Search

Background Pharmacological therapies of proven efficacy in coronavirus disease 2019 (COVID-19) are still lacking. We have identified IFNβ-1a as the most promising drug to be repurposed for COVID-19. The rationale relies on the evidence of IFNβ anti-viral activity in vitro against SARS-CoV-2 and animal models resembling SARS-CoV-2 infection and on a recent clinical trial where IFNβ was indicated as the key component of a successful therapeutic combination. Methods This is a randomized, controlled, open-label, monocentric, phase II trial (INTERCOP trial). One hundred twenty-six patients with positive swab detection of SARS-CoV-2, radiological signs of pneumonia, and mild-to-moderate disease will be randomized 2:1 to IFNβ-1a in addition to standard of care vs standard of care alone. No other anti-viral drugs will be used as part of the regimens, both in the control and the intervention arms. IFNβ-1a will be administered subcutaneously at the dose of 44 mcg (equivalent to 12 million international units) three times per week, at least 48 h apart, for a total of 2 weeks. The primary outcome is the time to negative conversion of SARS-CoV-2 nasopharyngeal swabs. Secondary outcomes include improvement or worsening in a clinical severity score measured on a 7-point ordinal scale (including transfer to intensive care unit and death), oxygen- and ventilator-free days, mortality, changes in pulmonary computed tomography severity score, hospital stay duration, reduction of viral load measured on nasopharyngeal swabs, number of serious adverse events, and changes in biochemical markers of organ dysfunction. Exploratory outcomes include blood cell counts, cytokine and inflammatory profile, peripheral mRNA expression profiles of interferon-stimulated genes, and antibodies to SARS-CoV-2 and to IFNβ-1a. INTERCOP is the first study to specifically investigate the clinical benefits of IFNβ-1a in COVID-19 patients. Discussion Potential implications of this trial are multifaceted: should the primary outcome be fulfilled and the treatment be safe, one may envisage that IFNβ-1a be used to reduce the infectivity of patients with mild-to moderate disease. In case IFNβ-1a reduced the duration of hospital stay and/or ameliorated the clinical status, it may become a cornerstone of COVID-19 treatment. Trial registration EudraCT 2020-002458-25. Registered on May 11, 2020 ClinicalTrials.gov Identifier: NCT04449380

BACKGROUND Most models for outcome prediction in heart failure are under-utilized because complex or including non-routine clinical use variables. We aimed to develop a prognostic score for patients with stable heart failure, including only easily obtainable parameters. METHODS In 376 outpatients with heart failure (ejection fraction ≤40%), twelve variables were individually correlated with 5-year mortality. Those resulted significant predictors of cardiac and overall mortality were used to obtain a risk score. It was validated on a different sample of 325 patients previously enrolled in other clinical studies, according to tertiles of score. RESULTS Previous acute decompensated heart failure, atrial fibrillation, ejection fraction

The prospective evidence for the associations of gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) with risk of cancer in the general population is uncertain. We conducted a systematic review and meta-analysis of published prospective observational studies evaluating the associations of baseline levels of GGT and ALT with risk of overall (incidence and/or mortality) and site-specific cancers. Relevant studies were identified in a literature search of MEDLINE, EMBASE, Web of Science, reference lists of relevant studies to April 2014 and email contact with investigators. Study specific relative risks (RRs) were meta-analyzed using random effects models. Fourteen cohort studies with data on 1.79 million participants and 57,534 cancer outcomes were included. Comparing top versus bottom thirds of baseline circulating GGT levels, pooled RRs (95% confidence intervals) were 1.32 (1.15-1.52) for overall cancer, 1.09 (0.95-1.24) for cancers of the breast and female genital organs, 1.09 (1.02-1.16) for cancers of male genital organs, 1.94 (1.35-2.79) for cancers of digestive organs and 1.33 (0.94-1.89) for cancers of respiratory and intrathoracic organs. For ALT, corresponding RRs for overall cancer were 0.96 (0.94-0.99) and 1.65 (1.52-1.79) in European and Asian populations, respectively. There was an increased risk of cancers of the digestive organs 2.44 (1.23-4.84). The pooled RR for overall cancer per 5 U/L increment in GGT levels was 1.04 (1.03-1.05). Available observational data indicate a positive log-linear association of GGT levels with overall cancer risk. The positive association was generally evident for site-specific cancers. There are geographical variations in the association of ALT and overall cancer.

Aims: To evaluate the association between LOXIN, a new functional protective splicing isoform of the oxidized LDL receptor 1 (OLR1) gene, and the severity of coronary artery stenoses. Methods: We analyzed 100 consecutive patients with coronary artery disease (CAD) and 100 controls, all evaluated by a new molecular biology test using highly specific allele primers able to identify the single nucleotide variation (IVS4-14 A>G) in the OLR1 gene (Loxin Test - Technogenetics). All the patients and the controls underwent coronary angiography and, for quantitative evaluation, we used both vessel and stenosis score, and SYNTAX score to evaluate the severity of CAD. Moreover, we defined the prognostic localization of CAD as a critical stenosis (>50%) of the left main and/or proximal segment of left anterior descending artery (LAD). Finally, we evaluated a correlation with the presence of diabetes mellitus, dyslipidemia, hypertension, smoking and family history of CAD. Results: In this selected population, even though the 'AA nonrisk haplotype' is more frequent in the controls, we did not find any statistically significant correlation between the severity of CAD or the prognostic localization of critical stenosis and the difference of IVS4-14 A>G OLR1 genotype (P>0.05). CAD patients showed significantly higher frequencies of dyslipidemia and smoking (P

PURPOSE To evaluate the association between the severity and angiographic localization of coronary artery stenoses and clinical control of major traditional risk factors (RF). METHODS We analyzed 500 patients without known cardiovascular disease, undergoing coronary angiography for the diagnosis of coronary artery disease (CAD), with one or more major traditional RF, all in optimal clinical control. For the quantitative evaluation of CAD, we used a vessel and stenosis score to evaluate the severity of CAD. Moreover, we defined the prognostic localization of CAD as a critical stenosis (≥50%) of the left main (LM) and/or the proximal segment of the left anterior descending coronary artery (LAD). RESULTS The presence of RF was as follows: one in 14.2%, two in 40.6%, three in 35%, and more than three in 10.2% of the patients. Prognostic localization of critical stenosis on the proximal segment of LAD and/or LM was found in 174 patients (34.8%). The severity of CAD and prognostic localization of critical stenosis was not correlated with all of the conventional RF evaluated or their association (P>0.05). CONCLUSION In this population with optimally controlled traditional RF, the severity of CAD or prognostic localization on LM and/or proximal LAD was not correlated with the major RF analyzed.

Beta-blockers have been shown to improve left ventricular (LV) function in patients with heart failure. The aim of this study is to non-invasively assess, by means of in vivo 31P-magnetic resonance spectroscopy (31P-MRS), the effects of beta-blockers on LV cardiac phosphocreatine and adenosine triphosphate (PCr/ATP) ratio in patients with heart failure. Ten heart failure patients on full medical therapy were beta-blocked by either carvedilol or bisoprolol. Before and after 3 months of treatment, exercise testing, 2D echocardiography, MRS, New York Heart Association (NYHA) class, ejection fraction (EF), maximal rate-pressure product and exercise metabolic equivalent system (METS) were evaluated. Relative concentrations of PCr and ATP were determined by cardiac 31P-MRS. After beta-blockade, NYHA class decreased (from 2.2 ± 0.54 to 1.9 ± 0.52, P = 0.05), whereas EF (from 33 ± 7 to 44 ± 6%, P = 0.0009) and METS (from 6.74 ± 2.12 to 8.03 ± 2.39, P = 0.01) increased. Accordingly, the mean cardiac PCr/ATP ratio increased by 33% (from 1.48 ± 0.22 to 1.81 ± 0.48, P = 0.03). Beta-blockade-induced symptomatic and functional improvement in patients with heart failure is associated to increased PCr/ATP ratio, indicating preservation of myocardial high-energy phosphate levels.

Type 2 diabetes is associated with risk of cancer. Hyperinsulinemia and insulin resistance may be the link with cancer, but whether this is independent of the diabetes status, obesity/visceral obesity and metabolic syndrome is uncertain and the present study wanted to address this issue. Fifteen-year all-cause, CVD and cancer mortality data were obtained through the Regional Health Registry in 2,011 out of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes mellitus in Italy in which anthropometric and metabolic characteristics were collected. During the 15-year observation period, 495 deaths were registered: 221 CVD related and 180 cancer related. Age and sex were independently associated with all-cause, cancer and CVD mortality rates. Age- and sex-adjusted analysis showed that HOMA-IR, cigarette smoking and diabetes were independently associated with all-cause mortality; HOMA-IR, systolic blood pressure and fibrinogen were independently associated with CVD mortality; HOMA-IR and smoking habit were independently associated with cancer mortality. Individuals in the highest quintile of serum insulin had a 62% higher risk of cancer mortality (HR = 1.62 95% CI: 1.19-2.20; P

Objectives This study sought to assess the prevalence of normal levels of high sensitivity C-reactive protein (hsCRP) at the very onset of ST-segment elevation myocardial infarction (STEMI). Background Levels of hsCRP ≥2 mg/l identify individuals who benefit from lipid lowering and possibly anti-inflammatory agents, but how many patients develop infarction in spite of hsCRP levels Methods We studied 887 patients with unequivocally documented STEMI as the first manifestation of coronary disease and 887 matched control subjects from urban areas of Italy, Scotland, and China. Blood samples were obtained before reperfusion strategies Results hsCRP values were similar in samples obtained Conclusions The measurement of hsCRP, with a 2 mg/l cutoff, would not have predicted 41% of unequivocally documented STEMIs in 3 ethnic groups without evidence of previous coronary disease, thus indicating both its limitations as an individual prognostic marker and as an indicator of a generalized inflammatory pathogenetic component of STEMI. New specific prognostic and therapeutic approaches should be found for such a large fraction of patients at risk.

