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61.
Kopp MV Brauburger J Riedinger F Beischer D Ihorst G Kamin W Zielen S Bez Friedrichs F Von Berg A Gerhold K Hamelmann E Hultsch Kuehr J 《The Journal of allergy and clinical immunology》2002,110(5):728-735
BACKGROUND: Binding of allergens with IgE to the IgE receptors on mast cells and basophils results in the release of inflammatory mediators as sulfidoleukotrienes (SLTs), triggering allergic cascades that result in allergic symptoms, such as asthma and rhinitis. OBJECTIVE: We sought to investigate whether anti-IgE (Oma-lizumab), a humanized monoclonal anti-IgE antibody, in addition to specific immunotherapy (SIT) affects the leukotriene pathway. METHODS: Ninety-two children (age range, 6-17 years) with sensitization to birch and grass pollens and with seasonal allergic rhinitis were included in a phase III, placebo- controlled, multicenter clinical study. All subjects were randomized to one of 4 treatment groups. Two groups subcutaneously received birch SIT and 2 groups received grass SIT for at least 14 weeks before the start of the birch pollen season. After 12 weeks of SIT titration, placebo or anti-IgE was added for 24 weeks. The primary clinical efficacy variable was symptom load (ie, the sum of daily symptom severity score and rescue medication score during pollen season). Blood samples taken at baseline and at the end of study treatment after the grass pollen season were used for separation of leukocytes in this substudy. After in vitro stimulation of the blood cells with grass and birch pollen allergens, SLT release (LTC4, LTD4, and LTE4) was quantified by using the ELISA technique. RESULTS: Before the study treatment, SLT release to birch and grass pollen exposure did not differ significantly among the 4 groups. Under treatment with anti-IgE + SIT-grass (n = 23), a lower symptom load occurred during the pollen season compared to placebo + SIT-grass (n = 24, P =.012). The same applied to both groups receiving birch SIT (n = 23 and n = 22, respectively; P =.03). At the end of treatment, the combination of anti-IgE plus grass SIT, as well as anti-IgE plus birch SIT, resulted in significantly lower SLT release after stimulation with the corresponding allergen (416 ng/L [5th-95th percentile, 1-1168] and 207 ng/L [1-860 ng/L], respectively) compared with placebo plus SIT (2490 ng/L [384-6587 ng/L], P =.001; 2489 ng/L [1-5670 ng/L], P =.001). In addition, treatment with anti-IgE was also followed by significantly lower SLT releases to the allergens unrelated to SIT (grass SIT: 300 ng/L [1-2432 ng/L] in response to birch allergen; birch SIT: 1478 ng/L [1-4593 ng/L] in response to grass pollen) in comparison with placebo (grass SIT: 1850 ng/L [1-5499 ng/L], P =.001; birch SIT: 2792 ng/L [154-5839 ng/L], P =.04]. CONCLUSION: Anti-IgE therapy reduces leukotriene release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy independent of the type of SIT allergen used. 相似文献
62.
Falk W. Lohoff Marion Lautenschlager Johannes Mohr Thomas N. Ferraro Thomas Sander Jürgen Gallinat 《Neuroscience letters》2008
Vesicular monoamine transporters are involved in the presynaptic packaging of norepinephrine, dopamine and serotonin into storage vesicles. The vesicles release their content upon arrival of an action potential into the synaptic cleft. Dysregulation of monoaminergic neurotransmission has been long postulated to play a relevant role in the etiology of neuropsychiatric disorders. The gene encoding the vesicular monoamine transporter 1 (VMAT1/SLC18A1) maps to chromosome 8p21, a region where several linkage peaks overlap between schizophrenia, bipolar disorder and anxiety-related personality traits. In this study, we tested the hypothesis that the missence variation Thr136Ile in the VMAT1/SLC18A1 gene is associated with anxiety-related personality traits. We tested a total of 337 unrelated subjects of German descent (167 male, 170 female). All participants were carefully screened for psychiatric disorders. The self-report State–Trait Anxiety Inventory (STAI) was completed by all subjects. Genotypes were obtained for the Thr136Ile (rs1390938) variation in the VMAT1 gene for all subjects. Genotype effects on personality variables were computed with MANOVA including age as a co-variant and gender as independent factor (MANCOVA). Results show that STAI scores were significantly affected by genotype (F = 3.108; d.f. = 4,331; p = 0.015) and age (F = 7.233; d.f. = 2,331; p = 0.001) but not by gender. A gender-by-genotype effect was observed for both the STAI state (p = 0.052) and trait score (p = 0.035). Dissection of the group by gender and subsequent contrast analysis of the genotype effects performed within the female group showed significant results (STAI state: Thr/Ile vs. Ile/Ile: T = 4.408, p = 0.0004; STAI trait: Thr/Ile vs. Ile/Ile: T = 3.074, p = 0.009) but not in the male group. Our findings support the hypothesis that anxiety-related personality traits are associated with variation in the VMAT1/SLC18A1 gene. 相似文献
63.
