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《Expert opinion on pharmacotherapy》2013,14(4):615-628
Focal segmental glomerulosclerosis (FSGS) is not a disease but a lesion initially affecting the podocyte. Various factors may induce ‘secondary’ FSGS, including defects in molecules that contribute to the podocyte slit diaphragm permselectivity to albumin. They do not represent indications for immunosuppression and require symptomatic treatment only, comprising angiotensin 2 and endothelin antagonists. Primary (idiopathic) FSGS is possibly but not certainly of immunologic origin, owing to an elusive glomerular permeability factor (GPF), explaining relapse on a renal transplant and justifying an immunosuppressive treatment. The best prognostic feature of primary nephrotic FSGS is its response to corticosteroids. Alkylating agents are mostly ineffective in steroid-resistant forms. An association of corticosteroids and cyclosporine A (CsA) remains the mainstay of treatment, with a good tolerability when CsA dosage is low. A definite advantage of tacrolimus on CsA has not yet been established. Sirolimus appears ineffective and potentially harmful. Azathioprine is not indicated. A number of mostly uncontrolled trials indicate that mycophenolate mofetil might find an adjunctive place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the GPF has not led to practical treatment options. Anecdotal reports on rituximab are as yet too few to determine whether this monoclonal anti-CD20 antibody will find a place in the treatment of primary FSGS. 相似文献
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目的:建立一种稳定的小鼠足细胞损伤模型,为进一步研究足细胞的生物特性,以及其相关蛋白与肾性蛋白尿间的关系提供可靠保证。方法应用CCK8检测不同浓度的阿霉素(0.5μg/ml,0.25μg/ml,0.125μg/ml)分别作用24 h,48 h后,足细胞的抑制率;应用流式细胞术检测测定足细胞凋亡情况;应用R?T PCR检测裂孔膜关键因子nephrin, podocin的表达。结果0.25μg/ml的阿霉素作用24 h,抑制率接近50%;流式细胞术及R?T PCR均表明浓度为0.25μg/ml的ADR作用24 h后与正常组存在显著性差异。结论0.25μg/ml的阿霉素作用24 h建立的足细胞模型稳定可靠,可应用于足细胞研究。 相似文献
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Xuezhu Li Peter Y. Chuang Vivette D. D’Agati Yan Dai Rabi Yacoub Jia Fu Jin Xu Oltjon Taku Prem K. Premsrirut Lawrence B. Holzman John Cijiang He 《Journal of the American Society of Nephrology : JASN》2015,26(10):2361-2377
Nephrin is required during kidney development for the maturation of podocytes and formation of the slit diaphragm junctional complex. Because nephrin expression is downregulated in acquired glomerular diseases, nephrin deficiency is considered a pathologic feature of glomerular injury. However, whether nephrin deficiency exacerbates glomerular injury in glomerular diseases has not been experimentally confirmed. Here, we generated mice with inducible RNA interference–mediated nephrin knockdown. Short-term nephrin knockdown (6 weeks), starting after the completion of kidney development at 5 weeks of age, did not affect glomerular structure or function. In contrast, mice with long-term nephrin knockdown (20 weeks) developed mild proteinuria, foot process effacement, filtration slit narrowing, mesangial hypercellularity and sclerosis, glomerular basement membrane thickening, subendothelial zone widening, and podocyte apoptosis. When subjected to an acquired glomerular insult induced by unilateral nephrectomy or doxorubicin, mice with short-term nephrin knockdown developed more severe glomerular injury compared with mice without nephrin knockdown. Additionally, nephrin-knockdown mice developed more exaggerated glomerular enlargement when subjected to unilateral nephrectomy and more podocyte apoptosis and depletion after doxorubicin challenge. AKT phosphorylation, which is a slit diaphragm–mediated and nephrin-dependent pathway in the podocyte, was markedly reduced in mice with long-term or short-term nephrin knockdown challenged with uninephrectomy or doxorubicin. Taken together, our data establish that under the basal condition and in acquired glomerular diseases, nephrin is required to maintain slit diaphragm integrity and slit diaphragm–mediated signaling to preserve glomerular function and podocyte viability in adult mice. 相似文献
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目的:探讨芪卫颗粒干预糖尿病肾病小鼠足细胞损伤的作用机制。方法:28只8周龄KK-Ay小鼠成模后分为模型组和芪卫低剂量组、芪卫中剂量组及芪卫高剂量组,另8只C57BL/6J小鼠设为正常对照组。实验中纪录小鼠一般状况、血糖、24 h尿蛋白定量。治疗10周后检测小鼠肾功能指标血清肌酐及尿素氮,并称取小鼠肾脏,固定后行小鼠肾组织苏木精-伊红(HE)、Masson、过碘酸希夫(PAS)染色,并制作肾母细胞瘤基因(WT-1)免疫组化,结合软件分析计算小鼠肾小球足细胞数。蛋白质印迹法(Western Blot)检测小鼠肾脏中nephrin蛋白表达,实时荧光定量聚合酶链反应(PCR)检测nephrin mRNA的表达。结果:与模型组相比,芪卫颗粒治疗10周后小鼠体质量、血糖、24 h尿蛋白定量及血肌酐明显降低,并有效改善肾小球系膜增生等病理损害,保护足细胞数目。芪卫颗粒治疗后的nephrin蛋白表达量及mRNA表达量均显高于模型组。结论:芪卫颗粒可能通过调节nephrin表达而改善糖尿病肾病小鼠足细胞损伤。 相似文献
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Ruixia Ma Liqiu Liu Wei Jiang Yanjuan Yu Haifeng Song 《International journal of clinical and experimental pathology》2015,8(11):14063-14074
Diabetic nephropathy (DN) is the leading cause of end-stage renal failure, and podocyte injury plays a major role in the development of DN. In this study, we investigated whether tacrolimus (FK506), an immunosuppressor, can attenuate podocyte injury in a type 2 diabetic mellitus (T2DM) rat model with DN. Transmission electron microcopy was used to morphologically evaluate renal injury. The urinary albumin (UAL), creatinine clearance rate (Ccr) and major biochemical parameters, including glucose, insulin, serum creatinine (Scr), urea nitrogen, total cholesterol (CHO) and triglyceride (TG), were examined 12 weeks after the administration of FK506. The expressions of the canonical transient receptor potential 6 (TRPC6), nuclear factor of activated T-cells (NFAT) and nephrin were detected by Western blotting and qPCR. In the rat model of DN, the expressions of TRPC6 and NFAT were significantly elevated compared with the normal rat group; however, the treatment with FK506 normalized the increased expression of TRPC6 and NFAT and attenuated podocyte ultrastructure injury. UAL, Ccr and the biochemical parameters were also improved by the use of FK506. In cell experiments, FK506 improved the decreased expression of nephrin and suppressed the elevated expression of both TRPC6 and NFAT caused by high glucose in accordance with TRPC6 blocker . Our results demonstrated that FK506 could ameliorate podocyte injury in T2DM, which may be related to suppressed expressions of TRPC6 and NFAT. U73122相似文献