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Objectives This study sought to assess device-specific outcomes after implantation of bare-metal stents (BMS), zotarolimus-eluting Endeavor Sprint stents (ZES-S), paclitaxel-eluting stents (PES), or everolimus-eluting stents (EES) (Medtronic Cardiovascular, Santa Rosa, California) in all-comer patients undergoing percutaneous coronary intervention. Background Few studies have directly compared second-generation drug-eluting stents with each other or with BMS. Methods We randomized 2,013 patients to BMS, ZES-S, PES, or EES implantation. At 30 days, each stent group received up to 6 or 24 months of clopidogrel therapy. The key efficacy endpoint was the 2-year major adverse cardiac event (MACE) including any death, myocardial infarction, or target vessel revascularization, whereas the cumulative rate of definite or probable stent thrombosis (ST) was the key safety endpoint. Results Clinical follow-up at 2 years was complete for 99.7% of patients. The MACE rate was lowest in EES (19.2%; 95% confidence interval [CI]: 16.0 to 22.8), highest in BMS (32.1%; 95% CI: 28.1 to 36.3), and intermediate in PES (26.2%; 95% CI: 22.5 to 30.2) and ZES-S (27.8%; 95% CI: 24.1 to 31.9) groups (chi-square test 18.9, p 0.00029). The 2-year incidence of ST in the EES group (1%; 95% CI: 0.4 to 2.2) was similar to that in the ZES-S group (1.4%; 95% CI: 0.7 to 2.8), whereas it was lower compared with the PES (4.6%, 95% CI: 3.1 to 6.8) and BMS (3.6%; 95% CI: 2.4 to 5.6) groups (chi-square 16.9; p = 0.0001). Conclusions Our study shows that cumulative MACE rate, encompassing both safety and efficacy endpoints, was lowest for EES, highest for BMS, and intermediate for PES and ZES-S groups. EES outperformed BMS also with respect to the safety endpoints with regard to definite or probable and definite, probable, or possible ST. (PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY [PRODIGY]; NCT00611286) (C) 2014 by the American College of Cardiology Foundation

Background and objective: The coexistence of chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) increases with age. The occurrence, prognosis and therapeutic implications of concurrent COPD in elderly patients with CHF were investigated. Methods: One hundred and eighteen consecutive patients, ≥65 years old with ≥10 pack/years of smoking and with a verified diagnosis of CHF in stable condition, were enrolled. They were followed for a mean of 1029 (range 758–1064) days. All patients had spirometry and the diagnosis and classification of COPD were made according to Global Initiative for Chronic Obstructive Lung Disease guidelines. Results: The mean occurrence of COPD was 30% (90% confidence interval: 24–37%). At baseline in patients with CHF and COPD, there was a shorter 6-min walk distance, lower arterial oxygen tension, glomerular filtration rate and higher N-terminal pro-B-type natriuretic peptide (all P

Objectives The authors sought to compare the effect on inhibition of platelet aggregation (IPA) of prasugrel therapy versus tirofiban bolus with or without a post-bolus short drug infusion in ST-segment elevation myocardial infarction (STEMI) patients. Background The degree and rapidity of IPA after prasugrel alone with or without concomitant glycoprotein IIb/IIIa inhibition in STEMI patients is unknown. Methods A total of 100 STEMI patients randomly received prasugrel 60 mg versus 25 μg/kg tirofiban bolus with or without post-bolus 2-h infusion of tirofiban, with or without concomitant prasugrel. IPA at light transmission aggregometry was performed throughout 24 h. The primary endpoint was IPA stimulated with 20 μmol/l adenosine diphosphate (ADP) at 30 min. Results At 30 min, patients in the prasugrel group showed a significantly lower IPA to 20 μmol/l ADP stimulation as compared with tirofiban-treated patients (36 ± 35 vs. 87 ± 31, p Conclusions Our study shows that prasugrel administration leads to a suboptimal IPA for at least 2 h in STEMI patients. Yet, prasugrel, given in association with a bolus only of glycoprotein IIb/IIIa inhibitor, obviates the need of post-bolus infusion and almost completely abolishes residual variability of IPA after treatment. (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse [The FABOLUS PRO trial]; NCT01336348 )

IntroductionThe aim of our study was to establish the prevalence and the prognostic value of haematological abnormalities in children with cardiac failure.Patients and methodsA series of 218 consecutive children with a first diagnosis of idiopathic dilated cardiomyopathy were retrospectively examined. Haematological evaluation was performed at first diagnosis. Death or cardiac transplantation was the main outcome measure.ResultsThe median age was 0.6 years, ranging from 1 day to 15.8 years and median follow-up was 2.65 years, ranging from 0 to 17.2 years. After a median interval of 0.2 years, ranging from 0 to 8.7 years, 56 patients died and 25 were transplanted. Event-free survival at 1 and 5 years was 68% (95% confidence interval, 63–75%) and 62% (95% confidence interval, 56–69%). Blood levels of haemoglobin less than 10 grams per decilitre, urea over 8 millimoles per litre, and C-reactive protein over 10 milligrams per litre were found in 24%, 20%, and 24% of patients, respectively. The log-rank test showed that haemoglobin (p = 0.000) and C-reactive protein (p = 0.021) were predictors of death or transplantation. In the multivariate Cox model, haemoglobin (hazard ratio = 0.735; confidence interval = 0.636–0.849; p = 0.000) and urea (hazard ratio = 1.083; confidence interval = 1:002–1:171; p = 0.045) were predictive of poor outcome. Cubic spline functions showed that the positive role of haemoglobin on survival was linear for values less than 12 grams per decilitre and null for values more than 12 grams per decilitre. Adaptive index models for risk stratification and Classification and Regression Tree analysis allowed to identify the cut-off values for haemoglobin (less than 10.2 grams per decilitre) and urea (more than 8.8 millimoles per litre), as well as to derive a predictor model.ConclusionsIn children with idiopathic dilated cardiomyopathy, anaemia is the strongest independent prognostic factor of early death or transplantation.

Objectives: This study sought to investigate the evolving pattern over time of on-clopidogrel platelet reactivity (PR) and its relationship with genotype and clinical outcomes after percutaneous co...

Background The optimal duration of clopidogrel therapy after coronary stenting is debated because of the scarcity of randomized controlled trials and inconsistencies arising from registry data. Although prolonged clopidogrel therapy after bare metal stenting is regarded as an effective secondary prevention measure, the safety profile of drug-eluting stents itself has been questioned in patients not receiving ≥12 months of dual-antiplatelet therapy. Hypothesis Twenty-four months of clopidogrel therapy after coronary stenting reduces the composite of death, myocardial infarction, or stroke compared with 6 months of treatment. Study design PRODIGY is an unblinded, multicenter, 4-by-2 randomized trial. All-comer patients with indication to coronary stenting are randomly treated— balancing randomization —with bare metal stent (no active late loss inhibition), Endeavor Sprint zotarolimus-eluting stent (Medtronic, Santa Rosa, CA) (mild late loss inhibition), Taxus paclitaxel-eluting stent (Boston Scientific, Natick, MA) (moderate late loss inhibition), or Xience V everolimus-eluting stent (Abbott Vascular, Santa Clara, CA) (high late loss inhibition). At 30 days, patients in each stent group are randomly allocated to receive 24 or up to 6 months of clopidogrel therapy― primary end point randomization . With 1,700 individuals, this study will have >80% power to detect a 40% difference in the primary end point after sample size augmentation of 5% and a background event rate of 8%. Summary The PRODIGY trial aims to assess whether 24 months of clopidogrel therapy improves cardiovascular outcomes after coronary intervention in a broad all-comer patient population receiving a balanced mixture of stents with various anti-intimal hyperplasia potency.

