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目的:应用顺铂诱导Beagle犬急性肾损伤模型,评价新型尿液生物标志物的诊断效能。方法:通过对Beagle犬单次给予3 mg·kg-1顺铂静脉注射(iv),建立了急性肾损伤模型,应用ELISA和Luminex液相芯片方法检测分析尿液中9种新型生物标志物浓度,并与传统血清指标尿素氮(BUN)和肌酐(Cr)进行比较,结合肾脏组织病理学分析结果,用受试者工作特征曲线(ROC)评价尿液生物标志物的诊断效能。结果:组织病理学分析结果显示Beagle犬单次给予3 mg·kg-1,iv,d 7肾脏发生轻度的肾小管变性、坏死或再生,至d 21肾脏仍存在一定程度的肾小管变性、再生。尿液生物标志物分析结果发现在给药d 2,尿液中丛生蛋白(clusterin)、单核细胞趋化蛋白-1(MCP-1)、视黄醇结合蛋白(RBP)和谷氨酰转肽酶(GGT)浓度就开始显著增加(P<0.05),上升幅度明显高于BUN和Cr,到了给药d 21,尿液中clusterin和MCP-1仍保持较高水平(P<0.05),且分析结果与其个体动物组织病理变化具有良好的相关性。ROC分析表明尿液clusterin和MCP-1的药时曲线下面积(AUC)值分别为0.931和0.909,高于传统生物标志物BUN和Cr,具有较好的诊断效能。选择代表性生物标志物基因分析结果也证实给药后clusterin基因mRNA表达显著提高,进一步支持其预测肾毒性的特异性。结论:研究结果表明尿液clusterin和MCP-1可作为一种药物肾毒性的候选生物标志物,在药物的Beagle犬模型临床前安全性研究中具有良好的应用前景。  相似文献   
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Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.  相似文献   
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牙周前期实习教学是牙周病学教学的重要组成部分,是连接牙周理论大课和临床实习的桥梁。规范化牙周基础治疗的技能训练是牙周前期实习中最重要的部分,也是前期实习的难点。文章以北京大学口腔医学院牙周病学教研室多年来的教学经验为基础,从牙周前期实习的“道”(内涵和原则)和 “导”(策略和方法)为切入点,总结如何高质量地完成牙周前期实习教学,以期为全面推广规范化牙周前期实习教学提供借鉴。  相似文献   
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Blindness due to corneal diseases is a common pathology affecting up to 23 million individuals worldwide. The tissue‐engineered anterior human cornea, which is currently being tested in a Phase I/II clinical trial to treat severe corneal trophic ulcers with preliminary good feasibility and safety results. This bioartificial cornea is based on a nanostructured fibrin–agarose biomaterial containing human allogeneic stromal keratocytes and cornea epithelial cells, mimicking the human native anterior cornea in terms of optical, mechanical, and biological behavior. This product is manufactured as a clinical‐grade tissue engineering product, fulfilling European requirements and regulations. The clinical translation process included several phases: an initial in vitro and in vivo preclinical research plan, including preclinical advice from the Spanish Medicines Agency followed by additional preclinical development, the adaptation of the biofabrication protocols to a good manufacturing practice manufacturing process, including all quality controls required, and the design of an advanced therapy clinical trial. The experimental development and successful translation of advanced therapy medicinal products for clinical application has to overcome many obstacles, especially when undertaken by academia or SMEs. We expect that our experience and research strategy may help future researchers to efficiently transfer their preclinical results into the clinical settings.  相似文献   
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Chronic pelvic pain syndrome (CPPS) can be triggered by a various types of gynecological, gastrointestinal, urological, and musculoskeletal disorders. Recently, the role of the central nervous system has proven to be an integral part on the development of any chronic pain syndrome, including CPPS. However, owing to the complex and heterogeneous etiology and pathophysiology of CPPS, the establishment of effective therapeutic interventions remains challenging for both physicians and patients. Nonetheless, recent studies have pointed that medicinal plants and their secondary metabolites can be effectively used in CPPS therapy, besides contributing to restore the patients' quality of life and potentiate the conventional CPPS management. In this sense, this review aims to provide a careful overview on the biomedical data for the use of medicinal plants use and their secondary metabolites on CPPS management.  相似文献   
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Introduction: The therapeutic management of Parkinson’s disease (PD) is challenging and has not been fully resolved. The main challenges include motor fluctuations and levodopa-induced dyskinesia. Moreover, no disease-modifying or neuroprotective therapy is currently available.

Areas covered: This review focuses on α-synuclein aggregation inhibitors and their therapeutic role in PD, with special attention to heat shock proteins, immunotherapy (active and passive), the potential of targeting the Ser129 phosphorylation site, and the antibiotic possibilities.

Expert opinion: The induction of chaperones may provide beneficial strategy to target synucleinopathies, but further investigations are needed to find the best options. The promising preclinical results with immunotherapy suggest that it may be a valuable disease-modifying therapy in PD in the future. Clinical trials are currently in the initial phases, and future studies need to confirm the beneficial therapeutic effect in humans and clarify open questions as regards the exact mode of action and potential safety concerns. In case of covalent modifications, phosphorylation of α-synuclein is of outstanding importance; however, conflicting results and open questions exist which necessitate clarification. In vitro results suggest that several antibiotics may also influence α-synuclein aggregation, but these results are to be confirmed in the future.  相似文献   
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