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Diagnosis and management of Cancer therapeutics-related cardiac dysfunction is of crucial importance in breast cancer (BC) patients. The role of advanced echocardiographic techniques, such as deformation imaging, in the diagnosis and characterization of patients receiving cancer therapy has so far involved relatively small studies in the research setting. Therefore, we conducted a meta-analysis and systematic review of observational studies evaluating myocardial changes during chemotherapy detected through conventional echocardiographic parameters, such as 2D left ventricular ejection fraction (2D LVEF), and 2D Speckle tracking echocardiography (STE). The literature search retrieved 487 research works, articles, of which 17 were found to be pertinent with this topic. After full article review, 16 studies were considered suitable for the present analysis. Two separate analyses, one for the anthracyclines-based therapeutic regimen and one for the trastuzumab based therapeutic regimen, were performed. A significant reduction in 2D LVEF and 2D STE parameters during cancer therapy was found in both the investigations. Peak systolic global longitudinal strain demonstrated to be the most consistent 2D STE parameter in detecting early myocardial changes among all the studies. Thus, we confirmed the role of 2D STE for the early detection of myocardial damage, suggesting its crucial role in monitoring BC patients and eventually driving the introduction of cardioprotective treatment.

Aims: To assess the proportion of patients with heart failure and reduced ejection fraction (HFrEF) who are eligible for sacubitril/valsartan (LCZ696) based on the European Medicines Agency/Food and Drug Administration (EMA/FDA) label, the PARADIGM-HF trial and the 2016 ESC guidelines, and the association between eligibility and outcomes., Methods and Results: Outpatients with HFrEF in the ESC-EORP-HFA Long-Term Heart Failure (HF-LT) Registry between March 2011 and November 2013 were considered. Criteria for LCZ696 based on EMA/FDA label, PARADIGM-HF and ESC guidelines were applied. Of 5443 patients, 2197 and 2373 had complete information for trial and guideline eligibility assessment, and 84%, 12% and 12% met EMA/FDA label, PARADIGM-HF and guideline criteria, respectively. Absent PARADIGM-HF criteria were low natriuretic peptides (21%), hyperkalemia (4%), hypotension (7%) and sub-optimal pharmacotherapy (74%); absent Guidelines criteria were LVEF>35% (23%), insufficient NP levels (30%) and sub-optimal pharmacotherapy (82%); absent label criteria were absence of symptoms (New York Heart Association class I). When a daily requirement of ACEi/ARB ≥ 10 mg enalapril (instead of ≥ 20 mg) was used, eligibility rose from 12% to 28% based on both PARADIGM-HF and guidelines. One-year heart failure hospitalization was higher (12% and 17% vs. 12%) and all-cause mortality lower (5.3% and 6.5% vs. 7.7%) in registry eligible patients compared to the enalapril arm of PARADIGM-HF., Conclusions: Among outpatients with HFrEF in the ESC-EORP-HFA HF-LT Registry, 84% met label criteria, while only 12% and 28% met PARADIGM-HF and guideline criteria for LCZ696 if requiring ≥ 20 mg and ≥ 10 mg enalapril, respectively. Registry patients eligible for LCZ696 had greater heart failure hospitalization but lower mortality rates than the PARADIGM-HF enalapril group., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Background: Although current literature has shown that patients with Alzheimer's disease (AD) have worse locomotion compared with healthy counterparts, no studies have focused on the efficacy of exercise training in improving gait abnormalities including biomechanics and metabolic aspects, in this population., Objective: To verify the effectiveness of exercise training (ET) on gait parameters (i.e., speed, step and stride length, single and double support, and energy cost of walking (Cw)) in patients with AD with respect to a standard cognitive treatment (CT)., Methods: In this study, we included a small portion of data belonging to a larger study (ClinicalTrials.gov number, NCT03034746). Patients with AD (Mini-Mental State Examination 22±5) were included in the study. Gait parameters and Cw were assessed at baseline and after 6 months (72 treatment sessions) of treatment. ET included 90 min of aerobic and strength training. CT included 90 min of cognitive stimuli., Results: The 16 patients assigned to ET exhibited significant improvement of Cw (-0.9±0.1 J/kg·m-1), while differences in gait parameters were negligible. The effect on gait parameters were undetectable in the 18 patients assigned to CT (-0.2±0.5 J/kg·m-1)., Conclusions: Data from this study showed that ET program seems effective in improving Cw in patients with AD. Interestingly, the positive effect of ET on Cw was not coupled with ameliorations of patient's gait parameters, suggesting that the gain of metabolic aspects of locomotion were the main factors responsible for this positive result.

Background: Sympathetic activation in heart failure patients favors the development of ventricular arrhythmias, thus leading to an increased risk of sudden cardiac death. β1 - and β2 -adrenergic receptor polymorphisms have been linked to the risk of sudden death. Implantable cardioverter-defibrillators (ICD) are implanted in a large percentage of heart failure patients, and beyond preventing sudden cardiac death they provide a continuous monitoring of major ventricular arrhythmias and of their own interventions. We investigated whether functionally relevant β1 - and β2 -adrenergic receptor polymorphisms are associated with risk of ICD shocks, as evidenced in ICD memory., Methods: 311 patients with systolic heart failure were enrolled, and number and timing of shocks in ICD memory were recorded. Four selected polymorphisms were determined: β1 -adrenergic receptor polymorphisms Ser(49) Gly and Arg(389) Gly and β2 -adrenergic receptor polymorphisms Arg(16) Gly and Gln(27) Glu., Results: Only Ser(49) Gly was significantly correlated with time free from ICD shocks, both considering time to the first event in a Cox model (hazard ratio 2.117), and modeling repeated events with the Andersen-Gill method (hazard ratio 2.088). Gly allele carriers had a higher probability of ICD shock. The relationship remained significant even after adjusting for ejection fraction and beta-blocker dosage (hazard ratio 1.910)., Conclusions: Data from our study suggest that the β adrenoreceptor Gly 49 allele of the β1 -adrenergic receptor Ser(49) Gly polymorphisms may increase the risk of ICD shock in patients with heart failure, independent of beta-blocker dosage., (©2016 Wiley Periodicals, Inc.)

Objective: This study analyses dynamicchangesin dispersion of ventricularrepolarization over the time course of takotsubo cardiomyopathy (TC), and their relationships with clinical features and life-threatening arrhythmias., Methods and Results: All consecutive patients admitted to our division between January 2008 and December 2011 with a diagnosis of TC were analysed. Patients with prior myocardial infarction, symptoms-onset-to-admission time greater than 12 hours, an implanted pacemaker, or under treatment with drugs affecting QTinterval, were excluded. Standard 12-lead ECG recordings during the acute, subacute and chronic phases were collected for each patient. Twenty-four patients (23 women, 63 +/- 14 years) were includedin our analysis. Only one patient experienced ventricular arrhythmias (4.2%). Significant increases were observed in QT and QTc intervals (from 420 ?423 to 505 +/- 66 ms, P < 0.00001, and from 479 +/- 33 to 551 +/- 51 ms, P < 0.00001, respectively), QTdispersion (from 59 +/- 18 to 100 +/- 44 ms, P=0.0006), Tpeak-to-Tend (from 82 +/- 20 to 123 +/- 39 ms, P=0.00006) and Tpeak-to-Tend/QT (from 0.20 +/- 0.33 to 0.26 +/- 0.57, P=0.0003) during the subacute phase. All these parameters returned to baseline values in the chronic phase and did not show any significant differences between the acute and chronic phases., Conclusions: A marked increase in QTc, QT dispersion, Tpeak-to-Tend and Tpeak-to-Tend/QT was observed during the subacute phase; this increase was transient and reverted in allpatients before hospital discharge. Ofnote, these findings were not associated with an increased risk of life-threatening arrhythmias.

Background: Left ventricular (LV) dysfunction and remodeling are key pathophysiological features underlying disease progression in chronic heart failure (CHF)., Hypothesis: To describe the course of LV dysfunction and identify predictors and prognostic impact of changes in LV volumes and function in stable CHF patients under optimal therapy., Methods: There were 318 consecutive CHF outpatients who underwent a repeated echocardiographic evaluation at baseline and at 1 year and subsequently followed-up for at least 12 months. The end point of the study was all-cause mortality., Results: Mean LV ejection fraction (LVEF) was 33 ± 7% at baseline and 36 ± 9% at follow-up. Twenty-four percent of patients had an improvement of LVEF >5 absolute points (group 1); 58% remained stable (group 2), 17% worsened at >5 absolute points (group 3). Age, New York Heart Association class, diuretic dose, renal function, and baseline LVEF were independent predictors of LVEF improvement at 1 year. At the Cox analysis, patients in group 3 had a 4-fold higher risk of death when compared with group 1 (hazard ratio: 3.99, 95% confidence interval: 1.6-9.9, P = 0.002), independently of age, etiology, and symptoms severity., Conclusions: In stable CHF outpatients, LV function improves in 24% of cases; a modest decrease in LV systolic function is associated with a significantly higher risk of all-cause mortality, independent of other markers of disease severity., (© 2012 Wiley Periodicals, Inc.)

