Temperature-dependent electrical resistivity of macroscopic graphene nanoplatelet strips.

This paper studies the temperature dependence of the electrical resistivity of low-cost commercial graphene-based strips, made from a mixture of epoxy and graphene nanoplatelets. An equivalent homogenous resistivity model is derived from the joint use of experimental data and simulation results obtained by means of a full three-dimensional (3D) numerical electrothermal model. Three different types of macroscopic strips (with surface dimensions of cm2) are analyzed, differing in their percentage of graphene nanoplatelets. The experimental results show a linear trend of resistivity in a wide temperature range (-60°C to +60°C), and a negative temperature coefficient . The derived analytical model of temperature-dependent resistivity follows the simple law commonly adopted for conventional conducting materials, such us copper. The model is then validated by using the graphene strips as heating elements by exploiting the Joule effect. These results suggest that such materials can be used as thermistors in sensing or heating applications.

Comparison of benazepril-amlodipine and captopril-thiazide combinations in the management of mild-to-moderate hypertension.

OBJECTIVE: To compare the efficacy and tolerability of benazepril 10 mg + amlodipine 5 mg combination (BZ+AM) versus captopril 50 mg + hydrochlorothiazide 25 mg (CP+HT) combination. MATERIAL: 405 outpatients with mild-to-moderate arterial hypertension not adequately controlled by a monotherapy with ACE inhibitors or calcium channel blockers or diuretics entered this multicenter, double-blind, randomized, parallel-group study. METHOD: After a 2-week placebo run-in, 397 patients with sitting diastolic (D) blood pressure (BP) > 95 mmHg and/or sitting systolic (S) BP > 160 mmHg were randomized to receive either BZ+AM (201 patients) or CP+HT (196 patients) once daily for 12 weeks. Main outcome measure was sitting DBP and SBP values at the end of active treatment. The response rate was defined as the proportion of patients with either a final sitting DBP < 90 mmHg or decreased by at least 10 mmHg or a sitting SBP < 150 mmHg or decreased by at least 20 mmHg from baseline. RESULTS: The DBP and SBP values obtained with BZ+AM were, respectively, 2.7 and 3.7 mmHg lower than those obtained with CP+HT (both p < 0.001 vs. CP+HT). The response rate in the BZ+AM group (94.8%) was better than that observed in the CP+HT group (86.0%, p = 0.004). The incidence of adverse events was similar with the 2 treatment regimens (17.9% for both). CONCLUSIONS: These data suggest a higher antihypertensive efficacy of the fixed combination BZ 10 mg+AM 5 mg as compared with CP 50 mg+HT 25 mg.

A multicenter, randomized double-blind study of valsartan/hydrochlorothiazide combination versus amlodipine in patients with mild to moderate hypertension.

OBJECTIVE: To compare the antihypertensive efficacy and tolerability of a once-daily fixed valsartan/hydrochlorothiazide (HCTZ) combination and amlodipine in subjects with mild-to-moderate hypertension. SUBJECTS AND SETTING: In this multicentre, double-blind, randomized, comparative trial, 690 patients with sitting systolic blood pressure (BP) > or = 160 mmHg and sitting diastolic BP > or = 95 mmHg at the end of a 2-week placebo wash-out period were randomized to valsartan-based treatment (n = 342) or amlodipine (n = 348). METHODS: The patients received valsartan 80 mg o.d. or amlodipine 5 mg o.d for 4 weeks; in the case of an unsatisfactory blood pressure response, the treatments could be respectively changed to the fixed combination of valsartan 80 mg + HCTZ 12.5 mg o.d. or amlodipine 10 mg o.d. for a further 8 weeks. RESULTS: Both treatment approaches decreased systolic blood pressure and diastolic blood pressure to the same extent. The rate of responders to treatment at the end of fourth week (before up-titration) was 57.4% among the valsartan-treated patients and 61.9% among the amlodipine-treated patients (ns). At the end of the study, the rate of responders was not significantly different between the two groups (74.9 versus 72.1%). Valsartan-based treatment had a slightly lower incidence of adverse events (1.5 versus 5.5%; P = 0.006). CONCLUSIONS: The results of this trial demonstrate that the valsartan/hydrochlorothiazide combination and amlodipine are equally effective in lowering BP, and that the combination is better tolerated.