A fatty liver, which is a common feature in insulin-resistant states, can lead to chronic liver disease. It has been hypothesized that a fatty liver can also increase the rates of non-hepatic-related morbidity and mortality. Therefore, we wanted to determine whether the fatty liver index (FLI), a surrogate marker and a validated algorithm derived from the serum triglyceride level, body mass index, waist circumference, and γ-glutamyltransferase level, was associated with the prognosis in a population study. The 15-year all-cause, hepatic-related, cardiovascular disease (CVD), and cancer mortality rates were obtained through the Regional Health Registry in 2011 for 2074 Caucasian middle-aged individuals in the Cremona study, a population study examining the prevalence of diabetes mellitus in Italy. During the 15-year observation period, 495 deaths were registered: 34 were hepatic-related, 221 were CVD-related, 180 were cancer-related, and 60 were attributed to other causes. FLI was independently associated with the hepatic-related deaths (hazard ratio = 1.04, 95% confidence interval = 1.02-1.05, P < 0.0001). Age, sex, FLI, cigarette smoking, and diabetes were independently associated with all-cause mortality. Age, sex, FLI, systolic blood pressure, and fibrinogen were independently associated with CVD mortality; meanwhile, age, sex, FLI, and smoking were independently associated with cancer mortality. FLI correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), a surrogate marker of insulin resistance (Spearman's ρ = 0.57, P < 0.0001), and when HOMA-IR was included in the multivariate analyses, FLI retained its association with hepatic-related mortality but not with all-cause, CVD, and cancer-related mortality. Conclusion: FLI is independently associated with hepatic-related mortality. It is also associated with all-cause, CVD, and cancer mortality rates, but these associations appear to be tightly interconnected with the risk conferred by the correlated insulin-resistant state. © 2011 American Association for the Study of Liver Diseases

"\"Objective Trimetazidine may have beneficial effects on left ventricular (LV) function in patients with systolic heart failure. The authors assessed whether long-term addition of trimetazidine to conventional treatment could improve, along with LV function, resting whole body energy metabolism in patients with chronic systolic heart failure. Design Single blind randomised study. Setting University Hospital. Patients 44 patients with systolic heart failure receiving full medical treatment. Interventions Indirect calorimetry and two-dimensional echocardiography at baseline and after 3 months. Main outcome measures Whole body resting energy expenditure (REE), percentage of predicted REE, LV ejection fraction (EF), NYHA class, quality of life. Results Trimetazidine increased EF compared with conventional therapy alone (from 35 +\\\/- 8% to 42 +\\\/- 11% vs from 35 +\\\/- 7% to 36 +\\\/- 6%; p=0.02, analysis of variance for repeated measures). NYHA class and quality of life also improved compared with conventional therapy (p

Objective: To assess the ischemic threshold and stress-induced left ventricular dysfunction after high fat (HFM) and high carbohydrate (HCM) meals in patients with stable coronary disease. Methods: Twelve patients (68 +/- 7 years) underwent stress (treadmill exercise testing) echocardiography after fasting (8 h), after HFM and HCM (2 h). Time to 1 mm ST-segment depression (time to 1 mm) and stress wall motion score index (WMSI) were evaluated. Before eating and just before exercise testing glucose, insulin, triglycerides, total cholesterol and FFA levels were measured. Results: Results are expressed as medians (Q1-Q3). HFM did not affect exercise variables compared to fasting, whereas HCM reduced the ischemic threshold [time to 1 mm from 376 (343-493) to 297 (180-420) s, p = 0.003]. Compared to fasting [1.47 (1.31-1.66)], stress WMSI was higher after HCM [1.56 (1.44-1.69)] (p = 0.04) but not after HFM [1.56 (1.30-1.63)]. Glycemia and insulinemia were significantly higher after HCM, compared to fasting and HFM. Conclusions: In patients with coronary disease, exercise testing after a high carbohydrate meal results in a lower ischemic threshold and greater ischemia magnitude. Conversely, compared to fasting, a high fat meal does not induce additional detrimental effects. Hyperglycemia and hyperinsulinemia were the only metabolic determinants identified as potential metabolic mechanisms of this phenomenon. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

OBJECTIVE Some obese individuals have normal insulin sensitivity. It is controversial whether this phenotype is associated with increased all-cause mortality risk. RESEARCH DESIGN AND METHODS Fifteen-year all-cause mortality data were obtained through the Regional Health Registry for 2,011 of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes in Italy. Individuals were divided in four categories according to BMI (nonobese: RESULTS Obese insulin-sensitive subjects represented 11% (95% CI 8.1–14.5) of the obese population. This phenotype had similar BMI but lower waist circumference, blood pressure, fasting glucose, triglycerides, and fibrinogen and higher HDL cholesterol than obese insulin-resistant subjects. In the 15-year follow-up, 495 deaths (cardiovascular disease [CVD]: n = 221; cancer: n = 180) occurred. All-cause mortality adjusted for age and sex was higher in the obese insulin-resistant subjects (hazard ratio 1.40 [95% CI 1.08–1.81], P = 0.01) but not in the obese insulin-sensitive subjects (0.99 [0.46–2.11], P = 0.97) when compared with nonobese insulin-sensitive subjects. Also, mortality for CVD and cancer was higher in the obese insulin-resistant subjects but not in the obese insulin-sensitive subjects when compared with nonobese insulin-sensitive subjects. CONCLUSIONS In contrast to obese insulin-resistant subjects, metabolically healthy obese individuals are less common than previously thought and do not show increased all-cause, cancer, and CVD mortality risks in a 15-year follow-up study.

Objectives We sought to evaluate at 5 years the occurrence of cardiac death; cardiac death, and/or myocardial infarction (MI); cardiac death, MI, and/or stroke; target vessel revascularization; and major adverse cardiac and cerebrovascular events following percutaneous coronary intervention (PCI) with drug-eluting stent (DES) versus coronary artery bypass graft (CABG) in unprotected left main coronary artery lesions. Background Preliminary results at 1 year showed comparable occurrence of major adverse cardiac and cerebrovascular events in our center between PCI and CABG. Methods All consecutive patients with an unprotected left main coronary artery stenosis electively treated with DES implantation versus CABG in our center, between March 2002 and July 2004, were analyzed. A propensity analysis was performed to adjust for baseline differences between the 2 cohorts. Results We included 249 patients in the study: 107 were treated with PCI and DES implantation and 142 with CABG. At 5-year clinical follow-up, no difference was found between PCI and CABG in the occurrence of cardiac death (adjusted odds ratio [OR]: 0.502; 95% confidence interval [CI]: 0.162 to 1.461; p = 0.24). The PCI group showed a trend toward a lower occurrence of the composite end point of cardiac death and MI (adjusted OR: 0.408; 95% CI: 0.146 to 1.061; p = 0.06). Percutaneous coronary intervention was associated with a lower rate of the composite end point of death, MI, and/or stroke (OR: 0.399; 95% CI: 0.151 to 0.989; p = 0.04). Indeed, CABG was correlated with lower target vessel revascularization (adjusted OR: 4.411; 95% CI: 1.825 to 11.371; p = 0.0004). No difference was detected in the occurrence of major adverse cardiac and cerebrovascular events (adjusted OR: 1.578; 95% CI: 0.825 to 3.054; p = 0.18). Conclusions At 5-year clinical follow-up, there was still no difference in the occurrence of major adverse cardiac and cerebrovascular events between elective PCI with DES implantation and CABG in unprotected left main coronary artery lesions in this single-center experience. There was an advantage of PCI in the composite end point of death, MI, and/or stroke, whereas a benefit in the need for reintervention was still found in CABG.

