[Show abstract][Hide abstract] ABSTRACT: Ochratoxin A (OTA) is a secondary metabolite produced
by several Penicillium and Aspergillus species
with carcinogenic, hepatotoxic, nephrotoxic, teratogenic,
and immunosuppressive properties. OTA has
been implicated in the etiology of Balkan endemic
nephropathy and has been associated with an increased
incidence of tumours of the upper urinary tract. OTA
can occur in animal products as a result of either
direct contamination with toxigenic moulds or indirect
transmission (carryover) in animals fed with naturally
contaminated feed. The aim of the present study
was to evaluate the presence of OTA in serum samples
of slaughtered pigs. Serum samples were analysed
for OTA by an HPLC method. The limits of
quantification (LOQ) and determination (LOD) of the
method were 0.025 and 0.0125 ng/ml, respectively. The
recovery of OTA was 91.0±5%. Precision and accuracy
were within 8.9%. Fifty-one Italian (Tuscany)
pig serum samples (82% of 62 analysed) were found
to be naturally contaminated with OTA in the range
of 0.17–2.81 ng/ml. Similar OTA contamination was
observed in the serum samples collected from the same
farm. These results suggest that the amount of OTA in
pig blood is expressive of the general exposure of the
individuals to this mycotoxin and could be useful to
give a general outlook over the contamination of an
entire herd where the same diet was fed.
[Show abstract][Hide abstract] ABSTRACT: It is not known if diastolic abnormalities are independent of systolic dysfunction in arterial hypertension. We studied three groups of 10 male subjects of comparable mean age (31.6 ± 3.5 years), weight, and height: Athletes (A) (cyclists), essential hypertensive patients (H), and controls (C). Ultrasonic myocardial integrated backscatter signals (IBS) of the septum and the posterior wall were analyzed, while the systo-diastolic variation of the backscatter was considered as a cyclic variation index (CVIibs). Myocardial velocities across the left ventricular major axis were sampled at septum and lateral wall levels by pulsed-wave Doppler tissue imaging (DTI). CVIibs at the septum and the posterior wall were significantly lower in the hypertensive group in comparison with athletes and controls, who were comparable. Early diastolic myocardial velocity (Em) of the lateral wall and of the septum were significantly lower in hypertensives, while the late diastolic myocardial velocity (Am) was significantly higher in hypertensives in comparison with athletes. The Em/Amat the septum level was significantly lower in hypertensives in comparison with athletes and controls. Significant correlations were found between CVI and DTI parameters: CVIibs and Em/Am septum(r = 0.50, P < 0.002). Furthermore, significant correlations were found between mean arterial pressure (MAP) and Em/Am septum (r =−0.65, P < 0.001). Ultrasonic tissue characterization with the intrinsic contractility study and the evaluation of the regional diastolic function should, therefore, represent a new integrated diagnostic modality for the evaluation of left ventricular hypertrophied intramyocardial function. This study demonstrated that diastolic abnormalities of left ventricular function, in arterial hypertension, are related and progress with systolic intrinsic dysfunction.
[Show abstract][Hide abstract] ABSTRACT: Currently, there are no reports on the effects of enrofloxacin (EF), a fluoroquinolone antibiotic, on the cytochrome p450 enzymes in fish, although its use as antimicrobial agent in aquaculture has been put forward. Therefore, the in vivo and in vitro effects of EF on hepatic p450 enzymes of sea bass, a widespread food-producing fish, have been evaluated. Sea bass pretreated with a single dose of EF (3 mg/kg i.p.) or with three daily doses of EF (1 mg/kg i.p.) markedly depressed the microsomal N-demethylation of aminopyrine, erythromycin, the O-deethylation of 7-ethoxycoumarin, ethoxyresorufin and the 6beta-testosterone hydroxylase. In vitro experiments showed that EF at 10 microM inhibited the above-mentioned activities and, in particular, the erythromycin N-demethylase (ERND) and 6beta-testosterone-hydroxylase, likely dependant on a p450 3A isoform. When the nature of ERND inhibition by EF was specifically studied with sea bass liver microsomes, it was found that EF is a potent mechanism-based inhibitor, with K(i) of 3.7 microM and a K(inact) of 0.045 min(-1). An immunoblot analysis with anti p450 3A27 of trout showed that the p450 3A isoform, constitutively expressed in sea bass, is particularly susceptible to inactivation by EF. In vitro experiments with sea bass microsomes have also demonstrated that EF is oxidative deethylated by the p450 system to ciprofloxacin (CF) and that this compound maintains the ability to inactivate the p450 enzymes. The mechanism by which EF or CF inactivate the p450 enzymes has not been studied but an attack of p450 on the cyclopropan ring, present, both in EF and CF structure, with the formation of electrophilic intermediates (i.e. radicals) has been postulated. In conclusion, the EF seems to be a powerful inhibitor of p450s in the sea bass. Therefore, the clinical use of this antibiotic in aquaculture has to be considered with caution.
