全文获取类型
收费全文 | 9571篇 |
免费 | 638篇 |
国内免费 | 36篇 |
专业分类
耳鼻咽喉 | 130篇 |
儿科学 | 247篇 |
妇产科学 | 115篇 |
基础医学 | 1291篇 |
口腔科学 | 357篇 |
临床医学 | 753篇 |
内科学 | 2528篇 |
皮肤病学 | 361篇 |
神经病学 | 957篇 |
特种医学 | 246篇 |
外科学 | 1376篇 |
综合类 | 56篇 |
一般理论 | 4篇 |
预防医学 | 629篇 |
眼科学 | 239篇 |
药学 | 455篇 |
中国医学 | 21篇 |
肿瘤学 | 480篇 |
出版年
2024年 | 7篇 |
2023年 | 127篇 |
2022年 | 178篇 |
2021年 | 491篇 |
2020年 | 250篇 |
2019年 | 382篇 |
2018年 | 426篇 |
2017年 | 222篇 |
2016年 | 274篇 |
2015年 | 342篇 |
2014年 | 434篇 |
2013年 | 559篇 |
2012年 | 852篇 |
2011年 | 858篇 |
2010年 | 405篇 |
2009年 | 366篇 |
2008年 | 631篇 |
2007年 | 604篇 |
2006年 | 594篇 |
2005年 | 495篇 |
2004年 | 425篇 |
2003年 | 353篇 |
2002年 | 360篇 |
2001年 | 59篇 |
2000年 | 53篇 |
1999年 | 53篇 |
1998年 | 43篇 |
1997年 | 59篇 |
1996年 | 47篇 |
1995年 | 39篇 |
1994年 | 28篇 |
1993年 | 14篇 |
1992年 | 17篇 |
1991年 | 15篇 |
1990年 | 16篇 |
1989年 | 16篇 |
1988年 | 13篇 |
1987年 | 5篇 |
1986年 | 9篇 |
1985年 | 9篇 |
1984年 | 13篇 |
1982年 | 16篇 |
1981年 | 11篇 |
1980年 | 13篇 |
1977年 | 7篇 |
1976年 | 7篇 |
1975年 | 4篇 |
1974年 | 7篇 |
1973年 | 8篇 |
1962年 | 4篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
921.
Mario Jiz Jennifer F. Friedman Tjalling Leenstra Blanca Jarilla Archie Pablo Gretchen Langdon Sunthorn Pond-Tor Hai-Wei Wu Daria Manalo Remigio Olveda Luz Acosta Jonathan D. Kurtis 《Infection and immunity》2009,77(5):2051-2058
Schistosomiasis remains a public health concern in developing countries, and rapid reinfection fostered by continued exposure to contaminated water sources necessitates a vaccine to augment current mass treatment-based control strategies. We report isotype-specific (immunoglobulin A [IgA], IgE, IgG1, IgG4, and IgG) antibody responses to soluble worm antigen preparation and the recombinant vaccine candidates rSj97, rSj67, and rSj22 from a Schistosoma japonicum-infected cohort in Leyte, the Philippines, where schistosomiasis is endemic. Sera were collected from infected individuals 1 month posttreatment with praziquantel, and antibody responses were measured using a bead-based multiplex platform. Reinfection was monitored by stool sampling every 3 months, and data up to 1 year were included in the analysis (n = 553). In repeated-measures models, individuals with detectible IgE responses to rSj97 had a 26% lower intensity of reinfection at 12 months posttreatment compared to nonresponders after adjusting for age, gender, village, exposure, pretreatment infection intensity, and clustering by household (P = 0.018). In contrast, IgG4 responses to rSj97 as well as rSj67 and rSj22 were associated with markedly increased reinfection intensity. When stratified by IgG4 and IgE responder status, individuals with IgE but not IgG4 responses to rSj97 (n = 16) had a 77% lower intensity of reinfection at 12 months compared to individuals with IgG4 responses but not IgE responses (n = 274), even after adjusting for potential confounders (P = 0.016). Together with our previously described protective cytokine responses, these data further support paramyosin as a leading vaccine candidate for human schistosomiasis japonica and underscore the importance of careful adjuvant selection to avoid the generation of blocking IgG4 antibody responses.Schistosomiasis, caused by parasitic helminths of the genus Schistosoma, remains a major public health concern and currently infects 200 million individuals with 600 million individuals at risk of infection in 74 developing countries (19). National control strategies focusing on mass chemotherapy with praziquantel have significantly reduced severe liver and urinary tract pathology; however, rapid reinfection with consequent subtle morbidities such as anemia, malnutrition, and cognitive impairment persist despite years of annual treatment (30). Continued exposure to contaminated water sources mandates alternative control strategies such as vaccine-linked chemotherapy (3).In vitro studies have demonstrated that schistosome larvae are susceptible to damage in the presence of sera from infected individuals together with leukocytes from uninfected donors, suggesting that