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41.
42.
Purpose. To find out if the physical instability of a lyophilized dosage form is related to molecular mobility below the glass transition temperature. Further, to explore if the stability data generated at temperatures below the glass transition temperature can be used to predict the stability of a lyophilized solid under recommended storage conditions.
Methods. The temperature dependence of relaxation time constant, , was obtained for sucrose and trehalose formulations of the monoclonal antibody (5 mg protein/vial) from enthalpy relaxation studies using differential scanning calorimetry. The non-exponentiality parameter, , in the relaxation behavior was also obtained using dielectric relaxation spectroscopy.
Results. For both sucrose and trehalose formulations, the variation in with temperature could be fitted Vogel-Tammann-Fulcher (VTF) equation. The two formulations exhibited difference sensitivities to temperature. Sucrose formulation was more fragile and exhibited a stronger non-Arrhenius behavior compared to trehalose formulation below glass transition. Both formulations exhibited <2% aggregation at t values <10, where t is the time of storage.
Conclusions. Since the relaxation times for sucrose and trehalose formulations at 5°C are on the order of 108 and 106 hrs, it is likely that both formulations would undergo very little (<2%) aggregation in a practical time scale under refrigerated conditions. 相似文献
43.
Aziz Elimadi Didier Morin Edith Albengres Anne-Marie Chauvet-Monges Valérie Allain Aimé Crevat Jean-Paul Tillement 《British journal of pharmacology》1997,121(7):1295-1300
- The effects of zidovudine (ZDV) and zidovudine triphosphate (ZDV-3P) on Ca2+-induced mitochondrial permeability transition (MPT), respiratory control ratio (RCR) and ATP synthesis have been investigated on isolated rat liver mitochondria.
- ZDV slightly but significantly decreased RCR and ATP synthesis but was ineffective in inhibiting MPT. In contrast, ZDV-3P did not alter RCR and ATP synthesis but strongly inhibited MPT (IC50=3.0±0.9 μM).
- The effect of ZDV-3P on mitochondrial swelling required a preincubation time. When incubated 10 min with mitochondria, ZDV-3P (8 μM) totally inhibited the rate of swelling.
- ADP, ATP and atractyloside, which are agents known to interact with the mitochondrial adenine nucleotide carrier (ANC), antagonized the effect of ZDV-3P on mitochondrial swelling. Indeed, the IC50 value of ZDV-3P increased from 3.0 to 17.4, 93.6 and 66.5 μM, in the presence of 20 μM, ADP, ATP or atractyloside, respectively.
- ZDV-3P did not displace [3H]-ATP from its mitochondrial binding site(s) whereas ADP and atractyloside did, suggesting that ZDV-3P and [3H]-ATP do not share the same binding sites.
- ZDV-3P did not affect either mitochondrial respiration or ATP synthesis but inhibited Ca2+-dependent mitochondrial swelling. It was concluded that mitochondrial toxic effects observed during the chronic administration of ZDV cannot be related to its active metabolite (ZDV-3P).
44.
The glassy state of nifedipine (NP) was prepared in the absence and presence of 2-hydroxypropyl--cyclodextrin (HP--CyD), and its crystallization and polymorphic transition behavior was investigated by differential scanning calorimetry (DSC) and powder X-ray diffractometry. In DSC thermograms, the glassy NP exhibited an en-dothermic peak at 48°C representing the glass transition of NP, an exothermic peak at 105°C for the crystallization to a metastable form of NP (Form B), an exothermic peak at 125°C for the polymorphic transition of Form B to a stable form of NP (Form A), and an endothermic peak at 171°C for the melting of Form A. The powder X-ray diffractogram of Form B was apparently different from that of Form A. In the presence of HP--CyD, the exothermic peak at 125°C for the Form B to A transition disappeared and a new en-dothermic peak appeared at 163°C. This new peak was ascribed to the melting of Form B, and the conversion of Form B to Form A was significantly suppressed in HP--CyD matrix. Upon storage at 60°C, the glassy NP was converted to Form A with an activation energy of 18 kcal/mol. The apparent dissolution rate of the NP/HP--CyD (molar ratio 1:1) increased in the order of glassy NP < Form A < Form B, because the glassy NP was readily converted to Form A upon contact with water, resulting in a lower dissolution rate. The present data suggest that HP--CyD is useful for the preparation of a fast dissolving form of metastable NP through glassy NP. 相似文献
45.
