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排序方式: 共有7048条查询结果,搜索用时 15 毫秒
91.
Kim Fejgin Jacob Nielsen Michelle R. Birknow Jesper F. Bastlund Vibeke Nielsen Jes B. Lauridsen Hreinn Stefansson Stacy Steinberg Helge B.D. Sorensen Troels E. Mortensen Peter H. Larsen Ib V. Klewe Søren V. Rasmussen Kari Stefansson Thomas M. Werge Pekka Kallunki Kenneth V. Christensen Michael Didriksen 《Neuropsychopharmacology》2014
92.
Lene Hansen Lars Christian PetersenBrian Lauritzen Jes Thorn ClausenSusanne Nedergaard Grell Henrik AgersøBrit Binow Sørensen Ida HildenKasper Almholt 《Thrombosis research》2014
Introduction
A humanised monoclonal antibody, concizumab, that binds with high affinity to the Kunitz-type protease inhibitor (KPI) 2 domain of human tissue factor pathway inhibitor (TFPI) is in clinical development. It promotes coagulation by neutralising the inhibitory function of TFPI and may provide a subcutaneous prophylaxis option for patients with haemophilia. We aimed to study biodistribution and pharmacokinetics (PK) of concizumab.Materials and Methods
Blockage of cellular TFPI by concizumab was measured by tissue factor/Factor VIIa-mediated Factor X activation on human EA.hy926 cells. Biodistribution of concizumab was analysed in rabbits by immunohistology, and the PK was measured in rabbits and rats.Results and Conclusions
Concizumab bound to cell surface TFPI on EA.hy926 cells and neutralised TFPI inhibition of Factor X activation. The antibody cross-reacted with rabbit TFPI, but not with rat TFPI, allowing for comparative PK studies. PK data in rats described a log-linear profile typical for a non-binding antibody, whereas PK data in rabbits revealed a non-linear, dose-dependent profile, consistent with a target-mediated clearance mechanism. Immunohistology in rabbits during target-saturation showed localisation of the antibody on the endothelium of the microvasculature in several organs. We observed a marked co-localisation with endogenous rabbit TFPI, but a negligible sub-endothelial build-up. Concizumab binds and neutralises the inhibitory effect of cell surface-bound TFPI. The PK profile observed in rabbits is consistent with a TFPI-mediated drug disposition. Double immunofluorescence shows co-localisation of the antibody with TFPI on the endothelium of the microvasculature and points to this TFPI as a putative target involved in the clearance mechanism. 相似文献93.
P Labarga P Barreiro A da Silva JM Guardiola R Rubio K Aguirrebengoa P Miralles J Portu MJ Téllez L Morano A Castro JA Pineda A Terrón J Hernández-Quero A Mariño MJ Ríos S Echeverría V Asensi E Vispo V Soriano;on behalf of PERICO Study Group 《The Journal of infectious diseases》2012,206(6):961-968
Background.?Ribavirin (RBV) exposure seems to be critical to maximize treatment response in human immunodeficiency virus (HIV)-positive patients with chronic hepatitis C virus (HCV) infection. Methods.?HIV/HCV-coinfected individuals naive to interferon were prospectively randomized to receive peginterferon-α-2a (180?μg/d) plus either RBV standard dosing (1000 or 1200?mg/d if <75 or ≥75?kg, respectively) or RBV induction (2000?mg/d) along with subcutaneous erythropoietin β (450?IU/kg/wk), both during the first 4 weeks, followed by standard RBV dosing until completion of therapy. Early stopping rules at weeks 12 and 24 were applied in patients with suboptimal virological response. Results.?A total of 357 patients received ≥1 dose of the study medication. No differences in main baseline characteristics were found when comparing treatment arms. Sustained virological response (SVR) was attained by 160 (45%) patients, with no significant differences between RBV induction and standard treatment arms (SVR in 72 of 169 patients [43%] vs 88 of 188 [47%], respectively). At week 4, undetectable HCV RNA (29% vs 25%) and mean RBV trough concentration (2.48 vs 2.14?μg/mL) were comparable in both arms, whereas mean hemoglobin decay was less pronounced in the RBV induction plus erythropoietin arm than in the RBV standard dosing arm (-1.7 vs -2.3?mg/dL; P?.005). Treatment discontinuation occurred in 91 (25%) patients owing to nonresponse and in 29 (8%) owing to adverse events. HCV relapse occurred in 34 patients (10%). Univariate and multivariate analyses identified HCV genotype 2 or 3 (odds ratio [OR], 10.3; 95% confidence interval [CI], 2.08-50.2; P?=?.004), IL28B CC variants (OR, 2.92; 95% CI, 1.33-6.41; P?=?.007), nonadvanced liver fibrosis (OR, 2.27; 95% CI, 1.06-5.01; P?=?.03), and rapid virological response (OR, 40.3; 95% CI, 5.1-314.1; P?.001) as predictors of SVR. Conclusions.?A 4-week course of induction therapy with high RBV dosing along with erythropoietin does not improve SVR rates in HIV/HCV-coinfected patients. Preemptive erythropoietin might blunt the benefit of RBV overdosing by enhancing erythrocyte uptake of plasma RBV. 相似文献
94.
95.
