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BACKGROUND AND OBJECTIVE: The impact of clinical guidelines (GL) on venous thromboembolism (VTE) prophylaxis was evaluated in a large Italian hospital with a before/after study. GL were effective in increasing the appropriateness of prophylaxis and in reducing VTE. Following this study, the aim was to estimate the impact of the adopted GL on costs and benefits through a cost-effectiveness analysis. METHODS: A decision-tree model was used to compare prophylaxis costs and effects before and after GL implementation. All patients were classified into four risk profiles (low, moderate, high, very high). Outcomes considered were: no event, asymptomatic VTE, symptomatic VTE, fatal pulmonary embolism and major bleeding. Patient risks and the probability of receiving prophylaxis were defined using data from the previous study. Outcome probabilities were derived from the literature. Regional Drg reimbursements and hospital figures were used for costing the events. RESULTS: Despite a marked increase in the number of patients receiving some form of prophylaxis, it was estimated that the introduction of GL reduced the average cost per patient related to VTE from euro210 to euro181 (-14%), with a parallel absolute decrease in VTE complications (-5%). Results are particularly relevant in the very-high-risk group. Sensitivity analysis confirmed the overall cost savings and gains in effectiveness. CONCLUSIONS: The implementation of locally adapted GL on VTE prophylaxis may lead to a benefit in terms of both costs and effects, especially for the highest-risk patients.

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BACKGROUND: Moderately elevated levels of homocysteine have been associated with an increased cardiovascular risk in type 2 diabetic patients. The role of methylenetetrahydrofolate reductase gene polymorphism is less clear. MATERIALS AND METHODS: We investigated the contribution of plasma homocysteine levels and the methylenetetrahydrofolate reductase gene polymorphism to the variability of carotid intima-media thickness in 124 consecutive Italian patients with type 2 diabetes mellitus. Fasting plasma homocysteine was measured by high-pressure liquid chromatography with an electrochemical detector; methylenetetrahydrofolate reductase genotypes were determined by polymerase chain reaction and restriction enzyme digestion. The carotid intima-media thickness was evaluated with high-resolution B-mode ultrasonography. RESULTS: Age, creatinine and plasma homocysteine levels showed a positive correlation with mean carotid intima-media thickness values, but only age and creatinine levels were still associated with mean carotid intima-media thickness values in the multivariate analysis. Plasma homocysteine levels were significantly higher in the patients bearing the 677T/677T genotype of the methylenetetrahydrofolate reductase polymorphism; mean carotid intima-media thickness values were not different in the three different methylenetetrahydrofolate reductase genotypes. CONCLUSION: In 124 Italian patients with type 2 diabetes mellitus, basal levels of plasma homocysteine, as well as methylenetetrahydrofolate reductase gene polymorphism, did not explain the variability of mean carotid intima-media thickness.

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BACKGROUND: To evaluate if being a twin is a condition at risk of developing metabolic abnormalities in the adult life 'per se' or as a consequence of the lower birth weight. METHODS: 48 monozygotic twins and 50 non-twin controls, both with parental diabetes, were compared; the two groups were comparable for age, sex and body mass index. RESULTS: Twins showed higher values of blood pressure, triglycerides, insulin resistance, fasting insulin, insulin AUCs and higher prevalence of the metabolic syndrome, and, inversely, lower birth weight. After adjustment for birth weight, no significant association was evident with the twin status. Birth weight was inversely associated with the presence of the metabolic syndrome or of at least one or more of its components, while the positive association with the twin status was not significant. CONCLUSIONS: Our data suggest that low birth weight is more relevant than the twin status as a risk factor for the metabolic syndrome and its components.

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OBJECTIVE: The aim of the study was to assess the relationship between QT interval prolongation and mortality in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: Data on survival after 5 years were obtained from 316 of 379 patients (83.3%) who took part in a study on the prevalence of diabetic neuropathy and QT interval prolongation. RESULTS: Mortality at 5 years was 6.32%. Patients who survived were significantly younger (P = 0.04), had a shorter duration of diabetes (P = 0.01), had lower systolic (P = 0.004) and diastolic (P = 0.03) blood pressure levels, and had a shorter QT interval corrected for the previous cardiac cycle length (QTc) (P = 0.000005) than subjects who died. In univariate analysis, patients had a higher risk of dying if they had a prolonged QTc (odds ratio [OR] 20.14 [95% CI 5.7-70.81) or if they were affected by autonomic neuropathy (3.55 [1.4-8.9]). QTc prolongation was the only variable that showed a significant mortality OR in multivariate analysis (24.6 [6.51-92.85]; P = 0.0000004). CONCLUSIONS: This is the first cohort-based prospective study indicating that QTc prolongation is predictive of increased mortality in type 1 diabetic patients.