Background: We investigated the possibility that transient coronary slow-flow as assessed during coronary angiography in patients with cardiac syndrome X may impair myocardial perfusion and the effects of this phenomenon on long-term prognosis. Methods: From 50 consecutive patients with cardiac syndrome X, we prospectively recruited 16 who exhibited coronary slow-flow during angiography. The remaining 34 patients served as controls. The slow-flow phenomenon was invariably worsened by nitrates and reversed by papaverine. During slow-flow, a dose of 99m-Tc-Methoxy-isobutyl-isonitrile (MIBI) was injected in 12 patients and SPECT imaging performed 1 h later. The perfusion study was repeated after 2 days at rest and, in 9 patients, at peak exercise after 10 +/- 4 days. Patients were then regularly followed-up. Results: All 12 patients had a significant MIBI defect in the regions served by the coronary artery that showed slow-flow just prior MIBI injection. After exercise, MIBI tomograms revealed a perfusion defect in 5 out of the 9 patients who underwent stress scanning. At 14 +/- 2 years follow-up, 1 patient with slow-flow had died and 4 developed significant coronary artery disease (CAD), while all patients of the control group were alive and none had developed significant CAD. Conclusions: These results show that the slow-flow phenomenon might be the cause of transient myocardial underperfusion in patients with angina and normal coronary arteries. Apparently, this phenomenon is associated with a worse cardiac prognosis. Therefore, patients with coronary slow-flow should be carefully followed-up. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Objective When used for epicardial ablation, unipolar devices do not predictably yield transmural scars. Bipolar radiofrequency proved highly effective on the animal model, but clinical experience is still initial. We describe acute electrophysiologic findings and follow-up results of epicardial ablation with a novel bipolar radiofrequency device. Methods A bipolar ablator was used to perform a simplified left atrial lesion set in 90 consecutive patients with atrial fibrillation undergoing open heart surgery. Pacing thresholds were assessed during surgery to validate 24 pulmonary vein encircling lines (12 patients). Follow-up was 100% complete. Results In 67 of 90 patients (84%), mitral valve disease was the main indication to surgery. Atrial fibrillation was continuous in 74 patients (82%) and intermittent in 16 patients (18%). Pacing threshold assessment showed a complete conduction block in 22 of 24 pulmonary vein couples (92%) after a single ablation and in all patients after doubling of the encircling lines. No complications related to the ablation procedure were recorded. The sinus rhythm restoration rate was 79% at 3 months, 87% at 6 months, and 89% (17/18 patients) at 1 year. Postablation organized arrhythmias consisted in right atrial flutter in 2 patients (2%) and left atrial flutter in 6 patients (7%). Conclusions Epicardial ablation with bipolar radiofrequency grants acute transmurality. A simplified lesion set proved highly effective in eliminating atrial fibrillation at 1-year follow-up. Our data suggest that addition of a lesion to the mitral annulus is advisable to prevent left atrial flutter.

Background. Progressive multifocal leukoencephalopathy (PML) remains a frequent and life-threatening complication of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Although one-half of patients with this disease will survive, the outcome is unpredictable at diagnosis, and prognostic markers are needed. Methods. JC virus (JCV) DNA levels were measured in cerebrospinal fluid (CSF) samples obtained from 61 HIV-infected patients with PML, including 38 patients who were treated with HAART and 23 patients who did not receive HAART, with use of real-time polymerase chain reaction. The diagnostic reliability of the assay was evaluated by comparing CSF findings with histopathological findings in patients with PML or other HIV-related diseases of the central nervous system. The prognostic value was assessed by comparing JCV DNA levels with survival and other patient variables. Results. The assay had a diagnostic sensitivity of 76% and specificity of 100%. In the first CSF sample obtained after onset of PML symptoms, JCV DNA values ranged from undetectable to 7.71 log copies/mL (median, 3.64 log copies/mL). JCV DNA levels >3.64 log copies/mL correlated significantly with shorter survival and lower CD4 + cell counts in patients not receiving HAART. However, neither relationship was found in patients who were treated with HAART. The analysis of sequential CSF samples obtained from 24 patients demonstrated a marked decrease in JCV DNA levels over time in HAART-treated patients showing PML stabilization, but not in untreated or HAART-treated patients with progressively fatal disease. Conclusions. Measurement of JCV DNA levels in CSF samples may be a useful virological marker for management of PML in patients receiving HAART.

It is not known whether cytokine levels in sputum may be used as outcome measures after parenteral antibiotic therapy in cystic fibrosis (CF) patients. Here, we assessed the effects of antibiotic therapy on cytokine levels in sputum and serum obtained from young CF patients. Thirty-two CF patients (14 females; mean age, 18.6 years; range, 11.4-35.7 years), consecutively admitted at the CF Center of Milan for parenteral antibiotic therapy during pulmonary exacerbation, were enrolled in the study. Before and after 21 days (range, 5-41) of intravenous antibiotic treatment, all patients underwent routine laboratory determinations (including white blood cell (WBC) count and C-reactive protein (CRP)), a chest X-ray, pulmonary function tests (forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) as % predicted), and sputum cultures. Interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha levels in serum and sputum samples were determined by means of immunometric assays. After therapy, FEV1 and FVC significantly improved (median increase of 7.5% and 8.5% predicted, respectively), while CRP and WBC count were significantly decreased (median values from 14 to 5.5 mg/dl and from 8,350 to 7,400 n/mm3, respectively). While levels of IL-6 and IL-10 in sputum were generally undetectable, IL-8 and TNF-alpha were always measurable, and IL-8 levels significantly decreased after antibiotic treatment (median values from 7,165 to 5,415 pg/ml). Following antibiotic therapy, IL-8 and TNF-alpha levels in sputum were inversely related with both FEV(1) and FVC. In conclusion, TNF-alpha and IL-8 levels in sputum of young CF patients with pulmonary exacerbation were always detectable and may be useful, noninvasive outcome measures to assess response to therapy in CF patients.

OBJECTIVE—Leptin and tumor necrosis factor (TNF)-α are associated with insulin resistance and cardiovascular disease. In vitro studies suggested that these effects may be mediated via overproduction of monocyte chemoattracting protein (MCP)-1/CCL2, which is a chemokine involved in the pathogenesis of atherosclerosis. RESEARCH DESIGN AND METHODS—In this study, fasting plasma leptin, soluble TNF-α receptor 2 (TNF-α-R2), and MCP-1/CCL2 concentrations were measured in 207 middle-aged women (age 61 ± 12 years, BMI 30.1 ± 6.6 kg/m2), including 53 patients with type 2 diabetes, 42 with impaired glucose tolerance, and 112 with normal glucose tolerance, to assess cross-sectionally their relationship with markers of atherosclerosis and, longitudinally over 7 years, whether their circulating levels were associated with cardiovascular disease (CVD) mortality. RESULTS—At baseline, leptin and TNF-α-R2 were not different among groups; meanwhile, MCP-1/CCL2 was increased in type 2 diabetes (P < 0.05). All showed significant associations with biochemical risk markers of atherosclerosis. In a univariate analysis, age, fasting insulin, leptin, and MCP-1/CCL2 were associated with CVD mortality at 7 years. When a multivariate analysis was performed, only age, leptin, and insulin retained an independent association with CVD mortality, with leptin showing a protective effect (hazard ratio 0.88; P < 0.02). CONCLUSIONS—In middle-aged women, MCP-1/CCL2, leptin, and TNF-α-R2 were all related to biochemical risk markers of atherosclerosis. MCP-1/CCL2 concentration was the only one to be increased in type 2 diabetes with respect to nondiabetic women and the only one to be associated with increased risk of CVD mortality after a 7-year follow-up period in the univariate analysis. In the multivariate analysis, neither MCP-1/CCL2 nor TNF-α-R2 was associated with CVD mortality, and inspection of the data showed that leptin, in both the univariate and multivariate analysis, was associated with a protective effect.

Study objective: To compare an unattended device for cardiorespiratory monitoring (POLYMESAM; MAP; Martinsried, Germany) [P-M] with classic nocturnal polysomnography (PSG) for diagnosis of obstructive sleep apnea (OSA) in children. Design: Clinical setting. Patients: Twelve children (age range, 3 to 6 years) with highly suspected uncomplicated OSA who underwent PSG and P-M on 2 consecutive laboratory nights in a balanced manner. Measurements: Respiratory indexes were compared for P-M (automated analysis), hand-scored revised P-M (P-Mrev), and PSG. Analysis of contingency for cutoff levels of respiratory disturbance index (RDI) of 5 and 10 and level of agreement between P-M, P-Mrev, and PSG by the concordance method were evaluated. Results: Nine of twelve children (75%) had a PSG RDI > 5, while 41.7% had an RDI > 10, indicating moderate-to-severe OSA. P-M sensitivity (78%) increased with the increase of the RDI cutoff, and P-Mrev sensitivity reached 100% at the cutoff of 10. The specificity was low for RDI > 5 and increased only modestly at RDI > 10 (P-Mrev, 57%). Seven of 12 children (increasing to 9 children with P-Mrev) and 9 of 12 children (increasing to 11 children with P-Mrev) were correctly classified by the P-M unit when cutoffs of 5 and 10 were considered, respectively. As far as the agreement level is concerned, P-M underestimated the incidence of obstructive hypopnea and overestimated the number of central apnea cases. P-Mrev improved the latter measure. Conclusion: Based on these data, the P-M device cannot be advocated for common use in a clinical setting, but it may have a role in urgent screening for highly suspected moderate-to-severe OSA. (CHEST 2003; 124:602– 607) Abbreviations: AHT total number of apnea and hypopnea events; CA central apnea; CI confidence interval; DE desaturation event; NPV negative predictive value; P-M POLY-MESAM; P-Mrev revised POLYMESAM; OA obstructive and mixed apnea; ODI oxygen desaturation index; OH obstructive hypopnea; OSA obstructive sleep apnea; PPV positive predictive value; RDI respiratory disturbance index; Sao2 arterial oxygen saturation; Sao2% percentage of arterial oxygen saturation

