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Aims: Ageing and comorbidities are increasing frailty/complexity of heart failure (HF) patients globally. We assessed evolving trends over two decades according to patients' age and time of recruitment in a nationwide cardiology setting in Italy., Methods and Results: Chronic HF outpatients recruited between 1999 and 2018 (N = 14,823) were divided into 3 cohorts: 1999-2005 (N = 5404); 2006-2011 (N = 3971); 2012-2018 (N = 5448). We analyzed temporal changes in clinical characteristics, therapies, and outcome (1-year all-cause mortality/cardiovascular hospitalization), overall and by age group: <65 (n = 5465); 65-79 (n = 6838); ≥80 (n = 2520) years old. Across enrolment epochs, comorbidities (atrial fibrillation, hypertension, obesity) increased by both epoch/age groups (p < 0.001), whereas the prevalence of ischemic etiology declined among patients ≥65 years (p = 0.05). Accordingly, the preserved LVEF phenotype (HFpEF) increased in all age categories (p < 0.001) over time. Moreover, the use of betablockers, mineralocorticoid-receptor antagonists and loop-diuretics rose by enrolment epoch in all age groups (p < 0.05). In parallel with these epidemiologic/treatment changes, age-adjusted survival free from cardiovascular hospitalization improved over time (p < 0.0001). However, divergent trends in the end-point components were apparent according to age groups: mortality decreased in patients<80 years, although hospitalizations remained stable in the youngest group, while subjects ≥65 years were less likely to be admitted for cardiovascular causes (all p < 0.005)., Conclusions: Over two decades in a cardiology outpatient setting, the prevalence of comorbid HFpEF increased in all age categories. Mortality improved among patients<80 years and cardiovascular hospitalizations decreased in patients≥65 years. These findings point to the value of cardiologist' input in the management of adult chronic HF patients at all ages., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Objectives : The most prevalent dementia are Alzheimer's disease and vascular dementia. There is evidence that cortical synaptic function may differ in these two conditions. Habituation of cortical responses to repeated stimuli is a well-preserved phenomenon in a normal brain cortex, related to an underlying mechanism of synaptic efficacy regulation. Lack of habituation represents a marker of synaptic dysfunction. The purpose of this study was to assess the habituation of somatosensory evoked potentials (SEPs) in 29 patients affected by mild-to-moderate Alzheimer's disease (AD-type) or vascular (VD-type) dementia. Materials and Methods : All patients underwent a clinical history interview, neuropsychological evaluation, and neuroimaging examination. SEPs were elicited by electrical stimulation of the right median nerve at the wrist. Six-hundred stimuli were delivered, and cortical responses divided in three blocks of 200. Habituation was calculated by measuring changes of N20 amplitude from block 1 to block 3. SEP variables recorded in patients were compared with those recorded in 15 age- and gender-matched healthy volunteers. Results : SEP recordings showed similar N20 amplitudes in AD-type and VD-type patients in block 1, that were higher than those recorded in controls. N20 amplitude decreased from block 1 to block 3 (habituation) in normal subjects and in VD-type patients, whereas in AD-type patients it remained unchanged (lack of habituation). Conclusions : The findings suggest that neurophysiologic mechanisms of synaptic efficacy that underneath habituation are impaired in patients with AD-type dementia but not in patients with VD-type dementia. SEPs habituation may contribute to early distinction of Alzheimer's disease vs. vascular dementia.

Background: Hyperkalaemia is a potential life-threatening electrolyte abnormality. Although renin-angiotensin-aldosterone system inhibitors (RAASi) are potentially life-saving, they may contribute to hyperkalaemia., Methods: The prevalence, comorbidities, comedications and 1-year outcomes of patients admitted or treated for hyperkalaemia were investigated in a large healthcare administrative database including 12 533 230 general population inhabitants. A similar analysis was performed in the Italian Network on Heart Failure (IN-HF), a cardiology registry of 1726 acute and 7589 chronic HF patients, stratified by serum potassium. General practice healthcare costs related to hyperkalaemia were also assessed. Hyperkalaemia was defined by hospital coding, potassium-binder prescription or serum levels (mild: 5-5.4, moderate-severe: ≥5.5 mmol/L)., Results: In the general population, the prevalence of hyperkalaemia was 0.035%. After excluding patients on haemodialysis, hyperkalaemia in the community (n = 2314) was significantly and directly associated with diabetes, chronic kidney disease, HF, RAASi prescriptions, 1-year hospitalisations and threefold annual healthcare costs, compared to age- and sex-matched non-hyperkalaemic subjects (n = 2314). In the IN-HF registry, hyperkalaemia affected 4.3% of acute and 3.6% of chronic patients and was significantly associated with diabetes, kidney disease and lesser use of RAASi, compared to normokalaemic patients. Among patients hospitalised for acute HF, those with hyperkalaemia at entry had significantly higher 1-year all-cause mortality compared with normokalaemic patients, even after adjustment for available confounders., Conclusions: Hyperkalaemia in the general population, although uncommon, was associated with increased hospitalisations and tripling of healthcare costs. Among HF patients, hyperkalaemia was common and associated with underuse of RAASi; in acutely decompensated patients, it remained independently associated with 1-year all-cause mortality., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: High-risk coronary atherosclerosis features evaluated coronary CT angiography (CCTA) were suggested to have a prognostic role. The present study aimed to evaluate the association of circulating biomarkers with high-risk plaque features assessed by CCTA., Methods: A consecutive cohort of subjects who underwent CCTA because of suspected CAD was screened for inclusion in the CAPIRE study. Based on risk factors (RF) burden patients were defined as having a low clinical risk (0-1 RF with the exclusion of patients with diabetes mellitus as single RF) or an high clinical risk (≥3 RFs). In all patients, measurement of inflammatory biomarkers and CCTA analysis focused on high-risk plaque features were performed. Univariate and multivariate logistic regression analysis were used to evaluate the relationship between clinical and biological variables with CCTA advanced plaque features., Results: 528 patients were enrolled in CAPIRE study. Older age and male sex appeared to be predictors of qualitative high-risk plaque features and associated with the presence of elevated total, non-calcified and low-attenuation plaque volume. Among circulating biomarkers only hs-CRP was found to be associated with qualitative high-risk plaque features (OR 2.02, p = 0.004 and 2.02, p = 0.012 for LAP and RI > 1.1, respectively) with borderline association with LAP-Vol (OR 1.52, p = 0.076); HbA1c and PTX-3 resulted to be significantly associated with quantitative high-risk plaque features (OR 1.71, p = 0.003 and 1.04, p = 0.002 for LAP-Vol, respectively)., Conclusions: Our results support the association between inflammatory biomarkers (hs-CRP, PTX- 3), HbA1c and high-risk atherosclerotic features detected by CCTA. Male sex and older age are significant predictors of high-risk atherosclerosis., Competing Interests: Declaration of competing interest Daniele Andreini declares the following conflict of interest: speaker bureau for GE Healthcare, research grant (to the Institution) from GE Healthcare and Bracco. The other authors have nothing to declare. Gianluca Pontone declares the following conflict of interest: Institutional fee as speaker and/or research grant from GE Helthcare, Bracco, Bayer, Medtronic, Heartflow., (Copyright © 2020 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

The recent definition of an intermediate clinical phenotype of heart failure (HF) based on an ejection fraction (EF) of between 40% and 49%, namely HF with mid-range EF (HFmrEF), has fuelled investigations into the clinical profile and prognosis of this patient group. HFmrEF shares common clinical features with other HF phenotypes, such as a high prevalence of ischaemic aetiology, as in HF with reduced EF (HFrEF), or hypertension and diabetes, as in HF with preserved EF (HFpEF), and benefits from the cornerstone drugs indicated for HFrEF. Among the HF phenotypes, HFmrEF is characterised by the highest rate of transition to either recovery or worsening of the severe systolic dysfunction profile that is the target of disease-modifying therapies, with opposite prognostic implications. This article focuses on the epidemiology, clinical characteristics and therapeutic approaches for HFmrEF, and discusses the major determinants of transition to HFpEF or HFrEF., Competing Interests: Disclosure: The authors have no conflicts of interest to declare., (Copyright © 2020, Radcliffe Cardiology.)

