Efficacy and safety of dabigatran in a "real-life" population at high thromboembolic and hemorrhagic risk: data from MonaldiCare registry.

OBJECTIVE: Dabigatran is a novel target specific oral anticoagulant for stroke prevention in non valvular atrial fibrillation. Little is still known about its real-world effectiveness and safety in the italian population. Aim of our study was to evaluate the efficacy and safety of dabigatran in a large single-center cohort of "real-life" italian population with non-valvular AF and to compare the results with those obtained from the RE-LY trial and the Medicare study. PATIENTS AND METHODS: We studied a prospective cohort of 2108 patients (1119 male; mean age 69.4 ± 9.4 years) who started the oral anticoagulant treatment with dabigatran 110 mg twice-daily (DAB 110; N = 1075; 51%) or 150 mg twice-daily (DAB 150; N = 1033; 49%). Follow-up data were obtained trough outpatients visits each 3-6 months for assessing the clinical status, adherence to treatment, occurrence of side effects and major cardiovascular complications. RESULTS: In DAB 150 group the mean age was 64.9 ± 8.8 years, 56.8% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 94.3% and HAS-BLED was ≥ 3 in 59.7%. In DAB 110 group (N = 1075) the mean age was 73.9 ± 7.5 years; 49.5% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 73.4% and HAS-BLED was ≥ 3 in 87.4% of DAB 110 patients. One patient taking Dabigatran 110 mg bid had ischemic stroke without significantly neurological sequelae. In both groups, no patient experienced hemorrhagic stroke during the follow-up period. 147 patients (6.9%) of MonaldiCare population reported adverse effects from treatment with dabigatran, of whom 121 patients (5.7%) discontinued therapy. We reported one case of subarachnoid hemorrhage (0.05%) in a patient with high thrombo-embolic and high hemorrhagic risk score who was taking dabigatran 150 mg bid and one case (0.05%) of bladder bleeding in a patient who was taking dabigatran 110 mg bid. No major gastrointestinal bleeding was observed in the MonaldiCare population. CONCLUSIONS: MonaldiCare registry showed a safety profile of both dosages of dabigatran regarding major of fatal bleeding in a "real life" single center italian population at high thromboembolic and hemorrhagic risk. The majority of MonaldiCare patients tolerated dabigatran treatment without significant side effects. The efficacy of dabigatran was demonstrated by very low prevalence of ictus/TIA, also when patients underwent electrical AF cardioversion independently of the transesophageal examination.

Retrospective analysis of 300 cases of paroxysmal supraventicular tachycardia by electrophysiological transesophageal study.

AIM: Paroxysmal supraventricular tachycardia (PSVT) is a very frequent type of arrhythmia. Atrioventricular nodal reciprocating tachycardia (AVNRT) and atrioventricular reciprocating tachycardia through extranodal accessory pathways (AVRT) are the most common types of paroxysmal supraventricular tachycardia. We describe our experience in diagnosing these tachycardia by electrophysiological transesophageal study (ETS). METHODS: Three hundred patients, 155 men and 145 women, (mean age, 37.2 +/- 16 years), with a history of palpitations underwent clinical evaluation and ETS. The clinical features of those with AVNRT and those with AVRT were compared. RESULTS: Of a total of 300 patients, tachycardia was diagnosed only in 234, of which 136 (58%) had AVNRT and 98 (42%) had AVRT. AVNRT patients were older than those with AVRT (P = or < 0.004); patients with AVRT had palpitations earlier (P = or < 0.0001). Dyspnea and asthenia were the most frequent symptoms in the AVNRT patients (P = or < 0,02; P = or < 0.04). There were statistically significant differences between the two patient groups in Wencke-bach time (P = or < 0.05), ventricular-atrial (V-A) interval (P = or < 0.03) and period of induced tachycardia (P = or < 0.04). CONCLUSIONS: ETS revealed important clinical and electrophysiological differences between patients with AVRT and those with AVNRT.

