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91.
Costentin C Hajj V Robert M Savéant JM Tard C 《Proceedings of the National Academy of Sciences of the United States of America》2011,108(21):8559-8564
Electron transfer may be concerted with proton transfer. It may also be concerted with the cleavage of a bond between heavy atoms. All three events may also be concerted. A model is presented to analyze the kinetics of these all-concerted reactions for homogeneous or electrochemical reduction or oxidation processes. It allows the estimation of the kinetic advantage that derives from the increase of the bond-breaking driving force resulting from the concerted proton transfer. Application of the model to the electrochemical reductive cleavage of the O-O bond of an organic peroxide in the presence of a proximal acid group illustrates the applicability of the model and provides an example demonstrating that electron transfer, heavy-atom bond breaking, and proton transfer may be all concerted. Such analyses are expected to be useful for the invention, analysis, and optimization of reactions involved in contemporary energy challenges as well as for the comprehension of major biochemical processes, a number of which involve electron and proton transfer together with cleavage of bonds between heavy atoms. 相似文献
92.
Hostetler ED Sanabria-Bohórquez S Fan H Zeng Z Gammage L Miller P O'Malley S Connolly B Mulhearn J Harrison ST Wolkenberg SE Barrow JC Williams DL Hargreaves RJ Sur C Cook JJ 《Nuclear medicine and biology》2011,38(8):1193-1203
Introduction
An 18F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque.Methods
Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood–brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with 18F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers.Results
[18F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC50=10.5±1.3 nM).Conclusions
[18F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted. 相似文献93.
94.
95.
Extra- and intracellular records were made from rat acute hippocampal slices to examine the effects of partial inhibition of Na(+)-K(+)-ATPases (Na(+)-K(+) pumps) on neuronal hyperexcitability. Bath application of the low-affinity cardiac glycoside, dihydroouabain (DHO), reversibly induced interictal-like epileptiform bursting activity in the CA1 region. Burst-firing was correlated with inhibition of the pumps, which was assayed by changes in [K(+)](o) uptake rates measured with K(+)-ion-sensitive microelectrodes. Large increases in resting [K(+)](o) did not occur. DHO induced a transient depolarization (5-6 mV) followed by a long-lasting hyperpolarization (approximately 6 mV) in CA1 pyramidal neurons, which was accompanied by a 30% decrease in resting input resistance. Block of an electrogenic pump current could explain the depolarization but not the hyperpolarization of the membrane. Increasing [K(+)](o) from 3 to 5.5 mM minimized these transient shifts in passive membrane properties without preventing DHO-induced hyperexcitability. DHO decreased synaptic transmission, but increased the coupling between excitatory postsynaptic potentials and spike firing (E-S coupling). Monosynaptic inhibitory postsynaptic potential (IPSP) amplitudes declined to approximately 25% of control at the peak of bursting activity; however, miniature TTX-resistant inhibitory postsynaptic current amplitudes were unaffected. DHO also reduced the initial slope of the intracellular excitatory postsynaptic potential (EPSP) to approximately 40% of control. The conductances of pharmacologically isolated IPSPs and EPSPs in high-Ca/high-Mg-containing saline were also reduced by DHO by approximately 50%. The extracellular fiber volley amplitude was reduced by 15-20%, suggesting that the decrease in neurotransmission was partly due to a reduction in presynaptic fiber excitability. DHO enhanced a late depolarizing potential that was superimposed on the EPSP and could obscure it. This potential was not blocked by antagonists of NMDA receptors, and blockade of NMDA, mGlu, or GABA(A) receptors did not affect burst firing. The late depolarizing component enabled the pyramidal cells to reach spike threshold without changing the actual voltage threshold for firing. We conclude that reduced GABAergic potentials and enhanced E-S coupling are the primary mechanisms underlying the hyperexcitability associated with impaired Na(+)-K(+) pump activity. 相似文献
96.
97.