Objectives: This study sought to assess whether coronary atherosclerosis analysis by coronary computed tomography angiography (CTA) may improve prognostic stratification among patients with diffuse coronary artery disease (CAD) BACKGROUND: Coronary CTA has recently emerged as a promising noninvasive tool for advanced analysis of coronary atherosclerosis., Methods: The multicenter CAPIRE (Coronary Atherosclerosis in outlier subjects: Protective and novel Individual Risk factors Evaluation) study is part of the GISSI Outlier Project. A prospective cohort of subjects who underwent coronary CTA for suspected CAD was enrolled. Based on risk factor (RF) burden, patients were defined as having a low clinical risk (0 to 1 RF with the exclusion of patients with diabetes mellitus as single RF) or at high clinical risk (3 or more RFs). Patients with 2 RFs were not enrolled in the study. Coronary CTA advanced plaque assessment was performed. Outcome measures were 3 combined endpoints: acute coronary syndrome (ACS), cardiac death + ACS, and cardiac death + ACS + late revascularization., Results: Among the 544 patients enrolled in the CAPIRE study, in 522 patients, a mean follow-up of 37 ± 10 months was obtained (16 patients were excluded due to 1 < segment involvement score <5 at core lab coronary CTA analysis and 6 patients were lost at follow-up). Higher atherosclerotic burden was found in patients with higher clinical risk, but prevalence of elevated noncalcified plaque volume did not significantly differ between low- versus high-risk patients. Quantitative plaque parameters by coronary CTA were associated with composite endpoints at multivariable analysis when corrected for univariate predictors. Elevated noncalcified plaque volume, expressed as dichotomic variable, was associated with all combined endpoints. Even if the low absolute number of events represents a limitation to the present study, patients with low noncalcified plaque volume had similar risk of cardiac events independently from the presence of multivessel disease, while patients with high noncalcified plaque volume had higher rates of cardiac events., Conclusions: The CAPIRE study confirmed the prognostic value of atherosclerosis assessment by coronary CTA, demonstrating high noncalcified plaque volume as the most ACS-predictive parameter in patients with extensive CAD. (GISSE Outliers CAPIRE [CAPIRE]; NCT02157662)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Data on the natural change in renal function in patients with chronic heart failure (HF) are limited., Methods and Results: Estimated glomerular filtration rate (eGFR) was assessed over 36 months in 6934 patients included in the GISSI-HF study. Associations from baseline, changes in renal function, and occurrence of cardiovascular death or HF hospitalization were assessed. Mean age was 67 years, mainly men (78%), and mean eGFR was 68 mL • min -1  • 1.73 m -2 . Change in eGFR in the 1st year was -1.5 ± 16 mL • min -1  • 1.73 m -2 , and over 36 months it was -3.7 ± 18 mL • min -1  • 1.73 m -2 . Over the latter period, only 25% deteriorated ≥1 Kidney Disease Outcomes Quality Initiatives (KDOQI) class of chronic kidney disease (CKD). Fifteen percent of patients had >15 mL • min -1  • 1.73 m -2 decrease in eGFR in the 1st 12 months. Lower eGFR was associated with outcome: hazard ratio (HR) 1.10, 95% confidence interval (CI) 1.08-1.10 (P < .001) per 10 mL • min -1  • 1.73 m -2 decrease, as well as every 10 mL • min -1  • 1.73 m -2 decrease over the 1st year (HR 1.10, 95% CI 1.04-1.17; P < .001). A deterioration in eGFR >15 mL • min -1  • 1.73 m -2 in the 1st year showed the highest risk of events (HR 1.22, 95% CI 1.10-1.36; P < .001)., Conclusions: Mean decrease in renal function over time in patients with chronic HF was modest. Only 25% deteriorated ≥1 KDOQI class of CKD after 3 years. Any decrease in eGFR over time was associated with strongly increased event rates., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Galectin-3 predicts prognosis in heart failure (HF) and may help to select HF patients in need of intensified therapy., Methods: This retrospective post hoc analysis included 219 patients from the Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-HF) and 631 patients from Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) with HF who had reduced ejection fraction and available galectin-3 plasma concentrations. The interaction between galectin-3, β-blockers, renin-angiotensin system (RAS) blockade, and spironolactone on outcome was evaluated in TIME-CHF and validated in GISSI-HF. End points were all-cause mortality and the composite of mortality with HF hospitalization or any hospitalization., Results: High galectin-3 concentrations were associated with adverse outcome in both cohorts and remained significantly associated with death after multivariate adjustment [hazard ratio 2.42 (95% CI 1.17-5.01), P = 0.02, in TIME-CHF; 1.47 (1.02-2.10), P = 0.04, in GISSI-HF). In TIME-CHF, patients with low galectin-3 plasma concentrations had a better prognosis when β-blockers were up-titrated, whereas patients with high galectin-3 plasma concentrations did not (interaction P < 0.05 for mortality and death with or without hospitalization). Opposite trends were seen for RAS blockade but were not statistically significant. Patients with high galectin-3 plasma concentrations had neutral prognosis when receiving spironolactone, whereas patients with low galectin-3 plasma concentrations had worse prognosis when receiving spironolactone (interaction P < 0.10 for death with or without hospitalization). In the GISSI-HF validation cohort, these interactions were confirmed for β-blockers (P < 0.05 for all end points) and consistent for RAS blockade (P < 0.10 for death with or without hospitalization), but inconsistent for spironolactone., Conclusions: Galectin-3 is a mediocre prognostic marker, and galectin-3 concentrations interact with the treatment effect of β-blockers and possibly RAS blockade in patients with systolic HF., (© 2015 American Association for Clinical Chemistry.)

Although it is generally accepted that cardiac ischemic events develop when coronary atherosclerosis (coronary artery disease [CAD]) has reached a critical threshold, this is true only to a first approximation. Indeed, there are patients with severe CAD who do not develop ischemic events; conversely, at the other extreme, individuals with minimal CAD may do. Similar exceptions to this paradigm include patients with diffuse CAD with a low risk factor (RF) profile and others with multiple RFs who develop only mild or no CAD. Therefore, the CAPIRE project was designed to investigate whether the specific study of these extreme outlier populations could provide clues for identification of yet unknown risk or protective factors for CAD and ischemic events. In the CAPIRE study, 481 subjects without previous symptoms or history of ischemic heart disease and normal left ventricular systolic function undergoing coronary computed tomography angiography have been selected based on coronary computed tomography angiography findings and cardiovascular RF profile. Therefore, in the whole population, 2 extreme outlier populations have been identified: (1) subjects with no CAD despite multiple RFs, and (2) at the opposite extreme, subjects with diffuse CAD despite a low-risk profile. Each subject has been characterized by clinical, anatomical imaging variables of CAD and baseline circulating biomarkers. Blood samples were collected and stored in a biological bank for further advanced investigations. The project is designed as a prospective, observational, international multicenter study with an initial cross-sectional analysis of clinical, imaging, and biomolecular variables in the selected groups and a longitudinal 5-year follow-up., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In the recent Italian Network on Heart Failure (IN-HF) Outcome registry, including 1,855 patients with acute heart failure (AHF), we reviewed the use of inotropes and their prognostic implication on in-hospital and 12-month mortality., Methods: IN-HF Outcome is a prospective, multicenter, observational, study involving 61 Italian cardiology centers. AHF patients have been enrolled over a 2-year period and followed-up for 1 year. Inotropes were used in 360 patients (19.4%)., Results: Patients who received inotropes had a more severe clinical and hemodynamic profile than those who did not and exhibited a significantly higher rate of in-hospital (21.4% vs 2.7%, p < 0.01) and 1-year (50.6% vs 17.7%, p < 0.01) mortality. At entry, systolic blood pressure (SBP) was ≤ 110 mm Hg in 58%, 111 to 130 mm Hg in 24.5%, and > 130 mm Hg in 17.5%. Multivariable analyses showed use of inotropes was the strongest predictor of all-cause death. These data were confirmed by propensity score analyses. According to SBP at entry, the 2 groups with SBP > 110 mm Hg who took inotropes, despite a more favorable clinical profile, exhibited a similar worse prognosis, particularly at 1 year: 56.3% (≤ 110 mm Hg), 43.7% (111-130 mm Hg), and 40.3% (>130 mm Hg) vs 17.7%., Conclusions: Inotropes were used in nearly 20% of the patient admitted for AHF, and this treatment was associated with a short-term to medium-term poor prognosis. An inappropriate use of inotropes in patients with normal to high SBP, and presumably preserved cardiac output, may have significantly contributed to affect the all-group outcome., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Clinical observational studies on heart failure (HF) deal mostly with hospitalized patients, few with chronic outpatients, all with no or limited longitudinal observation., Methods and Results: This is a multicenter, nationwide, prospective observational trial on a population of 5610 patients, 1855 hospitalized for acute HF (AHF) and 3755 outpatients with chronic HF (CHF), followed up for 1 year. The cumulative total mortality rate at 1 year was 24% in AHF (19.2% in 797 patients with de novo HF and 27.7% in 1058 with worsening HF) and 5.9% in CHF. Cardiovascular deaths accounted for 73.1% and 65.3% and HF deaths for 42.4% and 40.5% of total deaths in AHF and CHF patients, respectively. One-year hospitalization rates were 30.7% in AHF and 22.7% in CHF patients. Among the independent predictors of 1-year all-cause death, age, low systolic blood pressure, anemia, and renal dysfunction were identified in both acute and chronic patients. A few additional variables were significant only in AHF (signs of cerebral hypoperfusion, low serum sodium, chronic obstructive pulmonary disease, and acute pulmonary edema), whereas others were observed only in CHF patients (lower body mass index, higher heart rate, New York Heart Association class, large QRS, and severe mitral regurgitation)., Conclusions: In this contemporary data set, patients with CHF had a relatively low mortality rate compared with those with AHF. Rates of adverse outcomes in patients admitted for AHF remain very high either in-hospital or after discharge. Most deaths were cardiovascular in origin and ≈40% of deaths were directly related to HF.

