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Background Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development., Highlights ► In the IMPROVE study (n > 3000) variants at 1q24.3 were strongly associated with larger carotid diameters. ► The lead variant was associated with Abdominal Aortic Aneurysm (AAA) in meta-analysis of 5 studies (n > 50,000). ► Variants at 1q24.3 appear to be associated with vascular remodelling and risk of AAA.

Objective: Serum LDL conjugated diene concentration is a marker of oxidative modification of LDL. We investigated the relationship between LDL conjugated dienes and cross-sectional subclinical atherosclerosis assessed by carotid IMT in high-risk subjects of a multicenter study.Methods: Serum LDL conjugated dienes and ultrasonographically assessed carotid intima-media thickness (IMTmean, IMTmax and IMTmean-max) were available for 553 subjects from Finland, France, Italy, the Netherlands, and Sweden.Results: In multivariate regression analysis, gender (p Conclusions: There was a cross-sectional association between in vivo increased LDL oxidative modification and subclinical atherosclerosis after adjustment for traditional risk factors. The subjects in Northern countries of Europe had more oxidatively modified lipids per cholesterol in LDL particle than subjects in Southern countries. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

ObjectivesThe aim of this research was to assess the incidence, clinical predictors, and outcome of contrast-induced nephropathy (CIN) after primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI).BackgroundContrast-induced nephropathy is associated with significant morbidity and mortality after PCI. Patients undergoing primary PCI may be at higher risk of CIN because of hemodynamic instability and unfeasibility of adequate prophylaxis.MethodsIn 208 consecutive AMI patients undergoing primary PCI, we measured serum creatinine concentration (Cr) at baseline and each day for the following three days. Contrast-induced nephropathy was defined as a rise in Cr >0.5 mg/dl.ResultsOverall, CIN occurred in 40 (19%) patients. Of the 160 patients with baseline Cr clearance ≥60 ml/min, only 21 (13%) developed CIN, whereas it occurred in 19 (40%) of those with Cr clearance 75 years (odds ratio [OR] 5.28, 95% confidence interval [CI] 1.98 to 14.05; p = 0.0009), anterior infarction (OR 2.17, 95% CI 0.88 to 5.34; p = 0.09), time-to-reperfusion >6 h (OR 2.51, 95% CI 1.01 to 6.16; p = 0.04), contrast agent volume >300 ml (OR 2.80, 95% CI 1.17 to 6.68; p = 0.02) and use of intraaortic balloon (OR 15.51, 95% CI 4.65 to 51.64; p < 0.0001) were independent correlates of CIN. Patients developing CIN had longer hospital stay (13 ± 7 days vs. 8 ± 3 days; p < 0.001), more complicated clinical course, and significantly higher mortality rate (31% vs. 0.6%; p < 0.001).ConclusionsContrast-induced nephropathy frequently complicates primary PCI, even in patients with normal renal function. It is associated with higher in-hospital complication rate and mortality. Thus, preventive strategies are needed, particularly in high-risk patients.

Like their normal counterparts, leukemic blasts have recently been shown to respond to hemopoietic growth factors in both suspension culture and in semisolid media. In the present study, we have evaluated the proliferative response of 35 AML cases to colony-stimulating factors (CSFs) containing conditioned media derived from the human cell lines GCT, 5637, MO and MG U87, and to human recombinant IL-1 (rh-IL1), IL-3 (rhIL-3), GM-CSF (rhGM-CSF) and G-CSF (rhG-CSF). In the great majority of cases, an increase of 3 H-thymidine ( 3 H-TdR) uptake was obtained in response to at least one conditioned medium. The labeling index (LI) and the growth fraction (GF), evaluated in a restricted group of cases, were also increased by the growth factors, suggesting that they act by recruiting leukemic cells in cycle from the resting compartment. The ability of blast populations to form colonies was also studied. Conditioned media were found to induce or significantly increase the clonogenic capacity in 20 cases out of 22. The response of leukemic cells to human recombinant CSFs and rhIL-1, used alone or in combination, was also assayed. The results, in agreement with those obtained with conditioned media, show that each leukemic case displays a different pattern of response to CSFs, and that optimal growth conditions must be individually assessed. The possibility of increasing the fraction of cycling cells in AML populations may represent a way to render them more sensitive to cytostatic agents, with a view to new therapeutic strategies.

