95% confidence interval (CI). MAIN RESULTS: Only three randomised clinical trials could be included. Two of the trials had unclear allocation concealment. None was blinded regarding outcome assessment. In two trials, metformin was associated with significantly higher normalization of serum alanine aminotransferase (OR fixed 2.83, 95% CI 1.27 to 6.31 versus diet and OR fixed 7.75, 95% CI 2.37 to 25.35 versus vitamin E) and improvement of liver echographic response (OR fixed 5.25, 95% CI 1.09 to 25.21). An improvement of fatty infiltration was observed in a limited number of patients undergoing liver biopsy. In the single pioglitazone trial, a statistically significant improvement of NASH histology was demonstrated. AUTHORS' CONCLUSIONS: At present, there is insufficient data to either support or refute the use of drugs improving insulin resistance for patients with NAFLD, although current limited information suggests a favourable role of drugs improving insulin resistance. It is advisable to carry out large randomised trials on this topic employing clinically relevant outcome measures and adequate methodology, including blinded outcome assessment.

Epidemiological evidence for the non-random clustering of the components of the metabolic syndrome: multicentre study of the Mediterranean Group for the Study of Diabetes.

OBJECTIVE: To determine: (a) whether the components of metabolic syndrome (MetS) cluster more frequently than predicted by chance alone and (b) whether increased risk for MetS is associated also with values of each component below, but close to the cutoff points defining MetS. RESEARCH DESIGN AND METHODS: Anthropometrical and biochemical measurements were performed and a dietary questionnaire was filled-in in 1833 randomly selected non-diabetic subjects, 916 men and 917 women, 20-74 years old, in nine centres in five Mediterranean countries. The prevalence of MetS and of possible combinations of its individual components was measured. The expected frequencies of the above combinations were calculated according to the mathematical formula of probabilities. RESULTS: The overall prevalence of MetS was 27.2%, but varied greatly among countries, from 5.8% in Algeria to 37.3% in Greece. The observed prevalence of each combination diagnostic of MetS was higher than the expected by chance. Thus, the observed overall prevalence of MetS was also higher than the expected, 27.2 vs 24.0%, P=0.03. Furthermore, for each individual component (except high-density lipoprotein), as values in the normal range, approached the cutoff point, the risk of having MetS (i.e. clustering of the other components) increased significantly (odds ratio 2.2-4.6, P<0.001). CONCLUSIONS: The MetS is not related to the Mediterranean type of diet and its prevalence varies greatly among five Mediterranean countries. The clustering of the components defining the MetS is not due to chance and moreover even 'high normal' levels of each component confer increased risk for the syndrome.

Effects of dark chocolate on NOX-2-generated oxidative stress in patients with non-alcoholic steatohepatitis.

BACKGROUND: Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is considered a pathogenetic mechanism determining fibrosis and disease progression in non-alcoholic steatohepatitis (NASH). Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans. AIM: To analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH. METHODS: In a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (>85% cocoa) or 40 g/day of milk chocolate (<35% cocoa), for 2 weeks. sNOX2-dp, serum isoprostanes and CK-18 were assessed at baseline and after 2 weeks of chocolate intake. RESULTS: Compared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels. A significant difference for treatments was found in subjects with respect to sNOX2-dp, serum isoprostanes and serum CK-18. The pairwise comparisons showed that, compared to baseline, after 14 days of dark chocolate intake, a significant reduction in sNOX2-dp serum isoprostanes and CK-18 M30 was found. No change was observed after milk chocolate ingestion. A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes. CONCLUSION: Cocoa polyphenols exert an antioxidant activity via NOX2 down-regulation in NASH patients.

Insulin resistance, the metabolic syndrome, and nonalcoholic fatty liver disease.