Aims: Registries and surveys improve knowledge of the 'real world'. This paper aims to describe baseline clinical profiles, management strategies, and the in-hospital outcome of patients admitted to hospital for an acute heart failure (AHF) episode., Methods and Results: IN-HF Outcome is a nationwide, prospective, multicentre, observational study conducted in 61 Cardiology Centres in Italy. Up to December 2009, 5610 patients had been enrolled, 1855 (33%) with AHF and 3755 (67%) with chronic heart failure (CHF). Baseline and in-hospital outcome data of AHF patients are presented. Mean age was 72 ± 12 years, and 39.8% were female. Hospital admission was due to new-onset heart failure (HF) in 43% of cases. Co-morbid conditions were observed more frequently in the worsening HF group, while those with de novo HF showed a higher heart rate, blood pressure, and more preserved left ventricular ejection fraction (LVEF). Electrical devices were previously implanted in 13.3% of the entire group. Inotropes were administered in 19.4% of the patients. The median duration of hospital stay was 10 days (interquartile range 7-15). All-cause in-hospital death was 6.4%, similar in worsening and de novo HF. Older age, hypotension, cardiogenic shock, pulmonary oedema, symptoms of hypoperfusion, hyponatraemia, and elevated creatinine were independent predictors of all-cause death., Conclusion: Our registry confirms that in-hospital mortality in AHF is still high, with a long length of stay. Pharmacological treatment seems to be practically unchanged in the last decades, and the adherence to HF guidelines concerning implantable cardioverter defibrillators/cardiac resynchronization therapy is still very low. Some AHF phenotypes are characterized by worst prognosis and need specific research projects.

The IN-HF Outcome registry enrolled 1855 patients admitted for acute heart failure and 3755 outpatients with chronic heart failure seen at 64 cardiology units of the Italian Network-Heart Failure. We assessed gender-related differences in clinical characteristics, management, and short- and long-term mortality and morbidity outcomes. Women were older, more often hypertensive and with a higher prevalence of heart failure with preserved systolic function. Aggressive management was less frequent in women who underwent less often diagnostic and therapeutic procedures. We found no gender-related differences in either acute or long-term mortality nor in hospital readmissions.

Background: We investigated whether chronic headache related to medication overuse (MOH) is associated with changes in brain mechanisms regulating inhibitory cortical responses compared with healthy volunteers and episodic migraineurs recorded between attacks, and whether these changes differ according to the drug overused., Subjects and Methods: We studied 40 MOH patients whose symptoms were related to triptans alone, non-steroidal anti-inflammatory drugs (NSAIDs) or both medications combined, 12 migraineurs and 13 healthy volunteers. We used high-intensity transcranial magnetic stimulation over the primary motor cortex to assess the silent period from contracted perioral muscles., Results: In MOH patients the cortical silent period differed according to the type of headache medication overused: in patients overusing triptans alone it was shorter than in healthy volunteers (44.7 ± 14.2 vs. 108.1 ± 30.1 ms), but similar to that reported in migraineurs (59.9 ± 30.4 ms), whereas in patients overusing NSAIDs alone or triptans and NSAIDs combined duration of silent period was within normal limits (80.6 ± 46.4 and 103.8 ± 47.2 ms)., Conclusions: Compared with episodic migraineurs, MOH patients overusing triptans have no significant change in cortical inhibition, whereas those overusing NSAIDs have an increase in cortical inhibitory mechanisms. We attribute these changes to medication-induced neural adaptation promoted by changes in central serotonin neurotransmission.

Aims: The GISSI-HF trial showed that n-3 polyunsaturated fatty acids (PUFA), but not rosuvastatin, reduce morbidity and mortality in patients with symptomatic heart failure (HF) of any cause. The aim of this echocardiographic substudy of GISSI-HF was to investigate the effects of n-3 PUFA and of rosuvastatin on left ventricular (LV) function in such patients., Methods and Results: Six hundred and eight chronic HF patients were randomized to n-3 PUFA (n=312) or placebo (n=296); a second randomization was performed to rosuvastatin (n=212) or placebo (n=207). Echocardiographic examinations were recorded at baseline and at 1, 2, and 3 years; offline analysis was performed by a core laboratory to ensure consistent quantitative analysis. Baseline LV ejection fraction (EF) was 30% (95%CI 29-31). Left ventricular ejection fraction increased with n-3 PUFA by 8.1% at 1 year, 11.1% at 2 years, and 11.5% at 3 years vs. 6.3% at 1 year, 8.2% at 2 years, and 9.9% at 3 years in the placebo group (P=0.0050). No other echocardiographic parameter changed significantly. Rosuvastatin effects were not statistically significant., Conclusion: n-3 PUFA can provide a small but statistically significant advantage in terms of LV function in patients with symptomatic HF of any aetiology, already treated with recommended therapies.

Background: Randomized controlled trials have generated strong evidence on the efficacy of electrical device therapy in selected patients with heart failure (HF). The enrolment criteria of these three trials generated patient profiles that helped to shape current guidelines on chronic heart failure (CHF) treatment and sudden cardiac death (SCD) prevention. We investigated the prevalence of trial-generated profiles for implantable defibrillator or cardiac resynchronization therapy candidacy among HF outpatients; we explored differences between real-world and trial populations and we evaluated 1-year survival without device treatment., Methods: We reviewed Italian Network on Congestive Heart Failure (IN-CHF) registry patients (n = 4977) enrolled in a period (1995-2000) roughly concurrent with the MADIT-II and SCD-HeFT trials., Results: Regarding device eligibility, 14.5% IN-CHF patients at entry satisfied MADIT-II criteria, 6.8% satisfied CARE-HF criteria and as many as 47.9% fulfilled SCD-HeFT criteria. One-year overall mortality among non-implanted patients was 1.5 to 2-fold higher in each of these subgroups than in control arms of the corresponding trials. Among registry patients, different trial-profile combinations were associated with a wide range of 1-year outcomes (mortality, 8-35%; SCD/total mortality ratio, 0.35-0.57). Despite clear differences between registry and trial patients in pharmacological therapy (and clinical characteristics), none of the main drug classes independently predicted 1-year mortality in any of the IN-CHF subgroups., Conclusions: As many as half the IN-CHF outpatients fulfilled current criteria for device implantation. Various subgroups had higher 1-year mortality than patients in trial control arms - a finding that may not be entirely attributable to differences in drug therapy (especially beta blockers).