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to evaluate the accuracy of intermittent, harmonic power Doppler (HPD) during intravenous Levovist infusion in identifying myocardial perfusion abnormalities in patients with recent infarction. Fifty-five patients with first acute myocardial infarction, successfully treated by primary PTCA, were studied after 1 month by myocardial contrast echocardiography (MCE), 99mTc tetrofosmin single photon emission computed tomography (SPECT), and low dose dobutamine echocardiography (DE). Scoring myocardial perfusion as normal, moderately, or severely reduced; MCE and SPECT were in agreement in 71% of segments(k = 0.414). Discordance was mainly due to ventricular walls with normal enhancement by MCE and moderate perfusion abnormalities by SPECT. Scoring perfusion as present or absent, the agreement significantly improved up to 86% (k = 0.59). Sensitivity and specificity of HPD for identifying SPECT perfusion defects were 63% and 93%, respectively. The agreement between MCE and SPECT was higher(85%, k = 0.627)in patients with anterior infarction. An improvement in regional contractile function was noted after dobutamine in 79 dysfunctional segments. A normal perfusion or a moderate perfusion defect by MCE were detected in 71 of 79 of these segments, while a severe perfusion defect was observed in 59 of 85 ventricular segments without dobutamine-induced wall-motion improvement. Sensitivity and specificity by HPD in detecting segments with contractile reserve were 90% and 69%, respectively. Thus, intermittent HPD during Levovist infusion allows myocardial perfusion abnormalities to be detected in patients with recent infarction. This method has a limited sensitivity but a high specificity in detecting SPECT perfusion defects, and a good sensitivity but a limited specificity in detecting contractile reserve.
[Show abstract][Hide abstract] ABSTRACT: Grapefruit juice changes the pharmacokinetic parameters of a variety of drugs metabolized primarily by cytochrome P450 3A. In a three-phase crossover study, six male beagle dogs were administered 100 ml of water (control), 100 ml of commercial liquid grapefruit juice, or 10 g of freeze-dried grapefruit juice (equivalent to 100 ml of liquid grapefruit juice) with 100 ml of water, followed after 2 h by single oral dose of praziquantel (30 mg kg(-1)). After treatment, the dogs were sampled at different times. Determination of praziquantel and its metabolite 4'-hydroxy praziquantel (identified by GC/MS) was performed by HPLC. Liquid and freeze-dried grapefruit juice preadministration increased the C(max) of praziquantel about three-fold and the AUC 2.5- and 2.3-fold, respectively. The T(max) (0.75 h) was unaffected by liquid or freeze-dried grapefruit juice, while T(1/2) was 2.3- and 1.7-fold higher compared with controls. The amount of 4'-hydroxy praziquantel was also affected by both liquid and freeze-dried grapefruit juice administration: the AUC and C(max) increased four- and three-fold, respectively and the T(max) was significantly enhanced. These findings demonstrate that both freeze-dried grapefruit juice and commercial liquid grapefruit juice significantly increase plasma concentrations and T(1/2) of praziquantel in dogs.