Objective To evaluate the efficacy of a computer-based intensive training program of attention, information processing and executive functions in patients with clinically-stable relapsing–remitting (RR) multiple sclerosis (MS) and low levels of disability. Design, patients and interventions A total of 150 patients with RR MS and an Expanded Disability Status Scale (EDSS) score of ≤ 4 were examined. Information processing, working memory and attention were assessed by the Paced Auditory Serial Addition Test (PASAT) and executive functions by the Wisconsin Card Sorting Test (WCST). Twenty patients who scored below certain cut-off measures in both tests were included in this double-blind controlled study. Patients were casually assigned to a study group (SG) or a control group (CG) and underwent neuropsychological evaluation at baseline and after 3 months. Patients in the SG received intensive computer-assisted cognitive rehabilitation of attention, information processing and executive functions for 3 months; the CG did not receive any rehabilitation. Setting Ambulatory patients were sent by the MS referral center. Outcome measures Improvement in neuropsychological test and scale scores. Results After rehabilitation, only the SG significantly improved in tests of attention, information processing and executive functions (PASAT 3″ p = 0.023, PASAT 2″ p = 0.004, WCSTte p = 0.037), as well as in depression scores (MADRS p = 0.01). Neuropsychological improvement was unrelated to depression improvement in regression analysis. Conclusions Intensive neuropsychological rehabilitation of attention, information processing and executive functions is effective in patients with RR MS and low levels of disability, and also leads to improvement in depression.

Background— Inhibition of platelet aggregation after aspirin or clopidogrel intake varies greatly among patients, and previous studies have suggested that poor response to oral antiplatelet agents may increase the risk of thrombotic events, especially after coronary angioplasty. Whether this reflects suboptimal platelet inhibition per se, which might benefit from more potent antiplatelet agents such as tirofiban, is unknown. Methods and Results— We screened 1277 patients to enroll 93 aspirin, 147 clopidogrel, and 23 dual poor responders, based on a point-of-care assay, who underwent elective coronary angioplasty at 10 European sites for stable or low-risk unstable coronary artery disease. Patients were randomly assigned in a double-blind manner to receive either tirofiban (n=132) or placebo (n=131) on top of standard aspirin and clopidogrel therapy. The primary end point, consisting of troponin I/T elevation at least 3 times the upper limit of normal, was attained in 20.4% (n=27) in the tirofiban group compared with 35.1% (n=46) in the placebo group (relative risk, 0.58; 95% confidence interval, 0.39 to 0.88; P =0.009). The rate of major adverse cardiovascular events within 30 days in the tirofiban group also was reduced (3.8% versus 10.7%; P =0.031). The overall incidence of bleeding was low, likely explained by a substantial use of the transradial approach, and did not differ between the 2 groups. Conclusions— In low-risk patients according to clinical presentation who had poor responsiveness to standard oral platelet inhibitors via a point-of-care assay, intensified platelet inhibition with tirofiban lowers the incidence of myocardial infarction after elective coronary intervention.

To test the efficacy of a training course on the diagnosis and treatment of schizophrenia, tailored for the general practitioner.A course, in a 3-session format, was given to 215 primary care doctors from the city of Brescia and its province, in Italy. All 706 doctors working in primary care were asked to participate. Of these doctors, 30.5% took part in the study. The first session (215 doctors) assessed baseline knowledge of schizophrenia (June 2002), the second (173 doctors) gave formal teaching and assessed post-lesson knowledge (October 2002), and the third (130 doctors) evaluated the retention of knowledge after 8 months (July 2003). The main outcome measures were total number of schizophrenia symptoms identified, total number of antipsychotics identified, and knowledge about antipsychotic-related adverse events.Post-lesson, general practitioners could identify 6.5 more symptoms (p.001) and 4.9 more antipsychotics (p.001). Compared to baseline, 71.5% vs. 15.4% of doctors had a good knowledge of antipsychotic-related adverse events. Although a loss of knowledge was found after the 8-month follow-up, knowledge at the endpoint was significantly higher than at baseline for the 3 main outcome variables (p.001).The teaching course on schizophrenia for general practitioners was effective, and the knowledge gained after teaching was stable across time.

Summary Background Encouraging results concerning chronic obstructive nasal symptoms due to adenoid in pediatric population were reported by use of intranasal steroid for short period. Up to now, no data are available about outcomes of such therapy after long-term follow-up. We evaluated the utility of mometasone furoate aqueous nasal spray in children with adenoidal hypertrophy in long-term maintenance therapy. Methods All children affected by adenoidal hypertrophy and undergoing successful mometasone treatment for 4 months in a preceding trial were reassessed after a mean follow-up of 28 months. Based on the duration of maintenance therapy and eventual adenoid surgical treatment, three subgroups were identified: (1) children voluntarily suspending maintenance therapy and requiring surgery (Group A); (2) children continuing maintenance therapy but undergoing surgery (Group B); and (3) children continuing maintenance therapy but not undergoing surgery (Group C). Clinical and endoscopic evaluation in each group was compared to the assessment performed after the first 4 months of treatment. Results Six patients (Group A) voluntarily suspended maintenance therapy and underwent adenoidectomy. Either the overall symptom score or choanal obstruction of this group worsened compared to the previous trial. Adenoidal surgery was performed in another three children (Group B) for ear disease. Chronic obstructive nasal symptoms and adenoid size were unchanged compared to the preceding study. Finally, 12 patients were in Group C. The overall symptom score and choanal obstruction of this group showed a further significant improvement at this stage. Conclusions This study describes the first long-term follow-up of children undergoing mometasone furoate aqueous nasal spray treatment for adenoidal hypertrophy. Voluntary suspension of maintenance therapy favors surgery of this disorder, whereas its regular administration may lead to successful results.

Background. High ultrafiltration rate on haemodialysis (HD) stresses the cardiovascular system and could have a negative effect on survival. Methods. The effect of ultrafiltration rate (UFR; ml/h/ kg BW) on mortality was prospectively evaluated in a cohort of 287 prevalent uraemic patients in regular HD from 1 January 2000 to 31 December 2005. Patients: 165 men and 122 women, age 66 � 13 years, on regular HD for at least 6 months, median: 48 months (range 6–372 months). Mean UFR was 12.7 � 3.5 ml/h/kg BW, Kt/V: 1.27 � 0.13, body weight (BW): 62 � 13 kg, PCRn: 1.11 � 0.20 g/kg/day, duration of dialysis: median 240 min (range 180–300 min), mean arterial blood pressure (MAP) 99 � 9 mm/Hg. One hundred and forty nine patients (52%) died, mainly for cardiovascular reasons (69%). Multivariate Cox regression analysis was utilized to evaluate the effect on mortality of UFR, age, sex, dialytic vintage, cardiovascular disease (CVD), diabetes, dialysis modality, duration of HD, BW, interdialytic weight gain (IWG), body mass index (BMI), MAP, pulse pressure (PP), Kt/V, PCRn. Results. Age (HR 1.06; CI 1.04–1.08; P < 0.0001), PCRn (HR 0.17, CI 0.07–0.43; P < 0.0001), diabetes (HR 1.81, CI 1.24–2.47; P ¼ 0.007), CVD (HR 1.86; CI 1.32–2.62; P ¼ 0.007) and UFR (HR 1.22; CI 1.16–1.28; P < 0.0001) were identified as factors independently correlated to survival. We estimated the discrimination potential of UFR, evaluated at baseline, in predicting death at 5 years, calculating the relative receiver operating characteristic (ROC) curves and the cut-off that minimizes the absolute difference between sensitivity and specificity. Conclusions. High UFRs are independently associated with increased mortality risk in HD patients. Better survival was observed with UFR < 12.37 ml/h/kg BW. For patients with higher UFRs, longer or more frequent dialysis sessions should be considered in order to prevent the deleterious consequences of excessive UFR.

