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The relationship between hypertension, antihypertensive treatments and the risk of renal-cell cancer (RCC) remains still controversial. To evaluate the strength of the evidence provided by the epidemiological literature on this topic, a MEDLINE search of the papers published from 1966 to 2006 was performed. A total of 18 studies were included in the analysis. Pooled estimates of the effects of interest were obtained by fitting random effect models to the original data. The effects of some characteristics of the studies were considered as putative sources of heterogeneity of the estimates. Significant increased risks of RCC associated with hypertension (pooled odds ratio 1.62; 95% confidence interval: 1.24 to 2.12), as well as with the use of both diuretics (1.43; 1.12 to 1.83) and no diuretics (1.51; 1.21 to 1.87) antihypertensive drugs were observed. The effect of diuretics was significant in women (1.92; 1.59 to 2.33), but not in men (1.18; 0.93 to 1.49). Allowance for the known risk factors of RCC appreciably modified the effect of no diuretic antihypertensives making its pooled estimate not significant (1.17; 0.94 to 1.46). Although the pooled estimates show that both, hypertension and hypertensive therapy, are statistically associated with increased risk of RCC, experimental data and a closer look on the original data from epidemiologic literature, show that available evidence are still uncertain and need to be further investigated.

Background: Better therapeutic approaches for patients with Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL) resulted in high cure rates, at cost of serious late side effects. Second primary tumours are a major concern for long-term survivors, and breast cancer (BC) is the most common solid tumour among women treated for HD., Materials and Methods: Fifty-three women treated for primary BC with previous history of malignant lymphoma were identified in our institution, 35 with HD (66%), 18 (34%) with NHL. A comparison group was randomly selected from our database matching for each patient with previous lymphoma, two patients with primary BC (rate 1 : 2) for age, stage (pathological tumour size [pT] status and nodal status), year of diagnosis, and estrogen and progesterone status (positive versus negative). The primary end points were disease-free survival (DFS) and overall survival (OS)., Results: The two groups of patients were compared for biological features: histopathological diagnosis, grading, lymphatic invasion, c-erbB2 overexpression, and Ki-67. Considering these variables, no significant differences were observed between the two groups with the exception of Ki-67, which was found higher in those with previous HD or NHL (65% versus 49%, respectively, P = 0.0526, borderline significant). Comparing the two groups for treatment approach, no differences were found for surgical and medical therapy (endocrine therapy and chemotherapy). However, regarding patients with node-positive disease (14 versus 35 patients), five patients in the lymphoma group (36%), compared with 24 (69%) in the matched group received anthracycline-based therapy (P = 0.0345). As expected, radiotherapy was used very differently in the two groups, with 36% of patients in the study group undergoing intraoperative radiotherapy with electrons versus 10% in the control group (P = 0.0001). Five-year DFS was 54.5% for the study cohort compared with 91% for controls (P < 0.0001). Five-year OS percentages were also statistically different (86.6% and 98.6%, respectively, P = 0.031)., Conclusions: Previous history of malignant lymphoma is a negative prognostic factor for women diagnosed subsequently with BC. Some undertreatment of women with the latter might be hypothesised as the reason for the worse outcome. Influence of other variables, like previous exposure to cytotoxics, or some unknown biological features related to the previous disease and treatment, should still be investigated in the attempt to improve the dire outcome of these patients.

Objectives: Empirical-Bayes adjustment was used to investigate the effects of antibacterials on risk of arrhythmia in a large cohort study based upon automated record linkage., Study Design and Setting: The Prescription Drug Database of the Varese Province, Italy, was used to form a population-based cohort of patients who received at least one prescription of antibacterials for systemic use. All cohort members were followed-up from the beginning of each antibacterial therapeutic cycle up to 60 days afterward, identifying the first prescription of an antiarrhythmic drug and/or the first admission for arrhythmia. Standardized incidence ratios for eight classes of antibacterials, as well as for the specific antibacterial drugs, were estimated using both conventional methods and empirical-Bayes (EB) adjustment., Results: Using EB adjustment, overall precision was greatly enhanced compared to the conventional analysis. Statistical evidence of drug-induced dysrhythmic events was found for 17 drugs mostly belonging to Macrolides and Quinolones. Strongest proarrhythmic effects were found for Ciprofloxacin (standardized incidence ratio [SIR]: 1.98; 95% CI: 1.67, 2.34) and Erythromycin (SIR: 1.91; 95% CI: 1.20, 2.88)., Conclusion: Empirical-Bayes may mitigate some problems inherent the conventional analysis. Macrolides and Quinolones were associated with the highest number of positive signals of dysrhythmic events. This requires further investigation by other types of epidemiologic studies.