目的 探讨基于反馈教学(teach-back)的角色转型冲击模型在膝关节置换护理教学中的应用。方法 本研究将2020年8月至2022年8月到南京医科大学附属南京医院(南京市第一医院)骨科膝关节置换小组的50名实习护生作为研究对象,按进科先后顺序分为对照组和观察组,每组25人。对照组采用传统教学,观察组采用基于Teach-back的角色转型冲击模型教学。实习后评价护生考核成绩、转型冲击程度对护生综合能力的影响及教学满意度。采用SPSS 22.0进行t检验和Fisher确切概率法。结果 观察组实习护生转型冲击评价量表中身体、心理、知识和技能、社会文化与发展4个维度得分均低于对照组,差异有统计学意义(P<0.05)。观察组实习护生的护患沟通能力、护理实践能力、病情观察能力、健康教育能力、人文关怀能力、团队合作能力、临床思维能力及应急应变能力8个方面综合能力评分均高于对照组,差异有统计学意义(P<0.05)。观察组考核成绩明显优于对照组,差异有统计学意义(t=12.31、11.52,P均<0.001)。观察组教学满意度为100.00%(25/25),明显高于对照组的68.00%(17/25),差异有统计学意义(χ2=9.52,P=0.002)。结论 基于Teach-back的角色转型冲击模型有助于缓解实习护生进入临床工作时所面临的转型冲击,在提升实习护生综合能力的同时,教学满意度也得到提升。 相似文献
46.
CARROLL IWASIW DOLLY GOLDENBERG ELSIE MacMASTER SUSAN McCUTCHEON NANCY BOL 《Journal of clinical nursing》1996,5(6):381-388
- ? This study investigated residents' perspectives of their first 2 weeks in a long-term care facility (LTCF). Twelve residents were interviewed to determine their experiences during the first 2 weeks, their needs, priorities and expectations, and their views about how relocation from home could be facilitated. The constant comparative method of qualitative analysis (Glaser & Strauss, 1967) was used.
- ? Qualitative analysis of the audiotaped interviews revealed four main categories: emotional reactions, transition activities, reflecting on their situation, and connecting with a personal philosophy.
- ? Residents' responses indicated that if they had actively participated in the decision to be admitted, the adjustment to the LTCF was easier. Connecting with a personal philosophy was also a significant factor.
- ? Nursing implications include recognition of the importance of preparing residents for admission, involving them in the decision, and listening to their perspectives throughout the relocation experience.
47.
Yuansheng Tan Daming Li Renjie Song David Lawrence David O Carpenter 《Toxicological sciences》2003,76(2):328-337
The effects of exposure of acutely dissociated rat thymocytes to various polychlorinated biphenyl (PCB) congeners were examined using flow cytometry. Non-planar, ortho-substituted congeners caused a rapid cell death at low micromolar concentrations, while coplanar, dioxin-like congeners at the same concentration were without significant effect. The most potent of the congeners studied was PCB 52 (2,2',5,5'-tetrachlorobiphenyl), which had an IC50 of 3.96 microM at 20 min. Prior to loss of viability there was a decrease in mitochondrial membrane potential Delta Psi m, an accumulation of intracellular calcium, and a progressive leakiness of the plasma membrane. Application of PCB 52 in calcium-free medium reduced the calcium accumulation, but did not reduce cell death. Agents that depolarized mitochondria also did not induce the same degree of cell death caused by PCB 52. Cyclosporin A, which prevents opening of the mitochondria permeability transition channel, protected against cell death but did not protect against mitochondrial depolarization or calcium accumulation. Rapamycin and FK 506 at high concentration provided partial protection against cell death. These observations indicate that the ortho-substituted PCB 52 disrupts plasma, mitochondrial and endoplasmic reticulum membranes. We hypothesize that PCB 52 incorporates into lipid bilayers and with its bulky, three-dimensional ortho-substituted congener structure disrupts membrane function to a greater degree than coplanar congeners. 相似文献
48.
