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991.
药物发现早期通常在啮齿类模型上进行在体药效实验,以优化筛选,迅速发现先导化合物,但当采用预先或同时给药方式进行时,常有过高估计新化合物疗效的可能。不利于科学决策、降低成本、时间安排及合乎伦理地使用动物。放弃预先给药方式,在模型动物上监测重要的生理参数及系统地应用简单药代-药效动力学分析可以减少假阳性结果。 相似文献
992.
CE Riera C Menozzi-Smarrito M Affolter S Michlig C Munari F Robert H Vogel SA Simon J le Coutre 《British journal of pharmacology》2009,157(8):1398-1409
Background and purpose:
Oily extracts of Sichuan and Melegueta peppers evoke pungent sensations mediated by different alkylamides [mainly hydroxy-α-sanshool (α-SOH)] and hydroxyarylalkanones (6-shogaol and 6-paradol). We assessed how transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (TRPV1), two chemosensory ion channels, participate in these pungent sensations.Experimental approach:
The structure–activity relationships of these molecules on TRPA1 and TRPV1 was measured by testing natural and synthetic analogues using calcium and voltage imaging on dissociated dorsal root ganglia neurons and human embryonic kidney 293 cells expressing the wild-type channels or specific cysteine mutants using glutathione trapping as a model to probe TRPA1 activation. In addition, using Trpv1 knockout mice, the compounds'' aversive responses were measured in a taste brief-access test.Key results:
For TRPA1 activation, the cis C6 double bond in the polyenic chain of α-SOH was critical, whereas no structural specificity was required for activation of TRPV1. Both 6-shogaol and 6-paradol were found to activate TRPV1 and TRPA1 channels, whereas linalool, an abundant terpene in Sichuan pepper, activated TRPA1 but not TRPV1 channels. Alkylamides and 6-shogaol act on TRPA1 by covalent bonding whereas none of these compounds activated TRPV1 through such interactions. Finally, TRPV1 mutant mice retained sensitivity to 6-shogaol but were not responsive to α-SOH.Conclusions and implications:
The pungent nature of components of Sichuan and Melegueta peppers was mediated via interactions with TRPA1 and TRPV1 channels and may explain the aversive properties of these compounds. 相似文献993.
Francisco W Ferreira-da-Silva Roseli Barbosa Luiz Moreira-Júnior Tiago dos Santos-Nascimento Maria D de Oliveira-Martins relina N Coelho-de-Souza Francisco SA Cavalcante Vânia M Ceccatto Telma LG de Lemos Pedro JC Magalhães Saad Lahlou José H Leal-Cardoso 《Clinical and experimental pharmacology & physiology》2009,36(11):1068-1073
- 1 1,8‐Cineole is a non‐toxic small terpenoid oxide believed to have medicinal properties in folk medicine. It has been shown to have various pharmacological effects, including blockade of the compound action potential (AP). In the present study, using intracellular recording techniques, we investigated the effects of 1,8‐cineole on the electrophysiological parameters of neurons of the superior cervical ganglion (SCG) in rats.
- 2 1,8‐Cineole (0.1–6 mmol/L) showed reversible and concentration‐dependent effects on various electrophysiological parameters. At 3 and 6 mmol/L, but not at 0.1 and 1 mmol/L, 1,8‐cineole significantly diminished the input resistance (Ri) and altered the resting potential (Em) to more positive values. At 6 mmol/L, 1,8‐cineole completely blocked all APs within 2.7 ± 0.6 min (n = 12). In neurons exposed to 3 and 1 mmol/L 1,8‐cineole, the effects regarding excitability varied from complete AP blockade to minor inhibition of AP parameters. The depolarization of Em and the decrease in Ri induced by 6 mmol/L 1,8‐cineole were unaltered by 200 µmol/L niflumic acid, a well known blocker of Ca2+‐activated Cl? currents.
- 3 Significant correlations (Pearson correlation test) were found between changes in Em and decreases in AP amplitude (r = –0.893; P < 0.00282) and maximum ascendant inclination (r = –0.799; P < 0.0173), but not for maximum descendant inclination (r = 0.598; P < 0.117). Application of current to restore the transmembrane potential equal to control Em values in the presence of 6 mmol/L 1,8‐cineole resulted in the partial recovery of AP.