Aims/hypothesis: Post-prandial glucose may be a risk factor for cardiovascular disease and chronic diabetic complications. We tested the hypothesis that post-prandial hyperglycaemia is common in type 2 diabetes, even among patients in apparently good glycaemic control, and that simple clinical characteristics identify subsets of diabetic patients with frequent post-prandial hyperglycaemia., Subjects and Methods: Three self-assessed daily blood glucose profiles over a 1-week period, including 18 glucose readings before and 2 h after meals, were obtained from 3,284 unselected outpatients (men 51%; age 63+/-10 years) with non-insulin-treated type 2 diabetes mellitus attending 500 different diabetes clinics operating throughout Italy., Results: A post-prandial blood glucose value >8.89 mmol/l (160 mg/dl) was recorded at least once in 84% of patients, and 81% of patients had at least one Delta glucose > or =2.22 mmol/l (40 mg/dl). Among patients with apparently good metabolic control, 38% had >40% of post-prandial blood glucose readings >8.89 mmol/l (> or =4 of 9 meals in total), and 36% had >40% Delta glucose > or =2.22 mmol/l. In multivariate analysis adjusted for pre-prandial glucose levels, older age, longer duration of diabetes, absence of obesity, hyperlipidaemia and hypertension, as well as treatment with sulfonylureas, were significantly associated with greater glucose excursions after meals., Conclusions/interpretation: These results indicate that post-prandial hyperglycaemia is a very frequent phenomenon in patients with type 2 diabetes mellitus on active treatment; can occur even when metabolic control is apparently good; and can be predicted by simple clinical features.

Cancers of the upper aero-digestive tract (i.e., oral cavity, pharynx, larynx and oesophagus) are largely attributable to smoking and drinking habits, but the correct estimation of the dose-response relationship between alcohol and cancer risk is challenging. Step functions are widely used to estimate risks and to evaluate trends of continuous exposure. However, results are influenced by the selection of the reference category and cutpoints. More flexible models, like spline regression and fractional polynomial models, may be an attractive alternative for avoiding strict assumptions about the dose-response relationship. Data from a large series of hospital-based case-control studies conducted in Italy and the Swiss Canton of Vaud in the last 2 decades were reassessed to compare findings from logistic regression spline models and standard step function analysis. For all examined cancers, the risk increased to the consumption of 150 grams of ethanol per day (1.5 litre/day of wine), with a possible threshold effect emerging for cancer of the pharynx and larynx (<50 grams of ethanol per day) only. For higher consumptions, the risks flattened. Our study suggests that regression spline models can be useful to estimate the pattern of risk of a continuous exposure variable, such as alcohol consumption, and provide more accurate estimates than categorical analysis when ORs within each interval, especially in the reference category, are not homogeneous., (2004 Wiley-Liss, Inc.)

Background: Although it is well known that a variety of antibacterials may incidentally cause malignant arrhythmia, the list of drugs causing arrhythmia and the impact of these adverse effects are still uncertain. We investigated on this topic by using a large prescription database with different observational designs., Methods: Prescription data on all incident users of several antibacterial and antiarrhythmic drugs over the period July 1997 through December 1999 were retrieved from the Drug Prescription Database (DPD) of the Italian Province of Varese. The association between the use of antibacterial and antiarrhythmic drugs was investigated by applying prescription sequence symmetry, cohort and nested case-control designs., Results: Lower proarrhythmic effects were on an average obtained from prescription sequence symmetry approach with respect to both cohort and nested case-control. Evidence of association between exposure to drugs (erythromycin and ciprofloxacin) and the risk of arrhythmia was consistently found by the three approaches. No other signals were generated from the prescription sequence symmetry analysis. Two drugs (clarithromycin and levofloxacin) showed patterns compatible with an arrhythmic effect according to both cohort and nested case-control designs., Conclusions: Prescription databases are useful tools to explore drug safety through both conventional and emerging observational designs. In spite of its appealing features, prescription sequence symmetry design shows lower sensitivity with respect to conventional designs. Evidence about the association between the use of certain macrolides and fluoroquinolones and the onset of arrhythmia is confirmed by this study., (Copyright (c) 2004 John Wiley & Sons, Ltd.)