Aim: The aim of this paper was to compare the in-hospital management and outcome of patients on oral anticoagulation (OAC) undergoing coronary artery stenting (PCI-S) for ST-elevation myocardial infarction (STEMI) vs. other indications., Methods: One hundred and sixteen patients on OAC at the time of PCI-S who were prospectively enrolled in a multi-center, observational registry, were evaluated. Patients were segregated according to whether PCI-S was performed for STEMI (group 1) or other indications, such as non ST-elevation acute coronary syndromes, stable angina, silent ischemia, etc. (group 2), and the pharmacological and procedural management, as well as the in-hospital outcome, were compared., Results: No significant differences were observed in vascular access site, sheath size and type of stent implanted, nor was significantly different the use of glycoprotein IIb/IIIa inhibitors, and the use and dose of intravenous unfractionated heparin. Although not statistically different, the in-hospital occurrence of death (3.7% vs. 1.1%; OR 3.3; 95% confidence intervals [CI] 0.2-56.0), stent thrombosis (3.7% vs. 1.1%; OR 3.3; 95% CI 0.2-56.0) and major bleeding (7.4% vs. 2.2%; OR 3.4; 95% CI 0.4-25.9) was consistently about 3-fold higher in group 1., Conclusion: The in-hospital pharmacological and procedural management of OAC patients undergoing PCI-S for STEMI vs. other indications appears not different. Although not significantly different however, the in-hospital occurrence of major bleeding, as well as of death and stent thrombosis, appears substantially higher in patients treated for STEMI, warranting therefore further larger, prospective studies.

Soccer is a popular game practiced all around the world by teenagers. However, despite being a relatively safe sport, muscle-strain injuries during competitive matches are common compared to other team-sports. Few studies, to date, have investigated risk factors for soccer injuries using a multivariate survival model (e.g., Cox regression). The aim of this study was to use a multivariate survival model to investigate factors associated with an increased risk of thigh muscle strains, in young soccer players. A multivariate Cox regression was used to evaluate survival probability predictors for thigh muscle strains. 84 young male soccer players (16.4 ± 1.6 years) were followed for a season. Baseline tests were performed for body size, body composition, endurance, flexibility, and jump height from both a static position (SJ), and with a countermovement (CMJ); the percentage difference between the two types of jumps was also calculated (ΔJH). Cox regression result (hazard ratio; C.I. 95%) showed that: previous injuries (2.80; 1.19-6.54), ΔJH (0.79; 0.71-0.87), and stature (1.17; 1.06-1.25) were significantly correlated to thigh-strain survival probability. This study confirms that previous injuries are an important risk factor. However, we also report that a negative ΔJH and an elevated stature increased the probability of thigh strain. This could be explained by poor player coordination, influencing jumping ability, which may be even more evident in tall young players., (Published by Elsevier Ltd.)

Background: Prednisone at immunosuppressive doses after stenting has shown remarkable efficacy in reducing ischemic recurrences in nondiabetic patients with high post-procedural levels of C-reactive protein; the study aim was to compare the clinical outcome obtained in a control group of patients treated with bare metal stents versus 2 other study groups--bare metal stent plus oral prednisone or drug eluting stents--assuming similar optimal adjunctive medical treatment., Methods: Five tertiary Italian hospitals enrolled 375 nondiabetic patients with coronary artery disease and no contraindications to dual antiplatelet treatment or corticosteroid therapy in a randomized, controlled study performed between 2007 and 2009. Patients were allocated into 3 study groups: bare metal stents (controls), bare metal stents followed by a 40-day prednisone treatment, or drug-eluting stents. The primary endpoint was the event-free survival of cardiovascular death, myocardial infarction, and recurrence of ischemia needing repeated target vessel revascularization at 1 year as adjudicated by an independent clinical events committee., Results: One-year follow-up was obtained in all patients. Patients receiving bare metal stents alone as compared to those treated with prednisone or drug-eluting stents had lower event-free survival; the primary endpoint was 80.8% in controls compared to 88.0% in the prednisone and 88.8% in the drug-eluting stent groups, respectively (P=.04 and .006)., Conclusion: Compared with bare metal stents alone, prednisone treatment after bare metal stents or drug-eluting stent implantation result in a better event-free survival at 1 year., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Increased plasma levels of amino-terminal fraction of brain natriuretic peptide (NT-proBNP) and alterations of diastolic filling as described by Doppler transmitral flow pattern are well-known markers of decompensated heart failure (HF). Recently, some implantable defibrillators have allowed monitoring of intrathoracic impedance, which is related to lung water content, potentially indicating HF deterioration. The aim of this study was to assess the correlation between intrathoracic impedance and NT-proBNP and echo-Doppler transmitral flow indexes., Methods: Data were collected from 111 HF patients, in six Italian centers. All patients were on optimal medical therapy. Device diagnostics, echographic data, NT-proBNP determination, and clinical status as assessed by the Heart Failure Score (HFS) were registered at baseline, at bimonthly visits, and at unscheduled examinations due to HF decompensation or device alerts., Results: Over a median follow-up of 413 days, 955 examinations were performed. Intrathoracic impedance was significantly correlated with NT-proBNP (P = 0.013) and with mitral E-wave deceleration time (DtE) (P = 0.017), but not with HFS. At the time of confirmed alert events, NT-proBNP was significantly higher than during confirmed nonalert event examinations; DtE did not differ, whereas impedance was significantly lower., Conclusion: A decrease in intrathoracic impedance is inversely correlated with NT-proBNP and directly correlated with DtE. Intrathoracic impedance monitoring therefore has the physiologic basis for being a useful tool to identify early HF decompensation., (©2010, The Authors. Journal compilation ©2010 Wiley Periodicals, Inc.)

The demand for cystic fibrosis (CF) carrier testing is steadily growing, not only from individuals with raised a priori carrier risk, but also from the general population. This trend will likely exceed the availability of genetic counselors, making it impossible to provide standard face-to-face genetic counseling to all those asking for the test. In order to reduce the time needed to educate individuals on the basics of the disease, its genetic transmission, and carrier testing peculiarities, we developed an educational method based on an interactive computer program (IC). To assess the effectiveness of this program and to compare it to a classical genetic counseling session, we conducted a comparative trial. In a population setting of people undergoing assisted reproduction, 44 individuals were randomly assigned to either receiving standard one-on-one genetic counseling or education by the IC program. We measured pre- and post-intervention knowledge about CF genetic transmission and carrier testing. Starting from an equivalent baseline of correct answers to a specially designed multiple-choice questionnaire (47% in the counselor group and 45% in the computer group) both groups showed a highly significant and similar increase (reaching 84% in the counselor group and 85% in the computer group). The computer program under evaluation can successfully educate individuals considering genetic testing for CF., (Copyright © 2011 Wiley-Liss, Inc.)

A broad spectrum of concomitant disorders may complicate heart failure adding further morbidity and mortality risk. Comorbidities may be subdivided into cardiovascular and noncardiovascular. The first group includes hypertension, coronary artery disease, peripheral artery disease, cerebrovascular disease, arrhythmias and valvular heart disease. Noncardiovascular comorbidities include respiratory, endocrine, metabolic, nutritional, renal, hematopoietic, neurological as well as musculoskeletal conditions. In recent years, advances in the treatment of heart failure have not been attended by important changes in management of its comorbidities. They now seem to be major causes of the poor prognosis of heart failure patients. In this review we provide an updated summary of the epidemiological, pathophysiological and clinical characteristics of comorbidities as well as their potential impact for heart failure treatment., (2011 Italian Federation of Cardiology.)

Background: Cardiologists may prescribe antithrombotic therapy to patients with atrial fibrillation (AF), but prescription application mostly depends on general practitioners. The present study aims to assess frequency and appropriateness of antithrombotic therapy in general practice, as a function of thromboembolic risk factors, using the CHADS2 score., Methods: The computer records of 39 general practitioners were evaluated in order to identify patients with non-valvular AF; therapy and thromboembolic risk factors were recorded., Results: AF was documented in 951 patients; 96 (10.1%) had contraindications to oral anticoagulants. Among the remaining 850 patients, 292 (34.4%) did not receive antithrombotic therapy according to guidelines. In particular, 102 (12.0%) did not receive any antithrombotic treatment., Conclusions: Among general practitioners of the Veneto region (Italy), the application of guidelines on antithrombotic therapy in non-valvular AF is comparable, or even slightly better than that reported in published cohort studies, but it deserves further improvement. There is a need for targeted educational interventions and a better coordination between cardiologists and general practitioners.

