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41.
OBJECTIVE: Increased endothelin activity may play a role in the pathogenesis of vascular injury, a primary feature of systemic sclerosis (SSc; scleroderma). Our goal was to test the hypothesis that treatment with the oral endothelin receptor antagonist bosentan might improve vascular endothelial function in SSc patients. METHODS: A 4-week, prospective, parallel-group study compared 12 SSc patients who did not receive bosentan treatment with 12 patients who did receive treatment (125 mg/day) for pulmonary hypertension and/or digital ulcers. There were no differences in demographic and clinical characteristics or medications between the 2 groups. Baseline endothelial dysfunction was documented by decreased brachial artery ultrasound-derived flow-mediated dilation (FMD%; <5.5). Pulse wave analysis, venous occlusion plethysmography, and measurement of serum vascular markers were performed in parallel. RESULTS: FMD%, the main end point, increased significantly from a mean +/- SD of 3.1 +/- 1.3% to 8.4 +/- 2.6% after 4 weeks of bosentan treatment (P < 0.001, compared with a change from 2.4 +/- 1.6% to 2.4 +/- 2.2% in control patients). Arterial blood pressure, endothelium-independent vascular function, augmentation index, peripheral flow reserve, as well as circulating intercellular adhesion molecule 1, E-selectin, vascular endothelial growth factor, and endothelin 1 were not significantly affected by bosentan treatment. In patients continuously treated for 4 months, during which the dosage of bosentan remained at 125 mg/day (n = 5) or increased to 250 mg/day (n = 5), the 4-week results remained unchanged. CONCLUSION: Small doses of bosentan improve endothelial function without affecting hemodynamic parameters or endothelial activation-related processes, thus supporting a direct, reversible effect of endothelin in SSc-associated vascular injury. A long-term, controlled trial to examine the potentially global clinical benefit of endothelin receptor blockade in patients with early SSc may be warranted.  相似文献   
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Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and/or increased sensitivity of peripheral tissues to glucocorticoids may be associated with the dysmetabolic syndrome and its cardiovascular sequelae. In this prospective pilot clinical study, we examined possible associations between HPA axis activity and severity of cardiovascular disease. We measured morning serum cortisol and intima media thickness (IMT) of carotid and femoral arteries in 105 subjects before undergoing coronary angiography for suspected coronary artery disease (CAD). In a randomly selected 46 of these subjects, we obtained late afternoon and morning cortisol levels (after ultralow-dose dexamethasone [0.25 mg] treatment) and determined their genotype for the Bcl1 polymorphism of the glucocorticoid receptor gene, which has been associated with increased sensitivity to glucocorticoids. There was significant association between morning preangiography cortisol levels and the number of vessels with severe stenosis in the angiography, independently of age or sex (P = .002), and a trend for a positive correlation between morning cortisol and the IMT of the femoral artery (P = .057). Bcl1 G allele homozygotes had a significantly higher carotid IMT (P = .005) and a nonsignificant tendency for higher waist-hip ratio (P = .059). Hyperactivity of the HPA axis in anticipation of a stressful procedure, such as angiography, may be an index of CAD severity. Chronic HPA axis hyperreactivity combined with tissue hypersensitivity to glucocorticoids may contribute to more severe atherosclerosis and CAD.  相似文献   
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Background: Several antioxidants have been found to have conflicting results in attenuating myocardial reperfusion injury. These studies were done primarily in experimental protocols that did not approximate clinical situations.Objective: The aim of this study was to test the efficacy of 3 different antioxidants (ascorbic acid [AA], desferrioxamine, and N-acetylcysteine [NAC]) administered IV alone and in combination in a closed-chest pig model.Methods: Farm-raised domestic male pigs (aged 3-5 months, weight of 30-35 kg) were assigned to 1 of 5 groups to receive treatment as follows: group A, AA 100 mg/kg; group B, desferrioxamine 60 mg/kg; group C, a loading dose of NAC 100 mg/kg for 20 minutes and a 20-mg/kg maintenance dose; group D, all 3 drugs in combination; and group E, normal saline (control group). The infusion of all drugs was started 15 minutes before and completed 5 minutes after reperfusion, except for the administration of NAC, which was terminated 60 minutes postreperfusion. Myocardial ischemia (45 minutes) and reperfusion (210 minutes) were achieved percutaneously by circumflex artery balloon occlusion. Ejection fraction, left ventricular end-diastolic pressure (LVEDP), flow in the infarcted artery, and all ventricular arrhythmias were recorded. Oxidative stress was estimated by serial measurements of thiobarbituric acid reactive substance (TBARS) concentration in coronary sinus blood. Infarct size was assessed as a percentage of the area at risk (I/R ratio) using the tetrazolium red staining method.Results: The 25 pigs were divided into 5 groups of 5 pigs each. No significant between-group differences were found in I/R ratio or in oxidative stress (as measured by TBARS concentration). Group C developed significantly more ventricular atrhythmias than the control group (80% vs 0%, P = 0.02). No other differences among groups were found. LVEDP was significantly elevated in all treatment groups (mean LVEDP difference [SD] for group A, 6.0 [1.6] mm Hg; group B, 17.6 [1.9] mm Hg; group C, 3.6 [1.7] mm Hg; group D, 6.8 [3.2] and group E, 5.4 [3.4] mm Hg). LVEDP elevation was found to be significantly higher in group B compared with all the other groups (all, P < 0.001). No significant between-group differences were found in the other parameters measured.Conclusion: In this experimental pig model, the antioxidants AA, desferrioxamine, and NAC administered alone or in combination did not reduce the deleterious effects of reperfusion injury and specifically the extent of myocardial necrosis.  相似文献   
