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61.
62.
Eun-Joo Shin Yunsung Nam Thu-Hien Thi Tu Yong Kwang Lim Myung-Bok Wie Dae-Joong Kim Ji Hoon Jeong Hyoung-Chun Kim 《Archives of toxicology》2016,90(4):937-953
We investigated whether protein kinase C (PKC) is involved in trimethyltin (TMT)-induced neurotoxicity. TMT treatment (2.8 mg/kg, i.p.) significantly increased PKCδ expression out of PKC isozymes (i.e., α, βI, βII, δ, and ?) in the hippocampus of wild-type (WT) mice. Consistently, treatment with TMT resulted in significant increases in cleaved PKCδ expression. Genetic or pharmacological inhibition (PKCδ knockout or rottlerin) was less susceptible to TMT-induced seizures than WT mice. TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species. These effects were more pronounced in the WT mice than in PKCδ knockout mice. In addition, the ability of TMT to induce nuclear translocation of Nrf2, Nrf2 DNA-binding activity, and upregulation of γ-glutamylcysteine ligase was significantly increased in the PKCδ knockout mice and rottlerin (10 or 20 mg/kg, p.o. × 6)-treated WT mice. Furthermore, neuronal degeneration (as shown by nuclear chromatin clumping and TUNEL staining) in WT mice was most pronounced 2 days after TMT. At the same time, TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling was evident, thereby decreasing phospho-Bad, expression of Bcl-xL and Bcl-2, and the interaction between phospho-Bad and 14-3-3 protein, and increasing Bax expression and caspase-3 cleavage were observed. Rottlerin or PKCδ knockout significantly protected these changes in anti- and pro-apoptotic factors. Importantly, treatment of the PI3K inhibitor LY294002 (0.8 or 1.6 µg, i.c.v.) 4 h before TMT counteracted protective effects (i.e., Nrf-2-dependent glutathione induction and pro-survival phenomenon) of rottlerin. Therefore, our results suggest that down-regulation of PKCδ and up-regulations of Nrf2-dependent glutathione defense mechanism and PI3K/Akt signaling are critical for attenuating TMT neurotoxicity. 相似文献
63.
Prevalence of Potentially Inappropriate Prescribing Among Hong Kong Older Adults: A Comparison of the Beers 2003, Beers 2012, and Screening Tool of Older Person's Prescriptions and Screening Tool to Alert doctors to Right Treatment Criteria
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64.
65.
Anand Dayama Nikolaos Tsilimparis Stephen Kolakowski Nathaniel M. Matolo Misty D. Humphries 《Journal of vascular surgery》2019,69(1):156-163.e1
Background
Chronic limb-threatening ischemia (CLTI), defined as ischemic rest pain or tissue loss secondary to arterial insufficiency, is caused by multilevel arterial disease with frequent, severe infrageniculate disease. The rise in CLTI is in part the result of increasing worldwide prevalence of diabetes, renal insufficiency, and advanced aging of the population. The aim of this study was to compare a bypass-first with an endovascular-first revascularization strategy in patients with CLTI due to infrageniculate arterial disease.Methods
We reviewed the American College of Surgeons National Surgical Quality Improvement Program targeted lower extremity revascularization database from 2012 to 2015 to identify patients with CLTI and isolated infrageniculate arterial disease who underwent primary infrageniculate bypass or endovascular intervention. We excluded patients with a history of ipsilateral revascularization and proximal interventions. The end points were major adverse limb event (MALE), major adverse cardiovascular event (MACE), amputation at 30 days, reintervention, patency, and mortality. Multivariable logistic regression was used to determine the association of a bypass-first or an endovascular-first intervention with outcomes.Results
There were 1355 CLTI patients undergoing first-time revascularization to the infrageniculate arteries (821 endovascular-first revascularizations and 534 bypass-first revascularizations) identified. There was no significant difference in adjusted rate of 30-day MALE in the bypass-first vs endovascular-first revascularization cohort (9% vs 11.2%; odds ratio [OR], 0.73; 95% confidence interval [CI], 0.50-1.08). However, the incidence of transtibial or proximal amputation was lower in the bypass-first cohort (4.3% vs 7.4%; OR, 0.60; CI, 0.36-0.98). Patients with bypass-first revascularization had higher wound complication rates (9.7% vs 3.7%; OR, 2.75; CI, 1.71-4.42) compared with patients in the endovascular-first cohort. Compared with the endovascular-first cohort, the incidence of 30-day MACE was significantly higher in bypass-first patients (6.9% vs 2.6%; adjusted OR, 3.88; CI, 2.18-6.88), and 30-day mortality rates were 3.23% vs 1.8% (adjusted OR, 2.77; CI, 1.26-6.11). There was no difference in 30-day untreated loss of patency, reintervention of treated arterial segment, readmissions, and reoperations between the two cohorts. In subgroup analysis after exclusion of dialysis patients, there was also no significant difference in MALE or amputation between the bypass-first and endovascular-first cohorts.Conclusions
CLTI patients with isolated infrageniculate arterial disease treated by a bypass-first approach have a significantly lower 30-day amputation. However, this benefit was not observed when dialysis patients were excluded. The bypass-first cohort had a higher incidence of MACE compared with an endovascular-first strategy. These results reaffirm the need for randomized controlled trials, such as the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL-2) trial and Best Endovascular vs Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI), to provide level 1 evidence for the role of endovascular-first vs bypass-first revascularization strategies in the treatment of this population of challenging patients. 相似文献66.