Objectives This study was designed to investigate whether poor responders to thienopyridines after clopidogrel remain so even after ticlopidine administration (class effect) or whether a drug-specific effect exists between currently available thienopyridines. Background Whether clopidogrel poor responders also display inadequate platelet inhibition after ticlopidine administration remains undefined. Methods Platelet aggregation (PA) was measured in 143 patients, while they were taking aspirin, with light transmission aggregometry using adenosine diphosphate as an agonist at baseline (T0) and at clopidogrel steady state (T1). After T1,clopidogrel was stopped and substituted with ticlopidine. Then PA was assessed at ticlopidine steady state (T2). Resistance was defined as an absolute difference between T0and after-treatment (T1or T2) PA ≤10%. Results Clopidogrel and ticlopidine responsiveness was normally distributed; PA at T1did not differ compared with T2. Thirty (21%) and 28 (19%) patients were clopidogrel and ticlopidine nonresponders, respectively. Only 5 patients (3.5%) were nonresponders to both clopidogrel and ticlopidine (class effect), whereas 25 patients (83%) who were clopidogrel nonresponders at T1were responsive to ticlopidine, reaching a higher level of platelet inhibition at T2(PA 69 ± 15 vs. 44 ± 18, p Conclusions Poor responsiveness to either clopidogrel or ticlopidine at steady state was common, whereas nonresponders to both drugs were relatively infrequent (3.5%, 95% confidence interval 1.5% to 7.9%), suggesting that poor response to thienopyridines may frequently be a drug-specific mechanism.

Aims Brain natriuretic peptide (BNP), NT-proBNP and troponins are useful for the assessment of patients with heart failure. Few data exist about their serial changes and their prognostic value in patients with acute heart failure (AHF). Methods and results NT-proBNP and troponin-T plasma levels were measured at baseline, after 6, 12, 24, 48 h and at discharge in 116 consecutive patients with AHF and no evidence of acute coronary syndrome. NT-proBNP levels were 4421 pg/mL at baseline, declined after 24 h and reached their nadir at 48 h (2703 pg/mL). Troponin-T was detectable in 48% of patients. During a median follow-up of 184 days, 52 patients died or had a non-fatal cardiovascular hospitalisation. At a multivariable analysis including clinical and echo-Doppler variables, NT-proBNP plasma levels at discharge, detectable troponin-T plasma levels, and NYHA class at discharge were the only independent prognostic factors. Conclusion In patients with AHF, NT-proBNP levels decline 24 h after the initiation of intravenous therapy and troponin-T is detectable in 48% of cases. NT-proBNP levels at discharge, detectable troponin-T levels, NYHA class and serum sodium have independent prognostic value.

Objectives We sought to investigate whether the previously reported midterm clinical benefit of planned sirolimus-eluting stent (SES) implantation in patients with ST-segment elevation myocardial infarction (STEMI) was maintained over a 24-month time period. Moreover, the distribution of clinical events in relation to thienopyridine discontinuation was thoroughly investigated. Background No randomized data are currently available on the safety/benefit profile of SES in this subset of patients beyond 12 months. Methods Between March 2003 and April 2004, 175 patients with STEMI were randomly allocated to tirofiban infusion followed by SES or abciximab plus bare-metal stent (BMS). Complete follow-up information up to 720 days was available for all patients. Results The cumulative incidence of death, myocardial infarction (MI), or target vessel revascularization (TVR) remained lower in the tirofiban-SES compared with the abciximab-BMS group at 2 years (24.2% vs. 38.6%, respectively; hazard ratio [HR] 0.56 [95% confidence interval (CI) 0.33 to 0.98]; p = 0.038). The composite of death/MI was similar in the tirofiban-SES (16.1%) and the abciximab-BMS groups (20.5%, HR 0.77 [95% CI 0.38 to 1.55]; p = 0.43) while the need for TVR was markedly reduced (9.8% vs. 25.5%, respectively; HR 0.34 [95% CI 0.16 to 0.77]; p = 0.01) in the tirofiban-SES arm. The rate of confirmed, probable, or possible stent thrombosis did not differ in the 2 groups, nor the incidence of death/MI after thienopyridine discontinuation. Conclusions The midterm clinical benefit of planned SES implantation assisted by tirofiban infusion in STEMI patients was mainly carried over after 2 years with no overall excess of late adverse events after thienopyridine discon-tinuation.

Background Current treatment standards for patients undergoing primary percutaneous coronary intervention support early infusion of abciximab, followed by bare-metal stent (BMS) implantation. Whether the use of sirolimus-eluting stent (SES) would result in a further improvement of clinical outcomes remains to be proven. Similarly, whether tirofiban administered at high-bolus dose (HBD) followed by standard infusion is a valuable alternative to abciximab in the setting of ST-segment elevation myocardial infarction remains uncertain. Study Design Multicentre evaluation of single high-bolus dose tirofiban versus abciximab and sirolimus-eluting versus bare metal stent in acute myocardial infarction (MULTI-STRATEGY) is a phase III, open-label, multinational investigator-driven clinical trial evaluating, with a 2-by-2 factorial design, the safety/efficacy profile of 4 interventional strategies of reperfusion: tirofiban given at HBD (bolus of 25 μg/kg over 3 minutes), followed by an infusion of 0.15 μg/kg per minute for 18 to 24 hours versus abciximab and SES, as compared to BMS implantation in primary percutaneous coronary intervention. The coprimary objectives are (i) the evaluation of the effect of SES versus BMS on the incidence of major adverse cardiac events within 8 months of the index procedure and (ii) the degree of ST-segment resolution obtained after the mechanical intervention for the comparison of HBD tirofiban versus abciximab. The protocol mandates clinical follow-up for 5 years. Conclusions MULTI-STRATEGY will evaluate the role of SES and HBD tirofiban versus BMS and abciximab in the acute management of patients presenting with ST-segment elevation myocardial infarction.

OBJECTIVE. We evaluated the efficacy of mometasone furoate aqueous nasal spray in decreasing adenoid size and reducing the severity of chronic nasal obstruction symptoms in children affected by adenoidal hypertrophy.METHODS. Sixty children were recruited in a 2-stage, randomized, placebo-controlled trial. All patients complained of chronic nasal obstruction symptoms, and nasal endoscopy showed >75% choanal obstruction attributable to adenoid pads. In the first stage, 30 patients (group A) underwent mometasone treatment (50 μg per nostril per day) for 40 days, and 30 children (group B) received placebo. In the second stage, at the end of the first 40-day treatment period, patients in group A who showed subjective and objective clinical improvement were divided into 2 subgroups; group A1 (11 children) received topical intranasal steroid treatment on alternate days for the first 2 weeks per month, whereas group A2 (10 children) continued daily mometasone treatment for the first 2 weeks per month. After 3 months, all children were reassessed.RESULTS. Fifty-seven children completed the study according to the protocol. After the first treatment period, the severity of symptoms and adenoid size decreased for 21 patients (77.7%) in group A. No improvement was observed in the placebo group. After 3 months of additional therapy, group A2 patients demonstrated a more-pronounced reduction in adenoid size compared with group A1 patients. No statistically significant change in symptoms was identified. Mometasone treatment was well tolerated by all patients.CONCLUSIONS. Mometasone furoate aqueous nasal spray may be considered useful in decreasing adenoid pad size and the severity of symptoms related to adenoidal hypertrophy. Children with adenoidal hypertrophy that is not associated with tonsillar hypertrophy should be considered for intranasal mometasone treatment before surgery is planned.

A supplemented very-low-protein diet (sVLPD) seems to be safe when postponing dialysis therapy.Prospective multicenter randomized controlled study designed to assess the noninferiority of diet versus dialysis in 1-year mortality assessed by using intention-to-treat and per-protocol analysis.Italian uremic patients without diabetes older than 70 years with glomerular filtration rate of 5 to 7 mL/min (0.08 to 0.12 mL/s).Randomization to an sVLPD (diet group) or dialysis. The sVLPD is a vegan diet (35 kcal; proteins, 0.3 g/kg body weight daily) supplemented with keto-analogues, amino acids, and vitamins. Patients following an sVLPD started dialysis therapy in the case of malnutrition, intractable fluid overload, hyperkalemia, or appearance of uremic symptoms.Mortality, hospitalization, and metabolic markers.56 patients were randomly assigned to each group, median follow-up was 26.5 months (interquartile range, 40), and patients in the diet group spent a median of 10.7 months (interquartile range, 11) following an sVLPD. Forty patients in the diet group started dialysis treatment because of either fluid overload or hyperkalemia. There were 31 deaths (55%) in the dialysis group and 28 deaths (50%) in the diet group. One-year observed survival rates at intention to treat were 83.7% (95% confidence interval [CI], 74.5 to 94.0) in the dialysis group versus 87.3% (95% CI, 78.9 to 96.5) in the diet group (log-rank test for noninferiority, P0.001; for superiority, P = 0.6): the difference in survival was -3.6% (95% CI, -17 to +10; P = 0.002). The hazard ratio for hospitalization was 1.50 for the dialysis group (95% CI, 1.11 to 2.01; P0.01).The unblinded nature of the study, exclusion of patients with diabetes, and incomplete enrollment.An sVLPD was effective and safe when postponing dialysis treatment in elderly patients without diabetes.

