全文获取类型
收费全文 | 78158篇 |
免费 | 5305篇 |
国内免费 | 3207篇 |
专业分类
耳鼻咽喉 | 305篇 |
儿科学 | 1212篇 |
妇产科学 | 717篇 |
基础医学 | 8728篇 |
口腔科学 | 1899篇 |
临床医学 | 4494篇 |
内科学 | 8703篇 |
皮肤病学 | 1866篇 |
神经病学 | 7902篇 |
特种医学 | 1524篇 |
外国民族医学 | 5篇 |
外科学 | 4323篇 |
综合类 | 10169篇 |
现状与发展 | 3篇 |
预防医学 | 5331篇 |
眼科学 | 1286篇 |
药学 | 18597篇 |
14篇 | |
中国医学 | 7033篇 |
肿瘤学 | 2559篇 |
出版年
2024年 | 177篇 |
2023年 | 1076篇 |
2022年 | 1341篇 |
2021年 | 2648篇 |
2020年 | 2320篇 |
2019年 | 1983篇 |
2018年 | 1924篇 |
2017年 | 2245篇 |
2016年 | 2456篇 |
2015年 | 2607篇 |
2014年 | 4524篇 |
2013年 | 5643篇 |
2012年 | 4427篇 |
2011年 | 4919篇 |
2010年 | 3710篇 |
2009年 | 3599篇 |
2008年 | 3714篇 |
2007年 | 3756篇 |
2006年 | 3318篇 |
2005年 | 3003篇 |
2004年 | 2666篇 |
2003年 | 2298篇 |
2002年 | 1918篇 |
2001年 | 1636篇 |
2000年 | 1406篇 |
1999年 | 1280篇 |
1998年 | 1215篇 |
1997年 | 1145篇 |
1996年 | 1122篇 |
1995年 | 1026篇 |
1994年 | 929篇 |
1993年 | 790篇 |
1992年 | 790篇 |
1991年 | 731篇 |
1990年 | 711篇 |
1989年 | 664篇 |
1988年 | 616篇 |
1987年 | 553篇 |
1986年 | 589篇 |
1985年 | 840篇 |
1984年 | 772篇 |
1983年 | 580篇 |
1982年 | 581篇 |
1981年 | 548篇 |
1980年 | 488篇 |
1979年 | 333篇 |
1978年 | 258篇 |
1977年 | 193篇 |
1976年 | 171篇 |
1975年 | 121篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
991.
目的:探讨组蛋白乙酰化酶(histone acetylases,HATs)抑制剂漆树酸(anacardic acid,AA)改善胸主动脉缩窄术(thoracic aortic constriction,TAC)小鼠心肌纤维化的组蛋白乙酰化调控机制,为心肌纤维化的防治提供新靶点。方法:选择6~8周SPF级昆明小鼠为研究对象,按照随机数字表法将小鼠分为5组:正常(Normal)组、假手术(Sham)组、胸主动脉缩窄(TAC)组、胸主动脉缩窄+溶剂对照(TAC+Veh)组、胸主动脉缩窄+漆树酸(TAC+AA)组。12周后采用超声心动图检测各组小鼠模型构建情况;收集各组小鼠心脏组织进行以下检测:马松染色观察心肌组织纤维化情况;Western blot检测KAT8、H4K16ac、TGF-β1、SMAD3、CollagenⅠ、 CollagenⅢ蛋白表达情况;免疫共沉淀检测KAT8与H4K16ac的相互作用关系。结果:超声心动图表明TAC模型小鼠构建成功。马松染色结果表明,TAC组小鼠心脏较Sham组增大,心肌组织中胶原沉积增多,纤维化明显,而TAC+AA组较TAC组小鼠心脏缩小,心肌组织中胶原... 相似文献
992.
探讨术苓健脾胶囊(术苓)对2,4,6-三硝基苯磺酸(TNBS)诱导的大鼠实验性结肠炎的作用及其机制。采用2.5%TNBS灌肠制备大鼠实验性结肠炎模型。将大鼠随机分为正常组、模型组、肠炎宁(180 mg/kg)组以及术苓低剂量(40 mg/kg)、高剂量(120 mg/kg)组。造模后药物治疗7 d后处死大鼠。其间每日记录大鼠体重,观察大鼠疾病活动状态。实验结束后,取结肠组织进行HE病理学分析、检测结肠组织中髓过氧化物酶(MPO)酶活、诱导型一氧化氮合酶(iNOS)、炎性细胞因子(IL-6、IL-1β、IFN-γ、IL-10)及紧密连接蛋白(occludin、ZO-1)的表达水平,并检测血清中炎性细胞因子(IL-6、IL-1β)的含量。结果表明,与模型组相比,术苓给药显著缓解了TNBS造模引起的体重下降、疾病活动指数(DAI)升高,缓解了结肠组织的缩短、水肿以及病理学损伤,减少了炎性细胞浸润、隐窝的破坏与杯状细胞的丢失,降低了结肠组织MPO酶活性、iNOS与炎性细胞因子的水平,增加了结肠紧密连接蛋白的表达,同时降低了血清中的炎性因子的含量。结果表明,术苓通过降低炎性因子水平,增加肠道紧密... 相似文献
993.