Pharmacological Research 02/2003; 47(1):87-92. DOI:10.1016/S1043-6618(02)00251-7 · 3.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eight healthy Holstein-Friesian calves and 8 Massese lambs of either sex (10-15-days old) were used to evaluate the pharmacokinetics of thiamphenicol after intravenous (i.v.) and oral (p.o.) administration (30 mg/kg). Plasma concentrations of thiamphenicol were determined by high-performance liquid chromatography on blood samples collected over 24h following treatment. Pharmacokinetic variables of the drug were calculated for both species and after both administration routes. After intravenous administration of thiamphenicol, a rapid distribution phase was followed by a slower elimination phase and, when thiamphenicol was administered p.o., the bioavailability was about 60% in both species. The higher volume of distribution and the longer biological elimination half-lives in pre-ruminant compared with adult animals indicate that thiamphenicol distributes widely into the extravascular compartment of pre-ruminants. Interspecies differences were observed in the kinetic behaviour of thiamphenicol with respect to peak plasma concentration (C(max)), time of peak plasma concentration (T(max)), elimination half-life (T(1/2)) and total clearance (Cl(B)). In conclusion intravenous or oral administration of 30 mg/kg of thiamphenicol provides plasma concentrations higher than minimum effective concentrations inhibiting bacterial growth (MICs) against most pathogens in pre-ruminant lambs and calves.
Research in Veterinary Science 01/2003; 73(3):291-5. DOI:10.1016/S0034-5288(02)00110-8 · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess the role of intravenous myocardial contrast echocardiography (IMCE) in the prediction of left ventricular (LV) remodeling in patients with acute myocardial infarction (AMI). Sixty-three patients with AMI, who were successfully treated with acute coronary angioplasty, underwent IMCE and low-dose dobutamine echocardiography during hospital admission. IMCE was graded semiquantitatively on a score of 0 (no visible contrast effect), 0.5 (patchy myocardial contrast enhancement), and 1 (homogenous contrast effect). Patients were considered to have microvascular impairment if <50% of segments within the infarct-related area had score of 1. A mean perfusion score index was calculated for each patient. Patients with a good perfusion at IMCE (IMCE+) showed a lower creatine kinase peak (p = 0.001) and lower creatine kinase-MB (p = 0.01), and a better baseline regional contractile function compared with patients who had negative results at IMCE (IMCE-) (p <0.0001) and a higher amount of myocardial viability at low-dose dobutamine echocardiography (p = 0.03). At follow-up, a higher improvement in regional systolic function (p = 0.0006) was observed in IMCE+ patients, whereas IMCE- patients showed an evident increase in LV end-diastolic volume from baseline to 6-month follow-up (p <0.0001), implying LV remodeling, which has been associated with a higher incidence of adverse cardiac events (p = 0.005). By stepwise multiple regression analysis, microvascular impairment at IMCE was a significant independent predictor of LV remodeling (p <0.0001). Thus, IMCE seems to be an important diagnostic tool, able to predict LV remodeling in patients with AMI.
The American Journal of Cardiology 11/2002; 90(7):713-9. DOI:10.1016/S0002-9149(02)02595-X · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Quantitative myocardial contrast echocardiography was performed with harmonic power Doppler analysis using the background subtraction and Levovist (Schering AG, Berlin, Germany) as contrast agent in a triggered modality. Quantitative analysis of echocontrast was performed offline with PC software, obtaining the transit curves of microbubbles through the coronary capillary system. Coronary microcirculation in athletes showed a behavior substantially comparable with control participants, although at a higher level. Training determines a physiologic left ventricular hypertrophy that counterbalances the dilatation in the left ventricular chambers because of the higher blood volume in athletes compared with control participants. Angiogenesis and several functional adaptations (relaxation of small coronary arteries, increased production of nitric oxide by the coronary endothelium, or both), represent the potential mechanisms that allow an optimal distribution of oxygen and of substrates to the hypertrophied myocardium of the athletes.
Journal of the American Society of Echocardiography 08/2002; 15(7):678-85. DOI:10.1067/mje.2002.119259 · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aims of the present study were: (a) to demonstrate whether quantitative myocardial contrast echocardiography can detect the increase in coronary flow induced by dipyridamole infusion vasodilation through the myocardial opacification due to the transit of microbubbles, both at rest and after dipyridamole induced vasodilation; (b) to explore the coronary microcirculatory function before and after dipyridamole in two different models: asymptomatic and relatively young hypertensive patients with a mild degree of left ventricular hypertrophy, and healthy controls.