Objectives: EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease [EUROPA] demonstrates reduction in cardiovascular mortality and myocardial infarction for a possible vascular and antiatherosclerotic effect of angiotensin-converting enzyme (ACE) inhibition with perindopril. Our objective was to study the effect of perindopril on endothelial function and to verify its link to risk and occurrence of cardiovascular events. Methods: Blood from 1200 EUROPA patients was withdrawn at baseline and after 1 year of treatment with either perindopril or placebo to measure von Willebrand factor and from 45 healthy subjects and 87 EUROPA patients to study endothelial function at the cellular level by cultivating in vitro human umbilical vein endothelial cells. In this setting, we determined protein expression/activity of endothelial nitric oxide synthase and the rate of apoptosis. Plasma levels of angiotensin II, bradykinin, tumor necrosis factor α, and nitrite/nitrate were also measured. Results: The occurrence of cardiovascular events was related to von Willebrand factor at baseline ( P =0.013) that also significantly decreased after 1 year's treatment ( P

The aim of the present study was to investigate the consequences of chronic otitis media on inner ear function. Retrospective analysis of conventional pure-tone audiometry tests was carried out on 344 patients who were scheduled for surgical treatment of unilateral chronic otitis media without other risk factors for sensorineural hearing loss. Bone conduction thresholds of diseased ears were compared with those of contralateral, non-diseased ears. Selected clinical features were assessed among diseased ears to examine possible influences on inner ear function. Mean bone conduction threshold differences varied from 0.6 dB at 0.5 kHz to 3.7 dB at 4 kHz. These differences augmented with increasing duration of middle ear disease. Impaired hearing by bone conduction thresholds of diseased ears correlated with increased age at every frequency and with an interruption of the ossicular chain only at higher frequencies. The severity of sensorineural hearing loss correlated with longer duration of middle ear disease. Thus, surgical treatment of dry and apparently stable tympanic membrane perforation is warranted.

Objectives We sought to determine the safety and efficacy of high-dose bolus (HDB) tirofiban in high-risk patients undergoing percutaneous coronary intervention (PCI). Background The use of HDB tirofiban in the catheterization laboratory is controversial. In particular, in patients with acute coronary syndromes undergoing PCI, there is no evidence that tirofiban administered in the catheterization laboratory is superior to heparin alone. This finding probably reflects the suboptimal platelet inhibition when tirofiban is employed at RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) regimen. Methods A total of 202 patients (mean age 69 ± 8 years; 137 males [68%]) undergoing high-risk PCI, pretreated with thienopyridines, were consecutively randomized to HDB tirofiban (25 μg/kg/3 min, and infusion of 0.15 μg/kg/min for 24 to 48 h) or placebo immediately before the procedure and then followed for a median time of 185 days (range 45 to 324 days) for the occurrence of the primary composite end point of death, myocardial infarction, target vessel revascularization (TVR), and bailout use of glycoprotein (GP) IIb/IIIa inhibitors. Results The cumulative incidence of the primary end point was 35% and 20% in placebo and HDB tirofiban groups, respectively (hazard ratio 0.51, 95% confidence interval 0.29 to 0.88; p = 0.01). This difference was mainly due to the reduction of myocardial infarction and bailout use of GP IIb/IIIa inhibitors, with no significant effect on TVR or death. The safety profile did not differ between tirofiban and placebo. Conclusions The use of tirofiban, when administered at HDB, is safe and significantly reduces the incidence of ischemic/thrombotic complications during high-risk PCI.

Primary bare metal stenting and abciximab infusion are currently considered the best available reperfusion strategy for acute ST-segment elevation myocardial infarction (STEMI). Sirolimus eluting stents (SES), compared to bare metal stent (BMS), greatly reduce the incidence of binary restenosis and target vessel revascularisation (TVR), but their use on a routine basis results in a significant increase in medical costs. With current European list prices, the use of tirofiban instead of abciximab would save enough money to absorb the difference between SES and BMS.To assess whether in patients with STEMI the combination of SES with high dose bolus (HDB) tirofiban results in a similar incidence of major cardiovascular events (MACE) but in a lower binary restenosis rate after six months compared to BMS and abciximab.160 patients are required to satisfy the primary composite end-point, including MACE and binary restenosis. The study is ongoing: the current paper focuses on the methodology and demography of the first 100 patients so far enrolled. Patients randomised to HDB tirofiban (n = 50, mean age: 62 +/- 12, 40 males) and abciximab (n = 50, mean age: 63 +/- 12, 38 males) do not differ for medical history, presentation profile, medications at discharge, angiographic profile and creatine-kinase MB-fraction at peak.The results of the trial will be available by the end of 2004: they will be crucial for the cardiologists to know whether the gold standard for AMI treatment should be reconsidered after the introduction of SES into the clinical practice.

A latent variable model was applied to the results of an Italian multicenter nation-wide cross-sectional study to assess the earliest health effects due to mercury (Hg) exposure caused by occupation, dental amalgams (DENTAM) and fish eating (FISH). The studied population included subjects recruited from four different geographical areas. A total number of 122 workers from chloroalkali plants and production of thermometers and neon lamps formed the occupationally exposed group, whereas 196 subjects, recruited from the same areas and not occupationally exposed to mercury, formed the control group. Neuropsychological functions were assessed with neurobehavioral testing including vigilance, motor and cognitive function, tremor measurements, and with symptoms concerning neuropsychological and mood assessment. Neuroendocrine function was examined with the measurement of prolactin (PRL) level. Parameters of immunological and renal function were also measured. The target population was characterized by the number and surface of dental amalgams and consumption of fish. In the exposed workers the average urinary mercury (U-Hg) was 10.4+/-6.9 (geometric mean 8.3, range 0.2-35.2) microg/g creatinine, whereas in the control group it was 1.9+/-2.8 (geometric mean 1.2, range 0.1-33.2) microg/g creatinine. The preliminary results indicated that finger tapping (FT) and the Branches alternate movement task (BAMT) coordination test were associated with the occupational exposure (OCCEXP). PRL was significantly decreased among the exposed workers, and inversely related to U-Hg. Among the immunological and renal parameters, cytokine serum interleuchin-8 (sIL8) and beta(2) micro globulin (beta(2)MG) were lower in the exposed group and negatively correlated to U-Hg. Small-size fish consumption was associated to a beneficial effect on symptoms reporting. No effects were observed concerning dental amalgams. After first evaluating the relationship between mercury exposure and each indicator of effect, further assessment was performed to identify the earliest effects related to mercury exposure among those who resulted in being associated in the preliminary elaboration. Two latent variables "exposure" and "effect" were identified, integrating respectively the different forms of exposure (occupational, due to dental amalgams and fish consumption) and the indicators of effects (FT, BAMT, PRL, sIL8, beta(2)MG). Confounding factors (age, alcohol, body mass index (BMI)) were considered in the same model. This further analysis showed that an inverse association of occupational exposure to mercury with PRL and BAMT, with Hg-U mediating the effect on PRL, was predominant with respect to the other form of mercury exposure, the other indicators of effect and the confounders. In conclusion, this study supports the finding of alterations of neuroendocrine secretion and motor coordination at very low occupational exposure levels of inorganic mercury, below the current ACGIH Biological Exposure Index. These changes occur at lower levels than other subtle effects on the renal function and the immunitary system. On the contrary, dental amalgams and small-size fish consumption do not seem to be associated to any adverse health effect at these exposure levels.

