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91.
Walid-Sabri Hamadou Violaine Bourdon Sébastien Létard Fabienne Brenet Sofien Laarif Sawsen Besbes Angelo Paci Muriel David Virginie Penard-Lacronique Yosra Ben Youssef Mohamed-Adnène Laatiri François Eisinger Véronique Mari Paul Gesta Hélène Dreyfus Valérie Bonadona Catherine Dugast Hélène Zattara Laurence Faivre Testsuro Noguchi Abderrahim Khélif Chaker Ben Salem Patrice Dubreuil Hagay Sobol Zohra Soua 《Annals of hematology》2016,95(12):1943-1947
92.
Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency 下载免费PDF全文
Stefan D. Anker Stefan Schroeder Dan Atar Jeroen J. Bax Claudio Ceconi Martin R. Cowie Adam Crisp Fabienne Dominjon Ian Ford Hossein‐Ardeschir Ghofrani Savion Gropper Gerhard Hindricks Mark A. Hlatky Richard Holcomb Narimon Honarpour J. Wouter Jukema Albert M. Kim Michael Kunz Martin Lefkowitz Chantal Le Floch Ulf Landmesser Theresa A. McDonagh John J. McMurray Bela Merkely Milton Packer Krishna Prasad James Revkin Giuseppe M.C. Rosano Ransi Somaratne Wendy Gattis Stough Adriaan A. Voors Frank Ruschitzka 《European journal of heart failure》2016,18(5):482-489
Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient's burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research. 相似文献
93.
Brahimi F Matheson SL Dudouit F McNamee JP Tari AM Jean-Claude BJ 《The Journal of pharmacology and experimental therapeutics》2002,303(1):238-246
The Combi-Targeting concept postulates that a molecule termed combi-molecule (C-molecule) with binary epidermal growth factor receptor (EGFR) targeting/DNA-damaging properties and with the ability to be hydrolyzed to another EGFR inhibitor should induce sustained antiproliferative activity in cells overexpressing EGFR. Because we postulate that the EGFR affinity of the C-molecule and that of its hydrolytic metabolites are critical parameters for sustained potency against EGFR-overexpressing cells, we synthesized BJ2000 (IC(50) = 0.1 microM, competitive binding at ATP site), a novel C-molecule that can decompose into a 6-amino-4-anilinoquinazoline FD105 (IC(50) = 0.2 microM). Studies using the EGFR-overexpressing A431 cells revealed that BJ2000 could damage DNA and block epidermal growth factor-stimulated EGFR autophosphorylation by a partially irreversible mechanism. Blockade of EGFR autophosphorylation subsequently induced inhibition of mitogen-activated protein kinase activation and c-fos gene expression. Enzyme-linked immunosorbent assay and growth factor-mediated stimulation of proliferation assays in the EGFR-expressing NIH3T3HER14 demonstrated the preferential EGFR-targeting properties of BJ2000, and more importantly suggest that blockade of EGFR phosphorylation by this drug translate into significant growth inhibitory effects. These properties culminated into irreversible antiproliferative effects as confirmed by a sulforhodamine B assay. Five days after a 2-h treatment, BJ2000 retained significant antiproliferative effect in A431 cells, whereas its reversible metabolite FD105 almost completely lost its activity. This result in toto lend support to the Combi-Targeting concept according to which a molecular conjugate kept small enough to interact with EGFR and designed to degrade into another inhibitor of the same target plus a DNA-damaging species may induce sustained growth inhibitory effect in EGFR-overexpressing cells. 相似文献
94.
95.