Background: Implantable cardioverter defibrillators (ICDs) are increasingly employed in patients affected by congestive heart failure (CHF) and sleep disordered breathing (SDB) is frequent in this population., Hypothesis: To investigate SDB prevalence and influence on appropriate ICD discharges in CHF patients., Methods: A total of 22 consecutive ICD patients with systolic CHF (left ventricular ejection fraction [LVEF]< 45%) were studied by polysomnography., Results: A total of 17 (77.2%) showed SDB (apnea-hypopnea index [AHI]&#95; 10 events/hour). After controlling for LVEF and New York Heart Association (NYHA) class, AHI and severity of hypoxia during sleep results correlated to appropriate ICD discharges (r = 0.718; P < .001, r = - 0.619; P = .003, respectively)., Conclusions: Sleep disordered breathing is frequent in ICD recipients due to left systolic ventricular dysfunction and may increase the risk of ventricular arrhythmia and appropriate ICD discharges., (Copyright 2010 Wiley Periodicals, Inc.)

Objective: To investigate the usefulness of carotid ultrasound evaluation in predicting the presence and the extent of coronary artery disease in a consecutive series of patients., Design: We examined retrospectively 1337 patients in whom both coronary angiography and carotid ultrasound were evaluated, from 1995 to 2005. Markers of carotid artery disease were considered, such as intima-media thickness more than 0.90 mm, unstable plaque and severe stenosis (> or =70%). Carotid risk score was defined as the sum of these parameters. We considered as affected by significant coronary artery disease those patients with at least one lesion more than 50% within the main branches of the coronary arteries., Results: The markers of carotid atherosclerosis increased proportionally in patients with one-, two- or three-vessel coronary artery disease. At univariate analysis, intima-media thickness more than 0.90 mm was associated with an odds ratio of coronary artery disease of 2.28 (1.8-2.9) (P < 0.0001), unstable plaque 3.6 (2.3-5.7) (P < 0.001) and severe carotid stenosis 4.2 (2.0-8.7) (P = 0.0001). At multivariate analysis, the three markers mentioned above were independent risk factors for coronary artery disease even when considering other risk factors., Conclusion: We confirmed the usefulness of carotid ultrasound evaluation in predicting the presence and extent of coronary artery disease. Considering the high correlation between carotid and coronary artery disease, carotid screening is useful in patients with coronary artery disease. In patients with an occasional finding of a carotid risk score of at least 2, a careful search for coronary artery disease seems warranted.

Aim: Cystic Fibrosis (CF) Newborn Screening occasionally identifies neonates where a CF diagnosis can neither be confirmed nor excluded. To assess how parents of these infants cope with this ambiguous situation., Methods: Parents of 11 children with Ambiguous Diagnosis (group AD) were compared with parents of 11 children diagnosed with CF through neonatal screening [group Cystic Fibrosis Diagnosis (CFD)] and with parents of 11 Healthy Control children (group HC) matched for gender and age., Results: The emotional reaction to the inconclusive result was less pronounced in AD than in CFD (p = 0.003), and AD parents considered their infants as healthy as controls. Parents' anxiety about their child's health is stronger in CFD than in AD (p < 0.05) and HC (p < 0.001). Long-term emotional distress was rated similarly in AD and CFD, and greater than in HC (p = 0.0003). The parent/child relationship was less influenced in AD than in the CF group (p = 0.03). Seven AD and CFD parents changed their family planning projects., Conclusion: Inconclusive neonatal screening results appear to be understood and associated with lower anxiety levels than CF diagnosis. Concern about the child's health is similar to healthy controls and lower than in parents of CF children.

Purpose: In patients on oral anticoagulation (OAC) undergoing coronary stenting (PCI-S), procedural management and in-hospital outcome have never been specifically and prospectively investigated. Also, the contribution of early bleeding to the relevant hemorrhagic rate reported at follow-up with triple therapy of OAC, aspirin, and clopidogrel is largely unknown., Methods: Consecutive patients with indication for OAC undergoing PCI-S at 5 centers were enrolled and prospectively evaluated., Results: Out of 3410 patients undergoing PCI-S in the study period, indication for OAC was present in 4.8%. Femoral approach and bare metal stents were the most frequently used. During PCI-S, OAC was continued in about 30% of patients, whereas in about 20% heparin bridging was carried out. Glycoprotein IIb/IIIa inhibitors were rarely used (11%), whereas a standard bolus of unfractionated heparin was given in 93% of cases. Major adverse cardiovascular events (MACE) occurred in 4.8% of patients and major bleeding in 4.3%. No predictors of MACE or bleeding were identified, although the femoral approach was of borderline significance for major bleeding (OR 4.6, 95% CI 1.0-20.8; P = 0.05). A history of previous hemorrhage (OR 5.3, 95% CI 1.6-18.1; P = 0.007) predicted Carbofilm-coated stent implantation., Conclusions: A limited, albeit clinically relevant, proportion of patients undergoing PCI-S has indication for OAC. Procedural management appears not substantially different from that of common patients. In-hospital major bleeding is relevant and should be taken into account when evaluating the overall hemorrhagic rate at a medium- to long-term follow-up.

Objectives: Our aim was assess the prognostic value of midregional pro-atrial natriuretic peptide (MR-proANP) using a new immunoassay in patients with chronic heart failure (HF)., Background: Assessment of natriuretic peptides represents a useful addition in establishing the diagnosis of chronic HF. Their plasma values are powerful predictors of survival in chronic HF., Methods: We assessed MR-proANP in 525 chronic HF patients (derivation study: age 61 +/- 12 years, New York Heart Association (NYHA) functional class I/II/III/IV 6%/44%/41%/9%, N-terminal pro-B-type natriuretic peptide (NT-proBNP) 3,637 +/- 6,362 pg/ml) and validated our findings in 249 additional chronic HF patients (age 63 +/- 9 years, NYHA functional class I/II/III/IV 14%/50%/33%/3%, NT-proBNP 1,116 +/- 1,991 pg/ml)., Results: The MR-proANP levels (mean 339 +/- 306 pmol/l, range 24.5 to 2,280 pmol/l) increased with NYHA functional class (p < 0.0001). During follow-up (>6 months in survivors), 171 patients (33%) died. Increasing MR-proANP was a predictor of poor survival (risk ratio 1.35 per increase in standard deviation, 95% confidence interval 1.17 to 1.57; p = 0.0061), adjusted for NT-proBNP, age, left ventricular ejection fraction, NYHA functional class, creatinine, and body mass index (BMI). In receiver operating characteristic curve analysis of 12-month survival, the area under the curve for MR-proANP was 0.74 and that of NT-proBNP was 0.75 (p = 0.7). In a validation study, MR-proANP levels above the optimal prognostic cutoff value from the validation cohort remained a significant independent predictor of death. In chronic HF patients in NYHA functional class II to III and all subgroups of BMI and kidney function, MR-proANP added prognostic value to NT-proBNP. In patients with BMI > or =30 kg/m2, MR-proANP had higher prognostic power than NT-proBNP., Conclusions: Midregional proANP is an independent predictor of mortality in patients with chronic HF. Midregional proANP adds prognostic information to NT-proBNP.

In this review, we assessed the feasibility of total laparoscopic hysterectomy (TLH) in cases of very large uteri weighting more than 500 grams. We compared surgical outcomes and short term follow-up in 149 patients with the uterus weighing less than 350 g (group A: 40-350 g) and 100 patients with the uterus weighing more than 500 g (group B: 500-1550 g). We discovered no statistical difference between the 2 groups in terms of intraoperative complications (group A: 0%; group B: 2%) and postoperative stay (group A: 3.05 +/- 1.89 days; group B: 3.2 +/- 1.28 days). There were statistically significant differences between the 2 groups in terms of operative time (group A: 101.3 +/- 34.3 min; group B: 149.1 +/- 57.2 min.; p <.0001) and postoperative hospital stay length (group A: 2.8 +/- 0.7 days; group B: 3.5 +/- 1.7 days; p <.0001). No major complications occurred in either group. Postoperative minor complications were more frequent in group B (group A: 8.7%; group B: 18%; p = .03). Median time to well-being was comparable in both groups. In conclusion, TLH is a feasible surgical technique also in cases of very large uteri. An increase in operative time, intraoperative blood loss, hospital stay length, and postoperative minor complications can be expected as the uterine weight increases.

The prevalence of type 2 diabetes is increasing worldwide, and prevention of the disease is a key objective. Several clinical trials reported a consistent reduction in the incidence of newly diagnosed diabetes in high-risk patients treated with renin-angiotensin system-inhibiting drugs. In all those trials, however, diabetes reduction was either a post-hoc analysis result or a secondary endpoint. Therefore, we need the results of ongoing specific prospectively designed trials, with new-onset diabetes as the principal endpoint.

