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11.
Oie E Yndestad A Robins SP Børnerheim R Asberg A Attramadal H 《Basic research in cardiology》2002,97(3):239-247
Intervention with selective endothelin (ET)A receptor antagonists within 24 h after myocardial infarction (MI) in rats has
been reported to aggravate left ventricular (LV) remodeling. In contrast, beneficial effects are reported when initiation
of treatment is delayed 7 days or more after MI. However, bosentan, a mixed ETA/ETB receptor antagonist with low affinity for the ET receptors, has been shown to exert beneficial effects independent of the
time point of initiation of treatment after MI. The aim of the present study was to investigate to what extent early intervention
with a mixed ETA/ETB receptor antagonist with higher affinity at the ET receptors (SB 209670) would also exert beneficial effects on postinfarction
LV remodeling. After ligation of the left coronary artery, rats were randomized to treatment with SB 209670 (6.25 mg·kg−1 SC b.i.d., n = 10) or vehicle (n = 12) for 26 days, starting 48 h after MI. Treatment with SB 209670 adversely affected the
postinfarction remodeling process causing further dilatation of the LV (LV end-diastolic diameter: 10.4 ± 0.5 vs 9.1 ± 0.2
mm; LV end-systolic diameter: 8.5 ± 0.4 vs 7.2 ± 0.2 mm, P < 0.05). However, SB 209670 did not significantly affect infarct
size, compensatory cardiac hypertrophy, nor the myocardial mRNA levels of procollagen type I and III, and prolyl 4-hydroxylase
and lysyl oxidase, 2 important enzymes affecting collagen secretion, stability and functionality. In addition, SB 209670 had
no significant effects on LV collagen cross-linking or extent of fibrosis. Thus, our data demonstrate that early intervention
with a potent, mixed ETA/ETB receptor antagonist after MI may promote dilatation of the LV without significant alterations of infarct size and extracellular
matrix composition. Our data support the notion that the timing of initiation of ET receptor antagonism after MI is critical
and that potent ET receptor antagonists may be harmful during the first few days after MI.
Received: 1 September 2001, Returned for revision: 13 September 2001, Revision received: 6 December 2001, Accepted: 21 December
2001 相似文献
12.
目的探讨p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38 MAPK)特异性抑制剂SB203580对大鼠重症急性胰腺炎(SAP)的保护作用。方法以胆胰管逆行注射5%牛磺胆酸钠建立SD大鼠SAP模型。将45只SD大鼠随机分为3组,假手术组(SO组,n=15);SAP组(SAP组,n=15);SB203580治疗组(SB组,n=15)。术后3、6、12 h处死大鼠并取血。对胰腺进行病理组织学评分,测定大鼠腹水量。检测血清淀粉酶,ELISA法测定血清IL-6和IL-10水平。并采用免疫组化法观察大鼠胰腺组织p38 MAPK下游靶点P-ATF2表达情况。结果 SO组胰腺组织存在P-ATF2弱表达,SAP组各时间点P-ATF2表达水平明显升高(P<0.01),SB组各时间点表达水平较SAP组下降明显(P<0.01)。SAP组6、12 h时间点IL-6水平,3、6 h时间点IL-10水平,血清淀粉酶,腹水量明显高于SB组(P<0.05)。SAP组各时间点胰腺组织病理学积分显著高于SB组,差异有统计学意义(P<0.05)。结论阻断p38 MAPK信号传导通路可以明显缓解大鼠重症急性胰腺炎的病情。预示此信号传导通路可以为SAP的治疗提供一个有价值的标靶。 相似文献
13.
Retinal pigment epithelial (RPE) cells play critical roles in the maintenance of visual function, partly by secreting various biologically active factors that modulate the intraocular environment. Recent studies suggest involvement of Wnt proteins secreted by RPE cells in the pathogenesis of photoreceptor degeneration. In the present study, we examined, via the luciferase assay, the effect of media conditioned by RPE cells (RPE-CM) on activity of the canonical Wnt pathway in vitro. We isolated primary RPE cells from Long-Evans rats at P6-P9. In culture, these cells formed a monolayer with polygonal cell morphology and demonstrated repigmentation at confluency and immunoreactivity for ZO-1, a marker for tight junctions. To evaluate the effect of RPE-CM on the canonical Wnt pathway, we replaced the culture media of COS-7 cells transfected with (Tcf)(7)LUC, a multimeric Tcf-responsive element luciferase reporter construct, with RPE-CM and measured luciferase activity with or without Wnt3a or SB216763, a specific GSK3 inhibitor. RPE-CM did not enhance basal or Wnt3a-induced (Tcf)(7)LUC activity; instead, this activity decreased by 60%. RPE-CM also reduced SB216763-induced (Tcf)(7)LUC activity by 65%, which suggests that the inhibitory effect of RPE-CM is probably due to intracellular crosstalk rather than extracellular antagonism. RPE cells may thus be able to modulate the intraocular environment by regulating the canonical Wnt pathway. 相似文献
14.