Ebrahim Mayat Fabienne Lebrun Isabelle Sassetti Max Rcasens 《International journal of developmental neuroscience》1994,12(1)
The effect of postnatal age on phosphoinositide metabolism per se and on quisqualate-stimulated phosphoinositide metabolism was characterized in synaptoneurosomes prepared from nine different regions of the rat nervous system, namely the brainstem, cerebellum, cerebral cortex, colliculi, hippocampus, hypothalamus, olfactory bulb, spinal cord and striatum. In the hippocampus, striatum, cerebellum, cerebral cortex, brainstem, colliculus and spinal cord, the basal levels of inositol phosphate (inositol-1-phosphate+inositol-4,5-bisphosphate) formation were maximal two days after birth and declined steeply to steady-state levels from the age of 10 postnatal days. Similarly, in the olfactory bulb, basal inositol phosphate synthesis did not significantly change when measured during the period from postnatal day 10 to 42. The extent of [3H]-inositol labelling of phosphoinositides as a function of age presented similar profiles when measured in hippocampal, striatal, cerebellar and cerebral cortical synaptoneurosomes, i.e. maximal at perinatal ages and minimal at adult ages. In the hypothalamus, [3H]-inositol labelling of phosphoinositides showed an increase from postnatal day 12 to higher levels from postnatal days 14 to 18 subsequently followed by a dramatic increase from postnatal day 21 to 42. A similar developmental trend was also obtained for basal inositol phosphate synthesis.On the whole, four types of developmental profiles for quisqualate-stimulated inositol phosphate formation (expressed as the percentage of the basal level and as the difference between stimulated and basal levels of radioactive inositol phosphates) were obtained depending on the nervous system region studied. In the early, prenatally developed nervous system regions, namely the brainstem and the spinal cord, no postnatal stimulation peaks of quisqualate-induced inositol phosphate formation were recorded. This was also the case for the colliculi when the stimulation of IP formation was expressed as the difference in basal and stimulated levels of inositol phosphates. Secondly, in the olfactory bulb a region known to possess a continuous capacity for developmental plasticity both structurally and functionally during the first three weeks of postnatal development, a simultaneous sustained high level of quisqualate stimulation of phosphoinositide metabolism (fluctuating around 200% of the basal level) during the early postnatal period was evident. Thirdly, in regions of the central nervous system like the cerebellum, cerebral cortex, hippocampus and the striatum known to undergo intense developmental activity during the first two postnatal weeks, peaks of quisqualate-stimulated phosphoinositide metabolism were initially detected around the first week after birth in each of these brain areas. Finally, in the hypothalamus where structurally unique postnatal developmental processes are known to take place, quisqualate-induced inositol phosphate formation progressively increases with age to reach maxima at postnatal day 18. The transient increases in quisqualate responses in the cerebellum, hippocampus and striatum are probably specific to quisqualate since carbachol-stimulated phosphoinositide metabolism yielded different age-associated response patterns. Similar increases of carbachol- and quisqualate-mediated phosphoinositide hydrolysis were on the other hand assayed in cerebral cortical and hypothalamic synaptoneurosomes. EC50, values for quisqualate (the quisqualate concentration required to produce 50% of the maximal effect) at postnatal days 6 and 10 were not significantly different in each of four types of synaptoneurosomes: cerebellar, cerebral cortical, hippocampal and striatal. On the basis of these latter results, it was deduced that the peak of quisqualate-stimulated phosphoinositide metabolism does not materialize on the basis of changes in quisqualate metabotropic receptor affinity. In conclusion, the measurement of inositol phosphate formation in synaptoneurosomes prepared from different regions of the postnatally developing nervous system indicate that there is a temporal correlation between the increased activity of quisqualate-stimulated phosphoinositide metabolism mediated by specific metabotropic glutamate receptors and region-specific developmental events. This could suggest a key role for certain metabotropic glutamate receptors in the developmental plasticity of the nervous system. 相似文献
96.
Hostein I Debiec-Rychter M Olschwang S Bringuier PP Toffolati L Gonzalez D Forget S Escande F Morzuch L Tamborini E Faur N Pilotti S Dei Tos P Emile JF Coindre JM 《Journal of gastroenterology》2011,46(5):586-594
Background
Although most gastrointestinal stromal tumours (GIST) carry oncogenic mutations in KIT exons 9, 11, 13 and 17, or in platelet-derived growth factor receptor alpha (PDGFRA) exons 12, 14 and 18, around 10% of GIST are free of these mutations. Genotyping and accurate detection of KIT/PDGFRA mutations in GIST are becoming increasingly useful for clinicians in the management of the disease.Method
To evaluate and improve laboratory practice in GIST mutation detection, we developed a mutational screening quality control program. Eleven laboratories were enrolled in this program and 50 DNA samples were analysed, each of them by four different laboratories, giving 200 mutational reports.Results
In total, eight mutations were not detected by at least one laboratory. One false positive result was reported in one sample. Thus, the mean global rate of error with clinical implication based on 200 reports was 4.5%. Concerning specific polymorphisms detection, the rate varied from 0 to 100%, depending on the laboratory. The way mutations were reported was very heterogeneous, and some errors were detected.Conclusion
This study demonstrated that such a program was necessary for laboratories to improve the quality of the analysis, because an error rate of 4.5% may have clinical consequences for the patient. 相似文献97.