parasite-specific antibody-dependent cellular cytotoxicity (ADCC) plays a key role in parasite elimination (8). Subsequent investigations identified the role of protective immunoglobulin E (IgE), IgA, and IgG antibody isotypes (11, 23, 29) and the participation of eosinophils and mast cells in orchestrating this attack (7, 12). However, several studies have also demonstrated the presence of inhibitory antibodies which block schistosomular killing (22, 28). In particular, the antibody isotype IgG4 is a poor initiator of ADCC and blocks killing by competing with protective isotypes (29). These data suggest that schistosomes induce both protective and antagonistic antibody responses, which may alter the balance between parasite elimination and immune evasion (3).Consonant with in vitro studies, several immunoepidemiologic surveys conducted in areas where schistosomiasis is endemic have demonstrated associations between antibody responses to crude parasite antigens and reinfection outcomes in humans. Protective IgE responses to worm (17, 24) and egg (43) antigens have been described across schistosome species, as well as IgA responses mediating antifecundity effects (23). These cohort studies have also described antiparasite IgG4 (16, 24, 32), IgM, and IgG2 (5, 22, 28) as isotypes associated with susceptibility.Based on a model of antibody-mediated protection, the antigenic targets of both protective antibody isotypes and protective monoclonal antibodies have been identified in parasite extracts and genomic libraries. Numerous candidates have been identified (4), and a panel of the most promising of these was evaluated in immunoepidemiologic studies in Egypt (2), Brazil (35), and to a limited extent in China and the Philippines (1, 32). Despite this progress (3), only one vaccine candidate (Schistosoma haematobium glutathione S-transferase) has advanced to early-phase clinical trials (10).We have previously described cytokine responses to crude antigen preparations (soluble worm antigen preparation [SWAP], SEA) and defined vaccine candidates (Sj97, Sj67, and Sj22) in a cohort of schistosomiasis-infected individuals between 7 and 30 years old and residing in Leyte, the Philippines (31). Here, we extend this work by measuring isotype-specific (IgA, IgE, IgG1, IgG4, and total IgG, henceforth referred to as IgG) antibody responses to these antigens in the same cohort and evaluating their association with resistance to reinfection over 12 months of posttreatment follow-up. We report that IgE responses to rSj97 are associated with resistance to reinfection and are attenuated by IgG4. 相似文献
922.
Prolactin and 3alpha, 5alpha-reduced neurosteroids are implicated in maternal behavior. Sulpiride, an inductor of hyperprolactinemia, increased mRNA levels of 5alpha-reductase (5alpha-R), the key enzyme in the biosynthesis of these neurosteroids, indicating a possible interrelationship between prolactin levels and 5alpha-R, although the effects of sulpiride per se cannot be ruled out. In this study, we quantified mRNA levels of both 5alpha-R isozymes in prefrontal cortex of rats after the administration of metoclopramide, another inductor of prolactin secretion. The mRNA levels of both 5alpha-R isozymes were significantly increased in male and female rats by metoclopramide, although the effect was not identical to that of sulpiride. Therefore, other factors induced by these drugs, besides prolactin, may intervene in the regulation of both 5alpha-R isozymes. 相似文献
923.
Ana-María Simn Lucio Schiapparelli Pablo Salazar-Colocho Mar Cuadrado-Tejedor Luis Escribano Rakel Lpez de Maturana Joaquín Del Río Alberto Prez-Mediavilla Diana Frechilla 《Neurobiology of disease》2009,33(3):369-378
Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPPwt) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ42) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ42 were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ-independent pathogenic pathways in Alzheimer's disease. 相似文献
924.