Solid-state (13)C CP MAS NMR spectroscopy of mushrooms gives directly the ratio between proteins and polysaccharides.

The solid-state (13)C CP MAS NMR technique has the potential of monitoring the chemical composition in the solid state of an intact food sample. This property has been utilized to study mushrooms of different species (Pleurotus ostreatus, Pleurotus eryngii, Pleurotus pulmunarius, and Lentinula edodes), already characterized by chemical analyses for protein and dietary fiber components. Solid-state (13)C CP MAS NMR spectroscopy reveals a large difference in the ratio between the glucidic and the proteic resonances probably depending on the mushroom species. An accurate inspection by model compounds and suitable mixtures of proteins and saccharides gives a methodology to interpret these experimental data. A good correlation (R(2) = 0.93; R(2) = 0.81) has been obtained by comparing the NMR data with the results of the chemical analyses. The results suggest the possibility to perform a taxonomic study and/or a nutritional study on the basis of the ratio between protein and polysaccharide levels determined by NMR or chemical methodologies.

In vivo thrombin generation and activity during and after intravenous infusion of heparin or recombinant hirudin in patients with unstable angina pectoris.

In patients with unstable angina, intravenous heparin reduces thrombin activity but does not influence thrombin generation. Recombinant hirudin, a direct thrombin inhibitor, may be more effective in inhibiting both thrombin generation and activity. We measured the plasma levels of prothrombin fragment 1+2 (a marker of thrombin generation) and fibrinopeptide A (a marker of thrombin activity) in 67 patients with unstable angina enrolled in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial who were receiving either recombinant hirudin (31 patients) or heparin (36 patients). Blood samples were obtained at baseline (before any treatment), after 3 to 5 days of study drug infusion (immediately before discontinuation), and 1 month later. In the patients receiving recombinant hirudin, the prothrombin fragment 1+2 levels measured immediately before drug discontinuation were significantly lower than at baseline (P:=0.0014), whereas they had not changed in the patients receiving heparin; at this time point, the difference between patients receiving hirudin and those receiving heparin was statistically significant (P:=0.032). One month later, the prothrombin fragment 1+2 levels in both groups were similarly persistently high and did not differ from baseline. Fibrinopeptide A plasma levels at the end of infusion were significantly lower than at baseline in both treatment groups (P:=0. 0005 for hirudin and P:=0.042 for heparin) and remained lower after 1 month (P:=0.0001 for both hirudin and heparin). The fibrinopeptide A plasma levels were not different between patients treated with hirudin versus heparin at baseline, at the end of infusion, and after 1 month. Thus, in patients with unstable angina, in vivo thrombin generation and activity are reduced during intravenous infusion of recombinant hirudin. However, the inhibition of thrombin generation is not sustained, and after 1 month, the majority of patients have biochemical signs of increased thrombin generation.

Preoperative plasma levels of prothrombin fragment 1 + 2 correlate with the risk of venous thrombosis after elective hip replacement.

Better preoperative identification of those patients at high risk of developing a deep vein thrombosis (DVT) after hip surgery could reduce the incidence of this postoperative complication, which still occurs despite prophylaxis. One hundred fifty-nine patients undergoing elective total hip replacement and given anticoagulant prophylaxis, were investigated, looking for the presence of a hypercoagulable state, that represents one element of Virchow's triad predisposing to DVT. Plasma levels of three markers of coagulation activation, namely prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT) and D-dimer were measured using ELISA procedures and were correlated with the results of the postoperative phlebography. A high correlation (p < 0.001) between the preoperative plasma levels of F1 + 2 and the risk of postoperative venous thromboembolism was detected. The performance of TAT and D-dimer levels in predicting DVT was lower. These findings support the hypothesis that preoperative measurement of coagulation activation markers might be useful in predicting DVT following a total hip replacement.