BACKGROUND/AIMS: An association of nonalcoholic fatty liver disease with the insulin-resistant metabolic syndrome has been suggested. The aim of the study was to assess the association of fatty liver to different degrees of insulin resistance and secretion. METHODS AND RESULTS: The study was performed in 308 alcohol- and virus-negative consecutive patients attending a metabolic clinic, who underwent a complete clinical and biochemical work-up including oral glucose tolerance test and routine liver ultrasonography. Steatosis was graded as absent/mild, moderate, and severe. In nondiabetic subjects, a progressive (P < 0.05) increase in mean homeostasis model of insulin resistance was recorded from the group without steatosis to the groups with mild/moderate and severe steatosis. Severe steatosis was associated with the clustering of the five clinical and biochemical features proposed for the clinical diagnosis of the metabolic syndrome. Subjects with the metabolic syndrome with a more pronounced insulin resistance had a higher prevalence of severe steatosis (P < 0.01) compared with those with homeostasis model of insulin resistance below the median. CONCLUSIONS: The findings stress the heterogeneous presentation of patients with the metabolic syndrome when the diagnosis is based on the broad Adult Treatment Panel III clinical criteria and demonstrate that those who are more insulin resistant have a higher prevalence of severe steatosis.

Extra virgin olive oil use is associated with improved post-prandial blood glucose and LDL cholesterol in healthy subjects.

OBJECTIVES: Extra virgin olive oil (EVOO) is a key component of the Mediterranean diet and seems to account for the protective effect against cardiovascular disease. However, the underlying mechanism is still elusive. DESIGN: We tested the effect of EVOO, added to Mediterranean-type meal, on post-prandial glycemic and lipid profile. SUBJECTS: Post-prandial glycemic and lipid profile were investigated in 25 healthy subjects who were randomly allocated in a cross-over design to a Mediterranean-type meal added with or without 10 g EVOO (first study), or Mediterranean-type meal with EVOO (10 g) or corn oil (10 g; second study). Glycemic profile, which included glucose, insulin, dipeptidyl-peptidase-4 (DPP-4) protein and activity, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and lipid profile, which included, low-density lipoprotein (LDL) cholesterol (LDL-C), oxidized LDL (ox-LDL), triglycerides and high-density lipoprotein (HDL) cholesterol (HDL-C), were analyzed before and 2 h after the meal. RESULTS: In the first study, 2 h after meal, subjects who assumed a meal with EVOO had significantly lower blood glucose (P<0.001), DPP-4 protein (P<0.001) and activity (P<0.001), LDL-C (P<0.001) and ox-LDL (P<0.001) and higher insulin (P<0.05), GLP-1 (P<0.001) and GIP (P<0.05) compared with those without EVOO. The second study showed that compared with corn oil, EVOO improved both glycemic and lipid profile. Thus, a significantly smaller increase of glucose (P<0.05), DPP4 protein (P<0.001) and activity (P<0.05) and higher increase of insulin (P<0.001) and GLP-1 (P<0.001) were observed. Furthermore, compared with corn oil, EVOO showed a significantly less increase of LDL-C (P<0.05) and ox-LDL (P<0.001). CONCLUSIONS: We report for the first time that EVOO improves post-prandial glucose and LDL-C, an effect that may account for the antiatherosclerotic effect of the Mediterranean diet.

Erythrocyte fatty acid composition and gallstone disease: results of an epidemiological survey.

Within a cross-sectional study on the epidemiology of gallstone disease (GD) and its related factors, relation of GD to habitual dietary fat types has been investigated. Gallbladder status was assessed by ultrasound; fatty acid composition of the habitual diet was estimated by GLC of erythrocyte fatty acids. No differences in erythrocyte fatty acid composition were observed between women without gallstones, women with gallstones (aware and unaware of their condition), and women who had cholecystectomies. Multivariate analysis, including other diet-dependent and gallstone-related variables, showed no significant association between erythrocyte fatty acids and risk for gallstones. However, raised erythrocyte linoleic:saturated ratio was associated with increased risk for gallstones only in women with very low serum triglycerides. This latter finding needs further confirmation and is presently unexplainable. Our results suggest that dietary fatty acids do not play a major role in GD.