Background Exposure to environmental tobacco smoke (ETS) is associated with an increased risk of lung cancer, ischemic heart disease and respiratory diseases in non-smokers. Exposure is likely to be uneven in the population. Knowledge of its distribution is important for a better planning of preventive activities. Methods In the context of the Italian branch of the EPIC prospective investigation, in which we enrolled 47,000 volunteers, we have surveyed exposure to ETS and its determinants (age, social class, occupation). The purpose of the present paper is to contribute to identify the main sources of exposure in Italy. Results We found, in a sample of 21,588 Italian non-smokers, a prevalence of 0.337 (95% confidence interval, 0.336-0.337) in women and 0.537 (0.529-0.544) in men. Exposure was defined as at least 1 hr/day for at least one year. Exposure at work is by far the commonest source of exposure to ETS, with a strong difference between full-time and part-time jobs. The distribution of exposure by social class was uneven, with statistically significant odds ratios for higher social groups in the order of 0.4-0.5. White-collar workers are the occupational category mostly exposed, suggesting that the implementation of anti-smoking legislation is still incomplete in Italian offices. Conclusions The uneven distribution of ETS in the population is a matter of concern, since it contributes to the unequal distribution of health in different social groups.

Background: There is uncertainty regarding the association of occupational exposures with lung cancer. We have studied the association between 52 high-risk job titles and lung cancer incidence in a large prospective study, with more than 200,000 participants followed for more than 6 years and 809 incident cases of lung cancer. Methods: Hazard ratios and 95% confidence intervals were computed by the Cox proportional-hazard regression model, adjusting for country, age, sex, social class, diet, physical activity, and smoking habits. We used a CAREX-based job-exposure matrix to infer exposure to lung carcinogens. False-positive report probability was calculated as a measure of potentially false-positive results. Results: Eighteen occupations, mainly related with agriculture, constructions, and metal processing, were associated with increased risk. In addition, incidence tended to increase with the number of hazardous jobs reported. When the occupations were classified according to the presumed exposure to specific carcinogenic agents, the hazard ratios were 1.5 (95% confidence interval = 1.2–1.9) for asbestos, 1.4 (1.1–1.8) for heavy metals, 1.4 (1.1–1.8) for polycyclic aromatic hydrocarbons, and 1.6 (1.2–2.1) for work-related environmental tobacco smoke. The estimated population attributable risk for employment in at least 1 at-risk job was 16% in men and 12% in women. Conclusions: This large prospective study suggests that exposure to occupational lung carcinogens is still a problem, with such exposures producing moderate to large increases in risk.

We investigated the role of different CC chemokines, including regulated upon activation normal T cell expressed and secreted (RANTES), macrophage inflammatory protein-1α (MIP-1α), monocyte chemotactic protein-1 (MCP-1), and MCP-3 on virus replication in cultures established from CD8+ T cell-depleted peripheral blood mononuclear cells (PBMC) of HIV-infected individuals that were either cocultivated with allogeneic T cell blasts (ATCB) of uninfected individuals or directly stimulated by mitogen plus interleukin-2. RANTES was the only chemokine that showed a clear-cut suppressive effect on HIV replication in both culture systems, although inhibitory effects were frequently also observed with MIP-1α, MCP-3, and, occasionally, with MCP-1. In contrast, MCP-1 frequently enhanced HIV production in most patients’ cultures or cocultures that were characterized by secreting relatively low levels (