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AIMS: To evaluate the role of environmental intra-uterine factors in determining the birthweights of twins with increased susceptibility to diabetes and discordant for abnormal responses to the oral glucose tolerance test (OGTT) and verify the possible association of within-pair birthweight differences and metabolic abnormalities in adult life. METHODS: Forty-six monozygotic (MZ) and 32 dizygotic (DZ) twins were enrolled; 13 MZ twins were discordant for impaired glucose tolerance (IGT) and/or hyperinsulinaemia compared to their co-twins. RESULTS: The 13 MZ discordant twins showed significantly lower birthweights than their normal co-twins (P < 0.001). When dividing all twins in those with the highest birthweights within the couple and those with the lowest, all subjects with abnormal OGTT were found in the latter group (P < 0.0001). Within-pair birthweight difference was significantly higher in MZ twins with abnormal OGTT and the metabolic syndrome compared to normal MZ twins. The relative risk of developing the metabolic syndrome was 8.7 (1.6-46.9) when comparing the higher tertile of within-pair birthweight differences (> or = 0.450 kg) to the two lower tertiles (< 0.450 kg). Logistic regression analysis confirmed within-pair birthweight difference as a significant predictor of abnormal responses to the OGTT and the metabolic syndrome. CONCLUSIONS: These data suggest a causative role for environmental intrauterine factors on the determination of birthweight and support the hypothesis that within-pair birthweight difference, rather than an absolute low birthweight, is responsible for the metabolic abnormalities in the adult life.

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OBJECTIVE: The increased prevalence of cardiovascular events in type 2-diabetic patients with micro- or macroalbuminuria is not completely explained by an excess of conventional risk factors for atherosclerosis. Genetic polymorphism within the platelet glycoprotein IIIa has been implicated in the etiology of acute coronary syndromes. We tested the hypothesis that the PI(A1/A2) polymorphism could in part account for the increased cardiovascular risk of type 2-diabetic patients with micro- or macroalbuminuria compared to normoalbuminuric diabetic patients. RESEARCH DESIGN AND METHODS: We have examined the PI(A1/A2) polymorphism of the platelet glycoprotein IIIa in type 2-diabetic patients: 94 with micro-, macroalbuminuria, and 94 with normoalbuminuria, matched for age, sex and body mass index. PI(A) genotypes were performed by polymerase chain reaction and restriction enzyme digestion. RESULTS: There was no significant difference in the prevalence of PI(A2)-positive genotypes (either PI(A1/A2) or PI(A2/A2)) in the two groups of patients (chi2 = 0.19, df = 1 , p = 0.66). CONCLUSIONS: These results suggest that carriage of the platelet glycoprotein IIIa PI(A2) allele does not contribute to explain the increased cardiovascular risk associated with micro- or macroalbuminuria in type 2 diabetes.

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BACKGROUND: A number of reports have investigated the association between various gene polymorphisms and the phenotypic expression of myocardial infarction. No investigations have evaluated the prognostic role of genetic factors in young people with premature coronary disease. The aim of this study was to investigate the influence of genetic factors compared with that of conventional risk factors on follow-up events in a population of Italian young adults with myocardial infarction. METHODS AND RESULTS: The study population consisted of 106 young patients (mean age 40 +/- 4 years, range 23 to 45 years) with diagnosis of acute myocardial infarction. Clinical and genetic data from the group of patients with events during follow-up were compared with those from patients without events. The following genetic polymorphisms were tested: angiotensin I converting enzyme, angiotensin II type I receptor, apolipoprotein E (ApoE), endothelial constitutive nitric oxide synthase, and platelet glycoprotein IIIa. Coronary angiography was performed in 94 patients. Coronary angiography showed coronary artery disease in 93% of patients. During follow-up (46 +/- 12 months, range 25 to 72) the overall combined end points (cardiac death, myocardial infarction, and revascularization procedures) accounted for 21 events. Family history of coronary artery disease, smoking, stenosis of the left anterior descending artery at coronary angiography, and ApoE polymorphism (presence of epsilon4 allele) were significantly more prevalent (univariate analysis) in the group of patients with events. Logistic multivariate analysis showed that ApoE polymorphism (P =. 004, odds ratio [OR] 6.8, 95% confidence interval [CI] 2 to 22), family history (P =.005, OR 8.3, 95% CI 2 to 35), smoking after acute myocardial infarction (P =.008, OR 10.9, 95% CI 2 to 62), and left anterior descending coronary artery disease (P =.02. OR 6.6, 95% CI 1.3 to 33) were independent predictors of adverse events. CONCLUSIONS: Myocardial infarction at a young age is commonly characterized by evidence of multiple cardiovascular risk factors and by a favorable prognosis in short- and medium-term follow-up. Evidence of significant disease at coronary angiography suggests the presence of a premature atherosclerotic process. ApoE polymorphism (presence of epsilon4 allele) appears to be a strong independent predictor of adverse events, suggesting a remarkable influence in the accelerated coronary disease.