Background: Cystic fibrosis (CF) is a recessively inherited condition caused by mutation of the CFTR gene. Newborn infants with CF have raised levels of immuno-reactive trypsinogen (IRT) in their serum. Measurement of IRT in the first week of life has enabled CF to be incorporated into existing newborn screening (NBS) blood spot protocols. However, IRT is not a specific test for CF and NBS therefore requires a further tier of tests to avoid unnecessary referral for diagnostic testing. Following identification of the CFTR gene, DNA analysis for common CF-associated mutations has been increasingly used as a second tier test. The aim of this study was to survey the current practice of CF NBS programmes in Europe., Method: A questionnaire was sent to 26 regional and national CF NBS programmes in Europe., Results: All programmes responded. The programmes varied in number of infants screened and in the protocols employed, ranging from sweat testing all infants with a raised first IRT to protocols with up to four tiers of testing. Three different assays for IRT were used; in the majority (24) this was a commercially available kit (Delfia). A number of programmes employed a second IRT measurement in the 4th week of life (as the IRT is more specific at this point). Nineteen programmes used DNA analysis for common CFTR mutations on samples with a raised first IRT. Three programmes used a second IRT measurement on infants with just one recognised mutation to reduce the number of infants referred for sweat testing. Referral to clinical services was prompt and diagnosis was confirmed by sweat testing, even in infants with two recognised mutations in most programmes. Subsequent clinical pathways were less uniform. Multivariate analysis demonstrated a relationship between the age of diagnosis and the timing of the first IRT. More sweat tests were undertaken if the first IRT was earlier and the diagnosis was later., Conclusions: Annually these programmes screen approximately 1,600,000 newborns for CF and over 400 affected infants are recognised. The findings of this survey will guide the development of European evidence based guidelines and may help new regions or nations in the development and implementation of NBS for cystic fibrosis.

Background: The periodic administration of positive airway pressure combined with directed cough could aid mucus clearance in patients with cystic fibrosis (CF) and severe airway obstruction., Objective: To compare the short-term effect of positive expiratory pressure (PEP) physiotherapy via mask (mask PEP), continuous positive airway pressure (CPAP), and noninvasive positive-pressure ventilation (NPPV) physiotherapies on amount of sputum collected., Methods: Directed cough was standardized for each patient and used as the control treatment. We studied 17 patients with CF (mean +/- SD age 28 +/- 7 y) and severe airway obstruction (forced expiratory volume in the first second 25 +/- 6% of predicted) admitted for pulmonary exacerbation. Mask PEP, CPAP, NPPV, and the control treatment (directed cough) were administered in a random sequence. Each patient received each treatment twice a day (in 70-min sessions) for 2 consecutive days. We measured the wet and dry weight of sputum collected and the number of directed and spontaneous coughs during each session. Spirometry and pulse oximetry were conducted before and after each session. For mask PEP, CPAP, and NPPV, each patient gave a subjective score for the efficacy and tolerability of the treatment, compared to the control treatment., Results: There was no statistically significant difference in the dry weight of sputum collected: mask PEP 0.9 +/- 0.6 g, CPAP 0.8 +/- 0.4 g, NPPV 0.9 +/- 0.6 g, control treatment 1.0 +/- 0.8 g. There was a statistically significant difference in the wet weight of sputum collected: mask PEP 15.8 +/- 5.5 g, CPAP 13.7 +/- 5.5 g, NPPV 13.2 +/- 5.0 g, control treatment 14.0 +/- 5.0 g (p < 0.05), but that difference became nonsignificant when we took into account the number of spontaneous coughs. There were no statistically significant changes in the spirometry and pulse-oximetry values. The patients' subjective efficacy scores were similar for mask PEP, CPAP, and NPPV. Less fatigue was reported after NPPV and CPAP than after mask PEP., Conclusions: There were no differences in sputum clearance or pulmonary-function measures between mask PEP and short-term administration of either CPAP or NPPV combined with directed cough. After mask PEP these patients felt more tired than after CPAP or NPPV secretion-clearance therapy.

Background: Right ventricular function may be reduced in patients with idiopathic dilated cardiomyopathy (IDC). The prognostic implications of right ventricular dysfunction have not been investigated in this group of patients., Methods: In a series of 120 consecutive patients with IDC [defined as a left ventricular ejection fraction (LVEF) < 55%, normal coronary arteries and no other causes for left ventricular dysfunction], right ventricular function was prospectively evaluated by means of angiocardiography at the time of catheterization. A head-to-head comparison of ventricular volumes, ejection fraction, end-diastolic pressure, stroke work index and end-systolic pressure/volume ratio of the left and right ventricle was performed according to the Cox's proportional hazard method for the pre-defined end-point of transplant-free survival., Results: In the study population, LVEF was 31 +/- 11% and right ventricular ejection fraction (RVEF) was 34 +/- 10%. After a mean follow-up of 30 months (range 12-120 months), 26 patients died (22%) and 14 (12%) underwent heart transplantation. At univariate analysis, all the above mentioned parameters were significantly (P < 0.0001) associated with outcome except left and right ventricular end-systolic pressure/volume ratio. At multivariate analysis, independent predictors of transplant-free survival were RVEF (P = 0.001), right ventricular stroke work index (P = 0.015), right ventricular end-diastolic volume (P = 0.034) and left ventricular end-diastolic volume (P = 0.048), but not LVEF. The same relation holds true considering the end point of total mortality., Conclusions: Parameters of right ventricular function are strong predictors of survival in IDC, even in patients enrolled over a wide range of LVEFs. The present study suggests that right ventricular function should be evaluated in patients with IDC. A large non-invasive based study on right ventricular function in IDC appears to be warranted.

Background: An increased extracellular matrix (ECM) turnover has been associated with poor survival in patients with chronic heart failure (CHF) due to dilated cardiomyopathy (DCM). However, the influence of the accelerated collagen turnover on the progressive large artery stiffening process characterizing CHF has not been clarified. This is relevant because aortic stiffening imposes an additional systolic load and impairs exercise tolerance in CHF patients. Therefore, we investigated whether the serum aminoterminal propeptide of type III collagen (PIIINP), an established marker of ECM turnover and tissue fibrosis in DCM, was associated with aortic stiffness in DCM patients., Methods and Results: A total of 89 patients with clinical diagnosis of DCM (age 62 +/- 9 years, 80% men, mean ejection fraction 34% +/- 8%) were selected. Aortic pulse-wave velocity (PWV), a well-established marker of aortic stiffness, was measured by Doppler ultrasonography. Serum concentration of PIIINP was determined by radioimmunoassay. Mean aortic PWV was 5.7 +/- 2.3 m/s, and PIIINP was 5.0 +/- 1.3 microg/L. The variables correlated with aortic PWV were age (r = 0.33, P = .002), PIIINP (r = 0.30, P = .005), heart rate (r = 0.27, P = .02), stroke volume (r = -0.24, P = .03) and New York Heart Association class (r = 0.25, P = .02). In a multivariate analysis, age (P = .02) and PIIINP (P = .01) were independently related with aortic PWV, accounting for 27% of its variance., Conclusions: Higher serum PIIINP levels are independently associated with a stiffer aorta in DCM patients. This suggests that abnormalities in the ECM turnover might involve the proximal elastic vasculature and could partially explain the progressive large artery stiffening process characterizing CHF.

Aim: We sought to determine whether an invasive approach based on Swan-Ganz catheterization, coupled with a pharmacologic stressor, might help stratify prognosis in patients with severe heart failure and uniformly depressed indices of cardiac function., Methods: We studied 31 unselected consecutive patients with scalar doses of dobutamine (2.5-10 microg/kg/min) after baseline hemodynamic evaluation. Changes in stroke work index (SWI) from baseline to peak effect (stroke work reserve, SWR) were recorded, and patients classified as responders (SWR above the median) or non-responders to dobutamine (SWR below the median). One-year follow-up data were recorded., Results: All patients completed the dobutamine challenge test without complications. Dobuta-mine increased SWI from 17+/-9 to 26+/-13 mg/ beat/m2 (P<0.0001 vs baseline), with a median increase of 6.4 g/beat/m2. Basal SWI was not related to stroke work reserve. The only predictor of response to dobutamine was a smaller left ventricular end-diastolic volume (135+/-28 vs 205+/-90 mL/m2; P=0.007). After 1 year, only 7 patients were alive, while 10 had successful transplantation. Transplant-free survival was 47% in responders vs 0% in non responders (P=0.007). At multivariate analysis, none of baseline hemodynamic parameters was predictive of survival. Only age and a SWR above the median were significant independent predictors of survival in this model., Conclusions: This study allows us to draw the following conclusions: 1) 1-year mortality in severe heart failure remains extremely high; 2) baseline hemodynamics dos not predict survival; 3) a positive response to dobutamine identifies a subgroup with significant lower mortality at 1 year; 4) this response is an independent predictor of survival and is more likely to occur in the presence of a less dilated left ventricle.