Objective: The effect of short-acting inhaled beta(2)-agonists on mortality from chronic obstructive pulmonary disease (COPD) is controversial. Different observational designs were used to investigate about this topic., Study Design and Setting: A population-based case-control design was performed, by linking automated health databases from the Varese Province of Italy. Deaths of COPD generated from the cohort of 135,871 patients for whom at least one prescription for drugs used to treat COPD had been dispensed between 1997 and 1999 entered into the study as cases. Up to 20 controls were randomly selected for each case from the cohort after matching on gender, age, and date of cohort entry. Risk ratios were estimated using the case-control, case-crossover, and case-time-control approaches., Results: A total of 222 cases and 3022 controls met the inclusion criteria. Odds ratios (and corresponding 95% confidence intervals) corresponding to more than 0.5 defined-daily-doses were 2.6 (1.7, 4.0), 1.9 (1.1, 3.3), 2.1 (1.1, 4.0), and 2.3 (1.2, 4.6) by using crude and adjusted case-control, case-crossover, and case-time-control estimates, respectively., Conclusion: Evidence that higher doses of short-acting inhaled beta(2)-agonists are associated with higher mortality from COPD was consistently supplied by three observational approaches.

Background: To compare the strength of evidence provided by the epidemiological literature on the association between alcohol consumption and the risk of 14 major alcohol-related neoplasms and non-neoplastic diseases, plus injuries., Methods: A search of the epidemiological literature from 1966 to 1998 was performed by several bibliographic databases. Meta-regression models were fitted considering fixed and random effect models and linear and nonlinear effects of alcohol intake. The effects of some characteristics of the studies, including an index of their quality, were considered., Results: Of the 561 initially reviewed studies, 156 were selected for meta-analysis because of their a priori defined higher quality, including a total of 116,702 subjects. Strong trends in risk were observed for cancers of the oral cavity, esophagus and larynx, hypertension, liver cirrhosis, chronic pancreatitis, and injuries and violence. Less strong direct relations were observed for cancers of the colon, rectum, liver, and breast. For all these conditions, significant increased risks were also found for ethanol intake of 25 g per day. Threshold values were observed for ischemic and hemorrhagic strokes. For coronary heart disease, a J-shaped relation was observed with a minimum relative risk of 0.80 at 20 g/day, a significant protective effect up to 72 g/day, and a significant increased risk at 89 g/day. No clear relation was observed for gastroduodenal ulcer., Conclusions: This meta-analysis shows no evidence of a threshold effect for both neoplasms and several non-neoplastic diseases. J-shaped relations were observed only for coronary heart disease.

Several experimental studies have suggested that specific nutrients might play a role on the risk of liver damage. Nevertheless, few epidemiological studies have evaluated the role of diet on the risk of symptomatic liver cirrhosis, giving contradictory results. To evaluate the role of the intake of nutritional factors and dietary patterns on the risk of symptomatic liver cirrhosis and to examine their combined action with alcohol consumption we used data from the Italian Study on Liver Cirrhosis Determinants project. From 1994 to 1998 all the consecutive cirrhotic inpatients admitted to 19 Italian collaborative hospitals for signs of liver decompensation in whom the diagnosis of liver cirrhosis was made for the first time (259 cases) and one or two gender, age and area of residence matched individuals (416 controls) were recruited. Data on lifetime alcohol intake, usual consumption of 191 food items and on markers of hepatitis B and C viral infection were collected. The analysis of principal components identified a nutritional pattern positively correlated with vegetable and fruit intakes and negatively with animal and no-fruit sugar products. With respect to abstainers, relative risks in consumers of use < or = 25 and > or = 51 g/day of alcohol increased from 0.4 [95% confidence interval 0.0, 5.9] to 9.3 [1.3, 69.0] and from 2.1 [1.1, 4.2] to 18.1 [2.8, 118.3] for the lowest and the highest value of this nutritional pattern, respectively. Diet might therefore modulate the damaging effect of alcohol on the liver.