BackgroundDual blockade with trastuzumab and pertuzumab combined with neoadjuvant chemotherapy (NACT) has been increasingly used for HER2-positive tumours >2 cm and/or with positive axillary lymph nodes in order to evaluate pathologic response and obtain better surgical management. SB3 is a registered biosimilar trastuzumab approved following a phase III trial demonstrating similar efficacy in the neoadjuvant setting as trastuzumab. However, the study was done without pertuzumab.MethodThe database of the Danish Breast Cancer Group was used to extract data on all patients who started NACT with SB3 and pertuzumab between September 1, 2018 and August 31, 2019. The primary endpoint was pathological complete response (pCR) rate.ResultsIn total 215 patients received NACT and dual blockade. The median age was 55 (24–81). NACT used was cyclophosphamide and epirubicin followed by weekly paclitaxel (62% on six cycles, 35% on eight cycles) or other chemotherapy followed by weekly paclitaxel (3%). Overall, 56% of patients achieved pCR. 60 of 88 node-positive patients pre-NACT achieved ypN0(i-) after neoadjuvant treatment. pCR rate was significantly associated with estrogen receptor status and malignancy grade. An association with CEP17/HER2-ratio was assessed.ConclusionReal world data on dual blockade with SB3 and pertuzumab in combination with NACT in a nationwide population-based study show a pCR rate comparable to that seen in previous clinical studies. 相似文献
15.
The p38 MAPK inhibitor, SB203580, abrogates ischaemic preconditioning in rat heart but timing of administration is critical 总被引:4,自引:0,他引:4
There is debate concerning the involvement of p38 mitogen activated protein kinase (MAPK) in the mediation of ischaemic preconditioning.
Pharmacological inhibition of p38 MAPK with SB203580 has been reported to block preconditioning in some studies but not in
others. We hypothesised that this divergence could be due to differences in the timing of inhibitor administration. Isolated
rat hearts were perfused in the Langendorff mode and subjected to 35 min regional ischaemia followed by 120 min reperfusion.
Hearts were then double stained with Evans' blue and triphenyltetrazolium chloride to determine risk (R) and infarct zones
(I), expressed as I/R% ratios. Preconditioned hearts were subjected to 2 times 5 min global ischaemia with 10 min intervening
reperfusion. SB203580 10 μ M was perfused either during the preconditioning protocol (PC+SB-early), just prior to and during
the first 15 min of the lethal ischaemia (PC+SB-late) or prior to regional ischaemia in the absence of preconditioning. Ischaemic
preconditioning significantly limited infarct size (I/R 38.9 ± 3.0% in control vs 13.4 ± 2.4%, P < 0.01). In the PC+SB-early
group, preconditioning was still fully protective (I/R% 14.6 ± 1.0). However, in the PC+SB-late group, SB203580 completely
blocked the protection afforded by preconditioning (I/R% 33.6 ± 4.4%, P < 0.01 vs 13.4 ± 2.4% in preconditioned hearts, p
< 0.05). SB203580 alone did not affect infarct size when given prior to and during regional ischaemia (I/R 36.2 ± 2.7%). These
histological data are corroborated by a significant increase in p38 MAPK activation in the preconditioned hearts during sustained
ischaemia in comparison with the controls. In conclusion the activation of p38 MAPK during lethal ischaemia, but not during
the ischaemic preconditioning protocol, is essential for the mediation of protection and may resolve some of the earlier controversy
surrounding the use of SB203580 in preconditioning studies.
Received: 28 June 2000, Returned for revision: 21 July 2000, Revision received: 9 August 2000, Accepted: 13 September 2000 相似文献
16.
Nisharahmed I. Kherada Samantha SartoriMatthew I. Tomey Marco G. MennuniOmar A. Meelu Swathi RoyBibhu D. Mohanty Usman BaberRobert Pyo Jason C. KovacicJoseph Sweeny Pedro MorenoPrakash Krishnan George D. DangasRoxana Mehran Samin K. SharmaAnnapoorna S. Kini 《International journal of cardiology》2014
Objectives
To compare the outcomes of initial one-stent (1S) versus dedicated two-stent (2S) strategies in complex bifurcation percutaneous coronary intervention (PCI) using everolimus-eluting stents (EES).Background
PCI of true bifurcation lesions is technically challenging and historically associated with reduced procedural success and increased restenosis. Prior studies comparing initial one-stent (1S) versus dedicated two-stent (2S) strategies using first-generation drug-eluting stents have shown no reduction in ischemic events and more complications with a 2S strategy.Methods
We performed a retrospective study of 319 consecutive patients undergoing PCI at a single referral center with EES for true bifurcation lesions, defined by involvement of both the main vessel (MV) and side branch (SB). Baseline, procedural characteristics, quantitative coronary angiography and clinical outcomes in-hospital and at one year were compared for patients undergoing 1S (n = 175) and 2S (n = 144) strategies.Results
Baseline characteristics were well-matched. 2S strategy was associated with greater SB acute gain (0.65 ± 0.41 mm vs. 1.11 ± 0.47 mm, p < 0.0001). In-hospital serious adverse events were similar (9% with 2S vs. 8% with 1S, p = 0.58). At one year, patients treated by 2S strategy had non-significantly lower rates of target vessel revascularization (5.8% vs. 7.4%, p = 0.31), myocardial infarction (7.8% vs. 12.2%, p = 0.31) and major adverse cardiovascular events (16.6% vs. 21.8%, p = 0.21).Conclusion
In this study of patients undergoing PCI for true coronary bifurcation lesions using EES, 2S strategy was associated with superior SB angiographic outcomes without excess complications or ischemic events at one year. 相似文献17.