Background: The current study defined an optimal tumor size breakpoint to stratify localized renal cell carcinoma (RCC) into groups with significantly different cancer-related outcomes and proposed a revision of the TNM classification system., Methods: The authors analyzed the data from 1138 patients who had undergone partial or radical nephrectomy for localized RCC at 7 European urologic centers. The optimal pathologic size breakpoint was calculated using the martingale residuals from a Cox proportional hazards regression model., Results: The mean follow-up time was 87 months. The scatterplot of tumor size versus expected risk of death per patient suggested that an interval of 5-6 cm was appropriate. A total of 720 (63.3%) and 418 (36.7%) patients had tumors measuring < or = 5.5-cm and tumors measuring > 5.5-cm, respectively. Significant cancer-specific survival differences between the two groups of patients were reported in the series by all the centers participating in the study. On univariate analysis, the other variables found to be associated with cancer-specific survival were the patient's age, symptomatic tumor presentation, and the Fuhrman nuclear grade. On multivariate analysis, the pathologic stage of the primary tumor defined according to the 5.5-cm breakpoint was found to be an independent predictor of cancer-specific survival, as well as age, mode of presentation, and nuclear grade. According to the multivariate analysis, the authors clustered patients into 3 groups with statistically significant outcome differences: 1) patients with < or = 5.5-cm incidentally detected RCC; 2) patients with < or = 5.5-cm symptomatic RCC; and 3) patients with > 5.5-cm RCC. This cancer-related outcome stratification was valid regardless of the patient's age., Conclusions: The 5.5-cm breakpoint was found to be the optimal tumor size breakpoint with which to stratify patients with organ-confined RCC. The study supported the upgrade of the TNM classification system according to this breakpoint., (Copyright 2005 American Cancer Society)

Background: Peak oxygen uptake (peak VO2) and the regression slope of ventilation against CO2 production during exercise (VE/VCO2 slope) are powerful prognostic indicators in patients with chronic heart failure (CHF). Our purpose was to evaluate the influence of CHF etiology on peak VO2 and VE/VCO2 slope, independently of demographic, clinical, Doppler-echocardiographic and neurohormonal factors., Methods: Data were collected from 239 CHF patients referred for a cardiopulmonary exercise test as part of their clinical evaluation. Patients were stratified according to their CHF etiology (ischemic versus non-ischemic)., Results: The etiology of heart failure was ischemic in 143 patients (60%) and non-ischemic in 96 (40%). Patients with ischemic etiology, compared with those with non-ischemic etiology, showed a lower peak VO2 (15.4+/-4.2 versus 17.8+/-4.8 ml/kg/min, p<0.0001) and a steeper VE/VCO2 slope (38.1+/-6.8 versus 34+/-5.3, p<0.0001). In the univariate model, age (r=-0.36, p<0.0001), female sex (r=-0.21, p=0.001), ischemic CHF etiology (r=-0.26, p<0.0001) and NYHA class (r=-0.52, p<0.0001) correlated with peak VO2. At multivariate analysis, ischemic CHF etiology (beta=-0.23, p=0.001) was a predictor of peak VO2 (R(2)=0.49) independently of age (beta=-0.23, p=0.001), female sex (beta=-0.25, p=0.0006) and NYHA class (beta=-0.31, p<0.0001). Similarly, ischemic etiology (beta=0.29, p=0.001) predicted the VE/VCO2 slope (R(2)=0.38) independently of E/A ratio (beta=0.27, p=0.01) and resting heart rate (beta=0.22, p=0.01)., Conclusions: Etiology of heart failure may influence the functional capacity and the ventilatory response to exercise.

Following cystic fibrosis (CF) neonatal screening implementation, a high frequency of heterozygotes has been reported among neonates with elevated immunoreactive trypsinogen (IRT) and normal sweat chloride levels. We studied the relationship between normal IRT values and CF heterozygosity: 10,000 neonates were screened for CF by IRT measurement and tested for 40 CF mutations; the 294 carriers detected were coupled with newborns negative to the same genetic testing, and the two groups' IRT levels compared. Heterozygotes had higher IRT levels than their controls (mean 35.32 vs. 27.58 microg/L, P<0.001). Even within normal trypsinogen range, the probability of being a CF carrier increases with neonatal IRT concentration., (Copyright (c) 2005 Wiley-Liss, Inc.)

Background: The objective of the current study was to evaluate the reproducibility of the Fuhrman nuclear grading system as well as its independent predictive value in a series of patients with conventional renal cell carcinoma (RCC)., Methods: The authors selected 388 patients who had undergone surgical treatment for conventional RCC between 1986 and 2000. Pathology slides from the selected patients were reviewed by a single pathologist, who reassigned a Fuhrman nuclear grade and assessed the presence of tumor necrosis. The pathologist was blinded to both the original pathologic diagnosis and follow-up data. The kappa statistic was used to evaluate concordance between original and reviewed nuclear grades. The log-rank test was used for univariate analyses, and a Cox proportional hazards model was used for multivariate analyses., Results: The original Fuhrman nuclear grade was Grade 1 (G1) in 111 patients (28.6%), G2 in 141 patients (36.3%), G3 in 108 patients (27.8%), and G4 in 28 patients (7.3%). After pathology slide review, nuclear grades were reassigned as follows: G1 in 49 patients (12.6%), G2 in 138 patients (35.6%), G3 in 150 patients (38.7%), and G4 in 51 patients (13.1%). The grade of concordance was moderate (kappa=0.44; P <0.001). Univariate analyses identified three separate prognostic categories defined by nuclear grade (G1 and G2 vs. G3 vs. G4). Both the original and the reviewed Fuhrman nuclear grading systems were capable of independently predicting disease-specific survival in patients with conventional RCC., Conclusions: The interobserver reproducibility of Fuhrman nuclear grading was moderate. The substantial overlap in survival curves for G1 and G2 tumors provided an opportunity to cluster those categories, and the resulting three-tiered nuclear grading system was an independent predictor of cause-specific survival in patients with conventional RCC. Other independent predictors of survival included pathologic stage and tumor necrosis status.

Background: Peak oxygen consumption (pVO2) reflects oxygen extraction from the skeletal muscles, but is routinely corrected for body weight. We hypothesized that correcting pVO2 for lean tissue rather than total body weight would improve the prediction of prognosis in patients with chronic heart failure (CHF)., Methods and Results: A total of 272 CHF outpatients (mean age 61 +/- 12 years, New York Heart Association [NYHA] class 2.3 +/- 0.8) underwent a cardiopulmonary exercise testing and body composition assessment by dual-energy X-ray absorptiometry. During a median follow-up of 608 days (range 8-3656), 75 patients died. Univariate survival analysis showed strong survival prediction from pVO2 adjusted for total weight or lean tissue (chi2 17.7, P < .001; chi2 27.5, P < .0001, respectively). Both predicted survival significantly in bivariate analysis, (chi2 4.6, P = .032; chi2 16.6, P < .0001). The predictive effects were independent of exercise protocol (treadmill versus cycle ergometer) (both P < .001). Multivariate analysis showed that pVO2 adjusted for lean tissue had prognostic importance independently of NYHA class, ejection fraction, and ventilation and carbon dioxide production slope (P < .05 for each). In patients with NYHA class I and II (n = 160), pVO2 adjusted for lean tissue predicted outcome (P = .03)., Conclusion: Adjustment for lean tissue instead for body weight increases the prognostic power of pVO2, particularly in patients with mild heart failure.

Background: In chronic heart failure (CHF), changes in the extracellular space contribute to cardiac dysfunction. We aimed to determine whether aminoterminal-propeptide of type III procollagen (PIIINP), a marker of extracellular matrix turnover, might provide prognostic information in CHF patients., Methods and Results: A total of 101 consecutive CHF patients (mean age 61.7 +/- 8.7 years, 88% males) were followed up between 1999 and 2001. The combined endpoint of the study was death and hospitalization for heart failure. During follow-up there were 15 deaths and 11 hospitalizations for worsening heart failure. At the survival analysis, age (P = .02), New York Heart Association class (P = .014), s-creatinine (P = .014), plasma-PIIINP (p-PIIINP) levels (P = .005), left ventricular ejection fraction (LVEF) (P = .0002), and a restrictive mitral filling pattern (P = .0003) predicted event-free survival. At the multivariate analysis, p-PIIINP levels predicted outcome independently of other clinical variables, hormones, and echocardiographic and exercise testing variables (P < .05 in all models). In patients with LVEF <31%, the presence of p-PIIINP >4.7 microg/L levels was significantly associated with a higher risk of death and hospitalization as compared with the other patients (event-free survival rate at 12 months: 45% versus 95%; at 24 months: 27% versus 88%; at 36 months: 18% versus 85%, P < .0001)., Conclusions: In patients with CHF, PIIINP levels predict outcome independently of clinical status, hemodynamics and hormonal activation. PIIINP levels provide additional prognostic information to that of left ventricular function alone, suggesting that it may reflect more than cardiac extracellular matrix turnover.