Circulating platelet aggregates in an adult population sample. Relationships with the main coronary risk factors and cardiovascular diseases.

We have determined the reversible circulating platelet aggregates (CPA) in a sample taken from the general population (414 consecutive individuals of both sexes, aged 20--60 years), examined during the initial screening of a multifactor primary prevention trial for coronary heart disease. Our findings show that in the overall population, less than 10% of circulating platelets occur as reversible aggregates. No differences were observed with regard to sex, age or presence of non-acute cardiovascular disease. No significant correlations were found between the extent of CPA and the main coronary risk factors.

Individual serum bile aids in patients with primary hyperlipoproteinemias.

Fasting serum concentrations of the individual bile acids were measured by gas chromatography in 27 patients with primary hyperlipoproteinemia (8 type IIa, 7 type IIb and 12 type IV) and in 14 healthy subjects. Total serum bile acid levels were 1618 +/- 244 ng/ml (SE) in type IIa, 1296 +/- 251 ng/ml in type IIb and 15609 +/- 263 ng/ml in type IV hyperlipoproteinemia. These values did not differ significantly from values in the control group (1505 +/- 200 ng/ml). Serum levels of cholic acid were significantly higher in patients with type IIa (551 +/- 78 ng/ml) than in those with type IIb (190 +/- 57 ng/ml, P < 0.01) and type IV (240 +/- 57 ng/ml, P < 0.02), while intermediate values were recorded in the control group (384 +/- 49 ng/ml). Ursodeoxycholic acid was found in larger amounts in hyperlipidemic patients than in controls. No significant differences with respect to other bile acids were observed between the groups examined. According to the current concepts on the enterohepatic circulation of bile acids, the findings support the hypothesis that the intestinal absorption of cholic acid may differ in various types of hyperlipoproteinemia.

Unfavourable effects of colchicine in combination with interferon-alpha in the treatment of chronic hepatitis C.

BACKGROUND: The prognosis of chronic hepatitis depends on the progression of hepatic fibrosis. AIM: To investigate whether the antifibrotic drug colchicine, in combination with interferon-alpha has a role in the treatment of chronic hepatitis C. METHODS: Sixty-five HCV-RNA positive patients with chronic hepatitis were randomized to receive interferon-alpha, 6 MU t.i.w. for 6 months followed by 3 MU t.i.w. for further 6 months, with or without the adjunct of colchicine, 1 mg o.d., 6 days a week, for 3 years. We report an interim analysis after the first 18 months. RESULTS: Thirty-four patients received interferon-alpha and 31 received interferon-alpha and colchicine. The two groups were comparable for baseline data, including HCV-RNA levels, genotypes and histological grading/staging. Drop-outs and side-effects were similar. The proportion of patients who achieved alanine transaminase normalization or undetectable HCV-RNA at month 6 was higher in the interferon-alpha (68% and 47%, respectively) than in the interferon-alpha plus colchicine group (32% and 23%, P=0.004 and P=0. 04, respectively). End-of-treatment biochemical and virological response occurred in 41% and 29% of the interferon-alpha and 19% and 10% of the combination group, respectively (P=0.05 and P=0.05). Sustained biochemical response occurred in 26% of the interferon-alpha and 6% of the interferon-alpha plus colchicine group (P=0.03), corresponding percentages of sustained HCV-RNA loss being 21% and 3% (P=0.04). CONCLUSIONS: The combination of colchicine and interferon-alpha worsens the effectiveness of interferon-alpha alone in HCV chronic hepatitis. These alarming findings prompted us to interrupt the trial at this stage.

A randomized controlled trial of amantadine plus interferon-alpha2a vs. interferon-alpha2a alone in naive patients with chronic hepatitis C randomized according to the early virological response to interferon-alpha2a monotherapy.