- 4 The present study shows that 1,8‐cineole effectively blocks the excitability of SCG neurons, probably through various mechanisms, one of which acts indirectly via depolarization of the neuronal cytoplasmatic membrane.
994.
Saskia FA Duijts Hester SA Oldenburg Marc van Beurden Neil K Aaronson 《BMC women's health》2009,9(1):15
Background
Premature menopause is a major concern of younger women undergoing adjuvant therapy for breast cancer. Hormone replacement therapy is contraindicated in women with a history of breast cancer. Non-hormonal medications show a range of bothersome side-effects. There is growing evidence that cognitive behavioral therapy (CBT) and physical exercise can have a positive impact on symptoms in naturally occurring menopause. The objective of this study is to investigate the efficacy of these interventions among women with breast cancer experiencing treatment-induced menopause. 相似文献995.
Janneke Hatzmann Heleen Maurice-Stam Hugo SA Heymans Martha A Grootenhuis 《Health and quality of life outcomes》2009,7(1):72
Background
Parents of chronically ill children are at risk for a lower Health Related Quality of Life (HRQoL). Insight in the dynamics of factors influencing parental HRQoL is necessary for development of interventions. Aim of the present study was to explore the influence of demographic and disease related factors on parental HRQoL, mediated by employment, income, leisure time, holiday and emotional support in a comprehensive model. 相似文献996.
E Chanudet H Ye J Ferry CM Bacon P Adam HK Müller‐Hermelink J Radford SA Pileri K Ichimura VP Collins RA Hamoudi AG Nicholson AC Wotherspoon PG Isaacson MQ Du 《The Journal of pathology》2009,217(3):420-430
The genetic basis of MALT lymphoma is largely unknown. Characteristic chromosomal translocations are frequently associated with gastric and pulmonary cases, but are rare at other sites. We compared the genetic profiles of 33 ocular adnexal and 25 pulmonary MALT lymphomas by 1 Mb array–comparative genomic hybridization (CGH) and revealed recurrent 6q23 losses and 6p21.2–6p22.1 gains exclusive to ocular cases. High‐resolution chromosome 6 tile‐path array–CGH identified NF‐κB inhibitor A20 as the target of 6q23.3 deletion and TNFA/B/C locus as a putative target of 6p21.2–22.1 gain. Interphase fluorescence in situ hybridization showed that A20 deletion occurred in MALT lymphoma of the ocular adnexa (8/42 = 19%), salivary gland (2/24 = 8%), thyroid (1/9 = 11%) and liver (1/2), but not in the lung (26), stomach (45) and skin (13). Homozygous deletion was observed in three cases. A20 deletion and TNFA/B/C gain were significantly associated (p < 0.001) and exclusively found in cases without characteristic translocation. In ocular cases, A20 deletion was associated with concurrent involvement of different adnexal tissues or extraocular sites at diagnosis (p = 0.007), a higher proportion of relapse (67% versus 37%) and a shorter relapse‐free survival (p = 0.033). A20 deletion and gain at TNFA/B/C locus may thus play an important role in the development of translocation‐negative MALT lymphoma. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
997.
A comparative study of buccal mucosa graft and penile pedical flap for reconstruction of anterior urethral strictures 总被引:2,自引:0,他引:2
SA Ying-long XU Yue-min QIAN Yong JIN San-bo FU Qiang ZHANG Xin-ru ZHANG Jiong GU Bao-jun 《中华医学杂志(英文版)》2010,123(3):365-368
Anterior urethral strictures, where the length is more kthan 2 cm, are best treated by substitution urethroplasty with either preputial/penile skin flaps or free grafts.1 The use of dartos pedicled flaps has many advantages in terms of increased survival thanks to its own vascularization. Recently, buccal mucosa has become increasingly popular among urologists for urethral replacement when local penile skin is unavailable. Both penile skin flaps and buccal mucosa grafts have emerged as reliable urethral substitutes with comparable long-term results. These urethral substitutes are traditionally placed on the ventral aspect of the stricture and have a success rate of about 85%. 相似文献
998.