Two groups of strictly age-matched males were studied (case-control study): 10, relatively young and asymptomatic essential hypertensive patients with a mild degree of left ventricular hypertrophy with a normal left ventricular function, and 10 healthy controls. The main findings were: the microbubbles' appearance area was significantly lower in hypertensive patients than in controls (P<0.05) because of a significantly lower time to peak. The peak intensity at rest was higher in hypertensives than in controls (P<0.05); but the per cent increase after vasodilatory stimulus was significantly higher in controls (+71% in controls vs +31% in hypertensives; P<0.05). The microbubbles' disappearance area was comparable in both groups at rest; the per cent increase of this parameter after dipyridamole was significantly higher in controls (+124%) than in hypertensives (+90%) (P<0.05). The results achieved in this study documented that the coronary microcirculation in hypertensive patients presenting a mild degree of left ventricular hypertrophy, explored with quantitative myocardial contrast echocardiography, showed a different behaviour in comparison with controls, in the vasodilatory response to dipyridamole.
The coronary microcirculation in hypertensives showed a reduced vasodilation capacity of the resistance arterioles under dipyridamole induced vasodilatation, and a possible impairment of the endothelium dependent vasodilation. This happened despite an increase in the left ventricular mass, where the relation between capillary bed distribution and hypertrophied myocardium (rarefaction phenomenon) is not completely respected.
[Show abstract][Hide abstract] ABSTRACT: It is not known if diastolic abnormalities are independent of systolic dysfunction in arterial hypertension. We studied three groups of 10 male subjects of comparable mean age (31.6 +/- 3.5 years), weight, and height: Athletes (A) (cyclists), essential hypertensive patients (H), and controls (C). Ultrasonic myocardial integrated backscatter signals (IBS) of the septum and the posterior wall were analyzed, while the systo-diastolic variation of the backscatter was considered as a cyclic variation index (CVI(ibs)). Myocardial velocities across the left ventricular major axis were sampled at septum and lateral wall levels by pulsed-wave Doppler tissue imaging (DTI). CVI(ibs) at the septum and the posterior wall were significantly lower in the hypertensive group in comparison with athletes and controls, who were comparable. Early diastolic myocardial velocity (E(m)) of the lateral wall and of the septum were significantly lower in hypertensives, while the late diastolic myocardial velocity (A(m)) was significantly higher in hypertensives in comparison with athletes. The E(m)/A(m) at the septum level was significantly lower in hypertensives in comparison with athletes and controls. Significant correlations were found between CVI and DTI parameters: CVI(ibs) and E(m)/A(m) septum (r = 0.50, P < 0.002). Furthermore, significant correlations were found between mean arterial pressure (MAP) and E(m)/A(m) septum (r = - 0.65, P < 0.001). Ultrasonic tissue characterization with the intrinsic contractility study and the evaluation of the regional diastolic function should, therefore, represent a new integrated diagnostic modality for the evaluation of left ventricular hypertrophied intramyocardial function. This study demonstrated that diastolic abnormalities of left ventricular function, in arterial hypertension, are related and progress with systolic intrinsic dysfunction.
[Show abstract][Hide abstract] ABSTRACT: Praziquantel (PZQ) is a broadly effective trematocide and cestocide, widely employed in veterinary and human medicine. In view of several differences in both its pharmacokinetic profile in different animal species and in the cytochrome P450-dependent system between ruminant and nonruminant species, the present study was undertaken to determine the pharmacokinetics of this drug, its effects on the P450 system and the involvement of cytochrome P450 in its metabolism in 3-month-old lambs infested by Fasciola hepatica. Following both oral and i.m. administration, PZQ disposition was best described by a linear one-compartment open model with a rapid absorption and elimination. Although the PZQ dose used by the i.m. route was only half of that used by the oral route, the mean PZQ plasma concentration was higher after i.m. than after oral treatment. Oral treatment with 30 mg/kg/day of PZQ did not modify the mono-oxygenase activities tested, whilst the administration of PZQ at a dose of 60 mg/kg/day for 2 days caused a significant decrease in the P450 3A-dependent erythromycin N-demethylase and 6beta testosterone hydroxylase activities. From the incubation of microsomes from lambs not treated with PZQ, a single metabolite (PZQ 11b-OH or PZQ 1-OH) was identified by GC/MS analysis. By selective inhibition of the 3A subfamily performed with triacetyloleandromycin, the production of this metabolite declined by about 90% suggesting a prominent role of P450 3A isoforms in this oxidation. These features indicate that agents or drugs which are able to modulate P450 3A-dependent catalysis may interfere with the metabolism, bioavailability and therapeutic effects of PZQ.