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BACKGROUND: Wave reflections are implicated increasingly in clinical research. AIMS: The purpose of the present study was to investigate whether wave reflection indices are reproducible when measured repeatedly (more than twice) at longer time intervals, namely hour-to-hour and week-to-week, in healthy subjects; something that has not yet been examined. METHODS: Bland-Altman plots, the interclass correlation coefficients (ICC) and coefficient of variation were used for this purpose. Two series, with measurements repeated in triplicate, were performed in 22 healthy subjects: the first at intervals of 1 h and the second at 1-week time intervals. Augmentation index (AIx), heart rate-corrected AIx (AI@75) and arrival time of reflected waves at the central aorta (tr) were calculated by aortic pulse wave analysis. RESULTS: AIx and AI@75 presented very good to excellent reproducibility (ICC = 0.86) for hour-to-hour repeated measurements, while tr was also highly reproducible (ICC = 0.79). AIx, AI@75 and tr were substantially reproducible when measured repeatedly with 1-week intervals, providing ICCs greater than 0.70. Bland-Altman plots confirmed these results, indicating that more than 90% of AIx, AI@75 and tr measurements fell within two standard deviations of the mean difference. CONCLUSIONS: Wave reflections are substantially reproducible even when measurements repeated in triplicate are performed at longer time intervals (hours and weeks). A quantifiable amount of variation was reported, which should be taken carefully into consideration in interventional studies with repeated measurements and in observational studies investigating differences or correlations of these indices.  相似文献   
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The acute effects of the renin-angiotensin system (RAS) blockers may be important in some clinical settings. To assess the acute impact of such drugs on arterial function, we studied the effects of captopril 25 mg, quinapril 20 mg and telmisartan 80 mg on 100 hypertensive patients, according to a randomized, double-blind, placebo-controlled study. Central (aortic) blood pressure (BP) and augmentation index (AIx, a measure of wave reflections), as well as flow-mediated dilatation (FMD) of the brachial artery and forearm blood flow (FBF) (measures of conduit and resistance artery endothelial function, respectively), were evaluated before and 2 h after oral drug administration. Compared to placebo, captopril and quinapril decreased central systolic (by 7.5 mm Hg, P<0.05 and by 12.3 mm Hg, P<0.001) and diastolic BP (by 4.9 mm Hg, P<0.01 and by 8.4 mm Hg, P<0.001), whereas telmisartan had no significant effect (P=NS). Additionally, AIx was reduced after quinapril (absolute decrease of 7.2%, P<0.01) and marginally after captopril (decrease of 4.7%, P=0.07). Only quinapril led to a beneficial change of FMD (absolute increase of 2.7%, P<0.001). No treatment was related to significant changes of peak hyperaemic or 3-min hyperaemic FBF. In adjusted analyses, all the favourable alterations induced by quinapril were independent of potential confounding haemodynamic factors. Our data show that acute RAS inhibition with quinapril (20 mg) may be more beneficial in terms of arterial function and central haemodynamics compared to captopril (25 mg) or telmisartan (80 mg). Further studies are needed to investigate whether these acute arterial effects of quinapril are clinically significant.  相似文献   
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Coffee is one of the most widely used pharmacologically active beverages. The present study was designed to evaluate the acute effect of coffee ingestion on endothelial function in healthy individuals, and the potential role of caffeine. We studied 17 healthy young adults (28.9+/-3.0 years old; nine men), who were regular non-heavy coffee drinkers. The endothelial performance was estimated by endothelium-dependent FMD (flow-mediated dilatation) of the brachial artery before and 30, 60, 90 and 120 min after ingestion of a cup of caffeinated coffee (80 mg of caffeine) or the corresponding decaffeinated beverage (< 2 mg of caffeine) in two separate sessions, following a randomized single-blind cross-over design. There was no difference in baseline FMD values between the two sessions [7.78 compared with 7.07% after caffeinated and decaffeinated coffee respectively; P = NS (not significant)]. Caffeinated coffee led to a decline of FMD (7.78, 2.86, 2.12, 4.44 and 4.57% at baseline, 30, 60, 90 and 120 min respectively; P < 0.001). This adverse effect was focused at 30 (P = 0.004) and 60 min (P < 0.001). No significant effect on FMD was found with the decaffeinated coffee session (7.07, 6.24, 5.21, 7.41 and 5.20%; P = NS). The composite effect of the type of coffee consumed over time on FMD was significantly different (P = 0.021). In conclusion, coffee exerts an acute unfavourable effect on the endothelial function in healthy adults, lasting for at least 1 h after intake. This effect might be attributed to caffeine, given that decaffeinated coffee was not associated with any change in the endothelial performance.  相似文献   
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