A statistical-based approach to assessing the fidelity of combinatorial libraries encoded with electrophoric molecular tags. Development and application of tag decode-assisted single bead LC/MS analysis.

A statistical sampling protocol is described to assess the fidelity of libraries encoded with molecular tags. The methodology, termed library QA, is based on the combined application of tag decode analysis and single bead LC/MS. The physical existence of library compounds eluted from beads is established by comparing the molecular weight predicted by tag decode with empirical measurement. The goal of sampling is to provide information on overall library fidelity and an indication of the performance of individual library synthons. The minimal sampling size n for library QA is l0 x the largest synthon set. Data are reported as proportion (p) +/- lower and upper boundary (lb-ub) computed at the 95% confidence level (alpha = 0.05). As a practical demonstration, library QA was performed on a 25,200-member library of statine amides (size = 40 x 63 x 10). Sampling was conducted three times at n approximately 630 beads per run for a total of 1902 beads. The overall proportions found for the three runs were consistent with one another: p = 84.4%, lb-ub = 81.5-87.2%; p = 83.1%, lb-ub = 80.2-85.95; and p = 84.5%, lb-ub = 81.8-87.3%, suggesting the true value of p is close to 84% compound confirmation. The performance pi of individual synthons was also computed. Corroboration of QA data with biological screening results obtained from assaying the library against cathepsin D and plasmepsin II is discussed.

Pervasive developmental disorder and epilepsy due to maternally derived duplication of 15q11-q13.

Duplications of chromosome 15 have been reported in individuals with atypical autism, varying degrees of mental retardation, and epilepsy. The authors report the molecular analysis, neurophysiologic, and clinical evaluation of a 12-year-old boy with atypical autism and epilepsy due to a maternally derived 15q11-q13 duplication. Their findings suggest that this chromosomal region harbors genes for autism and possibly for partial epilepsy that may act in a dose-dependent manner.

[Doppler echography in the intraoperative assessment of the liver circulation: an experimental study in swine]. / L'eco-Doppler nella valutazione intraoperatoria del circolo epatico: studio sperimentale nel suino.

In this experimental study the authors report an experience in the evaluation of hepatic blood flow with intraoperative echo-Doppler during orthotopic liver transplantation and side-to-side or end-to-side portacaval shunt. Doppler ultrasonography studied the flow of portal vein, hepatic artery and inferior vena cava before the recipient hepatectomy, and after reperfusion during liver grafting. Furthermore echo-Doppler of the portal system was performed to confirm portacaval shunt efficacy. Usually intraoperative Doppler ultrasonography may give informations about the patency of the shunt and regarding the development of early hepatic artery thrombosis during liver transplantation, but often unclear is the exact evaluation of the velocity of the blood flow through the liver. Further experimental studies and clinical evaluations need to find safe parameters and markers of vascular alteration using this superior diagnostic procedure.

Responding for rewarding brain stimulation: cocaine and isradipine plus naltrexone.

Rats, fixed with chronically indwelling electrodes for electrical intracranial stimulation (ICS) of the lateral hypothalamus, were taught to press a bar for ICS. Once pressing rates became stable, during daily 20-min sessions, rats were given cocaine (5 or 20 mg/kg) before the sessions. When given daily, cocaine consistently enhanced rates of pressing. When a combination of small doses of isradipine (e.g., 1 mg/kg) and naltrexone (3 mg/kg) were given before cocaine administration. the combination blocked cocaine's enhancement of pressing for ICS. The combination, however, neither reduced rates of pressing below those observed under placebos (i.e., baseline conditions) nor reduced rates when no cocaine was given. Naltrexone and isradipine (in the dose used in the combination) by themselves did not block cocaine's effects. This profile of effects indicates that a combination of isradipine and naltrexone is apt to be useful in treating cocaine use disorders.

Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library.

An encoded 13,020-member combinatorial library was synthesized containing a statine core. Evaluation of this library with plasmepsin II, an aspartyl protease required for hemoglobin metabolism in the malaria parasite, led to the identification of potent and selective inhibitors as well as novel structure-activity relationships.