Unlabelled: A retrospective evaluation of asymptomatic subjects with persistent elevation of serum creatine kinase (CK) levels (hyperCKemia) was made in order to verify the presence of subclinical myopathy or idiopathic hyperCKemia and to define the most appropriate diagnostic pathway. Persistently increased serum CK levels are occasionally encountered in healthy individuals. In 1980 Rowland coined for them the term idiopathic hyperCKemia. Despite the increase of scientific knowledge, several healthy subjects with hyperCKemia still represent a problem for the clinician. We made a retrospective evaluation of 114 asymptomatic or minimally symptomatic individuals with incidentally detected persistent hyperCKemia. They underwent neurological examination and laboratory/instrumental evaluation. Skeletal muscle biopsy was performed and thoroughly investigated. Biochemical and genetic investigations were added in selected cases. Logistic regression analysis was applied. We diagnosed a neuromuscular disorder in 21 patients (18.4%), and found, by muscle biopsy and/or EMG, pathological but not conclusive findings in 57 subjects (50%). The statistic correlation between elevated serum CK levels and the probability of making a diagnosis changed according to the age of the patient., Conclusions: Muscle biopsy is the basic tool for screening asymptomatic subjects with hyperCKemia. It allowed us to make a diagnosis of disease in 18.4% of patients, and to detect skeletal muscle abnormalities in 38.6% of the subjects. Interestingly, 31.6% of individuals had completely normal muscle findings. These best fit the "diagnosis" of idiopathic hyperCKemia.

Background: Death rate for patients with ulcerative colitis has changed over last few decades. Recent studies indicate that cumulative long-term mortality is comparable to that in general population, and that deaths may depend on causes not strictly related to colonic disease., Aim: To evaluate overall and cause-specific mortality rate in a large group of Italian patients with ulcerative colitis., Methods: A total of 2,066 ulcerative colitis patients aged >18 years consecutively diagnosed in twenty Italian Gastroenterology Units between 1964 and 1995 were followed-up from diagnosis until 1997. Standardised Mortality Ratios and Relative Survival Ratios were calculated., Results: Overall mortality of patients with ulcerative colitis was comparable to that in general population with 93 deaths observed versus 92.1 expected (standardises mortality ratio, 1.0; 95% confidence interval, 0.8-1.2). Significantly higher mortality was observed in patients under 30 years of age at diagnosis (standardised mortality ratio, 2.7; 95% confidence interval, 1.3-4.9), and in those diagnosed before 1974 (standardised mortality ratio, 2.7; 95% confidence interval, 1.1-5.7). Proctocolitis and complications from surgery were mentioned in 11 and 5 certificates, respectively. A significant excess of deaths was observed for colorectal cancer (colon: standardised mortality ratio, 3.0; 95% confidence interval, 1.0-6.9; rectum: standardised mortality ratio, 4.4; 95% confidence interval, 1.2-11.3), and haemolymphopoietic neoplasms (standardised mortality ratio, 2.8; 95% confidence interval, 1.0-6.1), in particular multiple myeloma and non-Hodgkin lymphoma. A significant deficit of deaths was observed for cancer of the respiratory system (standardised mortality ratio, 0.3; 95% confidence interval, 0.1-1.0)., Conclusions: This study confirms that, also in Italy, mortality of patients with ulcerative colitis is comparable to that in general population. Only 12% of deaths were due to ulcerative colitis itself, whereas 10% of deaths were attributed to colorectal cancer. Deaths from colorectal cancer occurred, on average, 9 years after diagnosis of ulcerative colitis, suggesting that the risk of cancer is not limited to patients with long-standing colitis. As to mortality for causes unrelated to colitis, there was an excess of deaths due to malignancies of the haemolymphopoietic system.