Effects of valsartan on left ventricular diastolic function in patients with mild or moderate essential hypertension: comparison with enalapril.

OBJECTIVE: This study compares the effects of an AT1 angiotensin II receptor antagonist (valsartan) with those of an ACE inhibitor (enalapril) on left ventricular (LV) diastolic function in patients with mild or moderate essential hypertension and no evidence of LV hypertrophy at echocardiography. METHODS: A total of 24 patients (16 men, mean age 47 +/- 8 years) underwent radionuclide ambulatory monitoring (Vest) of LV function at rest and during upright bicycle exercise testing before and after two 4-week treatment periods with valsartan (80-160 mg/day orally) and enalapril (20-40 mg/day orally) according to a double-blind, crossover randomization scheme. RESULTS: In the overall population no differences between the two treatments were found in LV peak filling rate (PFR) either at rest or at peak exercise. In a subgroup analysis it was found that baseline PFR was normal (= 2.5 EDV/sec) in 12 patients (subgroup A) and impaired (< 2.5 EDV/sec) in the remaining 12 (subgroup B). In both subgroups, valsartan and enalapril induced a significant and comparable reduction of systolic and diastolic blood pressure. In subgroup A, valsartan and enalapril did not induce significant changes in PFR. In subgroup B, valsartan increased PFR both at rest (from 2.0 +/- 0.3 to 2.4 +/- 0.3 EDV/sec, P < 0.01) and at peak exercise (from 4.1 +/- 1.1 to 4.4 +/- 1.0 EDV/s, P < 0.05), whereas enalapril did not change PFR either at rest (2.0 +/- 0.4 EDV/s, P < 0.01 versus valsartan) or at peak exercise (3.7 +/- 1.1 EDV/sec, P < 0.05 versus valsartan). CONCLUSIONS: Valsartan-induced renin-angiotensin system blockade is able to improve LV filling in patients with mild or moderate essential hypertension and impaired diastolic function. These findings support the hypothesis of a contribution of the renin-angiotensin system in the control of LV diastolic function in these patients.

Benazepril causes in hypertension a greater reduction in left ventricular mass than does nitrendipine: a randomized study using magnetic resonance imaging.

To assess the comparative effects of benazepril and nitrendipine monotherapies on left ventricular mass index (LVMI) in hypertensive patients with echocardiographically determined left ventricular hypertrophy, patients with diastolic blood pressure (BP) > or = 100 mm Hg were randomized to benazepril, 10 mg, or nitrendipine, 20 mg, both given once or twice daily. After 4 weeks, only the responders (diastolic BP <90 mm Hg) entered a 5-month maintenance period. At baseline, and after 3 and 6 months, LVMI was blindly estimated by means of magnetic resonance imaging (MRI) and, for comparison, by means of echocardiography. Of the 50 randomized patients, three were excluded from the study as nonresponders after 4 weeks; moreover, two patients taking benazepril and one taking nitrendipine discontinued the treatment after 2 months for adverse effects. Both monotherapies reduced systolic and diastolic BP to a similar extent. After 3 months, MRI-estimated LVMI decreased by 21.5 g/m2 in the benazepril and 8.8 g/m2 in the nitrendipine group, with an adjusted mean difference between the two groups of 11.1 g/m2 (95% CI, 7.3-14.8 g/m2; p = 0.0001). After 6 months, it decreased by 23.6 g/m2 and 10.0 g/m2, respectively, with an adjusted mean difference of 11.3 g/m2 (95% CI, 7.5-15.5; p = 0.0001) in favor of benazepril. In conclusion, despite a similar antihypertensive effect, benazepril led to a greater reduction in MRI-measured LVMI than did nitrendipine (-16.2% vs. -7.2%) in hypertensive patients with left ventricular hypertrophy.