Aims and background The results of several randomized trials and meta-analyses have been reported on adjuvant treatment for early breast cancer and treatment guidelines have been defined accordingly, but detailed data are lacking on the appropriateness of treatment prescription in clinical practice. Methods We performed a prospective, observational, multicenter study to monitor the prescription, delivery and effectiveness of radiotherapy following conservative surgery for early breast cancer; 1610 patients treated with postoperative radiation to the breast in 1997 were entered by 12 centers in Lombardy, Italy. Here we report the results of a secondary analysis focused on the prescription of medical adjuvant treatment (1547 eligible patients). Results Chemotherapy only was prescribed to 526 patients (33%), hormonal therapy only to 539 (33%), and both treatments to 85 patients (5%); 460 women (29%) received no medical adjuvant treatment. We compared the collected data with guidelines defined in 1995 by the St Gallen Consensus Conference. Undertreatment was most frequent in node-negative patients at intermediate/high risk, no treatment (instead of tamoxifen or chemotherapy) being prescribed in 21–45% of cases. Node-negative patients at low risk, on the other hand, were overtreated with tamoxifen in 31% of cases. In node-positive, premenopausal women compliance with guidelines was far better, with a 91–96% rate of chemotherapy prescription. In node-positive, postmenopausal, estrogen receptor-positive patients chemotherapy was unduly prescribed in as many as 56% of cases. Comparison of clinical practice with the next version of the guidelines (1998) showed a somewhat better compliance. Conclusions Despite the availability of official and authoritative guidelines, adjuvant treatment prescription for early breast cancer in Lombardy in 1997 was suboptimal, especially in well-defined subgroups of patients.

Background: Fas ligand (Fas-L), which is expressed by melanoma cells, can be cleaved from cell membranes and become soluble (soluble Fas-L, sFas-L). No previous study examined sFas-L levels in patients affected with all clinical stages of melanoma. Objective: To investigate if sFas-L can be considered a serological marker for melanoma. Methods: Serological sFas-L values in 114 patients with melanoma and 25 controls were measured by using ELISA. Results: sFas-L values in patients were not significantly higher than in controls. They were not significantly different, moreover, when patient groups belonging to different clinical stages were compared with the control group. Two patients affected with distant metastases had the highest sFas-L values. Conclusion: sFas-L cannot be considered, within the limits of this study, as a serological marker for the detection of melanoma. Further studies are needed to evaluate whether sFas-L can be used as a marker for disease progression and/or prediction of therapy outcome.

Objective: The ‘double-orifice’ (DO) technique has been recently proposed as an additional option in mitral valve repair (MVR). However, little is known regarding the long-term postoperative outcome and the predictors of DO results. Therefore, the aim of this study was to evaluate our clinical series and to identify prognostic factors of DO repair. Methods: From 1992, 75 patients underwent DO procedure because of severe mitral regurgitation. The study population consisted of 48 male and 27 female patients with a mean age of 58 ^ 13 years (range 16‐80 years). The aetiology of mitral incompetence was Barlow disease in 30 cases, rheumatic disease in 18 cases, acute or healed endocarditis in 16 cases and other causes in 11 cases. Carpentier rigid ring was used in 38 patients, whereas autologous pericardium was used in 24 patients. Thirteen patients had no annuloplasty procedure. Statistical analysis included univariate and multivariate Cox proportional models to evaluate the predictors of the DO failure. Results: There were four hospital and three late deaths with a survival rate of 92% at 8 years. Mean follow-up was 42 ^ 24 months (range 1‐93 months). Twelve patients underwent reoperation (five cases of early failure) and had valve replacement, leading to 80% freedom from reoperation at 8 years. At follow-up, 13 patients had no mitral regurgitation, 36 patients had trivial or mild mitral incompetence, whereas eight patients had moderate or severe mitral insufficiency at transthoracic echocardiography. Preoperative low left ventricular ejection faction, pulmonary arterial hypertension and marked left atrial enlargement were predictorsOP , 0:05U of DO failure at univariate analysis. Pericardial annuloplasty was also a risk factorOP , 0:05U for unsuccessful DO repair at long term. Cox proportional multivariate analysis confirmed left atrial dilatation, pulmonary hypertension and pericardial annuloplasty as independent predictors of unfavourable postoperative results. Conclusions: This study suggests that preoperative factors, like pulmonary hypertension and severe left atrial dilatation, may predict late DO failure. Our findings also indicate that pericardial annuloplasty may negatively influence mitral valve reconstruction at long term when DO is employed in MVR. q 2001 Elsevier Science B.V. All rights reserved.

Aims We studied the induction of monocytic inducible nitric oxide synthase expression and the tumour necrosis factor-alpha system in patients with congestive heart failure. Methods and Results Forty-three congestive heart failure patients and 15 healthy subjects were studied. Antigenic tumour necrosis factor-a and its soluble receptors, measured by ELISA. were increased in chronic heart failure and the increase was related to the clinical severity of the syndrome (tumour necrosis factor-a from 8.2 +/- 5.2 in NYHA class II to 18.2 +/- 7.2 in class III and 26.9 +/- 13.2 pg, ml(-1) in class IV, P < 0.0001 classes III and IV vs class II; soluble tumour necrosis factor receptor I from 1.0 +/- 0.2 in class II to 2.3 +/- 1.1 in class III and 5.5 +/- 3.2 ng. ml(-1) in class IV, P < 0.0001 classes III and IV vs class II; soluble tumour necrosis factor receptor II from 2.7 +/- 0.7 in class II to 4.9 +/- 1.9 in class III and 8.4 +/- 5.0 ng.ml(-1) in class IV, P < 0.002 classes III and IV vs class II). Monocytic inducible nitric oxide synthase assessed by Western blot, was expressed only in congestive heart failure patients (13 out of 43). The association among monocytic inducible nitric oxide synthase expression, tumour necrosis factor-alpha system activation, neurohormones and other clinical parameters was studied. The univariate logistic regression showed that inducible nitric oxide synthase expression was strictly associated with NYHA class (P < 0.05), antigenic tumour necrosis factor-alpha (P < 0.01) and its soluble receptors (P < 0.05). The multivariate analysis showed that antigenic tumour necrosis factor-alpha was the only predictor for monocytic inducible nitric oxide synthase expression (P < 0.05, RR = 2.75, CI 1.34-5.43). Conclusions Inducible nitric oxide synthase is expressed in circulating monocytes of patients with severe congestive heart failure. This phenomenon is linked to the activation of the tumour necrosis factor-alpha system. (C) 1999 The European Society of Cardiology.

The contractile properties of muscle are usually investigated by analysing the force signal recorded during electrically elicited contractions. The electrically stimulated muscle shows surface oscillations that can be detected by an accelerometer; the acceleration signal is termed the surface mechanomyogram (MMG). In the study described here we compared, in the human tibialis anterior muscle, changes in the MMG and force signal characteristics before, and immediately after fatigue, as well as during 6 min of recovery, when changes in the contractile properties of muscle occur. Fatigue was induced by sustained electrical stimulation. The final aim was to evaluate the reliability of the MMG as a tool to follow the changes in the mechanical properties of muscle caused by fatigue. Because of fatigue, the parameters of the force peak, the peak rate of force production and the peak of the acceleration of force production (d2F/dt2) decreased, while the contraction time and the half-relaxation time (1/2-RT) increased. The MMG peak-to-peak (p-p) also decreased. The attenuation rate of the force oscillation amplitude and MMG p-p at increasing stimulation frequency was greater after fatigue. With the exception of 1/2-RT, all of the force and MMG parameters were restored within 2 min of recovery. A high correlation was found between MMG and d2F/dt2 in un-fatigued muscle and during recovery. In conclusion, the MMG reflects specific aspects of muscle mechanics and can be used to follow the changes in the contractile properties of muscle caused by localised muscle fatigue.