Journal of Veterinary Pharmacology and Therapeutics 09/2001; 24(4):251-9. DOI:10.1046/j.1365-2885.2001.00341.x · 1.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The plasma kinetics and tissue distribution of enrofloxacin (EF) were investigated in the seabass (Dicentrarchus labrax) after administration by oral gavage and by bath. Plasma and tissue concentrations of EF and of its metabolite ciprofloxacin (CF) were determined by HPLC. After oral treatment (5 mg/kg bw), EF was slowly absorbed and eliminated (Cmax=1.39±0.67 μg/ml at 8 h; T1/2=25 h). EF was distributed efficiently to the extravascular compartment, with concentrations in liver constantly higher than in muscle and skin. Bath treatment (5, 10 or 50 ppm for 4, 8 or 24 h) resulted in plasma and tissue levels that significantly correlated with water drug concentration or time of exposure to medicated water. CF was detected constantly in liver, occasionally in plasma, but never in muscle and skin, suggesting a low degree of metabolic conversion of EF in the seabass. After oral treatment at 5 mg/kg and bath treatment at 50 ppm for 4 h or at 5 ppm for 24 h, ratios between EF peak concentrations in plasma and tissues and MICs of EF against the most common fish pathogens exceeded those indicated as optimal to ensure the bactericidal efficacy of the drug. These dosages of EF are proposed for performing therapeutic trials in the seabass.
[Show abstract][Hide abstract] ABSTRACT: The pharmacokinetics of cephalexin, a first generation cephalosporin, were investigated in dogs using two formulations marketed for humans, but also often employed by practitioners for pet therapy. Cephalexin was administered to five dogs intravenously and intramuscularly as a sodium salt and by the oral route as a monohydrate. The dosage was always 20 mg/kg of active ingredient. A microbiological assay with Sarcina lutea as the test organism was adopted to measure cephalexin concentrations in serum. The mean residence time (MRT) median values after intravenous (i.v.), intramuscular (i.m.) and oral administration (p.o.) were 86 min, 200 min, and 279 min, respectively. After i.m. and oral dosing the peak serum concentrations (24.2 +/- 1.8 micrograms/mL and 20.3 +/- 1.7 micrograms/mL, respectively) were attained at 90 min in all dogs and bioavailabilities were 63 +/- 10% and 57 +/- 5%, respectively. The time course of the cephalexin serum concentrations after oral administration was best described by a model incorporating saturable absorption kinetics of the Michaelis-Menten type: thus in the gastrointestinal tract of dogs a carrier mediated transport for cephalexin similar to that reported in humans, may exist. The predicted average serum concentrations of cephalexin after repeated i.m. and oral administration indicated that, in order to maintain the therapeutic concentrations, the 20 mg/kg b.w. dosage should be administered every 6-8 h.
Journal of Veterinary Pharmacology and Therapeutics 11/1999; 22(5):308-13. DOI:10.1046/j.1365-2885.1999.00208.x · 1.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The disposition of a combination of antimony (Sbv) (12.8 mg/kg) and aminosidine (AM) (10 mg/kg) in 10 healthy Beagle dogs after multiple subcutaneous injections is described. Sbvplasma concentrations were determined by atomic absorption spectrometry, and AM by ion-pair liquid chromatography, using a fluorimetric detector. Sbvreached Cmaxat 60 min, and for about 1 h plasma levels were homogeneously stabilized between 10.78 and 11.76 microgram/mL; by 12 h, Sbvplasma concentrations were close to the detection limit (0.3 microgram/mL). AM Cmaxvalues were recorded after 1 h (30.6+/-3.11 microgram/mL, mean +/- SD), and plasma levels reached values close to the detection limit (0.15 microgram/mL) between 7 and 8 h after injection. Sbvkinetic parameters did not appear modified by the presence of AM. Moreover, repeated injections of the combination did not modify the kinetic behaviour of the two drugs and did not alter the renal function of the animals. The superimposition analysis of the Sbvdata suggests that a twice daily injection of the metal at a dose of 12.8 mg/kg would be sufficient to maintain inhibitory Sbvconcentrations similar to those recorded in humans.