Objective: To estimate parameters of the function relating alcohol consumption with the risk of coronary heart disease and to identify the sources of heterogeneity in the parameter estimates., Methods: A search of the epidemiological literature from 1966 to 1998 was performed using several bibliographic databases. Meta-regression models were fitted to evaluate non-linear effects of alcohol intake on the relative risk. The effects of some characteristics of the studies, including an index of their quality, were considered as putative sources of heterogeneity of the estimates. Publication bias was also investigated., Findings: Among the 196 initially reviewed articles, 51 were selected. Since qualitative characteristics of the studies were significant sources of heterogeneity, the pooled dose-response functions were based on the 28 cohort studies with higher quality. Risk decreased from 0 to 20 g/day (RR = 0.80; 95% CI: 0.78, 0.83); there was evidence of a protective effect up to 72 g/day (RR = 0.96; 95% CI: 0.92, 1.00) and increased risk above > or = 89 g/day (RR = 1.05; 95% CI: 1.00, 1.11). Lower protective effects and harmful effects were found in women, in men living in countries outside the Mediterranean area and in studies where fatal events were used as the outcome. Evidence of publication bias for moderate intakes and of heterogeneity of the estimates across studies for higher intakes were found., Conclusions: The degree of protection from moderate doses of alcohol should be reconsidered. Further research investigating the effect of drinking patterns on the risk of coronary heart disease should be performed. Caution in making general recommendations is needed.

The observational evaluation of alcoholics' treatments requires a combined analysis of alcoholic behaviour during treatment and of adherence to therapeutic programmes. The application of survival analysis techniques in this setting has been explored in this study. Two hundred and seventy alcoholics admitted to 15 Italian treatment units in a 1-year period were followed-up for 2 years, recording date and length of every recurrence episode and of definitive or transitory interruption of the planned treatment. An extensive use of several survival analysis techniques was made. The length of time between the start of the treatment and the first episode of relapse did not give a reliable measure of frequency of failures. Conversely, the length of time between the start of treatment and withdrawal appeared to be unbiased. The cumulative proportions of treatment-compliant patients (and the corresponding 95% confidence intervals) were 71% (66-76%), 63% (57-69%) and 53% (47-60%) after 6 months, 1 year and 2 years respectively from the start of treatment. Cumulative abstinence duration before withdrawal was significantly and positively associated with the risk of first, of definitive, and of every episode of treatment interruption. This first application of survival analysis techniques to the combined study of alcoholic behaviour and of adherence to treatment can improve our knowledge of treatment evaluation. Our results suggest that compliance to treatment is an objective and versatile outcome measure. Long-term follow-up studies aimed to elucidate the determinants of withdrawal should be performed.

Objective: To compare the strength of the evidence provided by the epidemiological literature on the association between alcohol consumption and the risk of six cancers (oral cavity, oesophagus, colorectum, liver, larynx, breast), hypertension, cerebrovascular diseases, gastric and duodenal ulcer, liver cirrhosis and other chronic liver diseases, pancreatitis and injures and adverse effects., Methods: A search of the epidemiological literature from 1966 to 1998 was performed by several bibliographic databases. Meta-regression models were fitted considering fixed and random models and linear and non-linear effects of alcohol intake on the risk of each condition. The effects of some characteristics of the studies including an index of their quality were considered as putative sources of heterogeneity of the estimates. Publication bias was also investigated by asymmetry of funnel plots., Results: Of the 397 initially reviewed studies, 200 were selected for meta-analysis. Since qualitative characteristics of the studies were often significant sources of heterogeneity among them, the estimates of the pooled dose-response slopes were based only on the 123 studies with higher quality score and/or reporting adjusted estimates of relative risks. Higher alcohol-related risks were found for liver cirrhosis, neoplasms of the upper respiratory and digestive tracts, haemorrhagic stroke and injuries and adverse effects. Weaker but significant associations were found for colorectum, liver and breast cancers, essential hypertension and chronic pancreatitis. For all these conditions, low intakes, corresponding to daily consumption of two drinks or two glasses of wine (25 g/day), have shown significant risks. Ischaemic stroke and gastric and duodenal ulcer seem independent of alcohol intake. The area in which the study was performed, the study's design and the outcome variable differently affected the slopes., Conclusions: The small number of sufficiently reliable studies, the strong indications of heterogeneity across them and the suspicion of publication bias suggest that there is a great need for well-conducted epidemiological studies performed in several countries, to examine the dose-response relationship between alcohol intake and the risk of several alcohol-related conditions, as well as the role of drinking pattern in determining the risk.