Combination of naltrexone and fluoxetine on rats' propensity to take alcoholic beverage.

Naltrexone (NTX) and fluoxetine (FLU) are useful for treating alcoholism and depression, respectively. Furthermore, these afflictions covary. Given the possibility that people might be prescribed NTX and FLU concurrently, we assessed the effects of these two agents on rats' propensity to drink an alcoholic beverage. Rats were given 65 days of access to a sweetened alcoholic beverage and water for 2 hr daily. At first, they took little ethanol, but after 20 days, they took on average 2.0 to 2.5 g/kg of ethanol, daily during the 2-hr session. They also took sufficient water to maintain their health. After 30 days, they were divided into four groups to receive, 30 min before the drinking session, 1 of 4 different kinds of injections. For the next 20 days, one group received placebo daily. Another group received 5 mg/kg of NTX daily and another 5 mg/kg of FLU daily. The fourth group received both 5 mg/kg of NTX and 5 mg/kg of FLU daily. After 20 days, the doses of NTX and FLU were doubled across an additional 10 days. Both NTX and FLU reduced rats' intake of alcoholic beverage. The combinations of NTX and FLU, however, were no more effective in reducing rats' intake of alcoholic beverage than either alone. Also, the small dose of NTX seemed to lose its effectiveness with repeated administrations. A second experiment confirmed the conclusion that small doses of NTX lose their effectiveness in suppressing intake of alcoholic beverage across repeated administrations. In summary, data provide no support for the idea that FLU and NTX would act synergistically to reduce propensity to take alcoholic beverages.

Maximal blood lactate level acts as a major discriminant variable in exercise testing for coronary artery disease detection in men.

BACKGROUND: The interpretation of exercise stress testing for coronary artery disease detection is affected by the many differences in chosen variables and mathematical methods. We conducted a prospective trial to evaluate a global muscle fatigue parameter--the blood lactate level achieved at maximal exercise--as a method of distinguishing between diseased and nondiseased coronary status. METHODS AND RESULTS: We evaluated 236 consecutive male patients without previous myocardial infarction who had been referred for the diagnosis of coronary artery disease. None of the patients had cardiomyopathy, severe cardiac heart failure, or valvular heart disease. Blood lactate concentration at maximal exercise was measured as well as other classic variables. Correlations between variables and coronary status as assessed by coronary arteriography were described using receiver operating characteristic (ROC) curves and logistic regression analysis. The first four most powerful variables (lactate level, maximal power output, exercise duration, and percentage of maximal predicted heart rate), which are directly representative of the global functional capacity, showed values of 0.777, 0.775, 0.760, and 0.740, respectively, by ROC curve analysis. Mean +/- SD blood lactate level at peak exercise reached 7.68 +/- 2.70 mmol/L in the 153 diseased and 10.56 +/- 2.75 mmol/L in the 83 nondiseased patients (P < .0001). After adjustment for other variables, blood lactate level remained a significant predictor of coronary artery disease by logistic regression analysis (adjusted odds ratio, 1.2; confidence interval, 1.04 to 1.4). CONCLUSIONS: Global muscle fatigue as assessed by lactate levels in the blood at maximal exercise appears to be a powerful distinguisher of diseased and nondiseased coronary status.

Flecainide single oral dose for management of paroxysmal supraventricular tachycardia in children and young adults.