The Veterinary Journal 06/1999; 157(3):315-21. DOI:10.1053/tvjl.1998.0301 · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We explored the role of microcirculation integrity following the chronic occlusion of an infarct-related artery to assess the behaviour of collateral circulation during and after reperfusion by coronary angioplasty
Eighteen patients with a proximally occluded left anterior descending artery and firm evidence of intercoronary collateral circulation were studied with selective coronary angiography and selective intracoronary myocardial contrast echocardiography, before coronary angioplasty, and at 5 and 15 min and 12 h later. Myocardial enhancement during myocardial contrast echocardiography was evaluated with a semiquantitative score (0-3), which was correlated to basal and 6 months' regional left ventricular wall motion results. 16/18 procedures were successfully performed; four patients with an inadequate acoustic window were excluded. Restenosis was evident at the 6 months' follow-up in two patients. Basal myocardial contrast echocardiography indicated that 81/192 segments from the left anterior descending coronary artery and 90/192 from the right coronary artery were perfused; no perfusion was observed in 21 segments either before or after coronary angioplasty. After coronary angioplasty, the angiographic intercoronary collateral circulation immediately disappeared, and myocardial contrast echocardiography revealed that there was a progressive reduction of segments perfused by the right coronary artery and an increase in segments perfused by the left anterior descending coronary artery. Regional left ventricular wall motion analysis demonstrated that there was abnormal motion in 51/192 segments. There was no improvement in segments with score 0 and abnormal motion after 6 months (100% sensitivity), but 16/17 segments with score 3 did show an improvement (98% specificity). The predictive value of intermediate scores (1-2) in detecting long-term improvement, was only 43%.
These data show that the adaptive mechanism observed in the behaviour of epicardial and microvascular circulation after reperfusion of a chronic occluded infarct-related artery can vary. In addition, this study clearly shows that microvascular integrity detected by myocardial contrast echocardiography can provide myocardial viability.
European Heart Journal 12/1998; 19(11):1681-7. · 14.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The goal of this study was to investigate the role of left ventricular outflow tract obstruction and myocardial hypertrophy on autonomic cardiac function in patients with hypertrophic cardiomyopathy.
The sympatho-vagal function was evaluated by spectral analysis of heart rate variability in 28 patients with hypertrophic obstructive cardiomyopathy, 22 patients with hypertrophic non-obstructive cardiomyopathy, 12 with systemic hypertension and left ventricular hypertrophy and 28 healthy subjects. Left ventricular out-flow tract pressure gradient in patients with hypertrophic cardiomyopathy was evaluated by echo-Doppler methods and the quantitative assessment of left ventricular hypertrophy was based on an echocardiographic index. At rest, patients with hypertrophic non-obstructive cardiomyopathy showed normal spectral patterns, while in patients with hypertrophic obstructive cardiomyopathy and in patients with systemic hypertension we observed, respectively, a significant reduction and increase in the low frequency component relative to the control (P < 0.05). During tilt, the physiological increases in the low frequency component and in the low to high frequency ratio were markedly blunted, or even reverted, only in patients with hypertrophic obstructive cardiomyopathy. In these patients, the heart rate increase during tilt was delayed in comparison to the other groups. Finally, in the hypertrophic obstructive cardiomyopathy group, the impairment of sympathetic activation (lack of increase in the low frequency component during tilt) was significantly correlated to the echocardiographic index of left ventricular hypertrophy (r = -0.800, P < 0.001) rather than to the left ventricular outflow tract pressure gradient (r = 0.295, P: ns).
Among patients with hypertrophic cardiomyopathy, only those with outflow tract obstruction show spectral signs of altered autonomic cardiac control. Within this group, the autonomic dysfunction appears to be correlated to myocardial hypertrophy rather than to left ventricular outflow tract obstruction.
European Heart Journal 01/1998; 19(1):146-53. · 14.72 Impact Factor