Background: Angiotensin-converting enzyme (ACE) is involved in the pathophysiology of chronic heart failure, and its activity is determined in part by a polymorphism of the ACE gene. We hypothesized that the benefits of spironolactone, which inhibits downstream elements of ACE-mediated abnormalities, may depend on ACE genotype., Methods: We randomly assigned 93 chronic heart failure patients to treatment with spironolactone (n = 47) or to a control group (n = 46) and followed them for 12 months. Genotype for the insertion/deletion polymorphism of the ACE gene was determined by polymerase chain reaction. An echocardiographic examination was performed at baseline and at the end of the 12 months., Results: The mean (+/- SD) age of the 93 patients was 62 +/- 9 years, and the mean New York Heart Association class was 2 +/- 1. The genotype was DD in 26 patients (28%). Forty-seven patients were assigned to spironolactone treatment (mean dose, 32 +/- 16 mg). In the treated group, only patients with a non-DD genotype showed significant improvement in left ventricular ejection fraction (3.0%; 95% confidence interval [CI]: 1.2% to 4.8%; P = 0.002), end-systolic volume (-23 mL; 95% CI: -36 to -11; P = 0.0005), and end-diastolic volume (-27 mL; 95% CI: -43 to -12; P = 0.001). In the multivariate analysis, the estimated net effect of treatment was 29 mL better (95% CI: -20 to 78 mL) for end-diastolic volume, 20 mL better (95% CI: -18 to 58 mL) for end-systolic volume, but 1.4% worse (95% CI: -3.4% to 6.2%) for left ventricular ejection fraction in patients with non-DD versus DD genotypes., Conclusion: The effects of spironolactone treatment on left ventricular systolic function and remodeling may in part depend on ACE genotype.

Background: Although several studies support the efficacy of specific immunotherapy in allergic asthma, its benefit compared with that of standardized pharmacologic intervention remains unknown., Objective: A double-blind, placebo-controlled trial in 72 patients with mild-to-moderate asthma and allergy to house dust mite (HDM; Dermatophagoides species) was conducted to assess the effects of specific immunotherapy added to guideline-adjusted pharmacologic treatment and allergen avoidance., Methods: After 1 observational year of pharmacologic treatment and standard measures of HDM avoidance, 2 groups of asthmatic subjects were randomly assigned to receive specific immunotherapy consisting of subcutaneous injections of either a mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae vaccine (n=41) or placebo (n=31) for 3 years. Medications were adjusted every 3 months according to the Global Initiative for Asthma guidelines., Results: The adjustment of treatment was associated with a reduction in asthma symptom scores in all subjects. The addition of specific immunotherapy was associated with a decrease in the number of subjects requiring rescue bronchodilators, an increase in morning and evening peak expiratory flow, and a reduced skin sensitivity to HDM extracts. The addition of specific immunotherapy had no significant effects on the cumulative dose of inhaled corticosteroids, asthma symptoms, lung volumes, or bronchial responsiveness to methacholine., Conclusion: These results suggest that specific immunotherapy added to pharmacologic treatment and HDM avoidance provides marginal but statistically significant clinical benefits, possibly by reducing the allergic response of asthmatic patients sensitized to HDM.

Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase, with primary known functions of converting angiotensin I into the vasoactive and aldosterone-stimulating peptide angiotensin II and inactivating bradykinin. There is high variability among individuals in ACE concentrations, mainly due to the presence of a genetic polymorphism. The ACE gene has, in fact, insertion/deletion polymorphism in intron 16, consisting of a 287-base pair Alu repeat sequence, with three genotypes: insertion polymorphism, insertion/deletion polymorphism, and deletion polymorphism. The genetic effect accounts for 47% of the total variance of serum ACE. The determination of this polymorphism has allowed researchers to study the implications of the ACE gene in many case-control studies of cardiovascular disease, including myocardial infarction and hypertrophic and dilated cardiomyopathy. We review the current knowledge about the ACE gene polymorphism and its implications in heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Interpretation of the results of studies about the role of this polymorphism are controversial. The repetition of epidemio-genetic studies and the creation of adequate experimental studies will help to definitively establish the pathogenetic role of the permanent increase in ACE expression associated with the deletion polymorphism genotype.

Objectives: To identify an optimal tumor-size breakpoint to distinguish between two groups with different prognoses in a large cohort of patients with localized renal cell carcinoma (RCC)., Methods: We reviewed the clinical records of 813 patients who had undergone surgical treatment for localized RCC from 1976 to 2000. The optimal breakpoint for the pathologic size was calculated by receiver operating characteristic curve analysis., Results: The receiver operating characteristic curve analysis identified 5.5 cm as the optimal breakpoint to predict cancer-specific survival rates. The pathologic size was 5.5 cm or less in 565 neoplasms (69.5%) and more than 5.5 cm in 248 (30.5%). In the multivariate analysis, the more predictive model included the 5.5-cm-or-less pathologic size breakpoint. The pathologic size of 7 cm or less was not an independent variable in this cohort of patients., Conclusions: In a large cohort of patients with localized RCC, 5.5 cm was the optimal breakpoint to classify patients with localized RCC into two subgroups with different prognoses; the 7-cm-or-less cutoff value was not an independent variable. The data obtained by analyzing a large cohort of consecutive patients should be validated by other large series with the prospective of redefining the TNM staging system.

In assessing the efficacy and the safety of a new drug, randomized clinical trials represent the standard scientific method. The selection of the best response variables in a clinical trial of a treatment in congestive heart failure patients is often not straightforward; the primary end point of a trial should be clinically relevant, directly related to the primary goal of the trial, and with favorable distributional properties. All-cause mortality is undoubtedly the most unbiased endpoint, but there is interest both in assessing cause-specific mortality and hospitalization rate and in evaluating 'soft' endpoints (functional status, exercise tolerance); the latter, in fact, are clinically relevant and potentially more useful in mild heart failure patients. Physiopathologic variables (e.g. left ventricular function) could provide information on drug action mechanism. In this paper, several recent large clinical trials are reviewed and the advantages and drawbacks of the response variables used, are analyzed.

Background: The presence of aortic valve sclerosis accounts for a higher rate of ischemic events and increased cardiovascular mortality. It may reflect coronary artery disease (CAD) because of a shared pathologic background., Hypothesis: We aimed to analyze whether the presence of aortic valve sclerosis might help in identifying patients with coronary atherosclerosis among those with severe nonischemic mitral regurgitation (MR), who undergo coronary angiography before surgery for screening, and not because of suspected ischemic heart disease., Methods: In all, 84 patients (mean age 64 +/- 9 years; 71% men) with mitral valve prolapse and severe regurgitation underwent echocardiography and coronary angiography. Aortic valve sclerosis was defined as focal areas of increased echogenicity and thickening of the leaflets without restriction of leaflet motion on echocardiography. Coronary artery disease was defined by the presence/absence of atherosclerotic plaques, independent of the degree of stenosis., Results: Coronary artery disease was diagnosed in 47.6% of patients with and 15.8% of those without aortic valve sclerosis (p = 0.008). On logistic regression analysis, the presence of aortic valve sclerosis predicted CAD (odds ratio 3.3, 95% confidence interval 1.03-10.5; p = 0.04) independent of age. In female patients, the risk ratio for CAD in the presence of aortic valve sclerosis was 9., Conclusions: Coronary artery atherosclerosis and aortic valve sclerosis are closely associated in patients with severe nonischemic MR.

Recent studies suggest that changes in the periphery, like those occurring in the skeletal muscles of patients with chronic heart failure, might play an important role in the origin of symptoms and exercise intolerance in this condition. Biochemical and histologic changes in the skeletal muscles of chronic heart failure patients relate with the degree of exercise intolerance better than hemodynamics parameters. A reduction in skeletal muscle mass represents another important determinant of exercise intolerance in chronic heart failure patients. The relationship between skeletal muscle changes and exercise intolerance suggests the possibility of modifying the peripheral changes in order to improve functional capacity in chronic heart failure patients. Recent studies have shown that the administration of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can improve the properties of the skeletal muscles. Similarly, exercise training allows improvement in peak oxygen consumption, which parallels important biochemical and histologic changes in the skeletal muscles.