D. J. Schendel Ralph Oberneder Christine S. Falk Petra Jantzer Susanne Kressenstein Barbara Maget Alfons Hofstetter Gert Riethmüller Elfriede Nößner 《Journal of molecular medicine (Berlin, Germany)》1997,75(6):400-413
Renal cell carcinomas belong to the small group of tumors that are able to induce antitumor responses. Here we describe two
general types of cytotoxic effector lymphocytes that can eliminate autologous tumor cells and discuss the role that major
histocompatibility complex encoded molecules play in governing their specificities. Improved understanding of the cellular
and molecular basis of renal cell carcinoma recognition opens new avenues of research with the potential to develop better
immunotherapies for patients with metastatic disease.
Received: 24 July 1996 / Accepted: 1 November 1996 相似文献
64.
During the past 10 years knowledge about the interactions between major histocompatibility complex (MHC) class I molecules
and the T-cell receptor (TCR) complex of cytotoxic T-cells (CTL) has developed dramatically. But the primary interest, both
with respect to structure as well as function, has concentrated on HLA-A and -B molecules because of their high sequence polymorphism
and their dominating presence at the cell surface. In contrast, HLA-C molecules seemed to be of only minor importance in the
cascade of immune reactions owing to their more limited polymorphism and reduced levels of surface expression. The inability
to define a number of antigen specificities had the result that HLA-C molecules were often neglected in studies of immune
response, transplantation, and disease association. More recently a new function has been identified for HLA class I molecules
where they act as inhibitors of the lytic capacity of natural killer (NK) cells and non-MHC-restricted T-cells. Moreover,
the understanding of this novel mode of negative regulation of cytotoxicity was remarkably influenced by HLA-C since these
were the first HLA class I molecules found to have such inhibitory potential. With this new inhibitory function serving as
an essential component of the immune system, HLA-C molecules can no longer be neglected. 相似文献
65.
Beasley MB Thunnissen FB Brambilla E Hasleton P Steele R Hammar SP Colby TV Sheppard M Shimosato Y Koss MN Falk R Travis WD 《Human pathology》2000,31(10):1255-1265
Pulmonary neuroendocrine tumors (NE) include a spectrum of tumors from typical carcinoid (TC) to atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). Little is known about prognostic predictors for AC because of its rarity. Survival analysis was performed on 106 ACs with clinical follow-up from the AFIP and the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). The tumors fulfilled the 1999 WHO/IASLC criteria for AC of a NE tumor with a mitotic rate of 2 to 10 per 2 mm(2) of viable tumor or coagulative necrosis. Multiple clinical and histologic features were analyzed by Kaplan-Meier and Cox regression analysis. Of the clinical features, higher stage (P = .003) and a tumor size of 3.5 cm or greater (P = .003) were associated with a worse prognosis. Features that were histologically unfavorable by univariate analysis were mitotic rate (P =.002), pleomorphism (P = .018), and aerogenous spread (P =.007). Histologically favorable features by univariate analysis were the presence of palisading (P = .008), papillary (P = .039), pseudoglandular (P =.026), and rosette (P = .022) patterns. Female gender showed a trend toward a poorer prognosis (P =.085) and was included in the multivariate model. Multivariate analysis stratified for stage showed mitoses (P<.001), a tumor size of 3.5 cm or greater (P =.017), and female gender (P =.012) to be the only negative independent predictors of prognosis and the presence of rosettes (P = .016) to be the only independent positive predictor. We further divided the AC into subgroups of low (2 to 5 mitoses/2 mm(2)) and high (6 to 10 mitoses/2 mm(2)) mitotic rate and compared the survival with TC and with LCNEC. Within the category of AC, the patients with a higher mitotic rate had a significantly worse survival than those with a lower mitotic rate (P<.001) stratified for stage. Five- and 10-year survival rates for AC (61% and 35%, respectively) stratified for stage were significantly worse than for TC and better than that for LCNEC and SCLC. Chemotherapy or radiation therapy was given in 12 of 52 and 14 of 52 cases, respectively, but the data were insufficient to evaluate tumor response. We conclude that AC is an aggressive neuroendocrine neoplasm with survival intermediate between TC and LCNEC and SCLC. Higher mitotic rate, tumor size of 3.5 cm or greater, female gender, and presence of rosettes are the only independent predictors of survival. Surgical resection remains the treatment of choice, and the role of chemotherapy and radiation therapy remains to be proven. 相似文献
66.