Stephen Hanessian 《ACS medicinal chemistry letters》2016,7(1):6-9
Current major advances in drug discovery
can be traced back to
pioneering contributions originating from academics over a century
ago. Living in a symbiotic yet noninvasive coexistence, the academic
community and the pharmaceutical industry have strived, each in their
own way, to develop the modern medicines that benefit humankind today.
The subject is presented from a historical and personal perspective. 相似文献
67.
68.
Stephen Price 《Acta neurochirurgica》2006,148(11):1221-1221
69.
Pulmonary hamartomas are usually an incidental finding and range in size from 1 cm to 8 cm in diameter in various series. We report a case of a massive pulmonary hamartoma (size 25.5 × 17.5 × 6.5 cm and weighing 1134 g) in a 61 year old male who presented with a short history of breathlessness. The tumour was arising from the medial border of the right lung and occupying most of the right chest extending in to the anterior mediastinum. The tumour was compressing the right lung and there was no evidence of infiltration into the surrounding structures. It was successfully treated by surgical resection and final histology was pulmonary hamartoma with predominantly adipose and leiomyomatous differentiation. 相似文献
70.
背景:对于脊椎以外的骨折而言,补充口服维生素D的预防作用和用量仍无定论。
目的:评估补充维生素D在预防老年髋骨骨折和非脊椎骨折方面的效果。
数据来源:使用MEDLINE、Cochrance对照试验记录(1960~2005年)以及EMBASE(1991-2005年),对英文和非英文文章进行系统回顾。通过与临床专家接触,通过检索美国社会骨和骨矿研究协会提供的参考文献和摘要(1995~2004年).进一步寻找更多的研究。检索词包括随机对照试验(randomized controlled trial,RCT)、临床对照试验、随机分配、双盲法、维生素D3、维生素D2;25-羟基维生素D、骨折、人类、老年、摔倒和骨密度。
研究选取:纳入的研究仅限于口服补充维生素D(维生素D3、维生素D2、补钙或不补钙)与补钙或安慰剂比较的双盲RCTs。试验于检查髋部骨折或非脊椎骨折的老年人(年龄≥60岁)中进行。数据提取:两位作者根据预先规定独立提取相关数据,其中包括研究质量指标。
数据综合:所有的汇总分析均以随机效应模型为基础。5项有关髋部骨折的RCTs(n=9294)和7项有关非脊椎骨折危险的RCTs(n=9820)符合我们的纳入标准。所有试验均使用了维生素D3。对髋部和非脊椎骨折预防研究的异质性亦进行观察,用低剂量(400IU/d)和高剂量(700~800IU/d)分别合并RCTs后异质性消失。与补钙或安慰剂相比,每天服700~800IU的维生素D可使髋部骨折的相对危险(relative risk,aa)下降26%(3项RCTs共计5572人;RR,0.74;95%可信区间[confidence interval,CI],0.61~0.88),使非脊椎骨折的相对危险下降23%(5项RCTs共计6098人;RR,0.77;95%CI,0.68~0.87)。每天服400IU的维生素D(2项RCTs共计3722人;髋部骨折RR,1.15;95%CI,0.88~1.50;非脊椎骨折RR,1.03;95%CI,0.86—1.24)未见明显获益。
结论:口服补充维生素D(700~800IU/d)可以降低尚能活动的老人或慈善机构收容的老年人发生髋部骨折和脊椎以外骨折的危险,每天口服400IU维生素D并不足以预防骨折。 相似文献