Autonomic effects of nicotine patch administration in habitual cigarette smokers: a double-blind, placebo-controlled study using spectral analysis of RR interval and systolic arterial pressure variabilities.

Nicotine patch administration is often used to sustain tobacco abstinence in smoking-cessation programs. There is some concern regarding safety issues, as a consequence of the sympathomimetic action of nicotine. We used spectral analysis of RR interval and (noninvasive) systolic arterial pressure (SAP) beat-by-beat variabilities in a crossover double-blind design to assess the autonomic effects of cigarette smoking, of transdermal nicotine, and of placebo. The study group consisted of 27 heavy smokers (age 43 +/- 2 years). The RR interval and its variability were significantly reduced in the smoking group, as compared with nicotine or placebo groups. The LF component of RR interval variability (in normalized units, nu), and the LF/HF ratio showed greatest values during smoking, as compared with placebo. Values of LF(RR) and LF/HF during nicotine patch treatment were slightly, but not significantly, greater than observed with placebo. No differences were observed in SAP and its variability components. The index alpha (a frequency domain measure of baroreflex gain) was minimal in the smoking period. Habitual cigarette smoking is associated with signs of sympathetic predominance in the autonomic control of the sinoatrial (SA) node. Nicotine patches produce only minor disturbances of autonomic regulation. This corroborates their safe use in smoking-cessation strategies.

Clinical utility of prothrombin fragment 1+2, thrombin antithrombin III complexes and D-dimer measurements in the diagnosis of deep vein thrombosis following total hip replacement.

BACKGROUND: Measurements of prothrombin fragment 1+2 (F1+2), thrombin antithrombin III complexes (TAT) and D-dimer plasma levels have been proposed as non-invasive screening tests to exclude postoperative deep venous thrombosis (DVT). We investigated the diagnostic efficacy of these coagulation activation markers to rule out postoperative DVT in patients undergoing hip surgery under antithrombotic prophylaxis. METHODS: In this substudy of a randomized double-blind thrombosis prophylaxis trial comparing three doses of desirudin (10, 15 or 20 mg b.i.d.) with unfractionated heparin (5000 IU t.i.d.) we used ELISA procedures to measure F1+2, TAT and D-dimer in 159 patients undergoing total hip replacement at baseline (day 0) and on postoperative days 1, 3 and 6. Bilateral venography was performed in all cases 8-11 days after surgery. RESULTS: For the F1+2 assay sensitivity ranged from 73 to 83% in the three postoperative days investigated, and negative predictive value (NPV) from 68 to 74%. For TAT and D-dimer sensitivity ranged from 71 to 73% and from 71 to 83% and NPV from 61 to 65% and from 61 to 74% respectively. INTERPRETATION: In terms of sensitivity and NPV F1+2 and D-dimer are equivalent and are superior to TAT. However, their accuracy is too low to rule out the presence of DVT after hip surgery under antithrombotic prophylaxis.

Combined therapy with benazepril and amlodipine in the treatment of hypertension inadequately controlled by an ACE inhibitor alone.