Neurohumoral control of gallbladder motility in healthy subjects and diabetic patients with or without autonomic neuropathy 总被引:4,自引:0,他引:4
Stefano Fiorucci MD Rachele Bosso MD Luciano Scionti MD Silvana Disanto MD Bruno Annibale MD Gianfranco Delle Fave Antonio Morelli MD 《Digestive diseases and sciences》1990,35(9):1089-1097
Patients affected by diabetes mellitus are reported to have an increased incidence of gallbladder abnormalities. The pathophysiologic mechanisms for this phenomenon are unclear. In the present study ultrasonography was used to determine gallbladder emptying in response to a meal or separate cephalic or hormonal stimulation in 21 diabetic patients and 10 healthy subjects. Gallbladder emptying and refilling after a meal were similar in diabetic patients and healthy subjects. When diabetics were divided according to the presence or absence of cardiac autonomic neuropathy (AN), a significant reduction of gallbladder emptying in response to cephalic stimulation was found in diabetics with AN (P<0.01 in comparison with diabetics without AN or healthy subjects). A dose-response curve of gallbladder emptying in response cerulein, a cholecystokinin analog, at concentrations of 0.25, 1, and 4 g/kg/min was evaluated. No differences of gallbladder emptying were found in the three groups of subjects, indicating that gallbladder sensitivity to hormonal stimulation is not changed in diabetic patients with or without AN. Diabetic patients with AN have a significant reduction of gastric acid output and pancreatic polypeptide (PP) secretion in response to cephalic stimulation (P<0.05 in comparison with diabetic patients without AN or healthy subjects). Cerulein-induced PP secretion was similar in all three groups of subjects (P>0.05). This study indicates that in diabetic patients with AN, gallbladder emptying as well as gastric acid and PP secretions induced by neural stimulation are markedly reduced in comparison to diabetics without AN. 相似文献
994.
M. Konermann J. Grötz B. Sorge-Hädicke B. Sanner 《Journal of molecular medicine (Berlin, Germany)》1990,68(21):1059-1065
Resümee Schwerwiegende gastroduodenale Erkrankungen sind bei fast der Hälfte aller Patienten, die sich einer Operation am offenen Herzen unterziehen müssen, auch bei Fehlen von Symptomen nachweisbar. Das erhebliche Überwiegen von Magenläsionen spricht dafür, daß die arteriosklerotisch bedingte Perfusionsminderung der Schleimhaut die entscheidende Ursache hierfür ist. Routinemäßige präoperative Ösophago-Gastro-Duodenoskopien können die nicht unerhebliche durch gastrointestinale Komplikationen bedingte postoperative Mortalität senken helfen.
Abkürzungen ASS Azetylsalizylsäure - J. Jahre - GI-Trakt Gastrointestinaltrakt 相似文献
Pathological changes in the upper gastrointestinal tract in patients awaiting open heart surgery
Summary While waiting for open heart surgery, in 153 patients (104 male, 49 female, 22–76 years of age) without gastrointestinal symptoms and/or history esophago-gastro-duodenoscopy was performed. 124 patients suffered from coronary heart disease, 29 from valvular defect, aneurysm of the sinus of Valsalva or tumor of the heart.In 47.1% endoscopy revealed serious abnormal findings: in 16.3% gastric ulcer, in 20.9% erosive gastritis, duodenal ulcer and erosive duodenitis in 5.2%, respectively, 1 case of gastric carcinoma, 2 of large polyps and 3 of reflux esophagitis of higher degree (totally 3.9%).In patients with coronary artery disease, the relation of erosive and ulcerous gastric lesions as compared with those of duodenal origin was 41, in patients with other cardiac diseases it was 21, respectively (p<0,001).Compared with a normal population, the incidence of pathological gastric findings was 54-fold higher in our patients, and 1.7-fold concerning duodenal lesions, respectively (p<0.001).51 patients on acethylsalicylic acid (160 mg/ die) showed pathologic findings in 41.2%, and 96 patients without ulcer-inducing therapy in 51%. Thus, low-dose Aspirin does not seem to have serious gastric side effects.The results of the study stress the necessity of routinely performed endoscopy of the upper gastrointestinal tract in patients awaiting open heart surgery. This will lead to a lower incidence of serious gastrointestinal complications postoperatively, which are known to have a high mortality.