Aim The prognostic utility of myocardial perfusion scintigraphy (MPS) in patients with angiographically normal coronary arteries has not been evaluated yet. Our aim was to determine the prognostic role of positive MPS in patients with angina, positive exercise test and smooth coronary arteries (syndrome X). Methods A total of 156 patients with angina, positive exercise test, positive MPS and normal coronary arteries and 172 patients with angina and positive exercise test who had negative MPS were selected for study. The primary endpoint was combined all-cause mortality and hospitalizations for cardiac causes. The secondary endpoint was hospitalization for cardiac causes. Results Kaplan–Meier analysis showed a greater ( p =0.001) incidence of the primary endpoint in patients with positive MPS, compared to those with negative MPS. Additionally, Kaplan–Meier analysis for cardiovascular hospitalization showed a significant difference ( p =0.003) between the two groups. Cox regression analysis, adjusted for age, sex, BMI and antianginal therapy confirmed a significant risk increase for patients with positive MPS, with a hazard ratio (HR)=3.20 (CI 95%: 1.14–9.02; p =0.028). Cox analysis for cardiovascular hospitalization also showed a significant risk increase for patients with positive MPS (HR=3.19; CI 95%: 1.13–9.00; p =0.03). Finally, Cox analysis showed that patients with positive MPS tend to have a higher risk to remain symptomatic in the follow-up period (HR=1.614; CI 95%: 0.999–2.607; p =0.51). Conclusions This study shows that inducible myocardial hypoperfusion at MPS in patients with syndrome X could discriminate patients with a more severe prognosis, especially in terms of further hospitalization and symptomatic burden.

Objective. The goal of this work was to assess retrospectively the role of wide/radical hysterectomy (RH) and pelvic lymph node dissection (LND) in endometrial cancer with cervical involvement. Methods. From 1984 to 1993, 82 patients with endometrial cancer and cervical involvement were surgically managed at our institution. Of 57 patients with stage II (59%) or III (41%) disease receiving no preoperative therapy, 22 (39%) had simple hysterectomy (SH) and 35 (61%) had RH. Forty-four patients (77%) had pelvic LND, and 38 (67%) had adjuvant radiotherapy (RT). Median follow-up was 70 months. Results. The 5-year disease-related survival (DRS) and recurrence-free survival (RFS) were 73 and 63%, respectively. Five-year DRS and RFS were 68 and 50%, respectively, in the SH group compared with 76% ( P = 0.1) and 71% ( P = 0.04) in the RH group. Distant recurrences occurred in 45% of patients with SH and in 23% with RH ( P = 0.08). Local recurrence rates did not differ significantly. Considering only stage II tumors, we did not observe any recurrence among patients with negative nodes who had RH, irrespective of the administration of adjuvant RT. By contrast, adjuvant RT improved local control (even if not significantly) in stage II patients who had SH. Five-year DRS of stage III patients was 47%, but it was improved by adjuvant RT in the subgroup of patients who had RH. Independent variables associated with prognosis were stage III disease, deep myometrial invasion, RH, and adjuvant RT. Conclusion. RH and adjuvant RT appear to improve prognosis in endometrial cancer with cervical involvement. In particular, radical surgery alone is therapeutic in stage II patients with negative nodes, irrespective of the administration of RT. By contrast, RT can possibly improve local control in stage II patients who previously had SH. Overall, stage III patients have a poor prognosis that can be improved by a combination of radical surgery and adjuvant RT; however, associated therapy directed to extrapelvic sites is probably needed in patients with extrauterine disease.

Background —Atrial fibrillation (AF) increases the morbidity of CABG. The pathophysiology is uncertain, and its prevention remains suboptimal. This prospective, randomized study was designed to define the role of cardiopulmonary bypass (CPB) and cardioplegic arrest in the pathogenesis of this complication. Methods and Results —Two hundred patients were prospectively randomized to (1) on-pump conventional surgery [(100 patients, 79 men, mean age 63 (40 to 77) years)] with normothermic CPB and cardioplegic arrest of the heart or (2) off-pump surgery [(100 patients, 82 men, mean age 63 (38 to 86) years)] on the beating heart. Heart rate and rhythm were continuously monitored with an automated arrhythmia detector during the first 72 hours after surgery. Thereafter, routine clinical observation was performed and continuous monitoring restarted in the case of arrhythmia. The association of perioperative factors with AF was investigated by univariate analysis. Significant variables were then included into a stepwise logistic regression model to ascertain their independent influence on the occurrence of AF. There were no significant baseline differences between groups. Thirty-nine patients in the on-pump group and 8 patients in the off-pump group had postoperative sustained AF ( P =0.001). Univariate analysis showed that CPB inclusive of cardioplegic arrest, postoperative inotropic support, intubation time, chest infection, and hospital length of stay were predictors of AF (all P Conclusions —CPB inclusive of cardioplegic arrest is the main independent predictor of postoperative AF in patients undergoing coronary revascularization.

Diabetes mellitus frequently complicates cirrhosis but the pathogenic mechanisms are unknown. To assess the contribution of reduced insulin action and secretion, 24 cirrhotic-diabetic patients waiting for liver transplant because of an unresectable hepatocarcinoma underwent an oral glucose tolerance test (OGTT) to assess the beta-cell function and an insulin clamp combined with [3-(3)H]glucose infusion to measure whole body glucose metabolism before and 2 years after the transplant. Seven cirrhotic nondiabetic patients, 11 patients with chronic uveitis on similar immunosuppressive therapy, and 7 healthy subjects served as control groups. Cirrhotic patients showed a profound insulin resistance, and diabetics in addition also showed increased endogenous glucose production (P

Age, female sex, and obesity are well-known risk factors for gallstones; in contrast the possible role of type 2 diabetes mellitus (type-2 DM) is controversial. One reason for this discrepancy might be that type 2 DM is often accompanied by obesity. Therefore, the aim of this study was to evaluate the importance of obesity and of type 2 DM, separately and together, as risk factors for gallstones. In all, 203 obese patients with normal glucose tolerance (obese NGT), 446 obese patients with type 2 DM (obese type 2 DM), 269 lean patients with type 2 DM (lean type 2 DM) and 250 lean subjects with a normal glucose tolerance (lean NGT) were evaluated by ultrasonography for the presence of gallstones. At univariate analysis patients with gallstones (177) were older and were more frequently affected by both obesity and type 2 DM, and had higher triglycerides and fasting blood glucose levels. At multiple logistic regression analysis, only age and obesity, both in the presence or in absence of type 2 DM, were strongly associated with gallstones (P < 0.001); diabetes alone had a lower level of statistical significance (P = 0.07). These data suggest that obesity is a stronger risk factor for gallstones than type 2 DM.

The aim of this study was to evaluate the controversial specificity of the plasma amino acid (AA)-consumption test in detecting pancreatic diseases by using two different quantitative methods. A total of 55 subjects: 13 healthy subjects, 13 patients with chronic pancreatitis (three mild/moderate, eight severe), 13 patients with pancreatectomy and complete suppression of the exocrine pancreatic secretion, eight patients with chronic liver disease (five with impaired synthetic function), and eight patients with chronic renal failure. Total plasma AAs were quantified by a colorimetric method (p-benzoquinone) in all subjects, at 0, 30, 45, and 60 min during and 30 min after minute 60 of i.v. cerulein infusion (50 ng/kg/h). Either total and individual AAs were quantified by chromatography (high-performance liquid chromatography; HPLC) in 10 healthy subjects, 10 patients with pancreatectomy, and 10 with chronic pancreatitis at 0 and 60 min after the start of the cerulein infusion. For the colorimetric method, healthy subjects had maximal percentage decreases of total AA concentrations not significantly different from those of patients with pancreatectomy and significantly higher than those of patients with chronic pancreatitis (p0.0001) or chronic liver disease (p0.001). Pancreatic function, as assessed by fecal elastase-1 test, was not significantly correlated to the maximal percentage decrease in total plasma AAs. For the chromatographic method, total AA concentrations were not significantly correlated to those determined by colorimetry. The concentration of each of the individual plasma AAs varied considerably in each group. Fecal elastase-1 values were normal (or = 200 microg/g) in all patients without pancreatic disease and in only one of 11 patients with chronic pancreatitis and exocrine insufficiency. The type of method used can explain the different results of the AA-consumption test. This test is not very specific for the pancreas.