In a multicenter, randomized, double-blind, placebo-controlled study, we evaluated the efficacy and tolerability of the combination of benazepril, 10 mg, and amlodipine, 2.5 or 5 mg once daily, compared with benazepril, 10 mg, monotherapy in patients with hypertension inadequately controlled with angiotensin-converting enzyme (ACE)-inhibitor monotherapy. After a 2-week placebo and 4-week single-blind benazepril, 10 mg once daily, run-in period, 448 patients, 213 men and 235 women, aged 24-73 years (mean, 55 years), with mean diastolic blood pressure (DBP) > or =95 and < or =120 mm Hg at the end of the benazepril run-in period, were randomized to receive one of the following treatments once daily for 8 weeks: (a) benazepril, 10 mg, plus placebo (BZ10); (b) benazepril, 10 mg, plus amlodipine, 2.5 mg (BZ10/AML2.5); or (c) benazepril, 10 mg, plus amlodipine, 5 mg (BZ10/AML5). Before the patients were admitted to the trial, at the end of the placebo run-in and the benazepril run-in period and at the end of weeks 4 and 8 of the treatment period, sitting and standing blood pressure (BP), heart rate (HR), and body weight were measured 22-26 h after the intake of the trial medication. Both BZ10/AML2.5 and BZ10/AML5 combinations showed better antihypertensive activity than did BZ10 monotherapy at the terminal visit as demonstrated by (a) the 24-h postdosing sitting and standing systolic BP (SBP) and DBP values, which were statistically lower with combination therapy than with BZ10; (b) the success rate, which was statistically higher with both the combinations (69.2% in the BZ10/AML2.5 and 65.8% in the BZ10/AML5 group) compared with the BZ10 group (40.5%). The tolerability was good in the three treatment groups. No significant abnormal laboratory data were detected. There was no difference in efficacy and safety/tolerability between the BZ10/AML2.5 and BZ10/AML5 groups.

Effect of transdermal nitroglycerin or N-acetylcysteine, or both, in the long-term treatment of unstable angina pectoris.

OBJECTIVES: This study was designed to evaluate whether the addition of transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy improves the natural history of unstable angina pectoris. BACKGROUND: Transdermal nitroglycerin is widely used to treat angina pectoris, but the development of tolerance is a major problem that may reduce its clinical efficacy. It has been suggested that the addition of N-acetylcysteine to nitroglycerin reverses the development of tolerance, potentiates the hemodynamic response to nitroglycerin and may improve in-hospital prognosis in unstable angina. METHODS: We assessed the efficacy of adding transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy in a randomized, double-blind, placebo-controlled trial involving 200 patients with unstable angina who were followed up for 4 months. RESULTS: Outcome events--death, myocardial infarction or refractory angina requiring revascularization--occurred in 31% of patients receiving nitroglycerin, 42% of those receiving N-acetylcysteine, 13% of those receiving nitroglycerin plus N-acetylcysteine and 39% of those receiving placebo (p = 0.0052). Kaplan-Meier curves showed a higher probability (p < 0.01) of no failure of medical treatment in the group receiving both nitroglycerin and N-acetylcysteine than in those receiving placebo, N-acetylcysteine or nitroglycerin alone. The combination of nitroglycerin and N-acetylcysteine was associated with a high incidence of side effects (35%), mainly intolerable headache, which was almost twice as frequent as in patients receiving nitroglycerin alone. CONCLUSIONS: The combination of nitroglycerin and N-acetylcysteine, associated with conventional medical therapy in the long-term treatment of patients with unstable angina, reduces the occurrence of outcome events. However, the high incidence of side effects limits the clinical applicability of this therapeutic strategy at least at the dosage used in the present study.

Coagulation activation markers in the prediction of venous thrombosis after elective hip surgery.