Background: Circulating pro-angiogenic cells (PACs) contribute to vascular and myocardial regeneration. A low level of PACs is associated with worse outcome in patients with coronary heart disease. However, little is known about PACs in heart failure (HF)., Methods and Results: Blood was sampled at baseline in 111 patients with HF, 67 from 5 Italian Centers and 44 from Frankfurt, Germany. In cultured mononuclear cells from peripheral blood, PACs were counted as double-stained by tetramethylindocarbocyanine-labeled acetylated LDL and fluorescein-5-isothiocyanate-labeled lectin. Mean age of the patients was 62 years, 12 were females, 66 had ischemic etiology, 26 were in New York Heart Association Class >II. Cutoffs for PACs were assessed by receiver operating characteristic curves, to identify the optimal cutoffs for PAC level in predicting outcomes. Mean level of PACs was 35+/-29 (mean+/-SD) cells/mm(2), 2- to 3-fold lower than in age-matched healthy volunteers, but unrelated to severity of HF, age, or sex. Over 2.5 years, 12 cardiovascular deaths and 47 first hospitalizations for cardiovascular reasons were recorded. After adjustment for demographic and clinical variables, elevated creatinine and natriuretic peptides, and PACs

Objective: To compare iron lung (ILV) versus mask ventilation (NPPV) in the treatment of COPD patients with acute on chronic respiratory failure (ACRF)., Design: Randomised multicentre study., Setting: Respiratory intermediate intensive care units very skilled in ILV., Patients and Methods: A total of 141 patients met the inclusion criteria and were assigned: 70 to ILV and 71 to NPPV. To establish the failure of the technique employed as first line major and minor criteria for endotracheal intubation (EI) were used. With major criteria EI was promptly established. With at least two minor criteria patients were shifted from one technique to the other., Results: On admission, PaO(2)/FiO(2), 198 (70) and 187 (64), PaCO(2), 90.5 (14.1) and 88.7 (13.5) mmHg, and pH 7.25 (0.04) and 7.25 (0.05), were similar for ILV and NPPV groups. When used as first line, the success of ILV (87%) was significantly greater (P = 0.01) than NPPV (68%), due to the number of patients that met minor criteria for EI; after the shift of the techniques; however, the need of EI and hospital mortality was similar in both groups. The total rate of success using both techniques increased from 77.3 to 87.9% (P = 0.028)., Conclusions: The sequential use of NPPV and ILV avoided EI in a large percentage of COPD patients with ACRF; ILV was more effective than NPPV on the basis of minor criteria for EI but after the crossover the need of EI on the basis of major criteria and mortality was similar in both groups of patients.

Patients with heart failure in the "real world" are often elderly and with multiple comorbid diseases. These conditions create a dilemma for the physician responsible for the treatment of heart failure and are associated with a substantial underutilization of evidence-based treatments. Clarifying the prognostic impact of comorbidities in heart failure could provide more precise risk stratification and optimize the management of these patients. The negative prognostic impact of concomitant diseases has been shown in several studies: in the TEMISTOCLE study, carried out in Italy on patients hospitalized for heart failure in Internal Medicine and Cardiology wards, the presence of comorbidities was associated with higher in-hospital mortality and prolonged length of stay. In the IN-CHF registry, enrolling out patients with heart failure in a cardiological setting, the rate of coexisting diseases is not very high according to the epidemiological characteristics of this population. Renal impairment, particularly in patients >70 years old, and chronic obstructive pulmonary disease (COPD) are frequent comorbid diseases in heart failure. Renal impairment has been recognized as an independent risk factor for morbidity and mortality in heart failure while the role of COPD is controversial. Patients with renal dysfunction and COPD have largely been excluded from randomized controlled trials for safety reasons, so data are scarce. In the IN-CHF registry the prevalence of elderly patients with renal impairment (serum creatinine > or = 2 mg/dl and age > or = 70 years) is 5.1%; this subgroup of patients has an increased risk for both 1-year death (28.1 vs 11.2%) and hospital admission (34.9 vs 22.5%) compared with the remaining population. The prescription pattern has been evaluated in the last years (2003-2005) and shows that angiotensin system inhibitors (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) as well as beta-blockers are less prescribed in these patients (78.9 vs 86.1% and 42.2 vs 55.9%, respectively). The prevalence of patients with COPD in the registry was 13.2%: considerable differences in COPD prevalence estimates exist in the general population depending on many factors such as method for diagnosis or lack of agreement on diagnostic criteria. COPD patients were older and with more severe symptoms; with respect to the pharmacological treatment, beta-blockers are significantly less prescribed in COPD patients while a similar proportion of patients are receiving angiotensin system antagonists. The adjusted analysis shows that COPD in not an independent predictor of 1-year mortality in this population while it is independently associated with 1-year all-cause hospitalization. Non-cardiovascular hospital admissions seem to be more influenced by the presence of this comorbidity than cardiovascular admissions.

Heart failure remains a growing public health problem, hospitalizations represent the main cost component of heart failure care and the poor quality of life of patients is often worsened by frequent admissions. A multidisciplinary approach and specific disease management programs are a potentially useful instrument to reducing hospitalizations in heart failure patients. These concepts have recently been discussed in a consensus document by all the Scientific Societies involved in the care of heart failure patients. The effectiveness of intervention programs delivering continuity of care by a multidisciplinary team achieved a promising reduction in admissions, but the results of the studies have not been univocal for category of strategies and about the effect on survival. Telephone intervention significantly decreased heart failure admissions but not all-cause admissions and mortality. The multicenter randomized DIAL study, comparing a centralized telephone intervention program delivering continuity of care by a multidisciplinary team with usual care in patients with heart failure, confirms these findings. After a mean 16-month follow-up, there was a benefit mostly due to a significant reduction in admissions for heart failure, but mortality was similar in both groups. Data on 9000 patients from the IN-CHF registry show that hospitalizations are a serious problem in Italy: 44% of the patients had at least one hospitalization for heart failure in the year prior to the entry visit and this is the most powerful independent predictor of rehospitalization during the follow-up. Nearly a quarter of the population with follow-up data availability (92%) has been rehospitalized in the year after enrollment; patients in advanced functional class (32.1% hospitalization rate) and with ischemic etiology (25.0%) are more likely to be hospitalized than those in NYHA class I-II and without ischemic etiology. In a survey carried out recently in Italy, in 1152 patients admitted for decompensated heart failure, readmission rate was even higher: more than 40% of patients have been readmitted once in the 6 months after discharge and 7.2% had two or more admissions.

In the last years the treatment of heart failure has radically changed due to the results of multicenter clinical trials. The antagonism of neurohormonal systems has proved to be the only strategy, which favorably modifies the prognosis of the patients with heart failure. Particularly, the effectiveness of angiotensin-converting enzyme (ACE)-inhibitors and beta-blockers has been proven in patients with heart failure and left ventricular dysfunction; more recently, angiotensin receptor blockers (ARBs) and aldosterone blockers have shown to improve the outcome in heart failure. The public health im portance of translating this body of evidence of research into clinical practice is paramount. We used data from the IN-CHF registry to examine changes in the use of pharmacological treatment from 1995 to 2005. The proportion of patients receiving an ACE-inhibitor was slightly higher in the 1995-2000 than after but this difference is not statistically significant. The use of "recommended therapies" as beta-blockers, aldosterone antagonists and ARBs increased significantly in these 10 years. The use of beta-blockers also increased significantly among elderly patients and patients in advanced NYHA class. Patients treated with the combination of ACE-inhibitors and ARBs are very few (1.1%), even if this association is now recommended by the European Society of Cardiology guidelines. The same analysis repeated after the CHARM and Val-HeFT publication shows that this association is used in 2.0% of the patients. The proportion of patients treated with a beta-blocker plus ACE-inhibitors plus ARB is only 0.8%. Use of digitalis and calcium channel blockers fell continuously from 1995 whereas use of diuretics and anticoagulants remained relatively constant. Statins are becoming widely used in this population (from 5 to 20%) even if the information on the effect of these drugs in heart failure is still incomplete.