The efficacy of a single oral dose of flecainide to terminate paroxysmal supraventricular tachycardia (PSVT) was evaluated in 25 children and young adults. The subjects were selected from a group of 35 patients with recurrent attacks of PSVT evaluated by means of electrophysiologic study and intravenous electropharmacologic testing with flecainide. In all 25 patients the induced PSVT was stopped by intravenous flecainide and was then no longer inducible or nonsustained. All patients had normal hearts. At least 48 hours after acute intravenous testing, 25 patients underwent electrophysiologic study with a transesophageal catheter and PSVT was induced in all of them: atrioventricular reentrant tachycardia in 16 and atrioventricular nodal reentrant tachycardia in nine. During stable tachycardia, a single oral dose of flecainide (2.9 +/- 0.3 mg/kg; 2.5 to 3.3 mg/kg) was administered. This approach was effective for termination of PSVT in 22 patients. The mean plasma level of flecainide at cessation of tachycardia was 277 +/- 92 ng/ml (150 to 500 mg/ml). All 22 patients who responded were given a single oral dose of flecainide for recurrences of PSVT during follow-up. During a period of 12 +/- 7 months (2 to 27 months) a total of 134 spontaneous episodes of PSVT were reported, and 127 of these episodes were terminated with periodic management. Thus oral periodic flecainide seems useful for management of PSVT in selected patients.

Electrophysiological effects and clinical efficacy of propafenone in children with recurrent paroxysmal supraventricular tachycardia.

Twenty-four patients aged 10.1 +/- 4.5 (mean +/- SD) years with recurrent paroxysmal supraventricular tachycardia underwent an electrophysiological study. Eleven patients had an overt and seven had a concealed accessory connection; six patients had no accessory connection. An orthodromic reciprocating tachycardia was inducible in 17 of 18 patients with an accessory connection, and an atrioventricular nodal reentrant tachycardia was inducible in four of six patients without accessory connection. After administration of propafenone, the sinus cycle length decreased. Intra-arterial, intranodal, and His-ventricle intervals and QRS duration increased. The atrial and ventricular effective refractory periods and anterograde and retrograde effective refractory periods of the atrioventricular node increased. The cycle length at which nodal second-degree block occurred increased. Of 18 patients with accessory connection, propafenone prolonged retrograde conduction in all, blocked anterograde conduction in five, and prolonged it in six. The drug terminated the orthodromic reciprocating tachycardia in all 17 patients and the atrioventricular nodal reentrant tachycardia in three of four patients. In three of four patients with atrioventricular nodal reentrant tachycardia and in 15 of 17 patients with orthodromic reciprocating tachycardia, the tachycardia was no longer inducible or nonsustained after propafenone. A follow-up of 26 +/- 10 months revealed that the drug when orally administered to all patients prevented recurrences of tachycardia in 15 of 18 patients with and in four of six patients without accessory connection. The results of short-term drug testing with propafenone predict the response to long-term oral therapy with this drug.

Electrophysiologic effects and clinical efficacy of flecainide in children with recurrent paroxysmal supraventricular tachycardia.

The electrophysiologic effects of intravenous flecainide were evaluated in 16 patients aged 9 +/- 4 years: 15 with recurrent paroxysmal supraventricular tachycardia (SVT) and 1 with overt accessory pathway and history of syncope. Eleven patients had an accessory pathway; it was concealed in 2, overt in 9 and in 10 of these patients an orthodromic atrioventricular reentrant tachycardia was induced. Five patients without accessory pathway had an atrioventricular nodal reentrant tachycardia. After intravenous flecainide (1.5 mg/kg) the effective refractory period of the atrium and ventricle increased significantly; the anterograde and retrograde effective refractory periods of the atrioventricular node did not. Flecainide blocked retrograde conduction in the accessory pathway in 4 patients (effective refractory period 245 +/- 41 ms) and anterograde conduction in 8 of 9 patients (effective refractory period 284 +/- 57 ms). The mean cycle length of orthodromic reciprocating tachycardia and atrioventricular nodal reentrant tachycardia increased significantly. After flecainide tachycardia was noninducible in 6 patients with orthodromic reciprocating tachycardia and in 1 with atrioventricular nodal reentrant tachycardia. It was inducible but nonsustained (less than or equal to 30 seconds) in 1 patient with orthodromic reciprocating tachycardia and in 3 with atrioventricular nodal reentrant tachycardia. Fifteen patients continued oral flecainide treatment for 19 +/- 11 months.(ABSTRACT TRUNCATED AT 250 WORDS)

[Electrophysiological effects and clinical efficacy of flecainide in childhood patients with supraventricular reciprocating paroxysmal tachycardia]. / Effetti elettrofisiologici ed efficacia clinica della flecainide in pazienti di età pediatrica con tachicardia parossistica reciprocante sopraventricolare.