DESIGN: This study was designed to evaluate, in a cohort of 1039 middle-aged men, the interaction between the duration and intensity of physical activity performed either during leisure time (competitive sports, walking, cycling) or work, and principal coronary disease risk factors. METHOD: A cohort of subjects aged 45-64 years were recruited in 1993. Subjects included both individuals who were physically active and those who were sedentary, and were age-matched. RESULTS: Leisure time physical activity was inversely related to levels of total cholesterol, triglycerides, and fibrinogen, and to diastolic and systolic blood pressure. High-density lipoprotein cholesterol level was directly related to leisure time activity. Working activity, even if strenuous, was not related to risk profile. Leisure time activity did not favorably influence lipid levels in smokers, obese subjects or those with known dyslipidemia. CONCLUSIONS: This study further reinforces the use of continuous diet and drug treatment in dyslipidemic subjects and in smokers, who have to refrain from smoking if they are to benefit fully from the effects of physical activity. Language: en

Aims The Bleeding Academic Research Consortium (BARC) classification has been proposed by consensus to standardize bleeding endpoint definition and reporting in cardiovascular clinical trials. There are no prospective studies on its prognostic impact. Methods and results We explored the association of BARC-defined bleeding with mortality and compared its prognostic value against two validated bleeding scales: the Thrombolysis in Myocardial Infarction (TIMI) and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) scales. Non-coronary artery bypass graft (CABG)-related bleedings within the PRODIGY trial were prospectively adjudicated by a blinded Clinical Event Committee and analysed according to multiple statistical modelling. At 2 years, bleeding occurred in 143 patients (7.1%) according to BARC Type 2, 3, or 5; in 50 patients (2.5%) according to TIMI minor or major; and in 61 patients (3.1%) according to GUSTO moderate or severe. One hundred sixty-three patients died (8.1%). After multivariable modelling, BARC Type 2, 3, or 5 bleeding was associated with increased 2-year mortality [hazard ratio (HR): 3.77; 95% confidence interval (CI): 2.37–5.98]. Bleeding Academic Research Consortium Type 3 or 5 was associated with an increased mortality rate at 2 years (adjusted HR: 7.72; 95% CI: 4.75–12.54) similar to that provided by TIMI (HR: 7.64, 95% CI: 4.53–12.87) or GUSTO (HR: 7.36, 95% CI: 4.38–12.34) criteria. Conclusions In a contemporary, all-comer percutaneous coronary intervention trial actionable BARC bleedings were associated with increased risk of mortality with BARC Type 3 or 5 bleedings providing a similar mortality risk to that posed by TIMI or GUSTO scales.

This study sought to assess device-specific outcomes after implantation of bare-metal stents (BMS), zotarolimus-eluting Endeavor Sprint stents (ZES-S), paclitaxel-eluting stents (PES), or everolimus-eluting stents (EES) (Medtronic Cardiovascular, Santa Rosa, California) in all-comer patients undergoing percutaneous coronary intervention.Few studies have directly compared second-generation drug-eluting stents with each other or with BMS.We randomized 2,013 patients to BMS, ZES-S, PES, or EES implantation. At 30 days, each stent group received up to 6 or 24 months of clopidogrel therapy. The key efficacy endpoint was the 2-year major adverse cardiac event (MACE) including any death, myocardial infarction, or target vessel revascularization, whereas the cumulative rate of definite or probable stent thrombosis (ST) was the key safety endpoint.Clinical follow-up at 2 years was complete for 99.7% of patients. The MACE rate was lowest in EES (19.2%; 95% confidence interval [CI]: 16.0 to 22.8), highest in BMS (32.1%; 95% CI: 28.1 to 36.3), and intermediate in PES (26.2%; 95% CI: 22.5 to 30.2) and ZES-S (27.8%; 95% CI: 24.1 to 31.9) groups (chi-square test = 18.9, p = 0.00029). The 2-year incidence of ST in the EES group (1%; 95% CI: 0.4 to 2.2) was similar to that in the ZES-S group (1.4%; 95% CI: 0.7 to 2.8), whereas it was lower compared with the PES (4.6%, 95% CI: 3.1 to 6.8) and BMS (3.6%; 95% CI: 2.4 to 5.6) groups (chi-square = 16.9; p = 0.0001).Our study shows that cumulative MACE rate, encompassing both safety and efficacy endpoints, was lowest for EES, highest for BMS, and intermediate for PES and ZES-S groups. EES outperformed BMS also with respect to the safety endpoints with regard to definite or probable and definite, probable, or possible ST. (PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY [PRODIGY]; NCT00611286).

Aims The purpose of this pre-specified analysis of the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY) was to assess device-specific outcomes relative to different duration of dual antiplatelet therapy (DAPT) after Everolimus- (EES), Paclitaxel (PES), Zotarolimus- (ZES-S) eluting, or bare metal stents (BMS). Methods and results We randomized 2013 patients to BMS, ZES-S, PES, or EES implantation. At 30 days, each stent group underwent up to 6 or 24 months clopidogrel therapy. The primary endpoint, which was a composite of death, myocardial infarction, or cerebrovascular accident, did not differ in patients receiving BMS [HR: 0.89 (95%CI: 0.54–1.45)], PES [HR: 0.74 (95%CI: 0.43–1.25)], or EES [HR: 0.63 (95%CI: 0.33–1.21)] implantation across DAPT groups, whereas it was significantly higher in ZES-S patients undergoing long when compared with short-term DAPT therapy (HR: 2.85, P = 0.0018), with positive interaction testing ( P -value = 0.004). At the 6-month landmark analysis, heterogeneity across stent types persisted for the primary study endpoint and other secondary clinical outcomes, whereas patients receiving PES showed a significantly higher rate of definite, probable and definite, probable, possible stent thrombosis in the short DAPT regimen. No association in absolute or relative terms was noted between stent potency in inhibiting intimal hyperplasia and greater vulnerability to shorter DAPT therapy. Conclusion Our study suggests that optimal duration of DAPT may be stent-specific and it does not support a clear association between stent potency and vulnerability to shorter DAPT therapy. Trial Registration clinicaltrials.gov Identifier: [NCT00611286][1]. [http://clinicaltrials.gov/ct2/show/[NCT00611286][1]?term=prodigy&rank=2][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00611286&atom=%2Fehj%2Fearly%2F2013%2F01%2F11%2Feurheartj.ehs460.atom [2]: http://clinicaltrials.gov/ct2/show/NCT00611286?term=prodigy&rank=2

Angiogenesis plays a crucial role in tumor growth and progression. Low expression of mineralocorticoid receptor (MR) in several malignant tumors correlates with disease recurrence and overall survival. Previous studies have shown that MR expression is decreased in colorectal cancer (CRC). Here we hypothesize that decreased MR expression can contribute to angiogenesis and poor patient survival in colorectal malignancies. In a cohort of CRC patients, we analyzed tumor MR expression, its correlation with tumor microvascular density and its impact on survival. Subsequently, we interrogated the role of MR in angiogenesis in an in vitro model, based on the colon cancer cell line HCT116, ingenierized to re-express a physiologically controlled MR. In CRC, decreased MR expression was associated with increased microvascular density and poor patient survival. In pchMR transfected HCT116, aldosterone or natural serum steroids largely inhibited mRNA expression levels of both VEGFA and its receptor 2/KDR. In CRC, MR activation may significantly decrease angiogenesis by directly inhibiting dysregulated VEGFA and hypoxia-induced VEGFA mRNA expression. In addition, MR activation attenuates the expression of the VEGF receptor 2/KDR, possibly dampening the activation of a VEGFA/KDR dependent signaling pathway important for the survival of tumor cells under hypoxic conditions.

Objective To identify the prevalence and risk factors of eustachian tube dysfunction after surgery for sinonasal cancer by observing the occurrence of middle ear effusion. Study design Historical cohort study. Setting Academic university hospital. Subjects and methods Clinical records of 112 patients surgically treated for sinonasal cancer over a 16-year period were evaluated. Initial bivariate analysis was followed by a multivariate logistic regression model. Results The best model included 2 variables: posterior extension of surgical resection (nasopharynx, soft palate, eustachian tube, pterygomaxillary fossa, parapharyngeal space) with an odds ratio of 5.662 (95% confidence interval [CI], 1.877-9.447) and postoperative radiotherapy with an odds ratio of 8.691 (95% CI, 4.187-13.194). Conclusion Despite the limited number of patients, the study gives a prediction of middle ear effusion based on 2 well-defined factors: surgical resection of anatomic structures involved in tubal function and adjuvant radiotherapy.