Cuervo R Hernández-Martínez R Chimal-Monroy J Merchant-Larios H Covarrubias L 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(10):3838-3843
Full limb regeneration is a property that seems to be restricted to urodele amphibians. Here we found that Polypterus, the most basal living ray-finned fish, regenerates its pectoral lobed fins with a remarkable accuracy. Pectoral Polypterus fins are complex, formed by a well-organized endoskeleton to which the exoskeleton rays are connected. Regeneration initiates with the formation of a blastema similar to that observed in regenerating amphibian limbs. Retinoic acid induces dose-dependent phenotypes ranging from inhibition of regeneration to apparent anterior-posterior duplications. As in all developing tetrapod limbs and regenerating amphibian blastema, Sonic hedgehog is expressed in the posterior mesenchyme during fin regeneration. Hedgehog signaling plays a role in the regeneration and patterning processes: an increase or reduction of fin bony elements results when this signaling is activated or disrupted, respectively. The tail fin also regenerates but, in contrast with pectoral fins, regeneration can resume after release from the arrest caused by hedgehog inhibition. A comparative analysis of fin phenotypes obtained after retinoic acid treatment or altering the hedgehog signaling levels during regeneration allowed us to assign a limb tetrapod equivalent segment to Polypterus fin skeletal structures, thus providing clues to the origin of the autopod. We propose that appendage regeneration was a common property of vertebrates during the fin to limb transition. 相似文献
96.
Simeón-Aznar CP Fonollosa-Plá V Tolosa-Vilella C Espinosa-Garriga G Ramos-Casals M Campillo-Grau M García-Hernández FJ Castillo-Palma MJ Sánchez-Román J Callejas-Rubio JL Ortego-Centeno N Egurbide-Arberas MV Trapiellla-Martínez L Gallego-Villalobos M Sáez-Comet L Velilla-Marco J Camps-García MT de Ramón-Garrido E Esteban Marcos EM Pallarés-Ferreres L Hidalgo-Tenorio C Sabio-Sánchez JM Gómez-de la Torre R Salvador-Cervello G Rios-Blanco JJ Gil-Aguado A Vilardell-Tarrés M 《Seminars in arthritis and rheumatism》2012,41(6):789-800
97.
Isabel F. Tresguerres DDS MD PhD Celia Clemente MD PhD Luis Blanco DDS MD PhD Ameen Khraisat BDS PhD Faleh Tamimi DDS PhD Jesús A.F. Tresguerres MD PhD 《Clinical implant dentistry and related research》2012,14(3):395-399
Purpose: The aim of this study was to assess the effect of local melatonin administration on bone osseointegration around implants in rabbit tibiae. Material and Methods: Ten female, 6‐month‐old New Zealand rabbits were randomly divided into two groups: the experimental group, where five rabbits were treated with local application of melatonin (3 mg) to implant sites when placed into the rabbit tibia, and the control group, those who where without additive materials. Four weeks later, animals were sacrificed; tibiae were dissected from soft tissues and fixed in buffered formaldehyde, and then included in methacrylate. Histological sections were performed to be studied under light microscopy and analyzed morphometrically to evaluate the amount of bone to implant contact (BIC), trabecular area density, and cortical area density. One‐way analysis of variance test was used for statistical evaluation. p < .05 was considered to be significant. Results: Histological evaluation showed more trabecular reaction in the melatonin group. Morphometrical analysis showed a statistically significant increase in trabecular BIC in the melatonin group when compared with the control group (24.61% ± 2.87 vs 13.62% ± 1.44; p < .01). Cortical BIC was decreased in the melatonin group, without statistical significance (71.08 ± 3.63 vs 76.28 ± 2.57; p = 0.31). Trabecular area density was increased significantly in the melatonin group (8.68 ± 1.61 vs 4.02 ± 0.36; p < .05). Cortical area density was decreased significantly in the melatonin group (91.31 ± 1.6 vs 95.7 ± 0.5; p < .05). Conclusion: Within the limitation of this animal study, local melatonin application at the time of implant placement might induce more trabecular bone at implant contact and higher trabecular area density. 相似文献
98.
Oyagüe RC Sánchez-Turrión A López-Lozano JF Montero J Albaladejo A Suárez-García MJ 《Odontology / the Society of the Nippon Dental University》2012,100(2):249-253
This study evaluated the vertical discrepancy of implant-fixed 3-unit structures. Frameworks were constructed with laser-sintered Co-Cr, and vacuum-cast Co-Cr, Ni-Cr-Ti, and Pd-Au. Samples of each alloy group were randomly luted in standard fashion using resin-modified glass-ionomer, self-adhesive, and acrylic/urethane-based cements (n = 12 each). Discrepancies were SEM analyzed. Three-way ANOVA and Student-Newman-Keuls tests were run (P < 0.05). Laser-sintered structures achieved the best fit per cement tested. Within each alloy group, resin-modified glass-ionomer and acrylic/urethane-based cements produced comparably lower discrepancies than the self-adhesive agent. The abutment position did not yield significant differences. All misfit values could be considered clinically acceptable. 相似文献
99.
100.
Paiva B Gutiérrez NC Rosiñol L Vídriales MB Montalbán MÁ Martínez-López J Mateos MV Cibeira MT Cordón L Oriol A Terol MJ Echeveste MA de Paz R de Arriba F Palomera L de la Rubia J Díaz-Mediavilla J Sureda A Gorosquieta A Alegre A Martin A Hernández MT Lahuerta JJ Bladé J San Miguel JF;PETHEMA/GEM 《Blood》2012,119(3):687-691
The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day +100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n = 140) and GEM2005 < 65y (n = 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P = .002) and persistent minimal residual disease by multiparameter flow cytometry at day +100 after HDT/ASCT (hazard ratio 8.0; P = .005) were the only independent factors that predicted unsustained CR. Thus, these 2 parameters may help to identify patients in CR at risk of early progression after HDT/ASCT in whom novel treatments should be investigated. 相似文献