The electrophysiologic effects of intravenous (i.v.) flecainide were evaluated in 13 patients (pts) with recurrent paroxysmal supraventricular tachycardia (PSVT): 6 pts had an overt accessory pathway, 2 a concealed anomalous pathway and 5 had an idionodal reentrant tachycardia (AVNRT). Another patients with overt preexcitation underwent electrophysiologic testing as part of a diagnostic investigation for syncope. After flecainide the effective refractory period of the right atrium and retrograde AV node, and anterograde and retrograde Wenckebach point significantly increased. The drug blocked retrograde conduction on the accessory pathway in 3 pts whereas anterograde conduction was blocked in all 7 pts with overt anomalous pathway. The mean cycle length of the atrioventricular reentrant tachycardia (AVRT) and of the AVNRT increased respectively from 269 +/- 34 msec to 332 +/- 25 msec (P less than .005) and from 286 +/- 9 msec to 380 +/- 64 msec (P less than .05). After i.v. flecainide, reentrant supraventricular tachycardia was no longer inducible in pts with AVRT and 1 with AVNRT, inducible but non sustained (less than or equal to 30 seconds in duration) in 1 pt with AVRT and in 3 with AVNRT. Thirteen pts continued oral flecainide treatment for a mean of 7.2 +/- 3.6 months (range 3 to 12 months). Tachycardia recurred in all 3 pts whose arrhythmia remained inducible and sustained after i.v. flecainide, and in 1 of 10 pts whose re-entrant supraventricular tachycardia was suppressed (6 pts) or inducible but non sustained (4 pts). Thus flecainide is an highly effective and well tolerated drug for the control of PSVT in infancy. The electrophysiologic drug testing with flecainide predicts its efficacy during chronic therapy in most patients.

[Electrophysiologic effects and clinical efficacy of propafenone in pediatric patients with paroxysmal supraventricular reentrant tachycardia]. / Effetti elettrofisiologici ed efficacia clinica del propafenone in pazienti di età pediatrica con tachicardia parossistica reciprocante sopraventricolare.

Twenty patients (pts) with recurrent paroxysmal supraventricular tachycardia (PSVT), 12 female and 8 male, aged 9.8 +/- 4.7 years, underwent an electrophysiologic study (EPS) in order to assess the effects of propafenone (Pf) administered intravenously (1.5 mg/Kg in 3'). Thirteen pts (Group I) had an accessory pathway (AP) which was concealed in 5 and overt in 8 and in 12 of them an orthodromic atrioventricular reentrant tachycardia (ORT) was induced. In 5 of 7 pts (Group II) without AP an idio-nodal reentrant tachycardia (AVNRT) was induced. After Pf the sinus cycle length decreased significantly from 668 +/- 165 to 612 +/- 109 msec and PA, AH, HV intervals and QRS duration increased significantly from 35 +/- 11, 71 +/- 18, 34 +/- 6 and 73 +/- 12 to 43 +/- 11, 87 +/- 15, 39 +/- 9 and 85 +/- 10 msec respectively. The atrial and ventricular effective refractory period (ERP) increased from 216 +/- 18 and 211 +/- 19 to 227 +/- 21 and 217 +/- 21 msec respectively. The anterograde and retrograde nodal ERP and anterograde and retrograde Wenckebach point increased from 240 +/- 48, 227 +/- 28, 278 +/- 37 and 287 +/- 38 to 270 +/- 58, 330 +/- 32, 340 +/- 59 and 408 +/- 37 msec respectively. Pf terminated the tachycardia (T) in all 12 pts of Group I after prolongation of the cycle length which increased from 299 +/- 46 to 383 +/- 69 msec.(ABSTRACT TRUNCATED AT 250 WORDS)