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1.
Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep 下载免费PDF全文
Flavio Torres Alejandro González‐Candia Camilo Montt Germán Ebensperger Magdalena Chubretovic María Serón‐Ferré Roberto V. Reyes Aníbal J. Llanos Emilio A. Herrera 《Journal of pineal research》2015,58(3):362-373
Pulmonary hypertension of the newborn (PHN) constitutes a critical condition with severe cardiovascular and neurological consequences. One of its main causes is hypoxia during gestation, and thus, it is a public health concern in populations living above 2500 m. Although some mechanisms are recognized, the pathophysiological facts that lead to PHN are not fully understood, which explains the lack of an effective treatment. Oxidative stress is one of the proposed mechanisms inducing pulmonary vascular dysfunction and PHN. Therefore, we assessed whether melatonin, a potent antioxidant, improves pulmonary vascular function. Twelve newborn sheep were gestated, born, and raised at 3600 meters. At 3 days old, lambs were catheterized and daily cardiovascular measurements were recorded. Lambs were divided into two groups, one received daily vehicle as control and another received daily melatonin (1 mg/kg/d), for 8 days. At 11 days old, lung tissue and small pulmonary arteries (SPA) were collected. Melatonin decreased pulmonary pressure and resistance for the first 3 days of treatment. Further, melatonin significantly improved the vasodilator function of SPA, enhancing the endothelial‐ and muscular‐dependent pathways. This was associated with an enhanced nitric oxide‐dependent and nitric oxide independent vasodilator components and with increased nitric oxide bioavailability in lung tissue. Further, melatonin reduced the pulmonary oxidative stress markers and increased enzymatic and nonenzymatic antioxidant capacity. Finally, these effects were associated with an increase of lumen diameter and a mild decrease in the wall of the pulmonary arteries. These outcomes support the use of melatonin as an adjuvant in the treatment for PHN. 相似文献
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Claudio Babiloni Giuliano Binetti Emanuele Cassetta Gloria Dal Forno Claudio Del Percio Florinda Ferreri Raffaele Ferri Giovanni Frisoni Koichi Hirata Bartolo Lanuzza Carlo Miniussi Davide V Moretti Flavio Nobili Guido Rodriguez Gian Luca Romani Serenella Salinari Paolo M Rossini 《Clinical neurophysiology》2006,117(2):252-268
OBJECTIVE: The present study tested the hypothesis that cortical electroencephalographic (EEG) rhythms. change across normal elderly (Nold), mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects as a function of the global cognitive level. METHODS: Resting eyes-closed EEG data were recorded in 155 MCI, 193 mild AD, and 126 age-matched Nold subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by LORETA. RESULTS: Occipital delta and alpha 1 sources in parietal, occipital, temporal, and 'limbic' areas had an intermediate magnitude in MCI subjects compared to mild AD and Nold subjects. These five EEG sources presented both linear and nonlinear (linear, exponential, logarithmic, and power) correlations with the global cognitive level (as revealed by mini mental state examination score) across all subjects. CONCLUSIONS: Cortical EEG rhythms change in pathological aging as a function of the global cognitive level. SIGNIFICANCE: The present functional data on large populations support the 'transitional hypothesis' of a shadow zone across normality, pre-clinical stage of dementia (MCI), and AD. 相似文献
4.
Heterogeneous response of individual multicellular tumour spheroids to immunotoxins and ricin toxin.