Olivier Facy Fran?ois Radais Sylvain Ladoire Delphine Delroeux Hervé Tixier Fran?ois Ghiringhelli Patrick Rat Bruno Chauffert Pablo Ortega-Deballon 《Journal of experimental & clinical cancer research : CR》2011,30(1):4
Background
The best method to deliver intraperitoneal chemotherapy (IPC) for peritoneal carcinomatosis from ovarian cancer is not well defined. The aim of this study was to assess the ability of hyperthermia and adrenaline to enhance the intratumoral accumulation of cisplatin in a rat model of peritoneal carcinomatosis.Methods
Four groups of 5 BDIX rats with ovarian peritoneal carcinomatosis underwent IPC with 30 mg/l of cisplatin according to the following conditions: normothermia at 37° for 1 or 2 hours, hyperthermia at 42°C for 1 hour or normothermia at 37°C for 2 hours with 2 mg/l adrenaline. Tissue platinum content was measured by atomic absorption spectroscopy. The effect of hyperthermia, adrenaline and the duration of exposure to the drug was measured in vivo (tissue concentration of platinum in tumor, abdominal and extra abdominal tissues) and in vitro (cytotoxicity on human ovarian cancer cells).Results
In vitro, hyperthermia and longer exposure enhanced the accumulation and the cytotoxic effect of cisplatin on cancer cells. In vivo, only the 2 hours treatment with adrenaline resulted in increased platinum concentrations. The rats treated with adrenaline showed significantly lower concentrations of cisplatin in extra peritoneal tissues than those treated with hyperthermia.Conclusion
Adrenaline is more effective than hyperthermia in order to enhance the intratumoral concentration of cisplatin in rats with peritoneal carcinomatosis from ovarian origin. It may also decrease the systemic absorption of the drug. 相似文献925.
Judith A Rosales-Avi?a Jorge Torres-Flores Adriana Aguilar-Lemarroy Carmen Gurrola-Díaz Georgina Hernández-Flores Pablo C Ortiz-Lazareno José M Lerma-Díaz Ruth de Celis óscar González-Ramella Esperanza Barrera-Chaires Alejandro Bravo-Cuellar Luis F Jave-Suárez 《Journal of experimental & clinical cancer research : CR》2011,30(1):112
926.
Georgina Hernandez-Flores Pablo C Ortiz-Lazareno Jose Manuel Lerma-Diaz Jorge R Dominguez-Rodriguez Luis F Jave-Suarez Adriana del C Aguilar-Lemarroy Ruth de Celis-Carrillo Susana del Toro-Arreola Yessica C Castellanos-Esparza Alejandro Bravo-Cuellar 《BMC cancer》2011,11(1):1-15
Background
Flaxseed (FS) is a dietary supplement known for its antioxidant and anti-inflammatory properties. Radiation exposure of lung tissues occurs either when given therapeutically to treat intrathoracic malignancies or incidentally, such as in the case of exposure from inhaled radioisotopes released after the detonation of a radiological dispersion devise (RDD). Such exposure is associated with pulmonary inflammation, oxidative tissue damage and irreversible lung fibrosis. We previously reported that dietary FS prevents pneumonopathy in a rodent model of thoracic X-ray radiation therapy (XRT). However, flaxseed's therapeutic usefulness in mitigating radiation effects post-exposure has never been evaluated.Methods
We evaluated the effects of a 10%FS or isocaloric control diet given to mice (C57/BL6) in 2 separate experiments (n = 15-25 mice/group) on 0, 2, 4, 6 weeks post a single dose 13.5 Gy thoracic XRT and compared it to an established radiation-protective diet given preventively, starting at 3 weeks prior to XRT. Lungs were evaluated four months post-XRT for blood oxygenation levels, inflammation and fibrosis.Results
Irradiated mice fed a 0%FS diet had a 4-month survival rate of 40% as compared to 70-88% survival in irradiated FS-fed mouse groups. Additionally, all irradiated FS-fed mice had decreased fibrosis compared to those fed 0%FS. Lung OH-Proline content ranged from 96.5 ± 7.1 to 110.2 ± 7.7 μg/ml (Mean ± SEM) in all irradiated FS-fed mouse groups, as compared to 138 ± 10.8 μg/ml for mice on 0%FS. Concomitantly, bronchoalveolar lavage (BAL) protein and weight loss associated with radiation cachexia was significantly decreased in all FS-fed groups. Inflammatory cell influx to lungs also decreased significantly except when FS diet was delayed by 4 and 6 weeks post XRT. All FS-fed mice (irradiated or not), maintained a higher blood oxygenation level as compared to mice on 0%FS. Similarly, multiplex cytokine analysis in the BAL fluid revealed a significant decrease of specific inflammatory cytokines in FS-fed mice.Conclusions
Dietary FS given post-XRT mitigates radiation effects by decreasing pulmonary fibrosis, inflammation, cytokine secretion and lung damage while enhancing mouse survival. Dietary supplementation of FS may be a useful adjuvant treatment mitigating adverse effects of radiation in individuals exposed to inhaled radioisotopes or incidental radiation. 相似文献927.