Manuel Pan Francesco Burzotta Carlo Trani Alfonso Medina Jose Suárez de Lezo Giampaolo Niccoli Miguel Romero Italo Porto Francisco Mazuelos Antonio Maria Leone Pedro Martín Valentina Coluccia Javier Suárez de Lezo Soledad Ojeda Filippo Crea 《Revista espa?ola de cardiología》2014,67(10):797-803
Introduction and objectives
To compare the 3-year incidence of major events in patients with bifurcation lesions treated with provisional sirolimus-eluting stents vs everolimus-eluting stents.Methods
A pooled analysis of 2 prospective randomized trials with similar methodology (SEAside and CORpal) was performed. In these trials, 443 patients with bifurcation lesions were randomly assigned to treatment with either sirolimus-eluting stents or everolimus-eluting stents. The clinical follow-up was extended up to 3 years to assess major adverse cardiovascular events (death or acute myocardial infarction or target vessel revascularization).Results
At 3 years, survival free of major adverse cardiovascular events was 93.2% vs 91.3% in the everolimus-eluting stent group vs the sirolimus-eluting stent group (P = .16). Exploratory land-mark analysis for late events (occurring after 12 months) showed significantly fewer major adverse cardiovascular events in the everolimus-eluting stent group: 1.4% vs 5.4% in the sirolimus-eluting stent group (P = .02).Conclusions
Provisional stenting with either sirolimus-eluting stents or everolimus-eluting stents in bifurcation lesions is associated with low rates of major adverse events at 3-years’ follow-up. The results of a subanalysis of events beyond 1 year, showing a lower event rate with everolimus-eluting stents than with sirolimus-eluting stents, suggest that studies exploring the long-term clinical benefit of the latest generation of drug-eluting stents are warranted. 相似文献18.
Hanne D. Hansen Cristian C. Constantinescu Olivier Barret Matthias M. Herth Janus H. Magnussen Szabolcs Lehel Agnete Dyssegaard Julie Colomb Thierry Billard Luc Zimmer Gilles Tamagnan Gitte M. Knudsen 《Journal of labelled compounds & radiopharmaceuticals》2019,62(1):34-42
So far, no suitable 5‐HT7R radioligand exists for clinical positron emission tomography (PET) imaging. [18F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non‐human primates (NHPs). Furthermore, we investigate species differences in 5‐HT7R binding with [3H]SB‐269970 autoradiography in post‐mortem pig, NHP, and human brain tissue. Specific binding of [18F]2FP3 was investigated by intravenous administration of the 5‐HT7R specific antagonist SB‐269970. [3H]SB‐269970 autoradiography was performed as previously described. [18F]2FP3 was synthesized in an overall yield of 35% to 45%. High brain uptake of the tracer was found in both pigs and NHPs; however, pretreatment with SB‐269970 only resulted in decreased binding of 20% in the thalamus, a 5‐HT7R–rich region. Autoradiography on post‐mortem pig, NHP, and human tissues revealed that specific binding of [3H]SB‐269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [18F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5‐HT7R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5‐HT7Rs in vivo and that part of the PET signal arises from targets other than the 5‐HT7R. 相似文献
19.
Jiangfeng Du Ivo W. M. Bleylevens Albert V. Bitorina Kanin Wichapong Gerry A. F. Nicolaes 《Chemical biology & drug design》2014,83(1):37-51
The use of multiple target conformers has been applied successfully in virtual screening campaigns; however, a study on how to best combine scores for multiple targets in a hierarchic method that combines rigid and flexible docking is not available. In this study, we used a data set of 59 479 compounds to screen multiple conformers of four distinct protein targets to obtain an adapted and optimized combination of an established hierarchic method that employs the programs FRED and Surflex. Our study was extended and verified by application of our protocol to ten different data sets from the directory of useful decoys (DUD). We quantitated overall method performance in ensemble docking and compared several consensus scoring methods to improve the enrichment during virtual ligand screening. We conclude that one of the methods used, which employs a consensus weighted scoring of multiple target conformers, performs consistently better than methods that do not include such consensus scoring. For optimal overall performance in ensemble docking, it is advisable to first calculate a consensus of FRED results and use this consensus as a sub‐data set for Surflex screening. Furthermore, we identified an optimal method for each of the chosen targets and propose how to optimize the enrichment for any target. 相似文献
20.