Objectives: We aimed to investigate the determinants of left atrial (LA) volume and its prognostic value in patients with dilated cardiomyopathy (DCM)., Background: Enlargement of the LA is a marker of mortality in the general population. Patients with DCM are characterized by a wide range of LA sizes, but the clinical role of this observation has been played down., Methods: A complete echocardiographic Doppler examination was performed in 337 patients (age 60 +/- 13 years; 84% male) with the diagnosis of DCM. Left atrial maximal volume (LA(max)) was measured at left ventricular (LV) end systole (four-chamber view; area-length method). Left ventricular end-diastolic and end-systolic volumes (LVEDV and LVESV) and ejection fraction (EF) were also measured. Mitral regurgitation (MR) was graded using a 5-point scale. Mitral E-wave (E) and A-wave (A) velocities, as well as their ratio (E/A), were measured off-line., Results: Determinants of LA(max) were: atrial fibrillation (r = 0.34, p < 0.0001), LVEDV (r = 0.46, p < 0.0001), EF (r = 0.40, p < 0.0001), MR (r = 0.39, p < 0.0001), and E/A ratio (r = 0.36, p < 0.0001). During follow-up (41 +/- 29 months), 77 patients died and 12 underwent heart transplantation. Univariate Cox analysis showed that LA(max) (hazard ratio [HR] 1.01, 95% confidence interval [CI] 1.007-1.013, p < 0.0001), LVESV (HR 1.003, CI 1.001-1.005, p = 0.0003), E/A ratio (HR 1.6, CI 1.3-2.005, p < 0.0001), and MR (HR 1.21, CI 1.03-1.44, p = 0.02) were related to the outcome. On bivariate Cox analysis, LA(max) predicted the prognosis independently of each determinant. Patients with a larger LA volume (LA(max)/m(2) >68.5 ml/m(2)) had a risk ratio of 3.8 compared with those with a smaller LA volume., Conclusions: In patients with DCM, LA volume is associated with LV remodeling, diastolic dysfunction, and the degree of MR. The maximal volume of the LA has an independent and incremental prognostic value, compared with all its determinants.

Background: The frequency and determinants of right ventricular (RV) dysfunction in patients with coronary artery disease (CAD) and reduced left ventricular (LV) function have not been thoroughly investigated., Methods: The study population consists of 80 consecutive patients, invasively evaluated at our centre. Entry criteria were: LV ejection fraction < 45%; angiographic evidence of obstructive CAD; disease history of more than 3 months' duration. Exclusion criteria were: recent myocardial infarction and unstable angina. All patients underwent cardiac catheterization with coronary, LV and RV angiography. RV dysfunction was defined as a RV ejection fraction < 35%, which corresponds to the mean-three standard deviations of controls., Results: Sixty-five patients (81%) had multi-vessel disease and 57 (71%) had a previous myocardial infarction. Mean LV ejection fraction was 31 +/- 8%. Mean RV ejection fraction was 46 +/- 11%. Right ventricular dysfunction was present in 14 patients (18%). An occluded proximal right coronary artery was associated with significantly lower RV ejection fraction (38 +/- 12% versus 47 +/- 10%; P = 0.009) but not LV ejection fraction (30 +/- 8% versus 32 +/- 9%; P = 0.444). However, at multivariate analysis, only pulmonary hypertension was an independent significant predictor of RV dysfunction (P < 0.001; OR: 1.13; CI: 1.06 -1.22)., Conclusion: Right ventricular dysfunction in patients with chronic ischaemic LV dysfunction is detected in less than 20% of cases. Proximal right coronary artery occlusion is associated with a reduced RV ejection fraction. However, the role of right coronary artery disease is overwhelmed by the haemodynamic burden of pulmonary hypertension, which represents the only independent predictor of RV dysfunction in our population.

Objectives: This study was designed to assess the effects of spironolactone (SP) on left ventricular (LV) function and exercise tolerance in patients with chronic heart failure (CHF)., Background: In severe heart failure (HF), SP improves survival, but the underlying mechanisms are not clear., Methods: We randomized 106 outpatients with HF to SP (12.5 to 50 mg/day) (group 1) or control (group 2). Complete echocardiography and cardiopulmonary exercise testing were performed at baseline and 12 months after randomization., Results: Left ventricular end-systolic volume at baseline and at follow-up was 188 +/- 94 ml and 171 +/- 97 ml in group 1 and 173 +/- 71 ml and 168 +/- 79 ml in group 2 (treatment group-by-time interaction, p = 0.03). Left ventricular ejection fraction at baseline and at follow-up was 33 +/- 7% and 36 +/- 9% in group 1 and 34 +/- 7% and 34 +/- 9% in group 2 (treatment group-by-time interaction, p = 0.02). At baseline, 9 patients in group 1 and 3 patients in group 2 had a restrictive mitral filling pattern, a marker of severe diastolic dysfunction; at follow-up, 3 patients in group 1 and no patient in group 2 improved their pattern. No patient in group 1 and 4 patients in group 2 worsened their pattern (chi-square, p = 0.02). Peak oxygen consumption increased significantly in patients treated with 50 mg of SP and decreased in group 2 (17.7 +/- 5.2 vs. 18.5 +/- 5.9 and 19.1 +/- 5.6 vs. 17.9 +/- 5.3, respectively; analysis of variance, p = 0.01)., Conclusions: Spironolactone improves LV volumes and function; furthermore, it improves exercise tolerance at the highest administered dose. Our data might explain the mortality reduction during aldosterone antagonism in patients with HF.

Objective: To assess whether serum uric acid, which is a marker of impaired oxidative metabolism, might correlate with left ventricular systolic and diastolic dysfunction in patients with chronic heart failure (CHF)., Background: Uric acid levels, which are frequently elevated in patients with CHF, correlate with leg vascular resistance. The effects of elevated levels of uric acid on cardiac function in patients with CHF have never been evaluated., Methods: We studied 150 outpatients with CHF who came to our heart failure clinic. Patients underwent a complete echo-Doppler examination, with measurement of mitral E wave and mitral A wave velocities, E/A ratio, E wave deceleration time (DtE), left ventricular volumes, ejection fraction, and stroke volume. A restrictive mitral filling pattern (RMFP) was defined as either E/A ratio >2 or E/A >1 and DtE <140 milliseconds., Results: Mean age was 62.2 +/- 7.8 years (86% male); 24 patients (16%) had an RMFP. Patients with an RMFP had significantly higher uric acid levels compared with patients without RMFP (0.48 +/- 0.14 mmol/L vs 0.38 +/- 0.08 mmol/L, respectively, P <.001). Uric acid levels correlated significantly with mitral E wave velocity (r =.22, P <.01), E/A ratio (r =.21, P <.05), DtE (r =.26, P <.01), and RMFP (P =.0001). There was no correlation between uric acid and left ventricular volumes, ejection fraction, or stroke volume. In a multivariate model, uric acid predicted DtE independently of renal function, diuretic dose, and left ventricular volumes., Conclusion: Elevated uric acid levels are associated with diastolic dysfunction in CHF. Xanthine oxydase inhibition in patients with CHF might theoretically result in an improvement of diastolic function.

Objectives: To identify independent predictors of cause-specific survival in patients affected by renal cell carcinoma (RCC)., Material and Methods: We evaluated retrospectively 675 patients who underwent in our department from 1976 to 1999 radical nephrectomy for RCC. Pathological stage of the primary tumor (TNM, 1997) was pT1 in 326 cases (48%), pT2 in 133 (20%), pT3a in 66 (10%), pT3b in 138 (20%) and pT4 in 12 (2%). According to TNM classification (Union International Contre le Cancer (UICC), 1997) the pathological stage was I in 303 cases (45%), II in 119 (18%), III in 150 (22%) and IV in 103 (15%). Histological grading was assigned according to Fuhrman's classification in only 333 cases: G1 in 25%, G2 in 35%, G3 in 33% and G4 in 7%., Results: Cause-specific survival was 77% at 5 years, 69% at 10 years, 64% at 15 years and 57% at 20 years. Five and 10 year cause-specific survival was, respectively 91.4 and 88.5% in pT1 tumors, 84.8 and 72.7% in pT2, 57.4 and 35.6% in pT3a, 47.2 and 33.6% in pT3b-c, and 29.6% in pT4 (P < 0.0001). In relation to the pathological stage according to TNM classification, 5 and 10 year cause-specific survival was, respectively 94 and 91.6% in stage I tumors, 89.7 and 78% in stage II, 63.4 and 46.4% in stage III and 28 and 16.3% in stage IV (P < 0.0001). In relation to the nuclear grade of the primary tumor 5 and 10 year cause-specific survival was, respectively 94 and 88% in G1 tumors, 86 and 75% in G2, 59 and 40% in G3 and 31% in G4 (P < 0.0001). At multivariate analysis pathological stage of the primary tumor, lymph nodes involvement, presence of distant metastases at diagnosis and nuclear grading resulted all independent predictors of cause-specific survival in patients with RCC., Conclusion: Pathological stage of primary tumors, lymph nodes involvement, presence of distant metastases at diagnosis and nuclear grading according to Fuhrman resulted all independent predictors of cause-specific mortality in patients with RCC.