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An excess of cardiovascular morbidity has been related to low birthweight. The aim of this study was to evaluate the relationship between low birthweight and levels of fibrinogen, lipoprotein(a), and albumin excretion rate, which are known risk factors for coronary artery disease. Seventy-two twins, with the same within-pair gender and normal glucose tolerance, were analyzed in order to avoid confounding factors, such as gestational age, birth order, or sex. Twins with the highest birthweights within the couple showed no significant difference of fibrinogen, lipoprotein(a), and albumin excretion rates compared with the twins with the lowest birthweights among the two co-twins. Moreover, no relevant correlation was found between birthweight and intra-pair birthweight differences and fibrinogen, lipoprotein(a), and albumin excretion rates. The lack of correlation between fibrinogen, lipoprotein(a), albumin excretion rate and birthweight, suggests that these factors do not contribute to the link between intrauterine malnutrition and increased cardiovascular risk.

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We investigated the possibility that the DNA HindIII polymorphism of human lipoprotein lipase (LPL) is associated with the severity of coronary artery disease (CAD) determined by angiography in young patients who survived a myocardial infarction (MI). Conflicting studies have explored the relationship linking CAD severity to the HindIII restriction site polymorphism at the LPL gene locus, and to our knowledge, no data are available from Italy. The patients were aged less than 45 years (mean age, 40.1 +/- 3.9 years); 83 were male and four were female. The 87 case-patients had a Q-wave or non-Q-wave infarction (67.3% and 32.7%, respectively); the MI was anterior (50.5%), lateral (41.7%), or inferior (7.8%). Analysis of coronary angiograms showed the absence of critical stenosis in 13.8% and the presence of monovessel disease in 50.6% and multivessel disease in 35.6% of the case-patients. The allelic frequency of the HindIII H(-) and H(+) allele was 0.37 and 0.63, respectively. There was a striking association between the HindIII polymorphism and the number of diseased vessels. The patients with HindIII(+/+) genotypes were significantly more likely to have double- or triple-vessel disease and less likely to have no significantly diseased vessels. In this study, we demonstrated that the homozygous form of the LPL HindIII(+) allele increases the risk of multivessel disease by a factor of 4 in an Italian group of young MI survivors. This association was independent from the smoking status and a positive family history for CAD and hypertension, which are known to predict CAD severity. The discrepancies in the results of these studies are difficult to explain. The lack of homogeneity in the study populations (age at which CAD occurred, number of enrolled patients, and geographical origin) and differences in the assessment of CAD severity may account for these conflicting results.

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BACKGROUND AND AIM: Studies of young patients with acute myocardial infarction (AMI) have demonstrated that conventional risk factors are usually responsible for their premature atherosclerosis. No account has yet been published of the risk profile of young Italians surviving an AMI. In this study, the conventional risk factors, lipids and apolipoproteins, and apolipoprotein E (APOE) allele distribution were evaluated in 98 consecutive AMI survivors (94 males, 4 females) aged 40.1 +/- 3.9 for at least three months after their acute event. These survivors were matched for age, sex, body mass index and presence of diabetes mellitus with 98 controls selected from subjects admitted to the same hospital for other reasons. METHODS AND RESULTS: Lipid profiles and APOE polymorphism were determined in both groups. Coronary angiography during hospitalization showed the absence of critical stenosis in 6.6% of the survivors, mono-vessel disease in 57.7%, and multi-vessel disease in 35.5%. The survivors had a higher frequency of smoking, hypertension, family history for coronary artery disease (CAD) and dyslipidemia, and a much greater frequency of 3 or more risk factors than the controls: Odd ratios (OR) 7.4, 95% confidence interval (CI) 2.5-18.6, p = 0.0000. Significant differences were found between the groups for triglycerides (p = 0.000002), total cholesterol (p = 0.003), LDL-cholesterol (p = 0.012), HDL-cholesterol (p = 0.0002), apolipoprotein AI (p = 0.00001), and Apolipoprotein B (p = 0.000001). No differences were observed in APOE allele distribution (APOE*4 0.11 vs 0.08, APOE*3 0.86 vs 0.89, APOE*2 0.03 vs 0.03), nor in lipid profile when both higher risk genotype (E3/4, E4/4, E2/4) and lower risk genotype groups (E2/2, E2/3, E3/3) were analysed. OR were calculated as measures of the association of the E4-positive genotypes with AMI. They indicated a non-significant increase in risk of AMI when the survivors were compared with the controls (OR 1.78, 95% CI 0.84-3.70, p = 0.13). CONCLUSIONS: This study provides further evidence that conventional coronary risk factors are usually present in young AMI patients. The APOE*4 allele was associated with a 1.8 non-significant increase in the risk of AMI in our group with premature CAD. Comparison with controls showed that the presence of three or more risk factors sharply increased the probability of premature CAD and that hyper-triglyceridemia is an independent risk factor. The data on APOE polymorphism are less certain and a larger study is needed.