Benson AB Arnoletti JP Bekaii-Saab T Chan E Chen YJ Choti MA Cooper HS Dilawari RA Engstrom PF Enzinger PC Fleshman JW Fuchs CS Grem JL Knol JA Leong LA Lin E May KS Mulcahy MF Murphy K Rohren E Ryan DP Saltz L Sharma S Shibata D Skibber JM Small W Sofocleous CT Venook AP Willett C;National Comprehensive Cancer Network 《Journal of the National Comprehensive Cancer Network : JNCCN》2011,9(11):1238-1290
928.
Daftarian P Chowdhury R Ames P Wei C King AD de Rivero Vaccari JP Dillon L Price J Leung H Ashlock B Mesri E Perez V Züchner S Reiser J Lemmon V Keane RW 《Hybridoma (2005)》2011,30(5):409-418
In vivo electroporation has become a gold standard method for DNA immunization. The method assists the DNA entry into cells, results in expression and the display of the native form of antigens to professional cells of the immune system, uses both arms of immune system, has a built-in adjuvant system, is relatively safe, and is cost-effective. However, there are challenges for achieving an optimized reproducible process for eliciting strong humoral responses and for the screening of specific immune responses, in particular, when the aim is to mount humoral responses or to generate monoclonal antibodies via hybridoma technology. Production of monoclonal antibodies demands generation of high numbers of primed B and CD4 T helper cells in lymphoid organs needed for the fusion that traditionally is achieved by a final intravenous antigen injection. The purified antigen is also needed for screening of hundreds of clones obtained upon fusion of splenocytes. Such challenges make DNA vaccination dependent on purified proteins. Here, we have optimized methods for in vivo electroporation, production, and use of cells expressing the antigen and an in-cell Western screening method. These methods resulted in (1) reproducibly mounting robust humoral responses against antigens with different cell localizations, and (2) the ability to screen for antigen eliminating a need for protein/antigen purification. This process includes optimized parameters for in vivo electroporation, the use of transfected cells for final boost, and mild fixation/permeabilization of cells for screening. Using this process, upon two vaccinations via in vivo electroporation (and final boost), monoclonal antibodies against nucleus and cytoplasmic and transmembrane proteins were achieved. 相似文献
929.
Javier Fernandez-Solari Juan Pablo Prestifilippo Valeria Rettori 《Archives of oral biology》2010,55(8):583-590
Objective
The aim of the present paper was to assess whether lipopolysaccharide (LPS)-induced inhibition of salivary secretion involves the activation of the endocannabinoid system and the participation of tumor necrosis factor (TNF)α in the submandibular gland.Design
Pharmacological approaches were performed by using CB1 and/or CB2 cannabinoid receptor antagonists, AM251 and AM630, respectively, injected into the submandibular gland, to study the participation of the endocannabinoid system in LPS inhibitory effects on metacholine-induced salivary secretion. To assess the participation of TNFα on LPS inhibitory effects, salivary secretion was studied in LPS treated rats after the intraglandular injection of etanercept, a soluble form of TNF receptor which blocks TNFα action. Finally, to evaluate the possible interplay between endocannabinoids and TNFα on the submandibular gland function reduced during LPS challenge, the salivary secretion was studied after the intraglandular injection of this cytokine alone or concomitantly with AM251 and AM630.Results
AM251 and AM630, injected separately or concomitantly, partially prevented LPS-induced inhibition of salivation. Also, anandamide synthase activity was increased in submandibular glands extracted from rats 3 h after LPS injection, suggesting that the endocannabinoid system was activated in response to this challenge. On the other hand, etanercept, prevented the inhibitory effect of LPS on salivary secretion and moreover, TNFα injected intraglandularly inhibited salivary secretion, being this effect prevented by AM251 and AM630 injected concomitantly.Conclusion
The present results demonstrate the participation of the endocannabinoid system and TNFα on salivary responses during systemic inflammation induced by LPS. 相似文献930.