Aims: To address the following questions: (1) Which words are preferred by different groups of orofacial pain patients to describe their pain experience? (2) Is it possible, based on such descriptions, to obtain a clinical differential diagnosis in these patients? (3) Is there any relationship between the verbal description of pain and self-rated quality of life (QOL)? (4) Can a pattern of modulation of pain language by affective variables (diffusion model) be recognized in orofacial pain patients, as it has in other chronic pain patients? and (5) If so, what might be the clinical usefulness of assessing pain language in these patients?, Methods: A total of 332 consecutive orofacial pain patients filled out an Italian Pain Questionnaire (the Italian analog of the McGill Pain Questionnaire) and were then divided into 6 diagnostic subgroups (sample 1) based on history and clinical findings. In a double-blind setting, the distribution of pain descriptors and indexes was statistically evaluated. From sample 1, a randomly selected sample of 121 patients (sample 2) also filled out a QOL categorical scale. The results of both tests in this sample were compared statistically., Results: Some significant differences among diagnostic subgroups were found for choice of descriptors and for pain intensity. When a patient's pain description was compared to the corresponding self-evaluation of QOL, a self-perceived worsening of QOL revealed a good correlation with an increase in the number of words chosen, pain intensity, and affective and sensory pain descriptors. A similar significant association was found between self-assessed anxiety and/or depression and the same items., Conclusion: Although trends in patients' choice of descriptors were evident, differential diagnosis based on only a pain questionnaire was not possible in the different groups of orofacial pain patients examined in this study. The present study suggests the presence of a phenomenon of diffusion in the language of those patients who were experiencing a worsening of their QOL as a result of pain and consequent psychologic distress. This observation can be of clinical usefulness by enhancing the sensitivity of the clinician to the suffering and affective distress experienced by the patient, and it also can be helpful in refining the therapeutic approach for each individual patient.

Background: An echocardiographic assessment of left ventricular (LV) diastolic dysfunction is still challenging when identifying a pseudonormal mitral pattern (PSE) in an unselected population. The present study analyzed and compared the accuracy of various parameters in correctly identifying a PSE pattern in patients with a broad range of ejection fraction (EF) and degree of mitral regurgitation., Methods: Eighty-two patients with E/A > or = 1 and an invasive determination of left ventricular end-diastolic pressure (LVEDP) were enrolled in the study. Mitral E wave (E(max)) and A (A(max)) velocities, E (DTe) and A (DTa) deceleration times, pulmonary vein systolic and diastolic velocities, and time velocity integrals were measured. The different duration between mitral and pulmonary vein A wave (A'-A) also was calculated. E(max) and E/A during Valsalva maneuver were measured and expressed as percentage compared with baseline. LV end-diastolic (LVD), end-systolic (LVS), and EF were measured from the apical four-chambers view (area-length method). Left atrial end-systolic (LA(max)) and end-diastolic (LA(min)) were measured from the apical four- and two-chambers views (area-length method). Left atrial filling volume (LA(fill)) was the difference between LA(max) and LA(min). Mitral regurgitant volume was estimated by the following equation: MR(vol) = 6.18 + (1.01 * LA(fill)) - (0.783 * PVs %)., Results: Thirty-two patients (age: 55 +/- 21 years; 75% male) had LVEDP < or = 18 mmHg and were classified as normal mitral pattern (Group 1). Fifty patients (age: 57 +/- 22 years; 76% male) had LVEDP > 18 mmHg, and were classified accordingly as having PSE (Group 2). At logistic univariate analysis, DTa (0.005), LV EF (0.01), A'-A (< 0.0001) and % E/A (0.03) were the more powerful predictors of PSE. A'-A had the highest global accuracy in identifying PSE in patients with reduced (90%) and normal (88%) LV EF., Conclusion: A'-A has the highest accuracy in identifying PSE in an unselected population. This parameters should be implemented in routine echocardiography since it allows additional information about LV diastolic function assessment.

Objective: To determine the prevalence of urinary incontinence (UI) in female patients (aged > or = 15 years) attending a cystic fibrosis (CF) centre, in whom stress UI could be common, as chronic coughing and sputum production are frequent symptoms associated with progressive lung disease in these patients., Patients and Methods: An anonymous questionnaire was completed by 176 women with CF (mean age 24.6 years, SD 5.8) during routine assessments as outpatients., Results: In all, 72 patients (41%) were classified as never incontinent; occasional UI was reported in 61 women (35%). Regular UI, occurring twice or more a month for at least two consecutive months in the last year, was reported in 43 patients (24%). Regular UI was associated with increasing age and a lower mean (SD) forced expiratory volume/s (of that predicted) than in women with no urinary symptoms, at 26.9 (6.5) years and 53.5 (23.5)%, and 23.1 (5.4) years and 65.5 (23.2)%, respectively (P < 0.01 and P < 0.05, respectively). All incontinent women recorded stress UI; coughing, laughing and physical activity were associated with UI in 92%, 33% and 21% of the patients, respectively., Conclusion: Stress UI is a common symptom in women with CF. As urine loss can be under-reported to the healthcare providers, women should be asked about incontinence as part of their routine follow-up. Pelvic floor muscle exercises are effective in treating stress UI and should be considered for those with CF and regular UI.

Background: Evidence for the role of right ventricular (RV) function is emerging in patients with heart failure of different etiologies. Studies conducted in dilated cardiomyopathy (IDC) showed a high prevalence of RV dysfunction unrelated to the severity of pulmonary hypertension. The aim of the study was to investigate the role of RV dysfunction in ischemic versus nonischemic patients., Methods: A series of 153 patients with left ventricular (LV) dysfunction (defined as a LV ejection fraction <45%) of either ischemic (n = 61, coronary artery disease [CAD] group) or nonischemic (n = 92, IDC group) origin were studied invasively. Besides routine catheterization data, RV volumes and ejection fractions were obtained angiographically. Reference data were collected in a control group of healthy subjects. RV dysfunction was defined as a RV ejection fraction <35% and ventricular concordance as a <10% difference between RV and LV ejection fraction. The LV/RV end-diastolic volume ratio was calculated to assess the relative dilatation of the ventricular chambers. Hemodynamic and angiographic data were compared in the 2 groups by univariate and multivariate logistic regression analysis., Results: Patients with IDC and CAD had comparable LV ejection fractions (29% +/- 3% vs 31% +/- 8%, P not significant) and mean pulmonary pressures (27 +/- 12 mm Hg vs 26 +/- 11 mm Hg, P not significant); the LV/RV end-diastolic volume ratio was identical in the 2 groups (1.26 +/- 0.4 vs 1.24 +/- 0.4, P not significant). RV ejection fraction was significantly lower in IDC compared with CAD (33% +/- 10 % vs 46% +/- 11%, P <.0001), with a prevalence of RV dysfunction in the IDC group of 65% compared with 16% in the CAD group (P <.0001); similarly, the prevalence of ejection fraction concordance was 74% versus 33%, respectively (P <.0001). At multivariate analysis, a low RV ejection fraction was a powerful independent predictor of IDC compared with CAD (odds ratio 0.91, 95% confidence interval 0.87-0.94, P <.0001). RV dysfunction had a positive predictive value of 75% and a negative predictive value of 78% for the diagnosis of IDC; for ventricular concordance, these values were 81% and 69%, respectively. The correlation between mean pulmonary artery pressure and RV ejection fraction was weaker in the IDC group compared with the CAD group (R(2) = 0.032, P =.047 and R(2) = 0.172,P <.0001, respectively)., Conclusion: In the presence of LV dysfunction, a reduced RV ejection fraction is a powerful marker for IDC compared with CAD, independent of age, pulmonary hypertension, LV function, and ventricular dimensions. These findings support the concept that IDC is frequently characterized by a biventricular involvement and that the presence of RV dysfunction represents a distinguishing feature of this disease.

Objectives: We sought to assess whether skeletal muscle mass might be a predictor of peak oxygen consumption (Vo2) and relation of the ventilation to carbon dioxide production (VE/VCo2) slope in patients with chronic heart failure (CHF) independent of clinical conditions, neurohormonal activation and resting hemodynamics., Background: A variety of abnormalities characterize skeletal muscle and contribute to exercise intolerance in patients with CHF. Skeletal muscle mass is a determinant of peak Vo2 both in healthy patients and in patients with CHF, but there are no reports on the independent predictive value of this parameter, which can be measured with great accuracy by whole-body dual energy X-ray absorptiometry (DEXA). The influence of skeletal muscle mass on VE/VCo2 slope is not known either., Methods: We prospectively evaluated 120 consecutive noncachectic patients with CHF. Every patient underwent a cardiopulmonary exercise test, an echo-Doppler examination and an evaluation of neurohormonal activation and body composition as assessed by DEXA., Results: At the univariate analysis, New York Heart Association (NYHA) class (p < 0.0001), age (p < 0.0001), male gender (p < 0.0001) and plasma renin (p < 0.0001) significantly related with peak Vo2. There was a significant correlation between lean mass and absolute peak Vo2 (r = 0.70, p < 0.0001) and VE/VCo2 slope (r = -0.27; p < 0.01). At the multivariate analysis, lean mass predicted peak Vo2 and VE/VCo2 slope independently of NYHA functional class, age, gender, neurohormonal activation and resting hemodynamics., Conclusions: Skeletal muscle mass is an independent predictor of peak Vo2 and VE/VCo2 slope in stable noncachectic patients with CHF. Future studies will determine whether an increase in skeletal muscle mass in the individual patient might result in an improvement in parameters of exercise capacity.