IN-CHF is a multicenter registry, designed in 1995 to compile a large clinical database on the epidemiological, clinical characteristics, management and outcomes of heart failure outpatients. Main objectives of IN-CHF registry were to provide cardiological centers with a software to collect data of outpatients during office visit, for educational purpose; and to enter local data into a national registry (IN-CHF registry), for scientific purpose. Entry into the database required a diagnosis of heart failure according to the guidelines of the European Society of Cardiology. The central coordinator of the project was the ANMCO Research Center. The Italian cardiological centers participating in the project are 142, they are well representing the entire country and from March 1995 to July 2005 collected data from 23 855 outpatients. The mean age of the patients was 65+/-13 years and 71.3% were men. Main etiologies were ischemic in 39.4%, hypertensive in 15.8 %, and due to dilated cardiomyopathy in 29%. More than half of the patients (55.3%) had a history of admission for heart failure within the last year; 25.8% of the patients were in NYHA class III-IV, 9.5% showed a heart rate > 100 bpm and 16.5% third heart sound. Left ventricular ejection fraction was severely depressed (< 30%) in 27.6% of the patients, while it was > 40% in 30.9%. Renal dysfunction was present in 3.6% of the patients (serum creatinine level > 2.5 mg/dl), pulmonary disease in 18.7%, diabetes in 16.8% and anemia (hemoglobin < 12 g/dl) in 18.7%. A history of arterial hypertension was common (30.3%); 20.0% and 18.5% of the patients showed atrial fibrillation and left bundle branch block, respectively. Data from our registry provide important insights into clinical and epidemiological characteristics of heart failure outpatients followed in Italian cardiological centers. Starting from this article, every 3 months, the most relevant epidemiological data collected by the IN-CHF investigators will be published.

Aim: We hypothesize that different patterns of chest wall (CW) kinematics and respiratory muscle coordination contribute to sensation of dyspnoea during unsupported arm exercise (UAE) and leg exercise (LE)., Methods: In six volunteer healthy subjects, we evaluated the volumes of chest wall (V(cw)) and its compartments, the pulmonary apposed rib cage (V(rc,p)), the diaphragm-abdomen apposed rib cage (V(rc,a)) and the abdomen (V(ab)), by optoelectronic plethysmography. Oesophageal, gastric and trans-diaphragmatic pressures were simultaneously measured. Chest wall relaxation line allowed the measure of peak rib cage inspiratory muscle, expiratory muscle and abdominal muscle pressures. The loop V(rc,p)/V(rc,a) allowed the calculation of rib cage distortion. Dyspnoea was assessed by a modified Borg scale., Results: There were some differences and similarities between UAE and LE. Unlike LE with UAE: (i) V(cw) and V(rc,p) at end inspiration did not increase, whereas a decrease in V(rc,p) contributed to decreasing CW end expiratory volume; (ii) pressure production of inspiratory rib cage muscles did not significantly increase from quiet breathing. Not unlike LE, the diaphragm limited its inspiratory contribution to ventilation with UAE with no consistent difference in rib cage distortion between UAE and LE. Finally, changes in abdominal muscle pressure, and inspiratory rib cage muscle pressure predicted 62% and 41.4% of the variability in Borg score with UAE and LE, respectively (P < 0.01)., Conclusion: Leg exercise and UAE are associated with different patterns of CW kinematics, respiratory muscle coordination, and production of dyspnoea.

Background and Aim: Dyslipidemia is one of the main risk factors for atherosclerosis, usually the underlying cause of cardiovascular diseases which are the major cause of morbidity and mortality in developed countries. The aim of this study was to assess the effects and the advantages of a combined dietary supplementation with PUFA n-3, vitamin E, niacin and gamma-oryzanol on lipid profile, inflammatory status and oxidative balance., Methods and Results: Fifty-seven dyslipidemic volunteers were randomly assigned to receive: placebo (group A, 19 subjects); PUFA n-3 and vitamin E (group B, 18 subjects); the same as B plus gamma-oryzanol and niacin (group C, 20 subjects). Lipid profile, reactive oxygen species (ROS), total antioxidant capacity (TAC), vitamin E, interleukin 1-beta (IL1-beta), tumor necrosis factor (TNF-alpha) and thromboxane B2 (TXB2) were determined at baseline (T0) and after four months (T1). All dyslipidemic subjects showed, at baseline, oxidative stress and, after four months, all biochemical markers improved significantly in groups treated with dietary supplementation. Particularly in group C all lipid patterns improved significantly., Conclusions: Our findings demonstrate that the strategy of combining different compounds, which protect each other and act together at different levels of the lipid chain production, improves lipid profile, inflammatory and oxidative status, allowing us to reduce the dose of each compound under the threshold of its side effects.

Background: Different methods of normalizing left ventricular (LV) mass for body size identify generally similar relative risks of adverse cardiovascular outcome but with variable prevalences of LV hypertrophy (H). Preliminary results from a population with high prevalence of obesity suggest that the population attributable-risk percent (PAR%) of LVH is substantially higher when LV mass is normalized for allometric power of height., Methods: We calculated the PAR% of LVH by different definitions in the cohort of the MAssa Ventricolare sinistra nell' Ipertensione (MAVI) study (n = 1019, 62% women), a population with low prevalence of obesity (22%, with only 3% and 0.1% in class II and class III obesity, respectively). Composite fatal and nonfatal cardiovascular events occurred in 53 participants (5.2%)., Results: Prevalence of LVH was between 28% and 56%, with slight greater values for height-based normalization. Age- and sex-adjusted hazard ratios were comprised between 1.37 and 1.44 for different measures of LV mass index. The PAR% was not meaningfully different among the different methods of normalization (between 47% and 56%), and height-based methods showed in general a performance similar to body surface area-based normalizations., Conclusions: In a large clinical population of hypertensive subjects with low prevalence of obesity, population risk attributable to LV hypertrophy was not meaningfully different in relation to the type of normalization of LV mass for body size. Height-based methods perform as well as body surface area-based ones. We suggest that the prevalence of obesity in hypertensive populations might substantially influence differences in population risk attributable to LVH identified by different methods of normalizing LV mass.

Introduction: To assess whether respiratory intermediate care units (RICUs) are cost effective alternatives to intensive care units (ICUs) for patients with exacerbation of chronic obstructive pulmonary disease (COPD)., Patients and Methods: Multi-centre, prospective, bottom-up cost study performed in 15 ICUs and 6 RICUs. COPD patients staying longer than 48 h were recruited; those coming from other ICUs/RICUs, with immune-deficiency or stroke, were excluded. After the ICU sample was standardised to the RICU distribution of the reason-for-admission and infusion of a vasoactive drug on admission, 60 ICU patients and 65 RICU patients remained, of the original 164 recruited. For each patient, besides clinical data on admission and discharge, daily information about the resources consumed were recorded and analysed in terms of their costs., Results: Total cost per patient was lower in RICUs than in ICUs (754 vs. 1507 Euro; P < 0.0001). In all items, except drugs and nutrition, we found a significant lower cost in RICUs. Dead patients were noticeably different in terms of disease severity between ICUs and RICUs, while surviving ones were not., Conclusions: Our study suggests that some COPD patients, less severe and with pure respiratory failure, could be successfully and less costly treated in RICUs.

Abstract Background Community and hospital studies have suggested that survival of patients with heart failure (HF) has increased; however, the causes of the improvement and the hospital readmission rates remain undetermined. Methods and Results We compared survival and hospital admission rates in 2 cohorts enrolled in a national registry of outpatients with HF secondary to left ventricular (LV) systolic dysfunction referred to cardiology centers in 1995 (n = 712) and 1999 (n = 603). One year after enrollment, 163 of 1315 patients (12%) were dead. Survival rates were 85% in the 1995 versus 91% in the 1999 cohort. Older age, New York Heart Association (NYHA) class III-IV, anemia, hyponatremia, hypotension, and a lower LV ejection fraction (LVEF) were associated to an increased risk of all-cause mortality by multivariate analysis. Furthermore a significant independent cohort effect was observed: the adjusted risk of death was 1.30 (95% CI 1.16-1.45) for the 1995 versus 1999 cohort (survival difference adjusted P = .0067). The proportion of patients admitted to hospital declined significantly in 1999 versus 1995, for all causes (20% versus 27%, P = .006), for cardiac causes (16% versus 22%, P = .002), and for worsening congestive heart failure (8% versus 15%, P = .0005). Survival free from HF admission was 69% in 1995 versus 84% in 1999 (adjusted P = .0001); NYHA class III-IV, hypotension, diuretics and a lower LVEF were associated to an increased risk of this combined end point by multivariate analysis, as well as the enrollment year (relative risk 1.38, 95% CI 1.22-1.56, P = .0039). Conclusion In a national cardiologic registry of outpatients with systolic HF, survival improved and hospital admissions decreased over a 4-year period. These results underscore the importance of networking and the careful implementation of practice guidelines to elevate standards of care.