BACKGROUND: Despite prophylaxis, deep vein thrombosis (DVT) after hip surgery continues to occur frequently. Thus it would be helpful if before surgery patients at higher risk of DVT could be identified and more adequate prophylaxis given. As part of an international study on the prevention of DVT after total hip replacement, we investigated whether preoperative levels of three coagulation activation markers, prothrombin fragment F1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT) and D-dimer, correlate with results of postoperative venography. METHODS: 159 patients undergoing total hip replacement were randomized to receive 10, 15 or 20 mg desirudin bid or 5000 IU unfractionated heparin tid immediately before surgery and then for 11 days, until bilateral venography was performed. Preoperative F1 + 2, TAT and D-dimer plasma levels were measured using ELISA procedures. As no difference among anticoagulant treatments or in the interaction between treatments and DVT was detected for any of the three variables, results are reported as pooled data. FINDINGS: The frequency of DVT was 18.8% in the low (0.75-1.33 nM) vs 65.7% in the high third of distribution (1.77-3.47 nM) of F1 + 2 (p < .001), 27.3% in the low (2.00-2.50 micrograms/l) vs 57% in the high third (5.10-61.00 micrograms/l) of TAT (p = .042), and 29.4% in the low (39-59 micrograms/l) vs 57.1% in the high third (129-651 micrograms/l) of D-dimer (p = .051). INTERPRETATION: Preoperative F1 + 2, TAT and D-dimer levels are associated with the risk of development of DVT after total hip replacement.

Twenty-four-hour blood pressure monitoring during treatment with extended-release felodipine versus slow-release nifedipine in elderly patients with mild to moderate hypertension: a randomized, double-blind, cross-over study.

OBJECTIVE: This double-blind, placebo-controlled randomized study was designed to compare the antihypertensive effect and tolerability of extended-release felodipine and slow-release nifedipine retard in elderly hypertensive patients. METHODS: Thirty patients of both sexes (mean age 71 years) with mild to moderate essential hypertension were recruited from our hypertension outpatient clinic. After a 2-week placebo period, felodipine extended-release (felodipine ER), 10 mg once daily, nifedipine slow-release retard (nifedipine SR), 20 mg twice daily or placebo were administered to each patient for 2 weeks according to a 3 x 3 latin-square design. At the end of each treatment period, the patients underwent 24-h noninvasive blood pressure monitoring. RESULTS: All of the patients completed the trial and no serious adverse experience was reported. In comparison with placebo, felodipine and nifedipine decreased mean 24-h diastolic blood pressure by 6.7 and 4.3 mmHg, respectively, with no significant difference between the two drugs. Mean 24-h systolic blood pressure also decreased after felodipine and nifedipine, with no difference between the two drugs. Both drugs reduced blood pressure variability, lowering the 24-h mean standard deviation of mean hourly blood pressure values. The trough:peak ratio for felodipine was 80% for systolic and 75% for diastolic blood pressure. CONCLUSION: Felodipine ER once daily lowers blood pressure in elderly hypertensives and is as effective as nifedipine SR twice daily. The high trough:peak ratio suggests that the dose and the between-dose interval of felodipine provides adequate therapeutic coverage.

Effects of benazepril and nicardipine on microalbuminuria in normotensive and hypertensive patients with diabetes.

Diabetic nephropathy is the most frequent cause of chronic renal failure. The onset of microalbuminuria in patients with diabetes mellitus, which seems to be related to blood pressure and the control of glycemia, is predictive of the development of true proteinuria. This multicenter, single-blind, randomized study examined the effects of benazepril and nicardipine on overnight microalbuminuria in 57 normotensive and 46 hypertensive diabetic patients. At the end of a 3-month placebo run-in period, the patients were stratified on the basis of the presence or absence of arterial hypertension and, within each stratum, randomized to receive one daily tablet of 10 mg benazepril or one tablet of 20 mg nicardipine twice daily for 6 months. Renal hemodynamics was investigated in 25 patients. Both drugs decreased overnight microalbuminuria throughout the study period, but benazepril was more effective than nicardipine (p = 0.025); in the patients with hypertension, both drugs led to a similar marked reduction in systolic and diastolic blood pressure. This study shows that benazepril was more effective than nicardipine in reducing overnight microalbuminuria in patients with diabetes mellitus, independently of their antihypertensive properties.

Treatment of hypertension associated with stable angina pectoris: favourable interaction between new metoprolol formulation (OROS) and nifedipine.