Elena M. Cornejo Castro Jens Waak Stephanie S. Weber Fabienne C. Fiesel Philipp Oberhettinger Monika Schütz Ingo B. Autenrieth Wolfdieter Springer Philipp J. Kahle 《Journal of neural transmission (Vienna, Austria : 1996)》2010,117(5):599-604
DJ-1 is a neuroprotective gene mutated in recessive Parkinson’s disease (PD). In addition to direct protective functions in neurons,
DJ-1 regulates neuroinflammatory signaling in primary mouse brain astrocytes. To assess the influence of DJ-1 on innate immunity
signaling in vivo, we have generated djr-1 knockout Caenorhabditis elegans. When grown on pathogenic gram-negative bacteria, djr-1
−/− worms showed stronger phosphorylation of p38 mitogen-activated protein kinase (PMK-1) and hyper-induction of PMK-1 target
genes. Thus, PD-associated DJ-1 contributes to regulation of innate immunity. 相似文献
98.
Vincent De Brouwere Fabienne Richard Sophie Witter 《Tropical medicine & international health : TM & IH》2010,15(8):901-909
The huge majority of the annual 6.3 million perinatal deaths and half a million maternal deaths take place in developing countries and are avoidable. However, most of the interventions aiming at reducing perinatal and maternal deaths need a health care system offering appropriate antenatal care and quality delivery care, including basic and comprehensive emergency obstetric care facilities. To promote the uptake of quality care, there are two possible approaches: influencing the demand and/or the supply of care. Five lessons emerged from experiences. First, it is difficult to obtain robust evidence of the effects of a particular intervention in a context, where they are always associated with other interventions. Second, the interventions tend to have relatively modest short‐term impacts, when they address only part of the health system. Third, the long‐term effects of an intervention on the whole health system are uncertain. Fourth, because newborn health is intimately linked with maternal health, it is of paramount importance to organise the continuum of care between mother and newborn. Finally, the transfer of experiences is delicate, and an intervention package that has proved to have a positive effect in one setting may have very different effects in other settings. 相似文献
99.
An 18-year-old man received two high-dose methotrexate cycles for the treatment of an osteosarcoma. Fifteen grams of methotrexate were infused over 6 hours. During the second cycle, co-administration of oxacillin (1g/8h) resulted in prolonged and marked elevation of methotrexate plasma concentrations. The patient experienced acute toxicity with renal failure, myelosuppression, mucitis, fever, and dermatologic abnormalities. After an initial improvement with folinic acid rescue and hemodialysis, the patient died. Oxacillin may thus inhibit the elimination of methotrexate. 相似文献
100.
Legay F Gauron S Deckert F Gosset G Pfaar U Ravera C Wiegand H Schran H 《Journal of pharmaceutical and biomedical analysis》2002,30(4):897-911
Zoledronic acid is a new, highly potent bisphosphonate drug under clinical evaluation. A radioimmunoassay has been developed to determine zoledronic acid concentration in human serum, plasma, and urine. The assay utilizes rabbit polyclonal antisera against a zoledronic acid-BSA conjugate and a [125I]zoledronic acid derivative as tracer in a competitive format adapted to microtiter plates. The assay shows a LLOQ 0.4 ng/ml in serum or plasma (interassay%CV=17%, accuracy 97%), 5 ng/ml in urine (21%, 98%). In 23 patients receiving 4, 8 or 16 mg of zoledronic acid, drug concentrations in plasma were dose proportional and showed a multiphasic profile, followed by a prolonged gradual decline to concentrations near the LLOQ. Zoledronic acid disposition in plasma and the recovery of only 40-50% of the dose in urine are consistent with the rapid and extensive uptake by and slow release from bone in parallel with renal clearance, typically shown by bisphosphonates. 相似文献