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Shamsah Kazani David J. Rowlands Ivan Bottoli Julie Milojevic Jose Alcantara Ieuan Jones Kenneth Kulmatycki Surendra Machineni Lidia Mostovy Ian Nicholls Jerry A. Nick Steven M. Rowe Nicholas J. Simmonds Raju Vegesna Jeroen Verheijen Henry Danahay Martin Gosling Phaninatha Sarma Ayalavajjala Robert Strieter 《Journal of cystic fibrosis》2021,20(2):250-256
BackgroundThis is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations.MethodsSafety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI2.5). Secondary endpoints included %predicted FEV1 and sweat chloride level.ResultsClass IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV1 increased by 6.46%, LCI2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del.ConclusionsIcenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations.ClinicalTrials.gov: NCT02190604 相似文献
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Dave P. Nichols Scott H. Donaldson Carla A. Frederick Steven D. Freedman Daniel Gelfond Lucas R. Hoffman Andrea Kelly Michael R. Narkewicz Jessica E. Pittman Felix Ratjen Scott D. Sagel Margaret Rosenfeld Sarah Jane Schwarzenberg Pradeep K. Singh George M. Solomon Michael S. Stalvey Shannon Kirby Jill M. VanDalfsen Steven M. Rowe 《Journal of cystic fibrosis》2021,20(2):205-212
Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis. 相似文献
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- The actions of several neuroleptic and tricyclic compounds were examined on the large conductance Ca2+-activated K+ (BKCa) channel present in neurones isolated from the rat motor cortex.
- Classical neuroleptic compounds including chlorpromazine and haloperidol applied to the intracellular surface of inside-out patches produced a concentration-dependent reduction in BKCa channel activity. Similar effects were observed when these compounds were applied to the extracellular surface of outside-out patches.
- In contrast, the atypical neuroleptic compounds clozapine and sulpiride did not affect BKCa channel activity (100 nM–1 mM) in either inside-out or outside-out patches, while 10 μM pimozide produced 73% of the inhibition produced by 10 μM chlorpromazine.
- BKCa channel activity was also unaffected by application of structurally related tricyclic compounds including the anti-cholinesterase tacrine and the anti-epileptic carbamazepine. The tricyclic antidepressant drug amitriptyline was found to inhibit BKCa channel activity but was much less effective than the classical neuroleptic compounds.
- It is concluded that compounds belonging to the classical neuroleptic group of drugs inhibit BKCa channel activity in the rat motor cortex in a structurally-specific manner. This observation may be of clinical significance as it may contribute to some of the side effects associated with classical neuroleptic drug therapy.
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Frankenfield DC Cooney RN Smith JS Rowe WA 《The American journal of clinical nutrition》1999,69(3):426-431
BACKGROUND: Determination of body composition during critical illness is complex because of various patient-related and technical factors. Bioelectrical impedance is a promising technique for the analysis of body composition; however, its clinical utility in critically injured patients is unknown. OBJECTIVE: The purpose of this study was to compare bioelectrical impedance with metabolic activity in healthy and critically injured patients. If bioelectrical impedance accurately determines body composition during critical illness, the slope between body-composition variables and oxygen consumption would be the same in critically injured and healthy subjects. DESIGN: There is a strong linear relation between body composition and metabolic activity. In the present study, body composition (fat-free mass and body cell mass) was determined by using bioelectrical impedance and resting metabolic activity (metabolic rate and oxygen consumption) by using gas exchange analysis in a group of healthy and critically injured subjects. The relation between these variables was compared by using linear regression to a similar relation established by hydrostatic weighing in a large historical control group. RESULTS: The slope of the line relating fat-free mass to resting metabolic rate was the same in the healthy and critically ill groups (P = 0.62) and each was similar to the slope of the line for the control group. However, in 37% of the critically injured group, overhydration contributed to an increase in fat-free mass, disturbing the relation with resting metabolic rate. The slope of the line relating body cell mass to oxygen consumption in our healthy and critically ill groups was almost identical. CONCLUSION: These results support the use of bioelectrical impedance to determine body cell mass in healthy and critically ill subjects. 相似文献
58.
Rowe AK Hirnschall G Lambrechts T Bryce J 《Bulletin of the World Health Organization》1999,77(12):988-995
Differences in the terms used to classify diseases in the Integrated Management of Childhood Illness (IMCI) guidelines and for health information system (HIS) disease surveillance could easily create confusion among health care workers. If the equivalent terms in the two classifications are not clear to health workers who are following the guidelines, they may have problems in performing the dual activities of case management and disease surveillance. These difficulties could adversely affect an individual's performance as well as the overall effectiveness of the IMCI strategy or HIS surveillance, or both. We interviewed key informants to determine the effect of these differences between the IMCI and HIS classifications on the countries that were implementing the IMCI guidelines. Four general approaches for addressing the problem were identified: translating the IMCI classifications into HIS classifications; changing the HIS list to include the IMCI classifications; using both the IMCI and HIS classification systems at the time of consultations; and doing nothing. No single approach can satisfy the needs of all countries. However, if the short-term or medium-term goal of IMCI planners is to find a solution that will reduce the problem for health workers and is also easy to implement, the approach most likely to succeed is translation of IMCI classifications into HIS classifications. Where feasible, a modification of the health information system to include the IMCI classifications may also be considered. 相似文献
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Clinically, the most apparent difference between the primary and permanent dentitions is the physiologic loss of the primary tooth by root resorption. Root resorption is associated with loss of integrity of the periodontal ligament (PDL), followed by recruitment of resorptive cells that remove root structure. We therefore cultured primary dentition PDL fibroblasts (PPDL cells) to investigate in vitro their production of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs), and the effects of soluble factors produced by these cells on osteoclast-like cell differentiation. These studies demonstrate that PPDL cells in vitro have a heterogeneous morphology, and they constitutively synthesize 92-kDa gelatinase, 72-kDa gelatinase, and 53/57-kDa procollagenase as well as TIMP-1, -2, and a third inhibitor of matrix metalloproteinase, as determined by substrate gel zymography and immunoblot analysis. Compared with PDL cells from the permanent dentition, PPDL cells generally produced a greater amount of collagenase but similar amounts of the gelatinases and inhibitors. PPDL cells were treated with pro-inflammatory cytokines to determine their effect on the expression of matrix-degrading enzymes and inhibitors. Interleukin-1alpha and tumor necrosis factor-alpha enhanced the constitutive expression of proteinases but not that of inhibitors in PPDL cells. Conditioned media from PPDL cell lines inhibited the differentiation of osteoclast-like cells in mouse bone marrow cultures. These findings indicate that PPDL cells may modulate the cascade of root resorption both by their regulated production of proteinases and inhibitors and by synthesis of unknown soluble factor(s) that may regulate osteoclast development. 相似文献