目的 建立GFP(绿色荧光蛋白)/Luciferase(荧光素酶,Luc)双标高效表达的人肝癌细胞系SMMC-7721-GFP/Luc,并建立该细胞的裸小鼠肝原位移植瘤动物模型,利用小动物活体成像系统观察裸小鼠肝原位移植瘤的生长及转移情况.方法 应用慢病毒转染的方法建立GFP/I.alC双标的SMMC-7721细胞系,接种于裸小鼠肝原位,采用活体成像技术监测该细胞在小鼠体内深部组织的表达情况.结果 成功建立了GFP/Luc双标表达率接近100%的SMMC-772l-GFP/Luc细胞系,进行裸小鼠肝原位移植后,应用活体成像系统可观察到裸小鼠肝原位早期的微小病灶和晚期移植瘤的生长情况.而且,随着肿瘤移植时间的延长,移植瘤体积的增大,活体成像检测到的发光面积逐渐增大,发光强度也逐渐增加.结论 活体荧光成像系统可直接观察肝原位移植瘤模型中肿瘤的生长及转移,有助于了解人肝癌的生物学行为及其特性,鉴于其敏感、直观,动态、可靠的优点,它将为肝癌的进一步研究提供极其有益的帮助. 相似文献
999.
Objectives
While highly active antiretroviral therapy (HAART) decreases long‐term morbidity and mortality, its short‐term effect on hospitalization rates is unknown. The primary objective of this study was to determine hospitalization rates over time in the year after HAART initiation for virological responders and nonresponders.Methods
Hospitalizations among 1327 HAART‐naïve subjects in an urban HIV clinic in 1997–2007 were examined before and after HAART initiation. Hospitalization rates were stratified by virological responders (≥1 log10 decrease in HIV‐1 RNA within 6 months after HAART initiation) and nonresponders. Causes were determined through International Classification of Diseases, 9th Revision (ICD‐9) codes and chart review. Multivariate negative binomial regression was used to assess factors associated with hospitalization.Results
During the first 45 days after HAART initiation, the hospitalization rate of responders was similar to their pre‐HAART baseline rate [75.1 vs. 78.8/100 person‐years (PY)] and to the hospitalization rate of nonresponders during the first 45 days (79.4/100 PY). The hospitalization rate of responders fell significantly between 45 and 90 days after HAART initiation and reached a plateau at approximately 45/100 PY from 91 to 365 days after HAART initiation. Significant decreases were seen in hospitalizations for opportunistic and nonopportunistic infections.Conclusions
The first substantial clinical benefit from HAART may be realized by 90 days after HAART initiation; providers should keep close vigilance at least until this time.1000.
非酒精性脂肪肝大鼠PPARα基因表达及脂代谢和胰岛素水平的变化 总被引:2,自引:0,他引:2
目的 观察非酒精性脂肪肝(NAFLD)大鼠肝组织中PPARα基因的表达,并用PPARα激动剂进行干预,探讨其与胰岛素抵抗、脂代谢紊乱的关系.方法 大鼠随机分为①正常对照组、②高脂模型组、③PPARα激动剂干预组,利用高脂饮食建立大鼠非酒精性脂肪肝模型.12周后,检测大鼠血脂、肝功能、血糖、胰岛素水平及胰岛素抵抗指数;RT-PCR法分析PPARα基因的表达;观察肝脏的形态学改变.结果 PPARα激动剂可降低NAFLD大鼠转氨酶、血脂水平及胰岛素抵抗指数,可促进NAFLD大鼠中PPARα基因的表达;肝脏形态学明显改善.结论 PPARα激动剂能改善NAFLD大鼠脂质代谢紊乱, 有明显的保肝降酶作用, 具有适度的胰岛素增敏作用.PPARα及其配体在NAFLD发病机制及治疗中的进一步深入研究,将为临床防治NAFLD提供新的思路. 相似文献