This was a double-blind, within-patient, crossover study to evaluate the effects of a new formulation of metoprolol on blood pressure (BP) and myocardial ischemia. Twenty outpatients with mild to moderate essential arterial hypertension, chronic stable angina pectoris and positive exercise test, after a 2-week baseline placebo period, were randomized to receive long-acting metoprolol (OROS) 14/190 mg o.d., nifedipine SR 20 mg b.i.d. or their combination in a sequence of a 3 x 3 Latin square design. Two patients withdrew from the study (1 for adverse event during metoprolol and 1 for rise of BP during nifedipine). Nifedipine, metoprolol and their combination significantly reduced the weekly number of angina attacks and nitroglycerin consumption with respect to baseline. The total number of ischemic events (at 24-hour ECG monitoring) significantly decreased after each treatment with respect to baseline. Twenty-four hours mean systolic and diastolic BP were reduced by both nifedipine alone and metoprolol alone; the combination of the two drugs led to a further decrease in both systolic and diastolic BP. The duration of silent ischemic episodes was significantly reduced by nifedipine and combination but not by metoprolol. On the other hand 24 hours symptomatic attacks/patient were significantly reduced by beta-blocker and combination, but not by nifedipine. Metoprolol alone and administered with nifedipine caused a decrease, with respect to placebo baseline, in 24-hour mean heart rate (HR) and reduced the increase of HR and systolic BP at the onset of ST depression during symptomatic ischemic episodes. The effort time and time to ST = -1 mm at treadmill were significantly increased by treatment with nifedipine alone, with metoprolol alone and with their combination, but the combination was more effective than the individual therapies. ST depression at peak exercise was significantly reduced by each treatment. The slopes of correlations between the ST-segment variation and systolic BP, HR and rate-pressure product during exercise, significantly decreased after all treatments with respect to placebo baseline, more with the combination therapy than with nifedipine alone and metoprolol alone. In conclusion, based on our results the favourable interaction of metoprolol OROS and nifedipine given concomitantly, is likely to be due to a better control, respect to each individual therapy, of the pathogenetic mechanism of myocardia ischemia: BP and HR increases during exercise and during symptomatic ischemic episodes are controlled by the beta-blocker and coronary vasoconstriction during silent ischemia is prevented by the calcium-antagonist.

A controlled study of the autonomic changes produced by habitual cigarette smoking in healthy subjects.

OBJECTIVES: An increased sympathetic drive, in view of its proarrhythmic, proatherosclerotic, and prothrombotic actions, could contribute to the elevated cardiovascular risk of habitual smokers. However, the underlying mechanisms are still debated. In this study we address the hypothesis that spectral analysis of RR interval and systolic arterial pressure short-term variabilities may be used to assess the complex autonomic changes produced by habitual cigarette smoking. METHODS: A cross-sectional design compared heavy (> 20 cigarettes/day) habitual smokers (n = 20; 40 +/- 3 years), with similar age controls. Spectral analysis of RR interval variability provided markers of the sympatho-vagal balance modulating the SA node, by way of the normalised low frequency (LF approximately equal to 0.10 Hz) and high frequency (HF approximately equal to 0.25 Hz) components. The LF component of systolic arterial pressure (SAP) variability assessed the sympathetic vasomotor modulation. The frequency domain index (alpha) measured the baroreflex gain of the SA node. Subjects were studied at rest, and during the sympathetic excitation produced by active standing. RESULTS: In smokers LFRR was, at rest, greater than in controls (70.6 +/- 3.8 vs 46.0 +/- 2.5 normalised units, nu); concurrently HFRR was reduced (22.1 +/- 3.2 vs 42.0 +/- 2.8 nu). Baroreflex gain and RR variance were also smaller in smokers. LFSAP was, instead, similar in the smokers and control groups. The standing induced increase in LFRR was blunted (P < 0.001) in smokers. CONCLUSIONS: Spectral analysis of RR interval and systolic arterial pressure variability indicates that habitual cigarette smoking induces selective alterations in neural control of the SA node. An increase at rest in markers of sympathetic modulation is accompanied by signs of reduced vagal drive and depressed baroreflex gain; while sympathetic vasomotor modulation appears similar in controls and smokers. Data are consistent with the hypothesis that autonomic alterations may contribute to the increased cardiovascular risk present in smokers.

