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1.
An overview of new pharmacological treatments for cerebrovascular dysfunction after experimental subarachnoid hemorrhage 总被引:10,自引:0,他引:10
Cerebral vasospasm and the resulting cerebral ischemia occurring after subarachnoid hemorrhage (SAH) are still responsible for the considerable morbidity and mortality in patients affected by cerebral aneurysms. Mechanisms contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia after SAH have been intensively investigated in recent years. It has been suggested that the pathogenesis of vasospasm is related to a number of pathological processes, including endothelial damage, smooth muscle cell contraction resulting from spasmogenic substances generated during lyses of subarachnoid blood clots, changes in vascular responsiveness and inflammatory or immunological reactions of the vascular wall.A great deal of experimental and clinical research has been conducted in an effort to find ways to prevent these complications. However, to date, the main therapeutic interventions remain elusive and are limited to the manipulation of systemic blood pressure, alteration of blood volume or viscosity, and control of arterial dioxide tension.Even though no single pharmacological agent or treatment protocol has been identified which could prevent or reverse these deadly complications, a number of promising drugs have been investigated. Among these is the hormone erythropoietin (EPO), the main regulator of erythropoiesis. It has recently been found that EPO produces a neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is systemically administered.This topic review collects the relevant literature on the main investigative therapies for cerebrovascular dysfunction after aneurysmal SAH. In addition, it points out rHuEPO, which may hold promise in future clinical trials to prevent the occurrence of vasospasm and cerebral ischemia after SAH. 相似文献
2.
促红细胞生成素心肌保护作用的研究进展 总被引:4,自引:0,他引:4
促红细胞生成素(erythropoietin,EPO)是一种造血细胞生长因子,主要用于治疗多种原因所致的贫血。近年来其非造血生物作用逐渐引起关注,EPO具有组织保护作用,这一作用涉及多种不同组织和细胞,心肌保护一直是心血管病研究领域重要、关键的课题。EPO对心肌保护的作用近两年已渐有报道,这无疑为临床心肌保护的研究提供了新的思路和方向。现就EPO心肌保护作用的相关研究成果、发现以及有待解决的问题作一综述。 相似文献
3.
The effects of recombinant human erythropoietin (rhEPO, RecormonR, CAS 122312-54-3) on the differential leucocyte counts and platelets of rabbits were investigated after the repeated application of a single dose of rhEPO. Therefore, 150 IU rhEPO (n = 5), 300 IU rhEPO (n = 6), or 600 IU rhEPO (n = 5) per animal was injected once on three separate occasions with an interval of 5–6 weeks between each injection. Six animals were used to study the potential effect of the solvent alone.rhEPO showed a significant time effect on the differential leucocyte counts and platelets of rabbits. The decrease in total white blood cells count (WBC) on the third, fourth and sixth day after rhEPO administration was due to a decrease in lymphocytes. These results support the hypothesis that the enhanced demand of one cell line leads to a down-modulation of the production of other cell line(s). 相似文献
4.
Haiwei Wu Binhui Ren Jiaquan Zhu Guohua Dong Biao Xu Changtian Wang Xiaogang Zheng Hua Jing 《European journal of cardio-thoracic surgery》2006,29(6):902-907
Objective: Based on the findings that erythropoietin (EPO) has been proved to be a multiple functional cytokine to attenuate ischemia–reperfusion (I/R) injury in various organs such as brain, heart, and kidney in animals, this experiment was designed to evaluate the effect of pretreatment with recombined human erythropoietin (rhEPO) on I/R-induced lung injury. Methods: Left lungs of rats underwent 90 min of ischemia and then were reperfused for up to 2 h. Animals were randomly divided into three experimental groups as sham group, I/R group, and rhEPO + I/R group (a single dose of rhEPO was injected intraperitoneally 3000 U/kg 24 h prior to operation). Lung injury was evaluated according to semi-quantitive analysis of microscopic changes, tissue polymorphonuclear neutrophils (PMNs) accumulation (myeloperoxidase (MPO) activity), and pulmonary microvascular permeability (Evan's blue dying method). Peripheral arterial and venous blood samples were obtained for blood–gas analysis after 5 min occlusion of right lung hilus at the end of reperfusion. The serum concentration of tumor necrosis factor (TNF)- was also measured by the method of enzyme-linked immunosorbent assay. Results: Histological injury scoring revealed significantly lessened lung alveolus edema and neutrophils infiltration in the rhEPO pretreated group compared with I/R group (p < 0.05). The rhEPO pretreated animals exhibited markedly decreased lung microvascular permeability (p < 0.05) and myeloperoxidase activity (p < 0.05). Blood–gas analysis demonstrated that the pretreated animals had significantly ameliorated pulmonary oxygenation function (p < 0.05). The serum concentration of tumor necrosis factor- in rhEPO pretreated group was markedly decreased compared with that of I/R group (p < 0.05). Conclusions: Pretreatment with rhEPO appears to attenuate I/R-induced lung injury. This function is partly related with the capacity that rhEPO inhibits the accumulation of polymorphonuclear neutrophils in lung tissue and decreases the systematic expression of tumor necrosis factor-. 相似文献
5.