Stopfer P Obermeier F Dunger N Falk W Farkas S Janotta M Möller A Männel DN Hehlgans T 《Clinical and experimental immunology》2004,136(1):21-29
The lymphotoxin-beta receptor (LTbetaR) pathway is critical for maintenance of organized lymphoid structures and is involved in the development of colitis. To investigate the mechanisms by which LTbetaR activation contributes to the pathology of chronic inflammation we used a soluble LTbetaR-Ig fusion protein as a competitive inhibitor of LTbetaR activation in the mouse model of chronic colitis induced by oral administration of dextran sulphate sodium. Strong expression of LTbeta which constitutes part of the LTalpha(1)beta(2) ligand complex was detected in colonic tissue of mice with chronic colitis. Treatment with LTbetaR-Ig significantly attenuated the development and histological manifestations of the chronic inflammation and reduced the production of inflammatory cytokines such as TNF, IL-1beta, and IL-6. Moreover, LTbetaR-Ig treatment significantly down-regulated mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression, leading to reduced leucocyte rolling and sticking in postcapillary and collecting venules and reduced extravasation into the intestinal mucosa as quantified by in vivo fluorescence microscopy. Thus, LTbetaR pathway inhibition ameliorates DSS-induced experimental chronic colitis in mice by MAdCAM-1 down-regulation entailing reduced lymphocyte margination and extravasation into the inflamed mucosa. Therefore, a combined treatment with reagents blocking T cell-mediated perpetuation of chronic inflammation such as LTbetaR-Ig together with direct anti-inflammatory reagents such as TNF inhibitors could constitute a promising treatment strategy for chronic colitis. 相似文献
67.
68.
The intracortical projections of neurons in layers II and upper III of tree shrew visual cortex were studied after terminal lesions in the supragranular layers of area 17. Examination for terminal degeneration was made using ultrastructural techniques. The majority of degenerating terminals were found in layers V and, to a lesser extent, VI, and were presynaptic to neural profiles in the following distribution: 80.5% on spines of small to medium size dendrites, 19% on dendrite shafts, and less than 1% on neuronal perikarya. Degenerating axons coursed in vertical bundles through layers III, IV, V and VI. These findings are similar to those previously described in rat visual cortex. 相似文献
69.
E Falk 《Circulation》1985,71(4):699-708
Extensive microscopic examination of epicardial arteries and myocardium was performed in 25 cases of sudden death due to acute coronary thrombosis. Eighty-one percent of the thrombi had a layered structure with thrombus material of differing age, indicating that they were formed successively by repeated mural deposits that caused progressive luminal narrowing over an extended period of time. This episodic growth of the thrombus was accompanied by intermittent fragmentation of thrombus in 73% of the cases, with peripheral embolization causing microembolic occlusion of small intramyocardial arteries associated with microinfarcts. The period of unstable angina before the final heart attack was, in all but one of 15 patients, characterized by such an ongoing thrombotic process in a major coronary artery where recurrent mural thrombus formation seemed to have alternated with intermittent thrombus fragmentation. The culmination of this "dynamic" thrombotic process in total vascular occlusion caused the final infarction and/or sudden death. 相似文献
70.
Effect of dexamethasone on symptoms of acute mountain sickness at Pikes Peak, Colorado (4,300 m) 总被引:1,自引:0,他引:1
P B Rock T S Johnson A Cymerman R L Burse L J Falk C S Fulco 《Aviation, space, and environmental medicine》1987,58(7):668-672
In a previous controlled study, dexamethasone (DEX) was shown to prevent acute mountain sickness (AMS) during exposure to simulated high altitude. To determine the effect of DEX during actual altitude exposure, 16 young men were treated with either DEX (4 mg every 6 h) or placebo for 48 h prior to and 48 h after being rapidly transported from sea level to the summit of Pikes Peak, CO (4,300 m). Symptoms of AMS were evaluated twice daily at Pikes Peak using the Environmental Symptoms Questionnaire and a clinical assessment. During treatment the mean symptom scores were higher for subjects taking placebo in 18 out of 20 comparisons. On an individual basis, 60% of the subjects receiving placebo met the criteria for being "sick" compared to 31% of subjects receiving DEX. Beginning 24 h after cessation of treatment, DEX subjects experienced a progressive increase in symptom scores which lasted through the end of the altitude sojourn (day 6). The results indicate that DEX is an effective prophylactic treatment for AMS in an actual mountain environment, but that AMS symptoms can occur if the drug is stopped abruptly. 相似文献