Markers of hemostatic system activation during thromboprophylaxis with recombinant hirudin in total hip replacement.

Coagulation activation markers were studied in 148 patients undergoing total hip replacement under recombinant-hirudin (Desirudin, Revasc) prophylaxis with the aim of investigating the efficacy and safety of this anticoagulant compared with heparin in terms of biological effects on coagulation variables and bleeding. Hirudin (10, 15 or 20 mg s.c. b.i.d.) or unfractionated heparin (5000 IU s.c. t.i.d.) was administered immediately before surgery and continued for 8-12 days. Activated partial thromboplastin time (aPTT), prothrombin activation fragment F1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT) and D-dimer were measured at baseline and on postoperative days 1,3 and 6, immediately before the morning injection. In comparison with baseline values, heparin had little effect on aPTT whereas the three hirudin doses prolonged aPTT significantly with no differences among the three doses. Moreover, there were no group differences in perioperative or cumulative blood loss or transfusion requirements. F1 + 2 fragment, TAT and D-dimer plasma levels were higher than at baseline during the entire postoperative period, with different trends (F1 + 2 increasing, TAT decreasing, D-dimer increasing, decreasing and then increasing again), but without significant differences among the four treatment groups. Our findings suggest that specific inhibition of thrombin seems a safe and efficacious mode of blocking thrombin activity after hip surgery although it does not prevent thrombin generation.

Interleukin-1 stimulates prostacyclin production by cultured human endothelial cells by increasing arachidonic acid mobilization and conversion.

Interleukin-1 (IL-1) induced slow, lasting activation of human endothelial cells (EC) to release prostacyclin (PGI2). This was accompanied by endogenous 3H-arachidonic acid (3H-AA) release and by a time-dependent increase in the cells' ability to convert exogenous AA. The continuous presence of IL-1 was not required, but about a 1-hour stimulation with the cytokine was sufficient to trigger the cells to synthesize PGI2 for several hours. The spectrum of 3H-AA conversion shows that, in addition to 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha also was raised after IL-1. The recovery of PGI2 synthesis after aspirin was faster in IL-1-treated EC than in control cells. These data define some of the characteristics of IL-1 stimulation of PGI2 and suggest that this process is mediated both by endogenous AA mobilization and by an increase in cyclooxygenase activity.

In vitro inhibition of human polymorphonuclear cell function by cloricromene.

Cloricromene, a coumarin derivative with antiaggregating and vasodilating properties, was tested in vitro on polymorphonuclear cell (PMN) adhesion to the endothelium, superoxide anion generation and chemotaxis. PMN adhesion was measured using cultured human umbilical vein endothelial cells (EC) either untreated or previously activated with interleukin-1 (IL-1). Cloricromene (5-50 microM) induced dose-related inhibition of PMN adhesion to untreated and IL-1 treated EC. Cloricromene also inhibited PMN superoxide generation induced by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or by N-formyl-methionyl-leucyl-phenylalanine (FMLP). PMN and monocyte chemotaxis was evaluated by a modification of the Boyden chamber technique. Cloricromene inhibited both types of cell motility induced by FMLP in a concentration-dependent fashion. The major cloricromene metabolite (cloricromene acid) had no effect on any of the biological parameters studied up to a concentration of 500 microM. HPLC measurement showed that cloricromene accumulated in PMN within a few minutes and levels of the drug were still high after 60 min. In contrast its acid metabolite was not taken up in a significant amount during incubation periods up to 60 min. We conclude that cloricromene inhibits a series of PMN activities in vitro. This effect might be of pharmacological interest in view of the role of PMN activation in different pathophysiological conditions.