R. Chignola R. Foroni A. Franceschi M. Pasti C. Candiani C. Anselmi G. Fracasso G. Tridente M. Colombatti 《British journal of cancer》1995,72(3):607-614
The cytoreductive effects of anti-transferrin receptor (anti-TfnR) immunotoxins (ITs) and of ricin toxin against tumour micromasses have been evaluated in a multicellular tumour spheroid (MTS) model. More than 600 (656) MTSs obtained with human breast carcinoma (MCF7) or rat glioblastoma (9L) cell lines were treated individually with ITs or toxin and the effects induced by the treatment were measured for each MTS as volume variation vs time by applying the Gompertz growth model. Two dose-dependent patterns of MTS growth were observed in MTSs of both cell lines in response to IT or toxin treatment: (1) complete inhibition of MTS growth (''sterilisation''); and (2) partial/complete inhibition (''heterogeneous response''). Within the range of IT or toxin concentrations resulting in partial inhibition of MTS growth, the sensitivity of treated MTSs was extremely heterogeneous (the cytoreductive effects varying between 0.1 and 4 logs of cells killed for a given IT or toxin concentration). Analysis of the post-treatment regrowth kinetics indicated that treated non-sterilised and control MTSs reached the same final limiting volumes. However, the doubling time estimated for the surviving cells of treated MCF7 and 9L MTSs ranged between 15 and 50 h, indicating that each MTS had individual growing potential. In conclusion, our results indicate that at substerilising IT concentrations individual heterogenicity of MTSs may greatly influence the cytoreductive potential of ITs. An implication of our study is that the efficacy of an IT treatment in eradicating disseminated micrometastases may not be predictable a priori. The MTS model that we describe in this paper may help in dissecting out factors limiting the effect of ITs in three-dimensional tumours. 相似文献
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Claudio Babiloni Giovanni Frisoni Mircea Steriade Lorena Bresciani Giuliano Binetti Claudio Del Percio Cristina Geroldi Carlo Miniussi Flavio Nobili Guido Rodriguez Filippo Zappasodi Tania Carfagna Paolo M Rossini 《Clinical neurophysiology》2006,117(5):1113-1129
OBJECTIVE: A relationship between brain atrophy and delta rhythmicity (1.5-4 Hz) has been previously explored in Alzheimer's disease (AD) subjects [Fernandez A, Arrazola J, Maestu F, Amo C, Gil-Gregorio P, Wienbruch C, Ortiz T. Correlations of hippocampal atrophy and focal low-frequency magnetic activity in Alzheimer disease: volumetric MR imaging-magnetoencephalographic study. Am J Neuroradiol. 2003 24(3):481-487]. In this study, we tested the hypothesis that such a relationship does exist not only in AD patients but also across the continuum of subjects with mild cognitive impairment (MCI) and AD. METHODS: Resting, eyes-closed EEG data were recorded in 34 MCI and 65 AD subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by LORETA. Cortical EEG sources were correlated with MR-based measurements of lobar brain volume (white and gray matter). RESULTS: A negative correlation was observed between the frontal white matter and the amplitude of frontal delta sources (2-4 Hz) across MCI and AD subjects. CONCLUSIONS: These results confirmed for the first time the hypothesis that the sources of resting delta rhythms (2-4 Hz) are correlated with lobar brain volume across MCI and AD subjects. SIGNIFICANCE: The present findings support, at least at group level, the 'transition hypothesis' of brain structural and functional continuity between MCI and AD. 相似文献
7.
New Insights into the Pathogenesis and the Therapy of Recurrent Focal Glomerulosclerosis 总被引:4,自引:0,他引:4
Recurrent focal glomerulosclerosis (FSGS) in renal allografts has remained a frustrating and enigmatic disease. Recent studies on gene mutations encoding podocin and other components of the slit-diaphragm in patients with native kidney nephrotic syndrome have underscored the heterogenecity of the idiopathic form of FSGS. While familial FSGS rarely recurs following transplantation, the sporadic variety of FSGS is associated with a 30% recurrence rate. The patients with the sporadic variety of FSGS who have homozygous or complex heterozygous podocin mutations have a low recurrence rate. In the other patients with sporadic FSGS, a more complex and likely multifactorial etiology accounts for the recurrence of FSGS. The role of CD80 expression on podocytes is intriguing but requires confirmation in kidney biopsies of patients with recurrent FSGS. Recent findings on podocin genomics, the permeability factor and CD80 expression may ultimately lead to a better understanding of recurrent FSGS as well as a more effective approach to its prevention and treatment. 相似文献
8.
Flavio Masi Benedetta Leggio Giulio Nanni Simona Scheggi M Graziella De Montis Alessandro Tagliamonte Silvia Grappi Carla Gambarana 《Neuropsychopharmacology》2003,28(4):683-693
Long-term acetyl-L-carnitine (ALCAR) administration prevents the development of escape deficit produced by acute exposure to unavoidable stress. However, it does not revert the escape deficit sustained by chronic stress exposure. Rats exposed to chronic stress show a low dopamine (DA) output in the nucleus accumbens shell (NAcS) and do not acquire an appetitive behavior sustained by the earning of vanilla sugar (VS) made contingent on the choice of one of the two divergent arms of a Y-maze (VS-sustained appetitive behavior, VAB), while control rats consistently do. The present study shows that ALCAR treatment in rats exposed to a 7-day stress protocol prevented a decrease in DA output in the NAcS and medial prefrontal cortex (mPFC) of rats, and that it strengthened the DA response to VS consummation in the same two areas. Moreover, rats treated with long-term ALCAR or exposed to chronic stress while treated with ALCAR acquired VAB as efficiently as control rats. Moreover, VAB acquisition in stressed rats treated with ALCAR coincided with the reversal of the deficits in escape and in dopaminergic transmission in the NAcS. Thus, repeated ALCAR treatment preserved the DA response to VS in chronically stressed rats and this effect appeared to be predictive of the rat's competence to acquire VAB. 相似文献
9.