New diagnostic and therapeutic aspects of the essential thrombocythemia are summarized. A series of 14 patients with essential thrombocythemia is reported.

We have analysed a series of 96 patients with multiple myeloma (MM) to the purpose to verify the prognostic meaning of the beta2-microglobulin (B2M) and the validity of the staging systems proposed by Bataille and Jacobson who use the B2M respectively associated to the serum C-reactive protein (CRP) and to the serum albumin. In our series of patients the serum level of B2M at the diagnosis was directly correlated with the myelomatous cellular mass. We have found besides an inverse correlation between B2M and survival. Also the serum level of CRP was inversely correlated with the survival, while a direct correlation was found between the serum albumin and the survival: ipoalbuminemia was confirmed as a predictive index of short survival. Staging our patients with MM according to the proposal of Bataille, we identified also in our series three prognostic groups with different median survival: respectively 72, 40 and 18 months. Applying finally the staging proposal of Jacobson to our series, four stages were individualized, with median survival respectively of 70, 52, 26 and 10 months. We confirm the prognostic value of the B2M in MM.

Background: Cardiovascular complications are frequently observed in patients with chronic obstructive pulmonary disease (COPD) admitted to respiratory intensive care units and may affect the prognosis. The aims of this study were to evaluate a) the prevalence of cardiovascular complications in patients with COPD exacerbation admitted to respiratory intensive care units, b) which parameters detected at admission were predictive of cardiovascular complications, and c) the prognostic role of cardiovascular complications., Methods: A series of 278 consecutive patients with COPD admitted to 11 Italian respiratory intensive care units between November 1997 and January 1998 has been retrospectively analyzed. All cardiovascular complications were recorded., Results: One hundred and ten patients (39.6%) developed cardiovascular complications: congestive heart failure 49 (17.6%), arrhythmias 40 (14.4%), shock 13 (4.7%), and hypotension 11 (4%). Multivariate analysis showed that the APACHE II score, ECG abnormalities (supraventricular ectopic beats, right and/or left ventricular hypertrophy) and digoxin therapy were independent predictors of cardiovascular complications. The overall mortality was 9% being 4.7% in patients without and 15.5% in patients with cardiovascular complications (p = 0.0044). Multivariate analysis showed that the APACHE II score, respiratory rate, pneumonia and end-stage respiratory diseases were independent predictors of mortality., Conclusions: Cardiovascular complications occurred in many patients with COPD exacerbation admitted to respiratory intensive care units, and identify a subset of patients with higher mortality.

A series of 24 consecutive patients affected by myelofibrosis with myeloid metaplasia was reviewed. The clinical-pathological features at onset were similar to those reported in literature; in particular in all the patients we observed splenomegaly and the typical leuko-erythroblastic picture in peripheral blood. The median survival of our series was of 57 months; the deaths were caused by severe anaemia and/or infection and/or haemorrhage; the blastic terminal transformations were rare. According to other authors, unfavourable prognostic factors in our patients were: male sex, advanced age, hepatomegaly, the presence of systemic signs, anaemia, leukocytosis, leukopenia, high number of circulating erythroblasts, thrombocytopenia, osteomyelosclerosis. We have confirmed the clinical value of three staging prognostic systems: the system proposed by Njoku based on haemoglobin level and reticulocytes number, the system proposed by Visani based on haemoglobin and circulating myeloid precursors number, the system proposed by Dupriez based on haemoglobin and white blood cells number.

Objective: To investigate in clinical practice the role of non-invasive mechanical ventilation in the treatment of acute respiratory failure on chronic respiratory disorders., Design: An 18 months prospective cohort study., Setting: A specialised respiratory intensive care unit in a university-affiliated hospital., Patients: A total of 258 consecutive patients with acute respiratory failure on chronic respiratory disorders., Interventions: Criteria for starting non-invasive mechanical ventilation and for endotracheal intubation were predefined. Non-invasive mechanical ventilation was provided by positive pressure (NPPV) ventilators or iron lung (NPV)., Results: The main characteristics of patients (70% with chronic obstructive pulmonary disease) on admission were (mean, SD or median, 25th-75th centiles): pH 7.29 (0.07), PaCO(2) 83 mm Hg (19), PaO(2)/FiO(2) 198 (77), APACHE II score 19 (15-24). Among the 258 patients, 200 (77%) were treated exclusively with non-invasive mechanical ventilation (40% with NPV, 23% with NPPV, and 14% with the sequential use of both), and 35 (14%) with invasive mechanical ventilation. In patients in whom NPV or NPPV failed, the sequential use of the alternative non-invasive ventilatory technique allowed a significant reduction in the failure of non-invasive mechanical ventilation (from 23.4 to 8.8%, p=0.002, and from 25.3 to 5%, p=0.0001, respectively). In patients as a whole, the hospital mortality (21%) was lower than that estimated by APACHE II score (28%)., Conclusions: Using NPV and NPPV it was possible in clinical practice to avoid endotracheal intubation in the large majority of unselected patients with acute respiratory failure on chronic respiratory disorders needing ventilatory support. The sequential use of both modalities may increase further the effectiveness of non-invasive mechanical ventilation.

The aim of this randomised study was to compare the effects of iron lung ventilation (ILV) with invasive mechanical ventilation (IMV) in patients with acute respiratory failure (ARF) due to exacerbation of chronic obstructive pulmonary disease. Forty-four patients with ARF were assigned either to ILV (22 patients) or IMV (22 patients). Primary end-points were the improvement in gas exchange and complications related to mechanical ventilation. On admission ILV and IMV groups did not differ in age, simplified acute physiology score II, arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2), arterial carbon dioxide tension (Pa,CO2) and pH. Compared with baseline, ILV and IMV induced a similar and significant improvement in Pa,O2/FI,O2, Pa,CO2 and pH after 1 h of treatment and at discontinuation of mechanical ventilation. Major complications tended to be more frequent in patients treated with IMV than in those treated with ILV (27.3% versus 4.5%), whereas mortality rate was similar (27.3% versus 18.2%). The ventilator-free days and the length of hospital stay were significantly lower in the ILV than in the IMV group. This study suggests that iron lung ventilation is as effective as invasive mechanical ventilation in improving gas exchange in chronic obstructive pulmonary disease patients with acute respiratory failure, and is associated with a tendency towards a lower rate of major complications.

Background: To date we lack official data on tipology of Diagnosis Related Groups (DRGs) and their quality in Italian Respiratory Intermediate Care Units (RICUs)., Aim: The objective of the study was to collect data on the activity of 26 Italian RICUs and to evaluate the quality of the DRGs generated., Methods: The primary and secondary diseases, the procedures carried out and their coding using the ICD9 system (valid Italy until 2000) were collected from the discharge forms of patients admitted to RICUs. To obtain the DRG, these codes were automatically recoded in the ICD9-CM classification system by Grouper 10. Afterwards, the same diseases and procedures were directly processed by the ICD9-CM classification system. Finally, in order to evaluate the quality of care, the DRGs generated by the ICD9 classification system were compared to DRGs generated by the ICD9-CM classification system., Results: The average weight of the patients cared for in an Italian RICU was 2.05 using the ICD9 classification system and 2.53 using the ICD9-CM classification system. Some non-complicated DRGs (80-97) or non specific DRGs (101-102) were set to zero; others, like DRG 87 appear due to the ability of the ICD9-CM classification system to recognise and accept the fifth digit of the Respiratory Failure code (518.81). The difference in terms of DRG scores generated by the two codification systems was 360.5 DRG points in favour of ICD9-CM. More than 1 million Euro of reimbursements have been lost, as the average national reimbursement for each DRG score is Euro 2,943.80., Conclusion: Severe pulmonary diseases determined the case mix of patients cared for in the Italian RICUs during the observed period. The Italian RICUs offer high quality assistance and are characterised by high mean weight per treated patient. However, the activity has been under-estimated due to the low sensitivity of the ICD9 classification system used in the recognition of the real disease and in the correct generation of relative DRG. The ICD9 classification system penalised the recognition of respiratory failure in particular.