BACKGROUND: An early virological response to interferon-alpha treatment is a strong predictor of sustained response, but it has never been exploited to stratify patients in clinical trials. AIM: To evaluate the efficacy of amantadine plus interferon-alpha compared with interferon-alpha alone in naive patients with chronic hepatitis C who were randomized on the basis of the early virological response to interferon-alpha. METHODS: One hundred and eighty-one patients received recombinant interferon-alpha2a (3 MU three times weekly) for 2 months and 164 were evaluated for early (i.e. month 2) virological response. Hepatitis C virus (HCV) RNA-negative patients (n = 66) were randomized to receive 3 MU of interferon-alpha three times weekly, with or without amantadine (200 mg/day); HCV RNA-positive patients (n = 98) were randomized to receive 6 MU of interferon-alpha three times weekly, with or without amantadine (200 mg/day). HCV RNA-positive patients at 6 months discontinued treatment, and all others completed 12 months. RESULTS: At month 6, HCV RNA-negative patients made up 54.2% of the interferon + amantadine group and 42.0% of the monotherapy group (P = 0.07). At month 12, HCV RNA-negative patients made up 38.5% of the interferon + amantadine group and 28.4% of the monotherapy group (N.S.). The sustained virological response rates were 21.6% and 20.9%, respectively (N.S.). CONCLUSION: The addition of amantadine does not enhance the sustained virological response to interferon-alpha in naive patients with chronic hepatitis C; however, an additive effect of amantadine occurs in the first 6 months, mainly in patients without an early response to monotherapy. Early response to interferon-alpha is a strong predictor of sustained virological response.

Intersexual differences in the serum-free amino acid pattern of young adults, normal obese aged subjects.

In a group of ethnically homogeneous subjects, intersexual differences and the effect of ageing on the pattern of serum free amino acid were studied. The amount of the amino acids: valine, isoleucine, leucine, tyrosine, phenylalanine, glutamic acid and ornithine was significantly greater in young males than in young females. Such intersexual differences were not observed in aged subjects. When comparing a group of aged obese females with a control group, no difference in the pattern of serum free amino acid was observed.

Red blood cell fatty acid composition in a sample of Italian middle-aged men on free diet.

Within the framework of a project of primary prevention of coronary heart disease the erythrocyte fatty acid composition was determined in 140 Italian middle-aged men on free diet. The linoleic/oleic ratio ranged from 0.27 to 0.96 pointing out remarkable differences in dietary fat intake. A negative correlation was observed between erythrocyte linoleic/oleic ratio and plasma cholesterol levels. This gives indirect support to the validity of this ratio as an index of adherence to cholesterol-lowering diets in long-term studies.

INTERSALT in Italy: findings and community health implications.

In INTERSALT, an international cooperative study on electrolytes and blood pressure, significant associations were found, in the pooled data for 52 centres, between systolic BP and sodium (Na) excretion, body mass index (BMI), high alcohol intake and low potassium (K) excretion. We have assessed the status of the four Italian centres (Mirano, Gubbio, Bassiano, Naples) on these variables. The four centres examined a total of 794 men and women aged 20-59 years. Combined values were similar to overall INTERSALT levels for daily Na excretion (170 mmol) and BMI (25 kg/m2). The Italian centres had slightly higher potassium excretions (57 vs. 55 mmol/day), a higher prevalence of drinkers and a greater average alcohol consumption. Participants were divided into those below or above median levels of Na, K, BMI, and by alcohol intake (below or above 300 ml/week). Both systolic BP and diastolic BP were found to be lower in the more favourable stratum, for each variable. When all four factors were combined, those below median Na excretion and BMI, above median K, and with alcohol intake less than 300 ml/week had age-adjusted systolic BP 7.5 mmHg lower than those with less favourable levels of all four variables. The difference in adjusted diastolic BP was 4.3 mmHg. The data indicate the potential for lower population average BP with improved lifestyles.