Josep Sul-Suso Flavio Arienti Cecilia Melani Mario Paolo Colombo Giorgio Parmiani 《European journal of immunology》1995,25(10):2737-2742
B7 co-stimulation is necessary to activate resting T cells upon antigen recognition by the T cell receptor. To see whether expression of B7 may render human melanoma cells able to stimulate T cells, a cloned melanoma line (Me1B6), which did not express B7-1, was transfected with the human B7-1 gene. In proliferation assays, B7-1 transfected cells (Me1B6/B7) showed greater stimulatory activity of allogeneic and autologous peripheral blood lymphocytes (PBL) compared to parental, non-transfected tumor cells. This effect was also seen when allogeneic CD8+ and CD4+ subpopulations were used as effectors. In these studies, activation of lymphocytes was B7-1-dependent and HLA classes I and II mediated. The higher proliferation correlated with an increased lytic activity by PBL stimulated with B7-1+ tumor cells against the untransfected Me1B6. Furthermore, PBL from a metastatic melanoma patient stimulated by Me1B6/B7 developed an higher lytic activity not only against Me1B6 but also against their autologous, B7-1? tumor. Finally, after Me1B6/B7 stimulation, PBL released interleukin (IL)-2 and interferon-γ, but not IL-4, suggesting a Th1-mediated response. These data support the use of B7-1 transfected melanoma cells in the therapeutic vaccination of melanoma patients. 相似文献
10.
Vincenti F 《BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy》1999,11(5):333-341
The central role that the cytokine interleukin-2 (IL-2) and its receptor (IL-2R) play in the induction of the immune response has been recognised for some time. IL-2R consists of 3 chains (alpha, beta and gamma). The alpha-chain (T cell activation antigen or CD25) is expressed only after T-lymphocyte activation. Therefore a monoclonal antibody targeting the alpha-chain can result in selective immunosuppression. The first generation anti-IL-2Ralpha monoclonal antibodies consisted of mouse and rat antibodies that were promising but not totally effective in clinical studies. The immunogenicity, short half-life and inability to recruit host effector functions such as antibody-dependent cell-mediated cytotoxicity associated with the rodent monoclonal antibodies limit their clinical use. Chimerisation or humanisation of these monoclonal antibodies resulted in antibodies with a predominantly human framework that retained the antigen specificity of the original rodent monoclonal antibodies. A fully humanised anti-IL-2R monoclonal antibody, daclizumab, and a chimeric anti-IL-2R monoclonal antibody, basiliximab, have undergone successful phase III pivotal trials in which they were well tolerated and effective in the immunoprophylaxis of patients undergoing renal transplantation. Daclizumab 1 mg/kg every other week for a total of 5 doses in patients administered standard triple immunosuppression who had received grafts from cadaver or living related donors saturated the IL-2Ralpha on circulating lymphocytes for at least 3 months after transplantation. The efficacy and safety of intravenous daclizumab 1 mg/kg prior to transplantation and again at 2, 4, 6 and 8 weeks postoperatively, in conjunction with standard dual or triple immunosuppression, were further assessed in 2 phase III clinical trials. In both trials, biopsy-proven rejection was significantly reduced 6 months after the transplantation. The half-life of daclizumab was 20 days. The addition of daclizumab did not increase the incidence of adverse events, infectious complications or malignancies. Basiliximab 20mg was administered on the day of and on day 4 after transplantation, in conjunction with standard dual immunosuppression, in 2 phase III trials involving cadaver and/or living related transplants. The incidence of biopsy-proven acute rejection at 6 months was significantly reduced with basiliximab. The half-life of basiliximab was 7 days. The drug was not associated with increased risks of adverse events, infectious complications or malignancies. In an ongoing study, patients receiving a maintenance immunosuppression regimen of prednisone, cyclosporin and mycophenolate mofetil were administered daclizumab or placebo. Biopsy-proven rejection was lower in the group receiving daclizumab, and coadministration with mycophenolate mofetil was well tolerated with no pharmacokinetic interactions. 相似文献