Hypoglycaemia is an important complication of insulin treatment in Type 1 diabetes mellitus (DM). Pancreas transplantation couples glucose sensing and insulin secretion, attaining a distinctive advantage over insulin treatment. We tested whether successful transplantation can avoid hypoglycaemia in Type 1 DM. Combined kidney and pancreas transplanted Type 1 DM who complied with good function criteria (KP-Tx, n = 55), and isolated kidney or liver transplanted non-diabetic subjects on the same immunosuppressive regimen (CON-Tx, n = 14), underwent 1-day metabolic profiles in the first 3 years after transplantation, sampling plasma glucose (PC) and pancreatic hormones every 2 hours. KP-Tx had lower PG than CON-Tx in the night and in the morning and higher insulin concentrations throughout the day. KP-Tx had lower PC nadirs than CON-Tx (4.40 +/- 0.05 vs 4.96 +/- 0.16 mmol l(-1), ANOVA p = 0.001). Nine per cent of KP-Tx had hypoglycaemic values (PG less than or equal to 3.0 mmol l(-1)) in the profiles, both postprandial and postabsorptive, whereas none of CON-Tx did (p < 0.02). In conclusion, after pancreas transplantation, mild hypoglycaemia is frequent, although its clinical impact is limited. Compared to insulin treatment in Type 1 DM, pancreas transplantation improves but cannot eliminate hypoglycaemia. (C) 1998 John Wiley & Sons, Ltd.

ATIII is decreased in sepsis and/or shock and its baseline value correlates with mortality. The efficacy of ATIII therapy on mortality was assessed in a selected group of patients admitted to the intensive care unit (ICU) in a double-blind, randomized, multicenter study.120 patients admitted to the ICU with an ATIII concentration70% were randomized to receive ATIII (total dose 24000 units) or placebo treatment for 5 days; 56 patients had septic shock.ATIII concentrations in the treated group remained constant throughout the treatment period (range 97-102%). The Kaplan-Meier analysis showed no difference in overall survival between the two groups: 50 and 46% for ATIII and placebo, respectively. Septic shock and hemodynamic support were unbalanced in the two groups at admission. Therefore the Cox analysis was carried out after adjusting for these two variables. Treatment with ATIII decreases the risk of death with an odds ratio (OR) of 0.56. Of the covariates analyzed, septic shock and the baseline multiple organ failure score were negatively associated with survival and plasma activity level was positively associated with survival with an OR of 0.97 for each 1% increase in the ATIII plasma concentration at baseline.The results of ATIII treatment in this population of patients suggests that replacement therapy reduces mortality in the subgroup of septic shock patients only.

BACKGROUND: The aim of this study was to evaluate, according to functional response, the neuroendocrine and inflammatory status in patients with chronic heart failure before and after therapy with carvedilol. METHODS AND RESULTS: Serum tumor necrosis factor-α (TNF-α) soluble receptors (sTNF-R1 and sTNF-R2), interleukin (IL)-10 and IL-18, chromogranin A (CgA) and brain natriuretic peptide (pro-BNP) were measured in 37 New York Heart Association class II to IV heart failure patients, at baseline and after 6 months of therapy with carvedilol. Patients were divided in two groups according to whether, following carvedilol, left-ventricular ejection fraction (LVEF) had increased by at least 5% (17 patients) or not (20 patients). Baseline LVEF was higher in nonresponders (38 ± 5 vs. 31 ± 7%, P = 0.002). In responders, LVEF increased from 31 ± 7 to 51 ± 7% (P < 0.0001), whereas in nonresponders it decreased from 38 ± 5 to 33 ± 7%, (P = 0.02). sTNF-R1 (P = 0.019) and sTNF-R2 (P = 0.025) increased in nonresponders, whereas they did not change in responders. After carvedilol, IL-10 was significantly higher in responders (P = 0.03). Conversely, no significant IL-18 and CgA changes were observed in either group. CgA was not significantly different between groups at baseline and after carvedilol in either group, whereas pro-BNP significantly increased in nonresponders (from 438 ± 582 to 1324 ± 1664 pg/ml, P = 0.04) and decreased in responders (from 848 ± 1221 to 420 ± 530 pg/ml, P = 0.08). CONCLUSION: Increased inflammatory activation observed only in heart failure patients not improving left-ventricular function after carvedilol may indicate that inflammation, either as a direct cause or as a consequence, is associated with progressive ventricular dysfunction. © 2012 Italian Federation of Cardiology

Between 1989 and 1993, 62 patients underwent Whipple pancreatoduodenectomy and 75 pylorus-preserving pancreatoduodenectomy (PPPD); 35 patients in the first group and 37 in the second had pancreatic adenocarcinoma while 17 and 21 patients respectively had periampullary adenocarcinoma. The aim of this retrospective study was the comparison of operative outcome, nutritional recovery and survival of patients who underwent these two operations. No significant differences were found between the two groups in operative mortality or morbidity, duration of gastric aspiration and time to start of solid meals. Patients who underwent PPPD had a better nutritional recovery: the increase of both body-weight and serum albumin level at 6 months after discharge was significantly higher for those who had preservation of the whole stomach (P < 0.001 and P < 0.05 respectively). No significant difference in survival was found between the two procedures when patients with pancreatic or periampullary adenocarcinoma were analysed separately.

This study evaluated the arousal pattern and sleep fragmentation in the sleep microstructure of heavy snorers and obstructive sleep apnoea (OSA) patients. Fifteen snorers [Group A, (A + H I) ≤ 10], 15 mild OSA (Group B, A + H I > 10 ≤ 30] and 15 moderate to severe OSA (Group C, A + H I > 30) were studied retrospectively analysing the number, duration and type of arousals according to scoring rules concerning definition (including delta bursts) and length (from 2 to 60 s) of phasic arousal events. The number of arousals per hour of sleep related to respiratory events was higher in Groups B and C, whilst in Group A there was a number of arousals not related to apnoea or hypopnoea. Daytime sleepiness, present in all three groups and measured by a subjective evaluation, correlated with both the number and EEG type of arousal, but not with the duration. Statistical analysis indicated that arousal index related to apnoea or hypopnoea was the best variable for determining the sleepiness risk in OSA and snorers. Sleep microstructure analysis seems a good scoring method for the detection of sleep fragmentation and arousals in relation to abnormal respiratory events.

Snoring is a prerequisite for obstructive sleep apnoea (OSA) and is known to run in families. Recent studies have provided sufficient evidence for a familial predisposition to OSA. In our study, 492 monozygotic and 284 dizygotic twins were contacted by telephone and asked to attend an interview which included questions of life habits, medical history, sleep habits and disorders, with particular emphasis on snoring. Our study showed that the probandwise concordance rate for habitual snoring was higher in monozygotic twins than in dizygotic ones, but the difference was not significant. The comparison of concordant pairs for habitual snoring vs. concordant pairs for non-snoring confirmed that habitual snoring is significantly associated with older age, male gender, higher body mass index (BMI), smoking and respiratory diseases. The multivariate analysis in the discordant groups confirmed that BMI is more strongly associated to habitual snoring in dizygotic twins than in the monozygotic ones. Our logistic analysis showed that other variables, such as smoking and respiratory diseases, are associated with habitual snoring in dizygotic pairs, but not in monozygotic ones. These findings suggest a genetic predisposition to habitual snoring.

OBJECTIVE To relate therapeutic issues, comorbidities and functional parameters to mortality/morbidity of mild/moderate heart failure patients. METHODS From our heart failure clinic, 372 heart failure patients (269 men, aged 66 ± 11 years), with stable heart failure and ejection fraction 45% or less were recruited. Survival curves were estimated according to the Kaplan-Meier method. Associations of protective/risk factors with cardiovascular mortality/morbidity were also evaluated. RESULTS One hundred and two patients (27%) died (aged 70 ± 10 years at diagnosis, 76 ± 10 at death) during follow-up (overall mortality at 60 months: 19.2%; mean follow-up period: 67 ± 44 months). Cardiovascular deaths were 64 (63% of total deaths, 44 men, age at diagnosis 70 ± 9). Cardiovascular mortality at 60 months was 12%; standardized mortality ratio was 5.9 for women and 6.8 for men. The remaining 38 patients (37% of total deaths, 30 men, age at diagnosis 70 ± 10) died of noncardiovascular causes. Overall, noncardiovascular mortality at 60 months was 7.2%; mean survival time from diagnosis to death was 63 ± 69 months (median 42, Q1 = 27.5, Q3 = 77.7). Average cardiovascular admission rate was 1.63 ± 1.84 admissions/patient. At multivariate analysis, only previous history of myocardial infarction [hazard ratio: 3.62 (1.70-7.73)], class of ejection fraction at diagnosis [hazard ratio: 0.36 (0.32-0.60)], acute cardiac decompensation at any time [hazard ratio: 1.55 (1.32-1.84)], implanted defibrillator [hazard ratio: 0.11 (0.01-0.83)] and use of statins [hazard ratio: 0.08 (0.007-0.42)] were independently associated with cardiovascular mortality. Factors associated to higher annual cardiovascular morbidity were age at diagnosis, chronic renal failure, diabetes, cardiac decompensation at any time, female sex and diuretic therapy. Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin-receptor-blockers reduced annual cardiovascular morbidity. CONCLUSION Survival in mild/moderate heart failure patients has consistently improved. Further improvements are warranted in terms of morbidity reduction.