Objective: To investigate the anti-inflammatory effect of erythropoietin (EPO) pretreatment on cardiomyocytes exposed to hypoxialreoxygenation injury (H/R) and explore the possible mechanism.
Methods: The cultured neonatal rats' ventricular cardiomyocytes were divided randomly into 4 groups, control group (C group), EPO pretreatment group (E group), EPO and pyrrolidine dithiocarbamate (PDTC) pretreatment group (EP group) and PDTC pretreatment group (P group). After 24 hours' pretreatment, the cardiomyocytes were exposed to H/R. After pretreatment and H/R, the expression of tumor necrosis factor- α (TNF- α ) gene in all the groups was detected by RT-PCR and Western blot. The nuclear factor- κ B (NF- κB) activity was detected by electrophoretic mobility shift assay (EMSA) and the inhibitor- κB α (Ⅰ- κB α) protein level was detected by Western blot.
Results: The decrement of Ⅰ- κB a protein and the increasing NF- KB activity were found in cardiomyocytes pretreated with EPO before H/R compared to other groups (t=3.321, 4.183, P〈0.01). However, after H/R, NF- κB activity and expression of TNF- α gene were significantly reduced, Ⅰ- κB a protein expression was increased in cardiomyocytes of E group compared to other groups (t=-3.425, 3.687, 3.454, P〈0.01). All theses changes caused by EPO pretreatment were eliminated by the intervention of PDTC (an antagonist to NF- κB) during pretreatment.
Conclusions: EPO pretreatment can inhibit the activation of NF- κB and upregulation of TNF- α gene in cardiomyocytes exposed to H/R through a negative feedback of NF- κB signaling pathway, and thus produces the anti-inflammatory effect. This might be one of the ways EPO produces the anti-inflammatory effect. 相似文献
Methods: The cultured neonatal rats' ventricular cardiomyocytes were divided randomly into 4 groups, control group (C group), EPO pretreatment group (E group), EPO and pyrrolidine dithiocarbamate (PDTC) pretreatment group (EP group) and PDTC pretreatment group (P group). After 24 hours' pretreatment, the cardiomyocytes were exposed to H/R. After pretreatment and H/R, the expression of tumor necrosis factor- α (TNF- α ) gene in all the groups was detected by RT-PCR and Western blot. The nuclear factor- κ B (NF- κB) activity was detected by electrophoretic mobility shift assay (EMSA) and the inhibitor- κB α (Ⅰ- κB α) protein level was detected by Western blot.
Results: The decrement of Ⅰ- κB a protein and the increasing NF- KB activity were found in cardiomyocytes pretreated with EPO before H/R compared to other groups (t=3.321, 4.183, P〈0.01). However, after H/R, NF- κB activity and expression of TNF- α gene were significantly reduced, Ⅰ- κB a protein expression was increased in cardiomyocytes of E group compared to other groups (t=-3.425, 3.687, 3.454, P〈0.01). All theses changes caused by EPO pretreatment were eliminated by the intervention of PDTC (an antagonist to NF- κB) during pretreatment.