Objective: The "International Prognostic Index" (IPI) has been published for patients with histological intermediate grade malignancy non-Hodgkin's lymphoma (NHL) according to the Working Formulation (WF). The IPI is based on pre-treatment clinical characteristics: age, performance status, Ann Arbor stage, extranodal sites, serum lactate-dehydrogenase concentration. We investigated whether the IPI also had prognostic value for NHL patients with a low grade malignancy or high grade malignancy according to the WF., Patients and Methods: Our series included 192 patients with NHL, diagnosed in a single institution between 1986 and 1998. In each patient the relationship among IPI, response to therapy and survival was investigated., Results: The IPI turned out to be of prognostic value for response rate and survival in our unselected cohort of patients, as well. In each of the three WF classes separately (low, intermediate, high grade malignancy), the four IPI classes showed going from low to high risk substantially decreasing response rates and survival percentages., Conclusions: The IPI is confirmed as an important tool for prognostic evaluation of NHL patients: an integration of IPI, histological grading and serum beta 2-microglobulin concentration is supported.

Background: In industrialized countries the prevalence of congestive heart failure (CHF) is increasing. Many clinical factors have been shown to influence the prognosis of CHF. The effect of a wide QRS on mortality is debated; while left bundle branch block (LBBB) has been already identified as a negative prognostic factor, the effect of right bundle branch block (RBBB) is still unknown. The aim of this study was to compare the association of these two intraventricular conduction defects on the prognosis of CHF., Methods: Data were derived from the Italian Registry of CHF. Entry in the Registry required that patients had a diagnosis of CHF based on the European Society of Cardiology guidelines. We analyzed the 1-year follow-up data of 5517 outpatients with CHF of different etiologies. The presence of a wide QRS was defined if the duration was > 120 ms., Results: A wide QRS was present in 2066 patients (37.5%), 25.2% with LBBB, 6.1% with RBBB, 6.2% with other intraventricular defects. At univariate analysis patients with complete LBBB had a significantly higher 1-year mortality than those without (16.1 vs 11.9%) but this was not true for complete RBBB (11.9 vs 11.9%). Even after multivariate adjustment, complete LBBB still remained an independent predictor of death (relative risk 1.36, 95% confidence interval 1.15-1.61)., Conclusions: LBBB but not RBBB is an independent predictor of death in CHF.

The aim of the present research was to verify the prognostic value of some histologic bone marrow parameters in chronic myeloproliferative disorders. Diagnostic bone marrow biopsies were revised in 38 patients with chronic myeloid leukaemia, 30 with polycythemia vera, 14 with essential thrombocythemia and 16 with idiopathic myelofibrosis-myeloid metaplasia. An unfavourable clinical evolution was associated to "granulocytic" histotype in chronic myeloid leukaemia, to "erythrocytic/granulocytic and/or megacaryocytic" histotype in polycythemia vera, to "cluster" distribution of megacaryocytes in essential thrombocythemia, to classical myelofibrosis without osteomyelosclerosis in myelofibrosis-myeloid metaplasia. Bone marrow biopsy in chronic myeloproliferative disorders provides independent diagnostic and prognostic data; we support its routine execution in this group of hematologic malignancies.

Bone sarcomas, such as osteosarcoma (OS) or Ewing sarcoma (ES), frequently arise in the intramedullary region of long bones. Patients affected by bone sarcomas are treated with preoperative aggressive chemotherapy immediately after diagnosis. After chemotherapy, patients undergo surgery that frequently entails the excision of wide bone segments. If a large segment of the bone is lost (defined as a critical defect) the patient undergoes bone reconstruction. Because bone marrow derived stromal stem cells (SSC) offer great promise for cell-based regenerative medicine in bone reconstruction, we investigated whether SSC could be isolated from chemotherapy-treated bone sarcoma patients. We also investigated whether chemotherapy modified SSC differentiation capability. We studied 9 SSC derived from OS and ES patients that had undergone chemotherapy and 5 SSC derived from bone sarcoma patients that had not undergone chemotherapy. SSC could be obtained from all the patients analyzed regardless of whether the patients received chemotherapy or not. Our results also showed that post-chemotherapy SSC can be cultured and expanded ex vivo, these cells retained the ability to differentiate toward the osteogenic lineage in vitro. In conclusion, our results support that SSC cells can be obtained from bone sarcoma patients that undergo chemotherapy and suggest that SSC can be used for cell-based bone reconstruction techniques in bone sarcoma patients treated with preoperative chemotherapy.

Background: Several large controlled trials have shown that beta blockers given to patients with heart failure (New York Heart Association functional class II-IV) reduce morbidity and mortality. Despite these impressive results, implementing the use of beta blockade in clinical practice appears slow and difficult. The BRING-UP study was designed to tackle this problem., Objectives: To accelerate the adoption of beta blockade in clinical practice; to provide an epidemiological estimate of the proportion of patients with heart failure suitable for this treatment in general cardiology care; and to assess effectiveness of these drugs outside the setting of clinical trials., Methods: The design of the study and recommendations derived from available evidence on the use of beta blockers were discussed with cardiologists during regional meetings. All consecutive heart failure patients in a one month period, whether treated or not with beta blockers, were eligible for the study. In each patient, the decision to prescribe a beta blocker was a free choice for the participating physicians. All centres were provided with carvedilol, metoprolol, and bisoprolol at appropriate doses; the choice of the drug and dosage was left to the responsible clinician. All patients were followed for one year., Results: 197 cardiological centres enrolled 3091 patients, 24.9% of whom were already on beta blocker treatment at baseline. beta Blockers were newly prescribed in 32.7% of cases, more often in younger and less severely ill patients. The mean daily dose of the drugs used at one year corresponded to about 70% of the maximum dose used in clinical trials. Starting treatment with beta blockers did not affect the prescription or dosage of other recommended drugs. The overall rate of beta blocker treatment increased over the year of the study from 24.9% to 49.7%. During the 12 month period, 351 deaths occurred (11.8%). In multivariate analysis, the use of beta blockers was independently associated with a better prognosis, with a relative risk of 0.60 and a lower incidence of hospital admissions for worsening heart failure., Conclusions: The implementation of beta blockers in clinical practice is feasible and could be accelerated. These drugs are associated with a lower mortality and reduced hospital admission rates, not only in clinical trials but also in the normal clinical setting.

40 subjects who had a transitory ischemic cerebral attack were treated with Mesoglycan and controlled for two consecutive years. Only four patients showed relapse of ischemic cerebral attacks. There was also noted a positive effect on the patients' quality of life, examined using psycometric scales.

Noninvasive mechanical ventilatory techniques include the use of negative and positive pressure ventilators. Negative pressure ventilators support ventilation by exposing the surface of the chest wall to subatmospheric pressure during inspiration, whereas expiration occurs when the pressure around the chest wall increases and becomes equal to or greater than atmospheric pressure. In this article, a description of negative pressure ventilators and the physiologic effects of negative pressure ventilation (NPV) is given, and the application of this technique in the long-term treatment of chronic respiratory failure is summarized. Many studies, although uncontrolled, have shown that long-term treatment with NPV can improve respiratory muscle function, arterial blood gases, and survival in patients with neuromuscular and chest wall disorders. NPV devices, however, are more cumbersome and difficult to use than home positive pressure ventilators (PPVs) and tend to predispose to obstructive apnoeas during sleep. In the last several decades, NPV has been supplanted by mask PPV. In experienced hands, NPV remains a second viable option in patients with neuromuscular and chest wall disorders who, for technical or other reasons, cannot be offered mask PPV. There is no evidence, however, that long-term treatment with NPV can improve respiratory muscle function, exercise endurance, quality of life, and survival in patients with severe chronic obstructive pulmonary disease.