Pediatric lead (Pb) exposure impacts cognitive function and behavior and co-exposure to manganese (Mn) may enhance neurotoxicity.To assess cognitive and behavioral function in adolescents with environmental exposure to Pb and Mn.In this cross sectional study, cognitive function and behavior were examined in healthy adolescents with environmental exposure to metals. The Wechsler Intelligence Scale for Children (WISC) and the Conners-Wells' Adolescent Self-Report Scale Long Form (CASS:L) were used to assess cognitive and behavioral function, respectively. ALAD polymorphisms rs1800435 and rs1139488 were measured as potential modifiers.We examined 299 adolescents (49.2% females) aged 11-14 years. Blood lead (BPb) averaged 1.71 μg/dL (median 1.5, range 0.44-10.2), mean Blood Manganese (BMn) was 11.1 μg/dL (median 10.9, range 4.00-24.1). Average total IQ was 106.3 (verbal IQ=102, performance IQ=109.3). According to a multiple regression model considering the effect of other covariates, a reduction of about 2.4 IQ points resulted from a two-fold increase of BPb. The Benchmark Level of BPb associated with a loss of 1 IQ-point (BML01) was 0.19 μg/dL, with a lower 95% confidence limit (BMLL01) of 0.11 μg/dL. A very weak correlation resulted between BPb and the ADHD-like behavior (Kendall's tau rank correlation=0.074, p=0.07). No influence of ALAD genotype was observed on any outcome. Manganese was not associated with cognitive and behavioral outcomes, nor was there any interaction with lead.These findings demonstrate that very low level of lead exposure has a significant negative impact on cognitive function in adolescent children. Being an essential micro-nutrient, manganese may not cause cognitive effects at these low exposure levels.

Myocardial injury during an episode of acute heart failure (AHF) may be important for patents' outcome. We hypothesised that an increase of cardiac troponin levels (cTnT) during hospitalisation, in patients with undetectable levels on admission (cTnT release), may be a more specific marker of myocardial damage. With this aim, we assessed the clinical and prognostic significance of high serum cTnT levels at the time of admission and that of cTnT release in 198 consecutive patients admitted for AHF and with no signs of acute coronary syndrome.cTnT levels were serially measured at the time of admission, and after 6 and 12 h, in 198 consecutive patients admitted for AHF and with no signs of acute coronary syndrome. cTnT was detectable (0.01 ng/mL) in 102 patients (52 %) and positive for myocardial necrosis (0.03 ng/mL) in 78 patients (39 %). Negative cTnT at the time of admission became positive at 6 and/or 12 h in 36 (18 %) patients. Patients with increased cTnT levels were more likely to have coronary artery disease, hypertension, diabetes, and renal dysfunction. During a median follow-up duration of 247 days (IQR 96-480 days), the detection of increased cTnT levels was associated with a higher rate of all-cause deaths and, for cTnT release, all-cause death and cardiovascular rehospitalisation rate. CTnT release was an independent predictor of all-cause death and cardiovascular rehospitalisation, along with glomerular filtration rate, and the administration of inotropic agents during the initial hospitalisation.Increased cTnT levels are a frequent finding in patients with AHF. They are more likely to occur in patients with comorbidities and are associated with poorer outcomes. cTnT release is an independent predictor of poorer outcomes.

OBJECTIVE: To investigate the risk of metachronous colorectal cancer (CRC), its impact on survival, and the risk of rectal cancer in a cohort of probands meeting the Amsterdam criteria. BACKGROUND: Several determinants of decision-making for the management of CRC in patients with a putative diagnosis of Lynch syndrome are scarcely defined, and many of them undergo segmental bowel resection instead of the advised total colectomy. METHODS: A retrospective cohort study was conducted on 65 probands of the Amsterdam-positive families who had surgery for primary CRC and at least 5-year surveillance thereafter. The rates of metachronous CRC and of rectal cancer were evaluated, together with their association with preoperatively available clinical predictors. Differences in overall survival between patients with and without metachronous CRC were evaluated using a time-dependent Cox model. RESULTS: Seventeen patients (26.2%) had metachronous CRC. No clinical feature was associated with an increased risk of its development. The risk of death in patients with metachronous CRC was 6-fold increased. Neither a 2-year interval endoscopic surveillance after surgery, nor total colectomy was associated with a significant reduction in metachronous CRC. Eighteen patients (23.7%) had rectal cancer at first presentation, 5 patients of the remainder (10.6%) developed rectal cancer after primary colon resection. Two patients undergoing total colectomy developed a metachronous rectal cancer (18.2%). A first-degree family history of rectal cancer was associated with an increased risk of rectal cancer. CONCLUSIONS: Probands of families fulfilling the Amsterdam criteria carry a high risk of rectal cancer and of metachronous CRC. Total proctocolectomy, or total colectomy and a 1-year interval of proctoscopic surveillance should be advised when a high risk of rectal cancer can be predicted.

The aim of this study was to investigate the effects of transcatheter aortic valve implantation (TAVI) on left ventricular (LV) hypertrophy and diastolic function in patients with severe aortic valve stenosis (AVS). There are few and conflicting data on LV mass remodeling and LV diastolic function after TAVI.Echocardiography and clinical assessment were performed at baseline and at 6 months in high-risk patients affected by severe AVS who underwent TAVI.One hundred thirty-five patients successfully underwent TAVI. Peak transvalvular aortic pressure gradient and mean transvalvular aortic pressure gradient were reduced from 87 ± 25 to 18 ± 7 mm Hg and from 54 ± 14 to 9 ± 4 mm Hg, respectively (P.001), accompanied by significant clinical improvement. The mean LV ejection fraction improved from 50 ± 13% to 54 ± 11% during follow-up (P = .009). At 6-month follow-up, interventricular septal wall thickness regressed from 14 ± 2 to 12 ± 1 mm and posterior wall thickness from 13 ± 3 to 11 ± 2 mm (P.001). LV mass and LV mass index decreased from 332 ± 106 to 228 ± 58 g (P.001) and from 191 ± 58 to 132 ± 30 g/m(2) (P.001), respectively. Ninety-seven patients (72%) showed improvements in LV diastolic filling pattern. The mean e' value increased from 4.1 ± 1.7 to 5.6 ± 2.2 cm/sec, and the mean E/e' ratio decreased from 24 ± 7 to 17 ± 6 (P.001) after TAVI.Significant LV mass reverse remodeling associated with improvement in LV systolic and diastolic function was found in patients with severe AVS 6 months after TAVI. These changes may have relevant clinical prognostic value.

Background— The optimal duration of dual-antiplatelet therapy and the risk-benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined. We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration–approved drug-eluting or bare-metal stents. Methods and Results— We randomly assigned 2013 patients to receive bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation. At 30 days, patients in each stent group were randomly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin. The primary end point was a composite of death of any cause, myocardial infarction, or cerebrovascular accident. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74–1.29; P =0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. Conclusions— A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause, myocardial infarction, or cerebrovascular accident. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00611286.

Aims Diabetic retinopathy (DR) is often asymptomatic even in its more advanced stages. Timely and repeated screening for DR avoids a late diagnosis of DR, but the high number of diabetic patients precludes a frequent screening; thus, the need for a method to identify patients at higher risk for DR becomes crucial. Methods A prospective analysis of 5034 type 2 diabetic patients followed from 1996 to 2007 and not affected by retinopathy at the time of the recruitment was performed. Patients were randomly divided (ratio 2:1) into two groups: the train data set and the test set (3327 and 1707 patients, respectively). Factors associated with the occurrence of DR were assessed by the Cox's proportional hazard model. Results Duration of diabetes, glycosylated hemoglobin, systolic blood Pressure, male gender, albuminuria and diabetes therapy other than diet were all significantly associated with the occurrence of DR. Conclusions The nomogram could help in ranking the type 2 diabetic patients at higher risk to develop DR and thus with a need for more frequent ophthalmologic checks, without enhancing neither the time nor the costs.