Conclusions: EPO pretreatment can inhibit the activation of NF- κB and upregulation of TNF- α gene in cardiomyocytes exposed to H/R through a negative feedback of NF- κB signaling pathway, and thus produces the anti-inflammatory effect. This might be one of the ways EPO produces the anti-inflammatory effect. 相似文献
6.
In vivo carbon monoxide exposure and hypoxic hypoxia stimulate immediate early gene expression 总被引:4,自引:0,他引:4
Bernhard Gess Konrad Wolf Michael Pfeifer Günter A. J. Riegger A. Kurtz 《Pflügers Archiv : European journal of physiology》1997,434(5):568-574
This study aimed to examine the influence of acute tissue hypoxygenation on the expression of immediate early genes in different
rat tissues. To this end male Sprague-Dawley rats were exposed to 0.1% carbon monoxide for 0.5, 1 and 6 h or to 9% oxygen
for 6 h and mRNA levels for c-jun, c-fos, c-myc and EGR-1 were assayed by RNase protection in hearts, kidneys, livers and lungs. We found that hypoxia increased c-jun mRNA levels between twofold (lung) and eightfold (liver) in all organs examined; c-fos mRNA increased between threefold (lung) and 20-fold (heart); c-myc mRNA increased between twofold (lung) and sixfold (heart); and EGR-1 mRNA increased between twofold (lung) and sixfold (heart).
Our findings suggest that acute tissue hypoxygenation is a general stimulus of the expression of immediate early genes in
vivo. With regard to the sensitivity to hypoxia, organ differences appear to exist in that the lung is rather insensitive,
whilst the heart is rather sensitive.
Received: 25 February 1997 / Received after revision: 17 June 1997 / Accepted: 19 June 1997 相似文献
7.
促红细胞生成素对海马CA1区缺血神经元凋亡和bcl-xl表达的影响 总被引:1,自引:0,他引:1
目的 :探讨促红细胞生成素 (Erythropoietin ,EPO)预处理的神经保护机制。方法 :采用 4-VO法制作大鼠全脑缺血模型。将SD大鼠随机分为假手术组、生理盐水组、EPO组。全脑缺血前 3h ,EPO组大鼠脑室立体定向注射重组人促红细胞生成素(rHu -EPO) 5μl,生理盐水组则给予等体积生理盐水 ,假手术组只进行假手术处理。观察缺血后 2 4h海马CA1区bcl -xl蛋白表达和缺血后 72h细胞凋亡。结果 :缺血后 2 4h ,EPO组海马CA1区bcl -xl蛋白表达与假手术组比较有显著差异 (P <0 .0 1) ,较生理盐水组表达增强 (P <0 .0 1)。缺血后 72h ,EPO组海马CA1区较生理盐水组有较少的凋亡细胞 (P <0 .0 1)。结论 :EPO预处理减少缺血海马细胞凋亡 ,促进bcl -xl蛋白表达可能参与了这种保护机制 相似文献
8.
Tom Klausen Troels Dirch Poulsen Niels Fogh-Andersen Jean-Paul Richalet Ove Juel Nielsen Niels Vidiendal Olsen 《European journal of applied physiology》1996,72(4):297-302
This study tested the hypothesis that the diurnal variations of serum-erythropoietin concentration (serum-EPO) observed in normoxia also exist in hypoxia. The study also attempted to investigate the regulation of EPO production during sustained hypoxia. Nine subjects were investigated at sea level and during 4 days at an altitude of 4350 m. Median sea level serum-EPO concentration was 6 (range 6–13) U·l–1. Serum-EPO concentration increased after 18 and 42 h at altitude, [58 (range 39–240) and 54 (range 36–340) U·l–1, respectively], and then decreased after 64 and 88 h at altitude [34 (range 18–290) and 31 (range 17–104) U·l–1, respectively]. These changes of serum-EPO concentration were correlated to the changes in arterial blood oxygen saturation (r = –0.60,P = 0.0009), pH (r = 0.67,P = 0.003), and in-vivo venous blood oxygen half saturation tension (r = –0.68,P = 0.004) but not to the changes in 2, 3 diphosphoglycerate. After 64 h at altitude, six of the nine subjects had down-regulated their serum-EPO concentrations so that median values were three times above those at sea level. These six subjects had significant diurnal variations of serum-EPO concentration at sea level; the nadir occurred between 0800–1600 hours [6 (range 4–13) U·l–1], and peak concentrations occurred at 0400 hours [9 (range 8–14) U·l–1,P = 0.02]. After 64 h at altitude, the subjects had significant diurnal variations of serum-EPO concentration; the nadir occurred at 1600 hours [20 (range 16–26) U·l–1], and peak concentrations occurred at 0400 hours [31 (range 20–38) U·l–1,P = 0.02]. This study demonstrated diurnal variations of serum-EPO concentration in normoxia and hypoxia, with comparable time courses of median values. The results also suggested that EPO production at altitude is influenced by changes in pH and haemoglobin oxygen affinity. 相似文献
9.