A descriptive analysis was performed in order to evaluate the completeness of follow-up and to explore the occurrence of malignancy in the Italian section of the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy) at the first follow-up for cancer incidence. The EPIC-Italy cohort consisted of 47,749 subjects, aged 35-65 years, who voluntarily accepted to participate in the project from 1992-1997. Tabulations of the enrolled subjects are presented by sex, age groups, population at risk and person-years as calculated at the first follow-up in 1998; alive, lost to follow-up and dead subjects were tabulated by sex and centers. Cancer occurrence is described by quality indexes of data collected and the lapse of time between the date of recruitment and date of diagnosis. External comparisons for each center and pooled data were carried out by calculation of standard incidence ratios (SIRs) using the rates of the population-based cancer registries covering the areas of EPIC Italian centers. Similarly, an internal comparison was also performed using as the reference population the EPIC-Italy center with the lowest crude cancer incidence rates. A total of 148,968 person-years (43,568 men and 105,400 women) was calculated as the denominator; the percentages of lost to follow-up were 1.34% for men and 0.9% for women. We found 781 malignancies (216 in males and 565 in females), 17 in situ breast cancers and 8 in situ cervical cancers. In men 65 malignant cases (30.1%) and in women 186 malignancies (32.9%) occurred in the first year following enrollment. The proportion of microscopically verified cancers was 93.1%. In pooled data for men, statistically significant SIRs of less than 1 were calculated for all cancer sites combined (SIR = 0.81), lung (SIR = 0.49) and bladder (SIR = 0.62), whereas statistically significant excesses of observed cases were found for melanoma and cancers of ill-defined sites within respiratory system and intrathoracic organs (ICD-0-2 = C39). In pooled data for women, none of the SIRs were statistically significant. For men, SIRs disaggregated by center showed statistically significant excesses of cases only in Florence for the thyroid (SIR = 5.01). For women, statistically significant excesses of observed cases were computed in Florence and Varese for breast cancer (SIRs, 1.36 and 1.27, respectively), Florence for uterine cancer NOS (SIR = 20.3) and Varese for kidney (SIR 2.24). Internal comparisons showed some evidence of an excess of cases in northern compared to southern centers. In conclusion, after an average follow-up of 3 years, nearly 99% of the enrolled individuals were traced and checked for their vital status. Cancer occurrence in women was not far from that expected in comparison to the local general population, whereas in men significantly fewer cases than expected were observed. This preliminary descriptive analysis will be used as a starting point for monitoring the validity of EPIC-Italy over time.

Aim: The principal aim of the REACT study (REassessment of Antihypertensive Chronic Therapy) was to achieve a comprehensive assessment of hypertension management in Italy from both the physician and patient points of view. Blood pressure control, global risk factors, target organ damage stratification, use of diagnostic examinations, prescribing practices and physician/patient satisfaction with the planned therapeutic regimen, as well as an assessment of patient quality of life were evaluated. A total of 1482 hypertensive patients and their physicians participated in this study. Experimental Design: REACT was a multicentre, non-intervention, cross-sectional, observational study of the management of hypertension in Italy. Hypertensive patients were selected from specialised clinics from the following sub-specialties: cardiology, internal medicine, geriatrics, diabetology and nephrology. Patient Population: Between 10 and 20 patients were enrolled in each of the 131 participating centres. Eligible patients had to have been diagnosed with primary hypertension for at least 1 year and been on stable antihypertensive therapy for at least 1 year. Enrolment began in March 2003 and concluded in March 2004. Conclusions: Hypertension management in Italy remains inadequate. This conclusion is based on poor control of blood pressure and cardiovascular risk factors, persistence of target organ damage, inadequate use of diagnostic tests and examinations, and a deficient therapeutic approach. Since this study was performed in patients with antihypertensive treatment established for at least 1 year and followed by expert specialist physicians, these findings are worrisome and indicate the need for more stringent and effective recommendations for the clinical management of hypertensive patients.