Duclos-Vallée JC Féray C Sebagh M Teicher E Roque-Afonso AM Roche B Azoulay D Adam R Bismuth H Castaing D Vittecoq D Samuel D;THEVIC Study Group 《Hepatology (Baltimore, Md.)》2008,48(2):407-417
The efficacy and safety of albinterferon alfa-2b (alb-IFN), a novel recombinant protein consisting of interferon alfa-2b genetically fused to human albumin, was evaluated in a phase 2b, open-label study of patients with genotype 1, chronic hepatitis C. In all, 458 IFN-alfa treatment-na?ve patients were randomized to 48-week treatment with peginterferon alfa (PEG-IFNalpha)-2a 180 microg one time per week (qwk), or alb-IFN 900 or 1,200 microg once every two weeks (q2wk), or 1,200 microg once every four weeks (q4wk), administered subcutaneously, plus weight-based oral ribavirin 1,000 or 1,200 mg/day. Hepatitis C virus RNA was measured by real-time polymerase chain reaction (limit of detection: 10 IU/mL). The primary efficacy endpoint was sustained virologic response (hepatitis C virus RNA <10 IU/mL 24 weeks after the end of treatment). By intention-to-treat analysis, sustained virologic response rates were 58.5% (69/118) with alb-IFN 900 microg q2wk, 55.5% (61/110) with 1,200 microg q2wk, and 50.9% (59/116) with 1,200 microg q4wk, and 57.9% (66/114) with PEG-IFNalpha-2a (P = 0.64 for overall test). Discontinuation rates due to adverse events were 9.3% with alb-IFN 900 microg q2wk, 18.2% with 1,200 microg q2wk and 12.1% with 1,200 microg q4wk, and 6.1% with PEG-IFNalpha-2a (P = 0.04). Hematologic reductions were lowest in the q4wk group and comparable across other groups. At week 12, mean treatment-associated missed workdays were significantly lower with alb-IFN 900 mug q2wk versus PEG-IFNalpha-2a (1.1 versus 4.3 days; P = 0.006). CONCLUSION: Alb-IFN administered q2wk or q4wk may offer comparable efficacy, with an improved dosing schedule, compared with PEG-IFNalpha-2a. 相似文献
98.
Karine Briot Julien Paccou Philippe Beuzeboc Jacques Bonneterre Béatrice Bouvard Cyrille B. Confavreux Catherine Cormier Bernard Cortet Jean-Michel Hannoun-Lévi Christophe Hennequin Rose-Marie Javier Eric Lespessailles Didier Mayeur Pierre Mongiat Artus Marie-Hélène Vieillard Françoise Debiais 《Revue du Rhumatisme》2019,86(2):125-133
99.
Cyrille B. Confavreux Jean-Baptiste Pialat Aurélie Bellière Marie Brevet Chantal Decroisette Agnès Tescaru Julien Wegrzyn Cédric Barrey Françoise Mornex Pierre-Jean Souquet Nicolas Girard 《Joint, bone, spine : revue du rhumatisme》2019,86(2):185-194
Bone is the third metastatic site after liver and lungs. Bone metastases occur in one out of three lung cancers and are usually of osteolytic aspect. Osteolytic bone metastases are responsible of long bone and vertebral fractures leading to restricted mobility, surgery and medullar compression that severely alter quality of life and that have a huge medico-economic impact. In the recent years, Bone Metastatic Multidisciplinary Tumour Board (BM2TB) have been developed to optimize bone metastases management for each patient in harmony with oncology program. In this review, we will go through all the different aspects of bone metastases management including diagnosis and evaluation (CT scan, Tc 99m-MDP bone scan, 18FDG-PET scan and biopsy for molecular diagnosis), systemic bone treatments (zoledronic acid and denosumab) and local treatments (interventional radiology and radiotherapy). Surgical strategies will be discussed elsewhere. Based on the last 2017-Lung Cancer South East French Guidelines, we present a practical decision tree to help the physicians for decision making in order to reach a personalized locomotor strategy for every patient. 相似文献
100.
Sphingosine 1-phosphate (S1P) evokes a plethora of physiological responses by stimulating members of a G protein-coupled receptor family, known as S1P receptors. Currently five different mammalian S1P receptor subtypes, S1P???, each with a different cellular expression pattern, were identified. The S1P? receptor in particular has attracted major interest throughout the pharmaceutical industry following the breakthrough discovery that this S1P receptor subtype is critically involved in the regulation of lymphocyte trafficking through secondary lymphoid organs. Since then, examples of synthetic S1P? agonists with lymphocyte reducing and immunomodulating activity demonstrated efficacy in numerous preclinical models of autoimmune disease and transplantation. Notably FTY720 (fingolimod), a pro-drug that is phosphorylated in vivo and converted into a non-selective S1P?,?,?,? receptor agonist, has been widely used to increase the understanding of S1P? receptor biology. Results from recently completed phase III clinical trials using FTY720 paved the way for this non-selective S1P? receptor agonist to become the first oral therapy in multiple sclerosis, with potential expansion into many other autoimmune diseases. This review briefly outlines the field of S1P? receptor biology and summarizes recent approaches in medicinal chemistry to discover potent and selective S1P? receptor agonists. In particular, the complexity of discovering a molecule akin to FTY720 but with an improved side-effect profile will be discussed. 相似文献