Objectives: We undertook a historical cohort study to compare, in terms of morbidity, mortality and long-term survival associated with lung cancer resection, a group of patients with previous lymphoproliferative disorders and a group without a hematological history. Methods: We identified 29 patients with a previous lymphoproliferative disorder who underwent lung cancer resection. These subjects (Group-A) were matched with 87 patients without a hematological history who underwent pulmonary resection during the same period (Group-B). Results: We found no significant difference between the two groups in length of hospitalization, comorbidities, spirometric parameters, type of surgery, histology, neoadjuvant chemotherapy, morbidity, mortality, median survival (Group-A = 37 months; Group-B = 52 months) and 5-year survival (Group-A = 37%; Group-B = 42%). The mean age of Group-A patients was significantly lower than that of Group-B patients (62 vs 66 years; p = 0.024). Group-A patients had a well differentiated lung cancer more frequently than Group-B patients (p = 0.001). Group-A patients had transitory bacteraemies more frequently than Group-B patients (p = 0.005). Multivariate Cox regression analysis showed that age (p = 0.01) and lung cancer stage (p = 0.04) were significantly associated with survival. Conclusions: Patients with lymphoproliferative disorders had a lower age and more differentiated lung cancers than those without lymphoproliferative disorders. Patients with lymphoproliferative disorders and those without a hematological history had similar morbidity, mortality and long-term survival after pulmonary resection. Distinguishing patients with and without a lymphoproliferative disorder seems to be of limited value in the decision-making process of evaluating the indications for surgical treatment of lung cancer. (C) 2012 Elsevier Ltd. All rights reserved. RI ciriaco, paola/H-5716-2012

Background 31-Phosphorus-magnetic resonance spectroscopy may provide pathophysiological insights into the high-energy phosphate metabolism of the myocardium as measured by phosphocreatine to adenosine triphosphate (PCr/ATP) ratio. Aim of the present study was to determine in vivo the relation between cardiac PCr/ATP ratio and heart rate in normal male subjects. Methods One hundred twelve apparently healthy, young male individuals (age 34 +/- 10 years) were prospectively evaluated. They underwent cardiac cine magnetic resonance imaging to assess left ventricular (LV) function and morphology and 3D-ISIS (31)P-magnetic resonance spectroscopy of the LV to assess the PCr/ATP ratio (a recognized in vivo marker of myocardial energy metabolism). Data were analyzed after segregation by tertiles of the resting PCr/ATP ratio. Results A significant inverse association between PCr/ATP ratios and resting heart rate was observed (Spearman.: r=-0.37; P < .0001). PCr/ATP ratios were also inversely associated with body mass index, diastolic blood pressure, wall mass and with insulin resistance, but in multiple regression analysis heart rate was found to be independently related to PCr/ATP. Conclusions The present study shows that resting heart rate is proportionally lower across tertiles of increasing PCr/ATP ratio of the LV in apparently healthy young male individuals, supporting the hypothesis that heart rate is a major determinant of cardiac energy stores. These findings may explain the prognostic role of heart rate in the general population as evidenced by previous large epidemiological studies. (Am Heart J 2011;162:136-41.)

The aim of this study was to estimate the diagnostic sensitivity of thyroid autoantibodies in individuals with a case-mix of subjects with thyroid disease representing that of the general population. We measured thyroid microsome (TMA), thyroid peroxidase (TPO), thyroglobulin (TGA) and thyroid-stimulating hormone (TSH) receptor (TRA) autoantibodies in subjects in the bottom (hyperthyroid end) and top (hypothyroid end) four percentiles of the TSH distribution from among participants in a population-based survey of individuals aged ≥40 years (the Cremona Study). TMA and TPO were the most sensitive autoantibodies in subjects in both the bottom percentiles (19.8% and 18.5%, respectively) and the top percentiles (51.2% and 53.8%, respectively) of the TSH distribution. TMA and TPO showed good agreement (kappa statistics 87.8%, 95% CI 80.1–95.5%) at both ends of the TSH distribution. TGA were the next most sensitive marker, although seldom detected if TMA or TPO were not present. TRA were detected only at the extremes of the TSH distribution (1st percentile, 31.8%; 100th percentile, 25.0%). We conclude that, among a case-mix of individuals with thyroid disease representing that of the general population, TMA and TPO are the most sensitive markers of thyroid disease. TGA only marginally increased the diagnostic sensitivity of TMA and TPO. TRA are sensitive markers of thyroid disease only at the extremes of thyroid function.

⁎ Corresponding author. Tel.: +39 02 26437366; fax: +39 02 26437358. E-mail address: gabriele.fragasso@hsr.it (G. Fragasso). Despite many advances in diagnosis and therapy, heart failure (HF) is still apparently related to poor prognosis, with reported mortality rates at 5-year over 40% (9% per year) — a six-fold adverse rate compared with the general population [1–3]. To address this important public health issue, we sought to determine morbidity and mortality rates in our population of chronic HF out-patients, followed-up in the heart failure clinic of our Institution and compare them with rates reported in previous surveys. Of a total of 403 systolic heart failure patients attending our clinic from March 1992 to December 2005 and on optimal medical and device therapy, 372 (269 males, age at diagnosis 66±11 yrs) were considered eligible for study analysis. The remaining 31 patients could not be traced. Patients lost at followup were tested for baseline variables (age, gender, NYHA class, ejection fraction) and were not statistically different compared with the group with complete followup. Mean follow-up from first diagnosis was 67±44 months (median 58.50, Q1=40.75, Q3=80.25). The diagnosis of HF was ascertained according to European Society of Cardiology criteria: I) symptoms of heart failure and II) objective evidence (by echocardiography) of cardiac systolic dysfunction (at rest) and (in cases where the diagnosis was in doubt) III) response to treatment directed towards heart failure. Criteria I and II had to be fulfilled in all cases. Furthermore, we selected only patients with a baseline ejection fraction (EF)≤45% (Simpson biplane). Cardiovascular mortality was calculated as the number of events per 1000 person-year at risk. Mortality and morbidity were compared with the national population by using standardized mortality ratios, referring to national data classified by age and sex (data from the Italian Central Statistics Institute – ISTAT – We found that application twice of 4.3 MHz intracardiac ultrasound for 60 s at an intensity of 1.0 W/cm were suitable parameters for higher efficiency of transfection and low percentage of myocardial tissue impairment. Furthermore, the EGFP mRNA of EGFP+MB/US group was significantly higher than those of other groups, which confirmed that that the combination of intracardiac ultrasonic exposure and intramyocardial injection of microbubbles could enhance gene transfection. The main findings of this investigation were: 1) the intracardiac ultrasonic exposure technology and injection system provides an accurate and reliable means of delivering an injectate transendocardially into the LV, 2) this system allows for the injection of a naked DNA gene into designated myocardial sites and results in successful gene transfer and protein expression. This novel approach could also obviously reduce gene and microbubble dosage. In sum, intramyocardial injection microbubble combination of intracardiac ultrasonic exposure can enhance gene expression. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [5].

OBJECTIVE - Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes. RESEARCH DESIGN AND METHODS - MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 12 years BMI 30.1 +/- 6.6 kg/m(2), 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990-1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files. RESULTS - At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (p < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality. CONCLUSIONS - In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target. OBJECTIVE Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes. RESEARCH DESIGN AND METHODS MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 ± 12 years, BMI 30.1 ± 6.6 kg/m2, 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990–1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files. RESULTS At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (P < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality. CONCLUSIONS In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target.

An incidence register for Type 1 diabetes was started in Lombardy in 1983-84 for people under 35 years of age. The main information source was the Regional Health Service record system, which provides anonymous reports on all patients discharged from public and private hospitals. Great care was taken to assure the quality of the data in the register. The clinical diagnosis was validated by examining the case notes. Completeness of the register was assessed using multiple independent sources of case ascertainment such as the list of the Youth Diabetics Association, the files of three hospital endocrinology centres, and the registry of conscripts rejected because of diabetes. The estimated age-adjusted (world standard) annual incidence rate was 6.04 per 100,000 in the group 0-18 years and 5.96 per 100,000 in the age group 0-14 years. Females had peak incidence at 11 years of age, males had peak incidence 2 years later. These results confirm the low occurrence of Type 1 diabetes in northern Italy. A seasonal variation in onset of Type 1 diabetes was seen.