Salicylate enhances necrosis and apoptosis mediated by the mitochondrial permeability transition. 总被引:1,自引:0,他引:1
Onset of the mitochondrial permeability transition (MPT) causes both necrotic and apoptotic cell death in cultured hepatocytes. Salicylate lowers the threshold for onset of the MPT. In this study, our aim was to determine whether nontoxic concentrations of salicylate potentiate MPT-mediated cell killing. In necrotic killing models to rat hepatocytes, salicylate (1 mM) enhanced calcium ionophore (Br-A23187)- and tert-butylhydroperoxide (t-BuOOH)-induced cell death, which was blocked or delayed by cyclosporin A (CsA, 2 microM), a specific inhibitor of the MPT. In hepatocyte apoptosis induced by tumor necrosis factor-alpha (TNF-alpha), salicylate accelerated cell killing after low-dose TNF-alpha (1 ng/ml), which by itself induced little apoptosis. Salicylate enhancement of apoptosis was associated with onset of the MPT and accelerated caspase 3 activation. Salicylate also augmented killing of MCF-7 human breast tumor cells by etoposide and PLC/PRF/5 human hepatoma cells by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, salicylate potentiates both necrotic and apoptotic cell killing by promoting onset of the MPT. Enhancement by salicylate of MPT-dependent apoptosis may play a role in protection by aspirin and other nonsteroidal anti-inflammatory drugs against colon, lung, and breast cancer. 相似文献
49.
C. Sukonpan T. Oost M. Goodnough W. Tepp E.A. Johnson D.H. Rich 《Chemical biology & drug design》2004,63(2):181-193
Abstract: Botulinum neurotoxin (BoNT) metalloproteases and related proteases are the most selective proteases known. X‐ray crystal structures suggest that the active sites of the native enzymes exist in catalytically incompetent forms that must be activated by substrate binding. In order to characterize the postulated substrate‐induced conformational changes for enzyme activation, we synthesized a series of transition‐state analog inhibitors in which the dipeptide cleavage site is replaced by tetrahedral intermediate analogs within the minimal substrate peptide sequence. In this paper, we report our efforts to design inhibitors of BoNT/A metalloprotease. We confirm that an effective substrate sequence for BoNT/A metalloprotease is a 17‐mer peptide corresponding to residues 187–203 of SNAP‐25. A more stable substrate, Nle202SNAP‐25 [187–203] was synthesized in order to develop an assay for proteolytic activity of BoNT/A metalloprotease that can be used to monitor time‐dependent inhibition. α‐Thiol amide analogs of Gln‐197 were incorporated via solid‐phase peptide synthesis into both 17‐mer minimal peptide substrate sequences. The synthesis, characterization and inhibition kinetics for the α‐thiol amide analogs of holotoxin A substrate are described. These substrate‐derived inhibitors were shown to be submicromolar inhibitors of BoNT/A catalytic activity. 相似文献
50.
It is widely believed that the improved survival of young people with chronic diseases will be associated with the development of appropriate services within the adult healthcare domain. There is, however, little evidence to suggest that this is happening at a rate commensurate with clinical requirements. This paper highlights the multiplicity of barriers that impede the development of transition services to facilitate the transfer of medical care from the paediatric to the adult domain. Different models of transition care are described, and the terms 'transfer' and 'transition' are differentiated. The clinical demand for service development is highlighted, as well as the need for specific research in this area of healthcare delivery. 相似文献