The APOE e4 allele influences the occurrence of AD by lowering the age at disease onset.1 A case–control study of two (Spanish and North American) populations suggested an e4-independent association between an A/T polymorphism in the APOE regulatory region ( APOE −491) and sporadic AD,2 stronger in Spanish than in North American patients, thus suggesting genetic heterogeneity. Subsequent observations in different populations have been conflicting,3-6 ranging from a much weaker e4-independent association of APOE −491 and AD (alone3 or in association with other APOE polymorphisms4) to no5 or even a protective effect6 on the development of AD. So far, no association has been reported between this polymorphism and the age at AD onset. To explore this issue, we examined APOE −491 and e polymorphisms in Italian patients with AD and control subjects. A total of 358 white patients (age at disease onset 67.3 ± 9.3 [mean ± SD] years) affected by clinically probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) criteria7 were enrolled. Patients were divided into those with an early onset (EO …

Background The prognosis for many children with cow's milk allergy (CMA) is remission within 3 years, and the clinical parameters that predict duration of disease have not been measured incrementally. Objective To prospectively determine prognostic predictors of tolerance in a random cohort of referrals using CMA workup outcomes as covariates and tolerance as the status variable in a duration model of CMA. Methods The 2001-2006 Milan Cow's Milk Allergy Cohort (MiCMAC) enrolled children referrals using double-blind, placebo-controlled food challenges (DBPCFCs) as study end points (confirmation of CMA; onset of tolerance). The Cox regression model was used to analyze all clinical factors that contributed to tolerance. Covariates analyzed were skin, gastrointestinal, and respiratory symptoms; history and demographics at presentation; age at diagnosis and DBPCFC outcomes; sensitization (skin and serum) by cow's milk protein fractions; sensitization to other food and inhalant allergens; total IgE levels; specific IgE concentrations for cow's milk protein fractions, other ingestants, and aeroallergens; and threshold doses at DBPCFC. Sensitization and DBPCFC were performed at 6-month intervals. Results A total of 112 infants were enrolled (mean [SD] age, 13.85 [9.84] months), and 59 achieved tolerance (mean [SD] age when tolerance was achieved, 27.58 [11.81] months). On univariate analysis, asthma and/or rhinitis at presentation was an independent predictor of persistence (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.26-3.82). On multivariate analysis, predictors of persistence were a fresh milk wheal diameter increment of 1 mm (HR, 1.18; 95% CI, 1.07-1.31) and a positive skin prick test result with soy (HR, 6.99; 95% CI, 1.56-31.25). Conclusions This is the first study, to our knowledge, to identify incremental biological predictors of delayed tolerance to cow's milk in children that should be integrated into DBPCFC schedules for CMA in infants.

Sensitive to the massive diffusion of purported metabolic and cardiovascular positive effects of green tea and catechincontaining extracts, many consumers of cardiovascular drugs assume these products as a "natural" and presumably innocuous adjunctive way to increase their overall health. However, green tea may interfere with the oral bioavailability or activity of cardiovascular drugs by various mechanisms, potentially leading to reduced drug efficacy or increased drug toxicity. Available data about interactions between green tea and cardiovascular drugs in humans, updated in this review, are limited so far to warfarin, simvastatin and nadolol, and suggest that the average effects are mild to modest. Nevertheless, in cases of unexpected drug response or intolerance, it is warranted to consider a possible green tea-drug interaction, especially in people who assume large volumes of green tea and/or catechin-enriched products with the conviction that "more-is-better".