Aims The addition of trimetazidine to standard treatment has been shown to improve left ventricular (LV) function in patients with heart failure. The aim of this study is to non-invasively assess, by means of in vivo P-31-magnetic resonance spectroscopy (P-31-MRS), the effects of trimetazidine on LV cardiac phosphocreatine and adenosine triphosphate (PCr/ATP) ratio in patients with heart failure. Methods and results Twelve heart failure patients were randomized in a double-blind, cross-over study to placebo or trimetazidine (20 mg t.i.d.) for two periods of 90 days. At the end of each period, all patients underwent exercise testing, 2D echocardiography, and MRS. New York Heart Association (NYHA) class, ejection fraction (EF), maximal rate-pressure product, and metabolic equivalent system (METS) were evaluated. Relative concentrations of PCr and ATP were determined by cardiac P-31-MRS. On trimetazidine, NYHA class decreased from 3.04 +/- 0.26 to 2.45 +/- 0.52 (P=0.005), whereas EF (34 +/- 10 vs. 39 +/- 10%, P=0.03) and METS (from 7.44 +/- 1.84 to 8.78 +/- 2.72, P=0.03) increased. The mean cardiac PCr/ATP ratio was 1.35 +/- 0.33 with placebo, but was increased by 33% to 1.80 +/- 0.50 (P=0.03) with trimetazidine. Conclusion Trimetazidine improves functional class and LV function in patients with heart failure. These effects are associated to the observed trimetazidine-induced increase in the PCr/ATP ratio, indicating preservation of the myocardial high-energy phosphate levels. AIMS: The addition of trimetazidine to standard treatment has been shown to improve left ventricular (LV) function in patients with heart failure. The aim of this study is to non-invasively assess, by means of in vivo 31P-magnetic resonance spectroscopy (31P-MRS), the effects of trimetazidine on LV cardiac phosphocreatine and adenosine triphosphate (PCr/ATP) ratio in patients with heart failure. METHODS AND RESULTS: Twelve heart failure patients were randomized in a double-blind, cross-over study to placebo or trimetazidine (20 mg t.i.d.) for two periods of 90 days. At the end of each period, all patients underwent exercise testing, 2D echocardiography, and MRS. New York Heart Association (NYHA) class, ejection fraction (EF), maximal rate-pressure product, and metabolic equivalent system (METS) were evaluated. Relative concentrations of PCr and ATP were determined by cardiac 31P-MRS. On trimetazidine, NYHA class decreased from 3.04+/-0.26 to 2.45+/-0.52 (P = 0.005), whereas EF (34+/-10 vs. 39+/-10%, P = 0.03) and METS (from 7.44+/-1.84 to 8.78+/-2.72, P = 0.03) increased. The mean cardiac PCr/ATP ratio was 1.35+/-0.33 with placebo, but was increased by 33% to 1.80+/-0.50 (P = 0.03) with trimetazidine. CONCLUSION: Trimetazidine improves functional class and LV function in patients with heart failure. These effects are associated to the observed trimetazidine-induced increase in the PCr/ATP ratio, indicating preservation of the myocardial high-energy phosphate levels.

OBJECTIVES This study sought to assess whether the long-term addition of trimetazidine to conventional treatment could improve functional class, exercise tolerance, and left ventricular function in patients with heart failure (HF). BACKGROUND Previous small studies have shown that trimetazidine may be beneficial in terms of left ventricular function preservation and control of symptoms in patients with post-ischemic HF. METHODS Fifty-five patients with HF were randomly allocated in an open-label fashion to either conventional therapy plus trimetazidine (20 mg three times daily) (28 patients) or conventional therapy alone (27 patients). Mean follow-up was 13 +/- 3 months. At study entry and at follow-up, all patients underwent exercise testing and two-dimensional echocardiography. Among the others, New York Heart Association (NYHA) functional class and ejection fraction (EF) were evaluated. RESULTS In the trimetazidine group, NYHA functional class significantly improved compared with the conventional therapy group (p < 0.0001). Treatment with trimetazidine significantly decreased left ventricular end-systolic volume (from 98 +/- 36 ml to 81 +/- 27 ml, p = 0.04) and increased EF from 36 +/- 7% to 43 +/- 10% (p 0.002). On the contrary, in the conventional therapy group, both left ventricular end-diastolic and -systolic volumes increased from 142 +/- 43 ml to 156 +/- 63 ml, p = 0.2, and from 86 +/- 34 ml to 104 +/- 52 ml, p = 0.1, respectively; accordingly, EF significantly decreased from 38 +/- 7% to 34 +/- 7% (p = 0.02). CONCLUSIONS In conclusion, long-term trimetazidine improves functional class and left ventricular function in patients with HF. This benefit contrasts with the natural history of the disease, as shown by the decrease of EF in patients on standard HF therapy alone.

Soon after the onset of type 1 diabetes, renal hypertrophy and hyperfiltration become manifest, particularly among patients who will subsequently develop diabetic nephropathy. Whether these early renal dysfunctions are involved in the pathogenesis of diabetic nephropathy is currently unclear. We evaluated, during the same day, kidney volume and glomerular filtration rate (GFR) in 146 patients with type 1 diabetes and normal renal function. All the individuals were then monitored for a mean of 9.5 ± 4.4 years for the development of microalbuminuria. Kidney volume and GFR were reevaluated in a subset of 68 patients 4 years after baseline. During follow-up, microalbuminuria developed in 27 of 146 diabetic patients. At baseline, kidney volume (312.8 ± 52.6 vs. 281.4 ± 46.1 vs. 236.8 ± 41.6 ml/1.73 m2, P < 0.05) but not GFR was increased in patients predisposed to microalbuminuria. Risk of progression was higher in patients with increased kidney volume (P = 0.0058). Patients predisposed to microalbuminuria showed a stable increase in kidney volume (P = 0.003), along with a faster decline of GFR (P = 0.01). Persistent renal hypertrophy and faster decline of GFR precede the development of microalbuminuria in type 1 diabetes. These findings support the hypothesis that renal hypertrophy precedes hyperfiltration during the development of diabetic nephropathy.

Background: Previous studies provide evidence for a significant reduction of coronary flow reserve after ingestion of meals of different compositions. A possible role of hyperinsulinemia and increased free fatty acid levels, which are deleterious during acute myocardial ischemia and reperfusion, has been hypothesized. We assessed in patients with stable coronary disease the effects of high-fat meals (HFMs) and high-carbohydrate meals (HCMs) on ischemic threshold and stress left ventricular function on placebo and after partial fatty acid inhibition by trimetazidine (TMZ). Methods: Ten patients (9 men, age 68 ± 7 years) were allocated to placebo and TMZ (40 mg TID), both administered in the 24 hours preceding testing, according to a randomized double-blind study design. All patients underwent stress (treadmill exercise testing according to the Bruce protocol) echocardiography after fasting (8 hours) and after an HFM and HCM (2 hours) either on placebo or on TMZ. Time to 1-mm ST-segment depression (time to 1 mm) and stress wall motion score index (WMSI) were evaluated. Results: An HFM did not affect exercise variables compared with fasting, whereas an HCM resulted in a reduction of the ischemic threshold (time to 1 mm from 402 ± 141 to 292 ± 123 seconds, P = .025). Compared with placebo, TMZ improved time to 1 mm after fasting, HFM, and HCM (432 ± 153 vs 402 ± 141, 439 ± 118 vs 380 ± 107, 377 ± 123 vs 292 ± 123, F1,9 = 26.91, P = .0006). Compared with placebo, on TMZ, stress WMSI decreased from 1.55 ± 0.25 to 1.29 ± 0.14 after fasting, from 1.57 ± 0.10 to 1.39 ± 0.28 after HFM, and from 1.64 ± 0.21 to 1.39 ± 0.21 after HCM (F1,9 = 37.04, P = .0002). Interestingly, stress WMSI on TMZ was never different from rest WMSI on placebo. Conclusions: In patients with coronary disease, exercise testing after an HCM results in more severe myocardial ischemia compared with that after an HFM. The observed beneficial effects of the partial fatty acid inhibitor TMZ seem to be unrelated to meal composition and are possibly caused by the better glucose use induced by the drug. © 2006 Mosby, Inc. All rights reserved

Human islets have chemotactic activity toward macrophages mediated by the secretion of monocyte chemoattractant protein-1 (CCL2/MCP-1) that negatively affect clinical outcome in islet after kidney recipients. The aim of the present work was to identify the donor features and the variables involved in the procedures of islet isolation associated with islet CCL2/MCP-1 release in vitro. We used a retrospective approach studying the outcome in 170 islet isolations. The univariate analysis demonstrated that CCL2/MCP-1 release was significantly associated with the surgical team in charge for organ harvesting, the proteins for dilution solution, the type of gradient, the type of enzyme, and the donor noradrenalin treatment. The multivariate analysis confirmed that the surgical team (P = 0.001) and the enzyme (P = 0.001) were independently associated with in vitro CCL2/MCP-1 islet release (r(2) = 17%). Strategies aimed to optimize the procedures of organ harvesting and islet isolation may reduce the pro-inflammatory properties of the preparation and therefore may improve islet engraftment.

