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981.
Ross OA Soto-Ortolaza AI Heckman MG Aasly JO Abahuni N Annesi G Bacon JA Bardien S Bozi M Brice A Brighina L Van Broeckhoven C Carr J Chartier-Harlin MC Dardiotis E Dickson DW Diehl NN Elbaz A Ferrarese C Ferraris A Fiske B Gibson JM Gibson R Hadjigeorgiou GM Hattori N Ioannidis JP Jasinska-Myga B Jeon BS Kim YJ Klein C Kruger R Kyratzi E Lesage S Lin CH Lynch T Maraganore DM Mellick GD Mutez E Nilsson C Opala G Park SS Puschmann A Quattrone A Sharma M Silburn PA Sohn YH Stefanis L Tadic V 《Lancet neurology》2011,10(10):898-908
Background
Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.Methods
LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab–Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.Findings
121 exonic LRRK2 variants were assessed in 15?540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab–Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15–1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35–3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab–Berber series (combined odds ratio 0·82, 0·72–0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20–2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36–1·07; p=0·087). In the Arab–Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33–15·09; p=0·012).Interpretation
The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity.Funding
Michael J Fox Foundation and National Institutes of Health. 相似文献982.
983.
Hazzan M Hertig A Buob D Copin MC Noël C Rondeau E Dubois-Xu YC 《Journal of the American Society of Nephrology : JASN》2011,22(7):1375-1381
Maintenance immunosuppression with cyclosporine A (CsA) can cause nephrotoxicity in renal transplant recipients. Identifying patients at increased risk for CsA nephrotoxicity may allow interventions to prolong graft survival. Here, we studied the effect of early CsA withdrawal or maintenance among 96 kidney recipients at risk for interstitial fibrosis and tubular atrophy (IF/TA) on the basis of tubular expression of vimentin and β-catenin in a protocol biopsy performed 3 months after transplant. In this retrospective analysis of biopsies collected during a randomized trial of early withdrawal of CsA or mycophenolate mofetil, the semiquantitative score of early phenotypic changes suggestive of epithelial-to-mesenchymal transition (EMT) progressed with time among those maintained on a CsA-containing regimen. EMT-positive grafts displayed a significantly higher IF/TA score and greater progression of the IF/TA score at 12 months (P=0.001 and 0.008, respectively). EMT-positive grafts exposed to CsA also had a greater decrease in estimated GFR compared with EMT-negative grafts exposed to CsA and EMT-positive grafts withdrawn from CsA exposure. Multivariable analysis revealed that the presence of EMT was an independent risk factor for a 10% decline in graft function up to 4 years posttransplant (odds ratio 4.49; 95% confidence interval 1.02 to 19.9). Collectively, these data demonstrate that changes consistent with EMT are strong prognostic biomarkers in renal transplant recipients exposed to CsA. 相似文献
984.
Colonic mucosubmucosal elongated polyp (CMSEP) is a distinctive non-neoplastic colorectal polyp characterized by pedunculated, elongated shape and is composed mainly of expanded submucosa with a normal mucosal lining. Only a small number of these polyps have been reported, exclusively from Japan. We report the clinicopathologic characteristics of 13 CMSEPs occurring in 11 patients, mostly from European ancestry. Ten of these polyps were resected during colonoscopy, and 3 were diagnosed in a patient who underwent sigmoid resection for diverticular disease. Among patients who had undergone a colonoscopy, 4 had altered bowel habit, and 1 suffered from abdominal discomfort; the other 5 patients had routine screening colonoscopy. Eight polyps were located in the sigmoid colon, 3 in the right colon, 1 in the rectosigmoid junction, and 1 in the descending colon. Polyp size ranged from 10 to 150 mm. Histologically, CMSEPs were characterized by unremarkable large bowel mucosa and submucosal stalk containing dilated thick-walled veins running parallel to the long axis of the polyp. Mucosal inflammation or fibromuscular proliferation characteristic of mucosal prolapse was absent. The pathogenesis of CMSEP may involve mechanical traction of the mucosa and the superficial submucosa during peristalsis in a fragile area of the colon. Despite the occasional large size, CMSEP is a benign lesion seldom leading to clinical complications. 相似文献
985.
986.
987.
Elbaz A Ross OA Ioannidis JP Soto-Ortolaza AI Moisan F Aasly J Annesi G Bozi M Brighina L Chartier-Harlin MC Destée A Ferrarese C Ferraris A Gibson JM Gispert S Hadjigeorgiou GM Jasinska-Myga B Klein C Krüger R Lambert JC Lohmann K van de Loo S Loriot MA Lynch T Mellick GD Mutez E Nilsson C Opala G Puschmann A Quattrone A Sharma M Silburn PA Stefanis L Uitti RJ Valente EM Vilariño-Güell C Wirdefeldt K Wszolek ZK Xiromerisiou G Maraganore DM 《Annals of neurology》2011,69(5):778-792
988.
989.
Strain Effects on the Electronic and Thermoelectric Properties of n(PbTe)-m(Bi2Te3) System Compounds
Owing to their low lattice thermal conductivity, many compounds of the n(PbTe)-m(BiTe) homologous series have been reported in the literature with thermoelectric (TE) properties that still need improvement. For this purpose, in this work, we have implemented the band engineering approach by applying biaxial tensile and compressive strains using the density functional theory (DFT) on various compounds of this series, namely BiTe, PbBiTe, PbBiTe and PbBiTe. All the fully relaxed BiTe, PbBiTe, PbBiTe and PbBiTe compounds are narrow band-gap semiconductors. When applying strains, a semiconductor-to-metal transition occurs for all the compounds. Within the range of open-gap, the electrical conductivity decreases as the compressive strain increases. We also found that compressive strains cause larger Seebeck coefficients than tensile ones, with the maximum Seebeck coefficient being located at −2%, −6%, −3% and 0% strain for p-type BiTe, PbBiTe, PbBiTe and PbBiTe, respectively. The use of the quantum theory of atoms in molecules (QTAIM) as a complementary tool has shown that the van der Waals interactions located between the structure slabs evolve with strains as well as the topological properties of BiTe and PbBiTe. This study shows that the TE performance of the n(PbTe)-m(BiTe) compounds is modified under strains. 相似文献
990.
Etienne-Grimaldi MC Formento P Degeorges A Pierga JY Delva R Pivot X Dalenc F Espié M Veyret C Formento JL Francoual M Piutti M de Crémoux P Milano G 《British journal of clinical pharmacology》2011,71(6):921-928