Background and Purpose —New advances in B-mode imaging technologies have led to improved quality in the detection of minute changes in the surface of intima-media thickness (IMT) and plaques. The new digital systems, with increased numbers of imaging channels, multiple frequency probes, and increased microprocessing speeds, now generate images comparable to those of the analog predecessors. Can these digital systems have reproducibility comparable to that of a pure analog system? We compared the Biosound 2000II (analog) system with the Esaote AU4 (digital) system. Methods —Twenty-two subjects were chosen who had varying degrees of IMT on the far wall of the common carotid artery. Common carotid IMT was determined twice: the first time with the analog system and the second time with the digital system. With each system, replicate scans were made within 2 weeks. Results —The intramethod agreement was high with the analog system, with a bias between readings of −0.010±0.033 mm, mean absolute difference of 0.027±0.020 mm, repeatability coefficient of 0.067, and correlation coefficient of 0.97. The digital system provided the highest reproducibility with a bias between readings of 0.002±0.016 mm, mean absolute difference of 0.012±0.011 mm, repeatability coefficient of 0.033, and correlation coefficient of 0.99. When the analog and digital systems were compared, the bias between readings was −0.011±0.024 mm with good agreement between the 2 systems; the repeatability coefficient was 0.047, with all points within ±2 SDs of the mean difference. The mean absolute difference between the 2 measurements was 0.018±0.015 mm with a correlation coefficient of 0.98. Conclusions —The digital system for IMT evaluation compares well with the more widely used analog system and provides a reliable technology for common carotid IMT measurement that can be applied to clinical trials.

Objective Genetic variants robustly associated with coronary artery disease were reported in the vicinity of the interleukin (IL)-5 locus, and animal studies suggested a protective role for IL-5 in atherosclerosis. Therefore, we set this work to explore IL-5 as a plasma biomarker for early subclinical atherosclerosis, as determined by measures of baseline severity and change over time of carotid intima-media thickness (cIMT). Methods We used biobank and databases of IMPROVE, a large European prospective cohort study of high-risk individuals (n = 3534) free of clinically overt cardiovascular disease at enrollment, in whom composite and segment-specific measures of cIMT were recorded at baseline and after 15 and 30 months. IL-5 was measured with an immunoassay in plasma samples taken at baseline. Results IL-5 levels were lower in women than in men, lower in the South than in North of Europe, and showed positive correlations with most established risk factors. IL-5 showed significant inverse relationships with cIMT change over time in the common carotid segment in women, but no significant relationships to baseline cIMT in either men or women. Conclusions Our results suggest that IL-5 may be part of protective mechanisms operating in early atherosclerosis, at least in women. However, the relationships are weak and whereas IL-5 has been proposed as a potential molecular target to treat allergies, it is difficult to envisage such a scenario in coronary artery disease., Highlights • Genetic and animal studies suggested a protective role for IL-5 in atherosclerosis. • We studied plasma IL-5 relationships to baseline and change over time in carotid IMT. • Significant relationships of IL-5 and cIMT were time, segment and gender specific. • High plasma IL-5 was related to slow progression of IMT in common carotid in women. • In general, IL-5 does not seem useful as biomarker for coronary artery disease.

Nonreplicating TS/A mammary adenocarcinoma cells expressing B7-2 (CD86) (TS/A-2) are more immunogenic than those expressing B7-1 (CD80) (TS/A-1), indicating that B7-1 and B7-2 display nonredundant costimulatory effects in inducing antitumor responses. Whereas transfection of B7-2 cDNA into TS/A-1 cells does not improve their immunogenicity, transfection of B7-1 cDNA into TS/A-2 cells (TS/A-2/1) decreases their immunogenicity in a manner that is directly related to the surface levels of B7-1. Ab blocking of B7-1 on TS/A-2/1 cells before their injection in vivo restores the higher immunogenicity characteristic of single B7-2 transfectants, indicating therefore that B7-1 actively modulates the B7-2-dependent costimulation. The expression of B7-1 also modifies quantitatively the balance of endogenous IFN-γ and IL-4 induced in vivo by TS/A-2 vaccines. In fact, we find that vaccination with TS/A-2/1 cells results in the production of more IFN-γ and less IL-4 than TS/A-2 vaccines, a pattern comparable to that induced by TS/A-1 cells. Thus, in the TS/A model of antitumor response, B7-1 modulates B7-2-dependent costimulatory effects in a dominant, noncompetitive way.