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BACKGROUND: The P1A1/P1A2 polymorphism of the platelet glycoprotein IIIa has been variably associated with an increased risk of coronary thrombosis. MATERIALS: We investigated the linkage between the P1A1/P1A2 polymorphism and the risk of myocardial infarction in 98 patients who suffered their first myocardial infarction at the age of 45 years or less and 98 well-matched control subjects without coronary artery disease. Lipid parameters were measured using conventional methods of clinical chemistry; P1A genotypes were determined by polymerase chain reaction and restriction enzyme digestion. RESULTS: There was no significant difference in the prevalence of P1A2-positive genotypes (either P1A1/P1A2 or P1A2/P1A2) between patients and control subjects (chi 2 = 0.66, d.f. = 1, P = 0.41). CONCLUSIONS: These results suggest that the P1A2 polymorphism of the platelet glycoprotein IIIa does not contribute to the genetic susceptibility to premature myocardial infarction.

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BACKGROUND: Diagnostic and therapeutic issues related to hepatitis C virus infection and autoimmune hepatitis are discussed. The authors report a 56 year old female patient with chronic hepatitis and both HCV-RNA positivity and a high titer of LKM-1 antibody on blood samples. METHODS: In the absence of clinical signs of autoimmunity the patient was started on interferon treatment. After four months she experienced a flare-up with a sharp increase of transaminases and a concomitant rise in LKM-1 titer. Viremia was persistently detected by PCR. As interferon therapy was discontinued transaminases and autoantibody titer fell to baseline values. A few months later she received immunosuppressive therapy, that resulted in a decrease in LKM1 titer and complete normalization of liver enzymes. Anti LKM-1 antibody was detected by indirect immunofluorescence, serum immunoblot assay (Western Blot), and enzyme immunoassay (ELISA). RESULTS AND CONCLUSIONS: Therapy of patients with HCV/LKM positive chronic hepatitis should be settled on an individual basis. Patients eligible for interferon treatment should be carefully selected and closely monitored because of the risk of adverse reaction.

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To evaluate the inheritance of cardiovascular risk parameters in subjects with increased susceptibility for non-insulin-dependent diabetes mellitus, we compared 25 pairs of healthy twins who were offspring of diabetic parents with 25 pairs without a parental history for type 2 diabetes mellitus (12 monozygotic and 13 dizygotic in each group). Environmental factors were also evaluated to avoid bias in the assessment of concordance. No significant difference was found in concordance between monozygotic and dizygotic twins for physical activity, diet, smoking, alcohol intake and living together or apart. Genetic analysis revealed a substantial heritability for weight, body mass index, percentage of body fat, lipoprotein(a), high density lipoprotein (HDL)- and HDL2-cholesterol, without significant differences between the two groups. We conclude that heritability of several cardiovascular risk parameters is not increased in subjects with increased susceptibility to type 2 diabetes mellitus.

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There has been no simultaneous evaluation of different aspects of insulin action in ageing. We studied 12 elderly (77 +/- 2 years) and 12 young (26 +/- 1 years) subjects with normal glucose tolerance and matched for sex, body mass index, lean body mass (LBM), blood pressure and physical activity, using a euglycaemic-hyperinsulinaemic clamp at about 350 pmol L-1 in combination with [3H]-glucose infusion. In the elderly group, hepatic glucose production was normal, fasting serum insulin and C-peptide were significantly increased (P = 0.001) and glucose utilization (34.4 +/- 2.4 vs. 44.4 +/- 3.2 mumol kg-1 LBM min-1, P = 0.02) and the percentage maximal suppression of C-peptide (58 +/- 6% vs. 79 +/- 5%, P = 0.02) during the clamp were reduced. Fasting plasma free fatty acid (FFA) and glycerol levels were similar in the two groups, but their percentage maximal suppression during the clamp was reduced in the elderly group (FFA 45 +/- 5% vs. 77 +/- 6%, P = 0.001; glycerol 43 +/- 5% vs. 76 +/- 3%, P = 0.001). Branched-chain amino acids (valine, leucine, isoleucine) and glucagon levels were similar in the two groups, both while fasting and during the clamp. Thus, insulin resistance in ageing appears selective on glucose utilization, inhibition of lipolysis and feedback inhibition of the B-cell secretion.