Abkürzungen ASS Azetylsalizylsäure - J. Jahre - GI-Trakt Gastrointestinaltrakt 相似文献
995.
Summary Azelaic acid, and other saturated dicarboxylic acids (C9-C12), are shown to be competitive inhibitors of tyrosinase (K
I azelaic acid = 2.73×10–3
M) and of membrane-associated thioredoxin reductase (K
I azelaic acid = 1.25×10–5
M). The monomethyl ester of azelaic acid does not inhibit thioredoxin reductase, but it does inhibit tyrosinase, although double the concentration is necessary compared with azelaic acid (K
I azelaic acid monomethyl ester = 5.24×10–3
M). Neither azelaic acid nor its monomethyl ester inhibit tyrosinase when catechol is used as a substrate instead of l-tyrosine. Therefore, the weak inhibitory action of azelaic acid on tyrosinase appears to be due to the competition of a single carboxylate group on this inhibitor for the -carboxylate binding site of the l-tyrosine substrate on the enzyme active site. Based on the inhibitor constant on tyrosinase, at least cytotoxic levels of azelaic acid would be required for the direct inhibition of melanin biosynthesis in melanosomes if this mechanism is responsible for depigmentation in the hyperpigmentation disorders lentigo maligna and melasma. Alternatively only 10–5
M azelaic acid is required to inhibit thioredoxin reductase. This enzyme is shown to regulate tyrosinase through a feedback mechanism involving electron transfer to intra-cellular thioredoxin, followed by a specific interaction between reduced thioredoxin and tyrosinase. Furthermore, the thioredoxin reductase/thioredoxin system is shown to be a principal electron donor for the ribonucleotide reductases which regulates DNA synthesis. Inhibition of thioredoxin reductase by azelaic acid provides a rationale for both its depigmenting property and the reversible inhibition of DNA synthesis observed in cultured epidermal cells and also in some of the bacteria associated with acne vulgaris. 相似文献
996.
The solubility and solution behavior of lauric acid (LA) and its 1:1 acid soap (potassium hydrogen dilaurate) were investigated at 32°C over a pH range of 2.5–8.5 and at varying KC1 concentrations to examine the self-association of this long-chain carboxylic acid under these conditions. LA's solubility in water exhibited the classical pH dependence of a monocarboxylic acid with no evidence of self-association. In 0.1 M KC1 between pH 6.3 and pH 7.3, filtered samples were turbid, suggesting the presence of high molecular weight aggregates (mesophase), which could be removed by ultrafiltration. The apparent LA solubility vs pH profile in ultrafiltered samples was consistent with a solid phase consisting of either the free acid (pH < 6.5) or potassium hydrogen dilaurate (pH > 6.5), again with no evidence of self-association to form low molecular weight species (dimers, etc.). Quasi-elastic light scattering (QLS) studies and mannitol trapping experiments indicated that vesicles were present in samples containing mesophase. The mesophase composition was characterized and a mass-action law for mesophase formation was developed to describe the apparent LA solubility versus pH in the mesophase region in terms of three parameters. The index of cooperativity, , indicated that the mesophase consists of approximately 25 molecules of LA with an acid:anion ratio, , of 1.7. The standard free energy of mesophase formation per mole of monomer was determined to be –6.3 kcal/mol. The aggregate size determined thermodynamically is several orders of magnitude less than that of the mesophase particle size determined by QLS measurements, suggesting that the LA monomer concentration in equilibrium with mesophase may be governed by a small unit domain of the vesicle. These observations may have a bearing on the thermodynamics of self-assembly of lipid bilayer membranes. 相似文献
997.
M. F. Jarvis C. J. Burns H. W. Pauls A. Assal J. S. Kim D. L. Cheney R. D. Youssefyeh 《Calcified tissue international》1993,52(5):372-377
Summary The present studies characterize the binding of [14C]citric acid to synthetic hydroxyapatite (HA) crystals. [14C]Citric acid specifically bound to HA and was dependent upon the concentration of HA in the assay. The binding of [14C]citric acid to HA reached equilibrium within 20 min and remained stable for at least 90 min. Dissociation of bound [14C]citric acid was biphasic in nature since both rapid and more slowly reversible binding components were detected. Saturation experiments also indicated that [14C]citric acid labeled two recognition sites with different affinity (KdH=42 nM and KdL=24,000 nM) and density (BmaxH=161 fmol/g HA and BmaxL=8.8 pmol/g HA). Ligand competition experiments revealed that compounds that are known to readily bind bone (e.g., sodium pyrophosphate, methylene diphosphonic acid, etidronate) potently inhibited the binding of [14C]citric acid to HA, whereas compounds known to have poorer affinity for bone (e.g., oxalic acid and GABA) did not. Computer analysis of these inhibition curves revealed specific ligand interactions at two different affinity recognition sites. The present results indicate that [14C]citric acid binds discrete sites on synthetic HA in a fashion consistent with a specific labeling of the bisphosphonate recognition site. Analysis of the binding of [14C]citric acid to HA provides a useful method to further explore the structure activity relationships of novel compounds that have binding affinity for bone. 相似文献
998.