This study sought to investigate the evolving pattern over time of on-clopidogrel platelet reactivity (PR) and its relationship with genotype and clinical outcomes after percutaneous coronary intervention.Whether on-clopidogrel PR and role of genotype differ over time is unknown.On-clopidogrel PR before percutaneous coronary intervention, and 1 and 6 months thereafter via VerifyNow P2Y12 (Accumetrics Inc., San Diego, California), CYP2C19*2, *17, CYP3A5*3, and ABCB1 polymorphisms were evaluated in 300 patients. Death, stroke, myocardial infarction, and bleedings were assessed up to 1 year.On-clopidogrel PR varied significantly over time, being higher at baseline than at 1 and 6 months after. From baseline to 1 month, 83 of 300 patients varied their response status. This was mainly due to baseline poor responders becoming full responders (75 of 83). Genotype justifies roughly 18% of this trend. CYP2C19*2 and *17 influence on PR was consistent over time, whereas that of ABCB1 appeared of greater impact at baseline. On-clopidogrel PR at 1 month independently best predicts ischemic and bleeding events. We found a therapeutic window (86 to 238 P2Y₁₂ reactivity units) with a lower incidence of both ischemic and bleeding complications. A risk score was created by combining genotype (ABCB1 and CYP2C19*2), baseline PR, and creatinine clearance to predict 1-month poor responsiveness and 1-year poor prognosis.In patients at steady state for clopidogrel undergoing percutaneous coronary intervention, PR decreases from baseline to 1 month. Genotype influences ≈18% of this trend. On-clopidogrel PR at 1 month is the strongest predictor of adverse outcomes, and this can be predicted by combining genotype to baseline phenotype and clinical variables.

To assess the risk from exposure to occupational stress and burnout in health care workers (HCW), a cross-sectional study was planned to compare objective data that can represent potential job stressors in hospital wards and subjective symptoms reported by the workers. Medical doctors, nurses and ancillary workers of the Internal Medicine Wards of a large public hospital in Northern Italy participated in the study. Three subjective questionnaires were administered: the Job Content Questionnaire (JCQ), the State-Trait Anxiety Inventory (STAI), the Maslach Burnout Inventory (MBI). In addition, seven objective parameters were collected as average during the 3 months period prior to the study: a) working understaffed; b) ratio number of patients/HCW on service; c) ratio number of HCW on sick leave/ HCW on service; d) number of skipped days off after night shifts; e) days of sick leave; f) number of deceased patients; g) number of accidents at work. A total group of 230 HCW were examined, employed in six different sub-units of the Medical wards. The female workers were 67.8% and the male workers 32.2%, the mean age was 37.4 yr (SD 9.3) in the total group of HCW, 35.1 yr (SD 7.9) in females and 42.3 yr (SD 10.3) in males. The average scores of subjective and objective parameters resulted significantly higher in the same sub-units. The correlation analysis showed that the subjective questionnaires were highly inter-related. The multivariate analysis showed that the days of sick leave were significantly related to the subjective questionnaires, and the subjective subscales of emotional exhaustion (from MBI), job demand and decision latitude (from JCQ) and STAIt were significantly related to some of the objective parameters. These results support the integrated use of multiple subjective and objective assessment as the most appropriate approach for the evaluation of occupational stress.

The disability, cognitive impairment, fatigue and depression are interacting features in multiple sclerosis (MS), whose relation is still unclear. The objective of this study was to evaluate in a sample of MS patients, the frequency of depressive symptoms, its predicting factors and relation with cognitive impairment, fatigue and disability. 255 consecutive MS patients and 166 healthy subjects were assessed for the presence of depressive symptoms with the Beck Depression Inventory-Fast Screen (BDI-FS). Patients with BDI-FS ≥ 4 were further investigated for the presence of neuropsychological impairment. Depressive symptoms were significantly more frequent and severe in patients than in controls. EDSS score was the only predicting factor of depression (3.5 = threshold EDSS score for depressive symptoms) in patients, whereas neuropsychological impairment was not correlated with BDI-FS and fatigue was found to be significantly correlated with attention, executive function and memory test scores, as well as with BDI-FS score in patients.

Three complexes of Pt(II) containing the chiral ligands 1-(tert-butoxycarbonyl)-(2S,4S)-2-[(diphenylphosphino)methyl]-4-(dibenzophospholyl)pyrrolidine, 1-(tert-butoxycarbonyl)-(2S-4S)-2-[(dibenzophospholyl)methyl]-4-(diphenylphosphino)pyrrolidine, and 1-(tert-butoxycarbonyl)-(2S,4S)-4-(dibenzophospholyl)-2-[(dibenzophospholyl)methyl]pyrrolidine were synthesized. Asymmetric hydroformylation of styrene was examined with use of platinum complexes of these three ligands, as well as Pt II BPPM, in the presence of stannous chloride as catalyst

This study sought to evaluate the impact of SYNTAX score (SXscore), and compare its performance in isolation and combination with the PAMI (The Primary Angioplasty in Myocardial Infarction Study) score, for the prediction of 1-year clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention.Patients with STEMI were excluded from the original SYNTAX score (SXscore) algorithm. Therefore, the utility of using the SXscore in this patient group remains undefined.SXscore was calculated retrospectively in 807 patients with STEMI enrolled in the randomized STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) clinical trials. Clinical outcomes of all-cause death, reinfarction, and clinically driven target vessel revascularization were subsequently stratified according to SXscore tertiles: SX(LOW) ≤ 9 (n = 311), 9SX(MID) ≤ 16 (n = 234), SX(HIGH)16 (n = 262).At 1-year follow-up, all clinical outcomes including mortality, mortality/reinfarction, major adverse cardiac events (MACE) (a composite of all-cause death, reinfarction and target vessel revascularization), and definite, definite/probable, and any stent thrombosis were all significantly higher in patients in the highest SXscore tertile. SXscore was identified as an independent predictor of mortality, MACE, and stent thrombosis out to 1-year follow-up. The combination SYNTAX-PAMI score led to a net reclassification improvement of 15.7% and 4.6% for mortality and MACE, respectively. The C-statistics for the SXscore, PAMI score, and the combined SYNTAX-PAMI score were 0.65, 0.81, and 0.73 for 1-year mortality, and 0.68, 0.64, and 0.69 for 1-year MACE, respectively.SXscore does have a role in the risk stratification of patients with STEMI having primary percutaneous coronary intervention; however, this ability can be improved through a combination with clinical variables. (Multicentre 2×2 Factorial Randomised Study Comparing Tirofiban Versus Abciximab and SES Versus BMS in AMI; NCT00229515).

Summary. Background: On top of aspirin, an abciximab bolusonly regimen results in a 30% drop in platelet inhibition at 6 h as compared with the on-label regimen. The concomitant administration of high loading dose clopidogrel, by bridging with abciximab bolus, may sustain suppression of platelet activity over time. Objectives: To investigate the non-inferiority of abciximab bolus-only and concomitant high loading dose clopidogrel vs. abciximab bolus + infusion with respect to the inhibition of platelet aggregation (IPA) as determined by light transmission aggregometry. Patients/Methods: Seventy-three patients with non-ST segment elevation acute coronary syndromes underwent double-blind randomization to abciximab bolus followed by a 12-h placebo infusion and concomitant 600mg clopidogrel vs. abciximab bolus + a 12-h infusion and 300 mg of clopidogrel. IPA was determined by light transmission aggregometry throughout 24 h. Clopidogrel poor responsiveness was defined as ‡ 50% 5 lmol L )1 ADP-induced maximum platelet aggregation. Results: In clopidogrel responders (n = 68), IPA after 20 lmol L )1 ADP at 4 h was 89% ± 13% in the bolus-only arm vs. 92% ± 14% in the bolus + infusion arm (P = 0.011 for non-inferiority). IPA after 5 or 20 lmol L )1 ADP and 5 or 15 lmol L )1 TRAP and the proportion of patients showing ‡ 80% IPA did not differ at any time point, irrespective of clopidogrel responsiveness status. Thirty-day outcomes were similar, whereas hemoglobin (0.91 ±0 .8 vs. 0.5 ±0 .7 gd L )1 ; P = 0.01) and platelet count mean drop (41.7 ± 57 vs. 18.6 ± 34 10 9 L )1 ; P = 0.042) were significantly reduced in the bolus-only arm. Conclusions: Withholding abciximab post-bolus infusion in patients receiving high loading dose clopidogrel does not impair platelet inhibition throughout 24 h, and has the potential to improve the safety profile of the drug at reduced costs.