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The present insulin preparations are not ideal for diabetes therapy by subcutaneous administration, subcutaneous insulin absorption is too slow to mimic the normal rapid increments of insulin in blood in response to nutrient intake. The absorption of insulin from subcutaneous tissue is influenced by many factors, among which the association state of insulin pharmaceutical form (hexameric) is the most important. This review describes the properties of insulin analogues, both rapid-acting and long-acting insulin analogues, designed by recombinant DNA technology with the aim of ameliorating absorption properties. Rapid-acting insulin analogues are characterised by one or a few amino acid substitutions to reduce intermolecular binding responsible for self-association. Because of largely reduced self-association they are absorbed substantially faster after subcutaneous injections than current regular insulin and determine lower insulin levels late after injection; thus short-acting analogues can be given with the meal and can minimise late hypoglycaemia. Long-acting insulin analogues have a slow absorption, providing constant basal insulinemic levels with lower day-to-day variation than current long-acting insulins. These properties are obtained by adding positive and/or removing negative charges thus increasing the isoelectric point of the molecule to about 7. In conclusion, insulin analogues represent an important goal in the therapy of diabetes and they can be a real opportunity for ameliorating glycaemic control.

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Interferon alfa (IFN) therapy is efficacious in chronic viral hepatitides. It may, however, cause adverse immunologic reactions in patients with concomitant autoimmune phenomena. A minority of patients with chronic type C hepatitis have antibodies against liver and kidney microsomes (anti-LKM) in serum. We therefore carried out this study to find out whether IFN is safe and efficacious also in this subgroup. We treated 92 consecutive cases of chronic hepatitis C with IFN. Twelve patients had anti-LKM< and the remaining 80 tested negative to the anti-LKM. The hepatitis C virus (HCV) infection was diagnosed on the basis of positive anti-HCV and HCV-RNA tests. We compared the clinical and virological virological results of the therapy and the side effects found in the two groups. We found that the response to therapy and the outcome after 1 year of follow-up were similar. Treatment was discontinued in one anti-LKM-positive patient because of a drastic increase in ALT levels at the fourth month of therapy. No untoward effect was observed in the other cases. Hepatitis C patients with anti-LKM may be exposed to an increased risk of an adverse hepatitic reaction while being treated with IFN. However, we found that the extent of the risk was minimal compared with the expected benefits of the therapy. IFN is therefore recommended as the first therapy to choose in these patients. They must, however, be monitored more closely for possible liver dysfunction than the ordinary hepatitis C patient.

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Microsomal antigen autoantibodies are typical of type 2 autoimmune hepatitis, and a strong association with chronic hepatitis C virus (HCV) infection has been reported in certain geographical areas. These autoantibodies have been denominated LKM-1 to differentiate them from those associated with thienylic acid-induced hepatitis (LKM-2) and from those seen in patients with chronic delta hepatitis (LKM-3). To investigate the antigenic specificity of autoantibodies associated with chronic hepatitis C and delta, we analyzed 52 LKM-1 positive serum samples from patients with chronic hepatitis C and 17 LKM-3 positive serum samples from patients with chronic delta hepatitis by indirect immunofluorescence and Western blotting (immunoblotting). Reactivity of subjects with chronic hepatitis C was heterogeneous: only 5 out of 52 LKM-1 positive patients, tested by Western blot, recognized a single protein of 50 kD, previously identified by Manns et al. with an immunogenic epitope of cytochrome P450IID6. Thirteen of the 52 patients also reacted with a 70 kD microsomal protein, and 12 out of 52 reacted only with a 59 kD protein. Twenty-two sera, notwithstanding the high titer in immunofluorescence, did not evidence any reactivity when tested by Western blot. The same sera tested positive in LKM-1 ELISA when solubilized human microsomal proteins were used. Fourteen out of 17 LKM-3 positive sera from patients with chronic hepatitis delta recognized a 55 kD microsomal protein in Western blot; three sera, HCV and HIV positive, did not react with any protein by Western blot. None of these sera was positive in ELISA LKM-1.(ABSTRACT TRUNCATED AT 250 WORDS)

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