Eberhard Ritz Burkhard Krempien Gabriele Klefisch Theresia Ritter Eva Krause 《Virchows Archiv : an international journal of pathology》1977,376(2):145-157
Summary Uremic women on hemodialysis with metabolic bone disease (hyperparathyroidism, osteomalacia resulting from defective vitamin D metabolism) and anemia (erythropoietin deficiency) are known to give birth to infants without bone disease or anemia. Therefore, skeletal development (enchondral and desmal bone formation) and hepatic erythropoiesis were evaluated in fetuses of uremic rats. These fetuses failed to show defective mineralisation or evidence of bone disease. Bolus injection of high doses of exogenous PTH into the maternal or fetal organism did not affect fetal bone histology. In addition, no apparent defect of bone mineralisation or bone formation was found in fetuses of ricketic rats. Normal mineralisation in the offspring of uremic rats may be explained by fetal hyperphosphatemia and/or insensitivity of fetal (woven) bone mineralisation to vitamin D.Absence of fetal anemia (normal hematocrits, normal density of hematopoietic cells in the liver) in the presence of maternal anemia is presumably due to the insensitivity of fetal erythropoiesis to erythropoietin.With the support of Deutsche Forschungsgemeinschaft 相似文献
10.
Peter Sandner Bernhard Gess Konrad Wolf Armin Kurtz 《Pflügers Archiv : European journal of physiology》1996,431(6):905-912
There is accumulating evidence from in vitro experiments that the gene expression of the vascular endothelial growth factor
(VEGF) is, like that of the erythropoietin (EPO) gene, regulated by the oxygen tension and by divalent cations such as cobalt.
Since the information about the regulation of VEGF gene expression in vivo is rather scarce, this study aimed to examine the
influence of hypoxia and of cobalt on VEGF gene expression in different rat organs and to compare it with that on EPO gene
expression. To this end male Sprague-Dawley rats were exposed to carbon monoxide (0.1% CO), hypoxia (8% O2 ) or to cobalt chloride (12 and 60 mg/kg s.c.) for 6 h. mRNA levels for VEGF- 188, -164, and -120 amino acid isoforms in
lungs, hearts, kidneys and livers were semiquantitated by RNase protection. For these organs we found a rank order of VEGF
mRNA abundance of lung >> heart > kidney = liver. EPO mRNA levels were semiquantitated in kidneys and livers. Hypoxia, CO
and cobalt increased EPO mRNA levels 60-fold, 140-fold and 5-fold, respectively, in the kidneys, and 11-fold, 11-fold and
3-fold, respectively, in the livers. None of these manoeuvres caused significant changes of VEGF mRNA in lung, heart or kidneys.
Only in the livers did hypoxia lead to a significant (50%) increase of VEGF mRNA. These findings suggest that, in contrast
to the in vitro situation, the expression of the VEGF gene in normal rat tissues is rather insensitive to hypoxia. In consequence,
the in vivo regulation of the VEGF and the EPO genes appear to differ substantially, suggesting that the regulation of the
VEGF and EPO genes may not follow the same essential mechanisms in vivo.
Received: 31 July 1995/Received after revision: 20 November 1995/Accepted: 27 November 1995 相似文献