C. Wolfrom R. Hepp R. Hartmann H. Breithaupt G. Henze 《European journal of clinical pharmacology》1990,39(4):377-383
Summary The pharmacokinetics of methotrexate (MTX), 7-hydroxymethotrexate (7-OHMTX), 2,4-diaminomethylpteroic acid (APA), folinic acid, and 5-methyltetrahydrofolate (5-MTHF) have been studied during 21 high-dose MTX (HDMTX) infusions (5 g·m–2 in 24 h) with leucovorin (LCV) rescue, a component of the therapy of 5 children with acute lymphoblastic leukemia (ALL).The median steady-state concentration of MTX was 66 mol·l–1. Three elimination half-lifes were determined for MTX: 1.8 h, 6.4 h and a terminal 15 h. The median systemic MTX clearance was 110 mg·m–2·min–1.The 7-OHMTX level increased during each infusion and a Cmax of 19 mol·l–1 was achieved at the end. Its initial half-life was 5 h and the terminal half-life was 12 h. Thus, the peak serum concentration ratio of 7-OHMTX to MTX was reached 24 h after the end of the infusion at a median ratio of 8.The MTX metabolite APA was detected in concentrations less than 0.06 mol·l–1. The median folinic acid level during rescue, 48 h after starting the infusion, was 7.0 mol·l–1 and 18 h following the last dose of LCV it was 0.44 mol·l–1, leading to ratios of folinic acid to MTX of 31 and 6, respectively. The median 5-MTHF level during rescue was 0.44 mol·l–1 with a median ratio of 5-MTHF to MTX of 2.Twenty infusions with 48 h MTX levels of less than 0.5 mol·l–1 were without marked toxicity. Only one patient with a 48 h MTX concentration of 5.5 mol·l–1 and a ratio of 5-MTHF to MTX of 0.08 suffered from ulcerating mucositis and septicaemia despite increased and prolonged LCV rescue. 相似文献
999.
The binding characteristics of valproic acid (VPA) and its pharmacologically active monounsaturated metabolite, E-2-VPA, to rat plasma proteins were compared. The plasma free fraction was determined by a rapid equilibrium procedure, which minimizes the interfering effects of nonesterified fatty acids liberated by in vitro lipolysis. Nonlinear binding behavior was observed with both compounds over their respective pharmacologic concentration range. Multiple binding-site models were invoked to explain the binding isotherm. The 2-unsaturated compound has a much higher affinity for the rat plasma proteins (mainly albumin) than its saturated precursor. The equilibrium association constants for the high- and intermediate-affinity sites were more than an order of magnitude higher with E-2-VPA than with VPA (104–106 versus 103
M
–1). This difference in binding affinity was also reflected by a lower plasma free fraction for E-2-VPA compared with VPA (<<10 versus >20% at total concentrations of less than 100 µg/ml). A more pronounced dose- and concentration-dependent variation in the distribution and clearance kinetics is predicted for the 2-unsaturated analogue compared to VPA. Also, the structural dependency in plasma protein binding observed with these branched-chain fatty acids may provide insights into the mechanism of interaction between fatty acyl molecules and albumin. 相似文献
1000.
The Effects of Permeation Enhancers on the Surface Morphology of the Rat Nasal Mucosa: A Scanning Electron Microscopy Study 总被引:2,自引:0,他引:2
A rat model has been developed to compare relative morphological changes in the nasal mucosa after exposure to potential membrane permeation enhancers. Scanning electron microscopy was used to characterize gross structural and specific cellular changes following exposure. Micrographs of the rat nasal mucosa were scored in four categories: (1) mucosal surface integrity, (2) ciliary morphology, (3) mucus/extracellular debris, and (4) presence of red blood cells. The order of increasing morphological damage resulting from a 5-min exposure to each surfactant was 0.5% Solulan C-24 0.5% Solulan C-24/0.5% sodium tauro-24,25-dihydrofusidate (STDHF) < 0.5% STDHF < 1.0% STDHF 1.0% Laureth-9 < 1.0% sodium taurodeoxycholate 1.0% sodium deoxycholate. The changes observed in the mucosal morphology after exposure to the various surfactants are in general agreement with data in the literature. This model is able to compare rapidly the relative morphological effects on the mucosal membrane of different nasal formulations. 相似文献