A dysfunction of dopaminergic systems with reduction of active dopamine, is well-known in cerebral involution. Twenty patients with mild-moderate pathological cerebral involution of atrophic and/or vascular origin, were treated with Selegiline (L-deprenyl), a monoamino-oxidase B inhibitor (10 mg/die for six months). Compared with a control group, Selegiline treated patients showed a statistically significant improvement in cognitive and behaviour capacities. At the end of investigation, "Mini Mental State" showed an improvement of 26.5% in Selegiline group and of 3.7% in control group (P < 0.01). "Echelle Clinique d'Aptitudes Intellectuelles" showed an improvement of 29.4% and of 10.8% respectively (P < 0.01). Selegiline treatment has shortened significantly the reaction times and has improved mnesic capacities. No side effects were observed during the study.

To evaluate the prognostic impact of left ventricular (LV) mass exceeding individual needs to compensate hemodynamic load, the percentage of excess of echocardiographic LV mass in relation to individual ideal value predicted by gender, stroke work, and height (in meter(2.7)) from a reference population was assessed in 1019 white hypertensives (627 women [24% obese] and 392 men [17% obese, P<0.02 versus women]) without prevalent cardiovascular disease or type 1 diabetes, from the Italian multicenter, prospective study MAVI. Low LV mass (<73% of predicted) was found in 36 patients (3.5%), 661 had appropriate LV mass, and 322 (37%) had inappropriate LV mass. During follow-up (35+/-11 months), 52 fatal or nonfatal primary cardiovascular events occurred. Age, systolic blood pressure, and LV mass as a percentage of the predicted value were significant predictors of cardiovascular events (all P<0.01), independently of gender, glycemia, antihypertensive treatments, and body mass index, even in subgroups with or without LV hypertrophy. Survival analysis showed that cardiovascular risk increased stepwise from the lowest to the highest quintile of LV mass as a percentage of predicted value (P<0.01). The excess LV mass showed incremental prognostic value compared with assessment of traditional LV mass (P<0.01). Thus, inappropriate LV mass predicts a risk of cardiovascular events, independently of risk factors, and remains a significant predictor of risk either in the presence or in the absence of traditionally defined LV hypertrophy.

30 patients, affected by chronic ethylic hepatopathy, were treated with 450 mg/daily of ursodeoxycholic acid (UDCA): after six months, a significant decrease of serum hepatic enzymes was noted. The addition of silymarin (400 mg/daily) to UDCA in other 30 patients, induced a further improvement of hepatic function.

The effects of Citicoline were investigated in 40 patients with pathological cerebral involution of atrophic origin. The dose was 1000 mg/die by parenteral injection for 4 weeks; 20 patients, after a wash-out of a week, received another cycle of Citicoline at the same doses for other 4 weeks. Citicoline treatment has shortened significantly the reaction times and has improved cognitive and behaviour capacities, evaluated according to the "Clifton test" and "Green Relatives Stress Scale". Better results were obtained in patients who received two cycles of therapy. No side effects were observed during the study.

Background: A deleterious effect of complete left bundle-branch block (LBBB) on left ventricular function has been established. Nevertheless, the independent effect of a widened QRS on mortality rate in congestive heart failure (CHF) is still controversial. Therefore, we carried out this analysis to determine whether LBBB is an independent predictor of mortality in CHF., Methods and Results: We analyzed the large Italian Network on CHF Registry of unselected outpatients with CHF of different causes. The registry was established by the Italian Association of Hospital Cardiologists in 1995. Complete 1-year follow-up data were available for 5517 patients. The main underlying cardiac diagnosis was ischemic heart disease in 2512 patients (45.6%), dilated cardiomyopathy in 1988 patients (36.0%), and hypertensive heart disease in 714 patients (12.9%). Other causes were recorded in the remaining 303 cases (5.5%). LBBB was present in 1391 patients (25.2%) and was associated with an increased 1-year mortality rate from any cause (hazard ratio, 1.70; 95% confidence interval, 1.41 to 2.05) and sudden death (hazard ratio, 1.58; 95% confidence interval, 1.21 to 2.06). Multivariate analysis showed that such an increased risk was still significant after adjusting for age, underlying cardiac disease, indicators of CHF severity, and prescription of angiotensin-converting enzyme inhibitors and beta-blockers., Conclusion: LBBB is an unfavorable prognostic marker in patients with CHF. The negative effect is independent of age, CHF severity, and drug prescriptions. These data may support the rationale of randomized trials to verify the effects on mortality rate of ventricular resynchronization with multisite cardiac pacing in patients with CHF and LBBB.

Background: The lack of patient triggering capability during negative pressure ventilation (NPV) may contribute to poor patient synchrony and induction of upper airway collapse. This study was undertaken to evaluate the performance of a microprocessor based iron lung capable of thermistor triggering., Methods: The effects of NPV with thermistor triggering were studied in four normal subjects and six patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) by measuring: (1) the time delay (TDtr) between the onset of inspiratory airflow and the start of assisted breathing; (2) the pressure-time product of the diaphragm (PTPdi); and (3) non-triggering inspiratory efforts (NonTrEf). In patients the effects of negative extrathoracic end expiratory pressure (NEEP) added to NPV were also evaluated., Results: With increasing trigger sensitivity the mean (SE) TDtr ranged from 0.29 (0.02) s to 0.21 (0.01) s (mean difference 0.08 s, 95% CI 0.05 to 0.12) in normal subjects and from 0.30 (0.02) s to 0.21 (0.01) s (mean difference 0.09 s, 95% CI 0.06 to 0.12) in patients with COPD; NonTrEf ranged from 8.2 (1.8)% to 1.2 (0.1)% of the total breaths in normal subjects and from 11.8 (2.2)% to 2.5 (0.4)% in patients with COPD. Compared with spontaneous breathing, PTPdi decreased significantly with NPV both in normal subjects and in patients with COPD. NEEP added to NPV resulted in a significant decrease in dynamic intrinsic PEEP, diaphragm effort exerted in the pre-trigger phase, and NonTrEf., Conclusions: Microprocessor based iron lung capable of thermistor triggering was able to perform assist NPV with acceptable TDtr, significant unloading of the diaphragm, and a low rate of NonTrEf. NEEP added to NPV improved the synchrony between the patient and the ventilator.

Study Objectives: Evaluation of the effectiveness of negative-pressure ventilation (NPV) with the use of the iron lung vs noninvasive positive-pressure ventilation (NIPPV) in the treatment of COPD patients with acute on chronic respiratory failure., Design: A retrospective case-control study., Setting: Four Italian respiratory intermediate ICUs., Patients: Of a total of 393 COPD patients admitted to the ICU in 1996, 53 pairs were treated with the iron lung (NPV group). Patients treated with NIPPV (NIPPV group) were matched according to mean (+/- SD) age (70.3 +/- 7.1 vs 70.3 +/- 6.9 years, respectively), sex, causes of acute respiratory failure (ARF), APACHE (acute physiology and chronic health evaluation) II score (22.4 +/- 5.3 vs 22.1 +/- 4.6, respectively), pH (7.26 +/- 0.05 vs 7.27 +/- 0.04, respectively), and PaCO(2) (88.1 +/- 11.5 vs 85.1 +/- 13.5 mm Hg, respectively) on admission to the ICU. The effectiveness of matching was 98.4%., Results: Five patients from the NPV group (9.4%) and seven patients from the NIPPV group (13.2%) needed endotracheal intubation (EI). The treatment failure rate (ie, death and/or need of EI) was 20.7% in the NPV group and 24.5% in the NIPPV group (difference was not significant). The mean duration of mechanical ventilation (29.6 +/- 28.6 vs 62.3 +/- 35.7 h, respectively) and length of hospital stay (10.4 +/- 4.3 vs 15 +/- 5.2 d, respectively) among the 35 concordant surviving pairs were significantly lower in the NPV group than in the NIPPV group (p = 0.001 and p = 0.001, respectively)., Conclusions: These data suggest that both ventilatory techniques are equally effective in avoiding EI and death in COPD patients with ARF. Prospective trials are needed to confirm these preliminary results.