Diabetes mellitus was diagnosed in 16 out of 1011 HIV-positive patients over a median follow-up of 289 days (person-year incidence 2.06, 95% confidence interval 1.18-3.33). Significant risk factors for the onset of diabetes were older age and antiretroviral therapy with stavudine or indinavir. Older men with HIV infection should be considered at higher risk of diabetes, and caution may be warranted in the use of both indinavir and stavudine in these patients.

Background Trimetazidine (TMZ) has been shown to partially inhibit free fatty acid oxidation by shifting substrate utilization from fatty acid to glucose. The aim of this study was to assess the effects of TMZ in patients with diabetes and ischemic cardiomyopathy. Methods Sixteen patients with diabetes and ischemic hypokinetic cardiomyopathy (all males) on conventional therapy were randomized to receive either placebo or TMZ (20 mg 3 times per day), each arm lasting 15 days, and then again to receive either placebo or TMZ for 2 additional 6-month periods, according to a double-blind, crossover design. At the end of each period, all patients underwent exercise testing, 2-dimensional echocardiography, and hyperinsulinemic/euglycemic clamp. Among the others, New York Heart Association class, ejection fraction, exercise time, fasting blood glucose, end-clamp M value (index of total body glucose disposal) and endothelin-1 levels were evaluated. Results Both in the short and long term (completed by 13 patients), on TMZ compared to placebo., ejection fraction (47+/-7 vs 41+/-9 and 45+/-8 vs 36+/-8%, P

Aims/hypothesis: Islet transplantation is a minimally invasive approach to curing Type I (insulin-dependent) diabetes mellitus. Success has recently been reported in patients receiving solitary islet transplants but the outcome in patients receiving islets together with, or after, kidney transplants has been limited and unpredictable.

Objective: The incidence of adenocarcinoma and bronchoalveolar carcinoma has increased in recent years. The aim of this study was to retrospectively evaluate radiological and pathological factors affecting survival in patients with bronchoalveolar carcinoma (BAC) or BAC associated with adenocarcinoma who underwent surgical treatment. Methods: From May 1988 to September 1999, 49 patients with BAC or BAC and adenocarcinoma underwent surgical treatment. Complete resection was performed in 42 patients. In these patients the impact of the following factors on survival was evaluated: stage, TNM status, radiological and pathological findings (percentage of bronchoalveolar carcinoma in the turnout, presence or absence of sclerosing and mucinous patterns, vascular invasion and lymphocytic infiltration). Results: Twenty-nine patients were male and 20 female. Mean age was 63 years. Five-year survival was 54%. Univariate analysis of the patients who kunderwent complete resection demonstrated a favourable impact on survival in stages Ia and Ib (P = 0.01) and in the absence of nodal involvement (P = 0.02) and mucinous patterns (P = 0.02). Mucinous pattern was also prognostically relevant at multivariate analysis (P = 0.02). In the 27 patients with stage Ia and Ib disease, univariate analysis demonstrated that the absence of mucinous pattern (P = 0.006) and a higher percentage of BAC (P = 0.01) favourably influenced survival. The latter data were also confirmed by multivariate analysis (P = 0.01). Conclusion: Surgical treatment of early-stage BAC and combined BAC and adenocarcinoma is associated with favourable results. However, the definition of prognostic factors is of utmost importance to improve the results of the treatment. In our series tumours of the mucinous subtype and with a lower percentage of BAC had a worse prognosis. (C) 2001 Elsevier Science B.V. All rights reserved. Objective: The incidence of adenocarcinoma and bronchoalveolar carcinoma has increased in recent years. The aim of this study was to retrospectively evaluate radiological and pathological factors affecting survival in patients with bronchoalveolar carcinoma (BAC) or BAC associated with adenocarcinoma who underwent surgical treatment. Methods: From May 1988 to September 1999, 49 patients with BAC or BAC and adenocarcinoma underwent surgical treatment. Complete resection was performed in 42 patients. In these patients the impact of the following factors on survival was evaluated: stage, TNM status, radiological and pathological findings (percentage of bronchoalveolar carcinoma in the tumour, presence or absence of sclerosing and mucinous patterns, vascular invasion and lymphocytic infiltration). Results: Twenty-nine patients were male and 20 female. Mean age was 63 years. Five-year survival was 54%. Univariate analysis of the patients who underwent complete resection demonstrated a favourable impact on survival in stages Ia and Ib (P = 0.01) and in the absence of nodal involvement (P = 0.02) and mucinous patterns (P = 0.02). Mucinous pattern was also prognostically relevant at multivariate analysis (P = 0.02). In the 27 patients with stage Ia and Ib disease, univariate analysis demonstrated that the absence of mucinous pattern (P = 0.006) and a higher percentage of BAC (P = 0.01) favourably influenced survival. The latter data were also confirmed by multivariate analysis (P = 0.01). Conclusion: Surgical treatment of early-stage BAC and combined BAC and adenocarcinoma is associated with favourable results. However, the definition of prognostic factors is of utmost importance to improve the results of the treatment. In our series tumours of the mucinous subtype and with a lower percentage of BAC had a worse prognosis.

Factors associated with residual insulin secretion and spontaneous remission in Type 1 diabetic patients are important in the evaluation of treatment aimed at modifying the natural history of Type 1 DM. We investigated the effect of parameters at onset on residual beta cell function in 215 Type 1 DM children and adolescents. Blood gas analysis, HLA, GAD and IA-2 antibodies before the start of insulin treatment were recorded for each patient. Residual C-peptide secretion was assessed by the glucagon test, and parameters of metabolic control (HbA1c and insulin dose U kg(-1) day(-1)) were examined at disease onset and after 3, 6, and 12 months. Residual C-peptide secretion throughout the first year of disease was significantly reduced in patients with disease onset before age 5. Multiple regression analysis showed that low pH at onset showed a significant and independent association with reduced C-peptide at 3 months (p = 0.02) and that the detection of GAD antibodies had a significant independent association with decreased C-peptide secretion at 6 months of follow-up (p = 0.02). Insulin requirement was higher in the youngest patients group and in patients with GAD antibodies. Spontaneous insulin remission (HbA1c

In previously thrombolysed patients, we analysed residual myocardial viability using the PET-FDG technique and correlated its presence and extent to the angiographic appearance of the infarct-related vessel and left ventricular function. Thirty-six patients who had undergone intravenous thrombolysis for acute myocardial infarction 4.8 +/- 7.2 months previously were studied. Coronary angiography, left ventriculography, and assessment of myocardial perfusion and metabolism were all performed within 1 week. All patients exhibited perfusion defects consistent with the clinically identified myocardial infarction site. Residual viability, as assessed by the PET-FDG technique, was present in 53% of cases. The infarct-related coronary artery was patent in 19 (53%) patients (TIMI grade 3, 79%); of the remaining 17 with occluded infarct-related arteries, 11 had collaterals to the infarct area. Significant FDG uptake was observed in 63% of patients with a patent infarct-related artery and in 41% of those with an occluded infarct-related artery. The same study protocol was adopted in a control group of 30 patients with myocardial infarction who did not receive thrombolysis. The number of infarct-related patent vessels was significantly lower in these patients (30 vs 53%) (TIMI grade 3, 56%), but the overall percentage of PET viability was again 53%. Qualitative analysis of the regional perfusion pattern showed that the magnitude and severity of the perfusion defect was similar in the two groups, regardless of the presence or absence of FDG uptake. Global left ventricular function was also similar in the two groups. However, regional wall motion was significantly better in the thrombolysed patients with a patent infarct-related artery than in those who had not received thrombolysis and whose culprit vessel was also patent. In conclusion, the results of our study support the notion that early recanalization of the infarct-related artery is critical for preserving left ventricular function. Although the number of patent infarct-related coronary arteries is greater and left ventricular function is better in successfully thrombolysed patients, the regional metabolic pattern does not apparently correlate with the patency of the infarct-related artery. This suggests that, in 'chronic' myocardial infarction, residual tissue viability as assessed by fluorodeoxyglucose uptake does not necessarily correlate with coronary recanalization. RI Lucignani, Giovanni/C-6773-2008

The prevalence and correlates of the early signs of renal, retinal and neurological microvascular complications were evaluated in 317 young patients with type I diabetes mellitus. Microalbuminuria was detected in 11% of patients and appeared to be strongly and positively related to HbA1c (p < 0.01) and less significantly to duration of diabetes (p < 0.02). Retinopathy was detected in 22.7% of patients and it was associated with duration of diabetes (p < 0.001). Peripheral neuropathy was detected in 18.5% of patients and there was a strong association with HbA1c (p < 0.01) and a weaker one with duration of diabetes (p < 0.05). Microalbuminuria was not detected in prepubertal patients while a similar frequency of retinopathy and neuropathy was observed in prepubertal and postpubertal patients. These results suggest that: 1) In short-term type I diabetic patients neuropathy is the most frequent microvascular complication, but after 10 years of diabetes, retinopathy exceeds the other complications; 2) Short-term metabolic control may influence the frequency of neuropathy and microalbuminuria but not retinopathy; 3) Puberty is involved in the appearance of microalbuminuria.