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M. S. Shaikh J. Rana D. Gaikwad U. Leartsakulpanich Premlata K. Ambre R. R. S. Pissurlenkar E. C. Coutinho 《Indian journal of pharmaceutical sciences》2014,76(2):116-124
Plasmodium falciparum dihydrofolate reductase is an important target for antimalarial chemotherapy. The emergence of resistance has significantly reduced the efficacy of the classic antifolate drugs cycloguanil and pyrimethamine. In this paper we report new dihydrofolate reductase inhibitors identified using molecular modelling principles with the goal of designing new antifolate agents active against both wild and tetramutant dihydrofolate reductase strains three series of trimethoprim analogues were designed, synthesised and tested for biological activity. Pyrimethamine and cycloguanil have been reported to loose efficacy because of steric repulsion in the active site pocket produced due to mutation in Plasmodium falciparum dihydrofolate reductase. The synthesised molecules have sufficient flexibility to withstand this steric repulsion to counteract the resistance. The molecules have been synthesised by conventional techniques and fully characterised by spectroscopic methods. The potency of these molecules was evaluated by in vitro enzyme specific assays. Some of the molecules were active in micromolar concentrations and can easily be optimised to improve binding and activity. 相似文献
84.
Maternal administration of granulocyte colony-stimulating factor improves neonatal rat survival after a lethal group B streptococcal infection 总被引:2,自引:0,他引:2
Novales JS; Salva AM; Modanlou HD; Kaplan DL; del Castillo J; Andersen J; Medlock ES 《Blood》1993,81(4):923-927
Maternally administered recombinant human granulocyte colony- stimulating factor (rhG-CSF) has been shown to cross the placenta and induce a peripheral neutrophilia and increases in the marrow and spleen neutrophil storage pools in fetal and newborn rats. In the present study, we have used this model system to investigate the efficacy of prenatally administered rhG-CSF on neonatal defense to a lethal challenge with Group B-beta hemolytic Streptococcus (GBS). Pregnant rats were injected with rhG-CSF twice daily beginning 6 days before parturition. At birth, all pups were infected with a dose of GBS that is lethal for 90% of infected pups (LD90). Survival was monitored daily for 5 days. Survival of infected pups from saline-treated mothers beyond 60 hours after infection was 10%. No difference in survival was observed among pups from mothers treated 2 and 4 days before parturition. In contrast, we determined that survival was 82.5% among infected pups from mothers treated for 6 days before parturition with rhG-CSF. Our results demonstrate that maternal administration of rhG- CSF augments neonatal defenses against a lethal bacterial challenge. 相似文献
85.
Louise Y. Sun Jack V. Tu Heather Sherrard Norvinda Rodger Thais Coutinho Michele Turek Elizabeth Chan Heather Tulloch Lisa McDonnell Lisa M. Mielniczuk 《Journal of cardiac failure》2018,24(9):568-574
Background
Differences in outcomes have previously been reported between urban and rural settings across a multitude of chronic diseases. Whether these discrepancies have changed over time, and how sex may influence these findings is unknown for patients with ambulatory heart failure (HF). We examined the temporal incidence and mortality trends by geography in these patients.Methods and Results
We conducted a retrospective cohort study of 36,175 eastern Ontario residents who were diagnosed with HF in an outpatient setting from 1994 to 2013. The primary outcome was 1-year mortality. We examined temporal changes in mortality risk factors with the use of multivariable Cox proportional hazard models. The incidence of HF decreased in women and men across both rural and urban settings. Age-standardized mortality rates also decreased over time in both sexes but remained greater in rural men compared with rural women.Conclusions
The incidence of HF in the ambulatory setting was greater for men than women and greater in rural than urban areas, but mortality rates remained higher in rural men compared with rural women. Further research should focus on ways to reduce this gap in the outcomes of men and women with HF. 相似文献86.
Abnormal T cell selection on nod thymic epithelium is sufficient to induce autoimmune manifestations in C57BL/6 athymic nude mice 下载免费PDF全文
Vronique Thomas-Vaslin Diane Damotte Monique Coltey Nicole M. Le Douarin Antonio Coutinho Josselyne Salaün 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(9):4598-4603
To investigate the role of primary T cell repertoire selection in the immunopathogenesis of autoimmune diseases, pure thymic epithelium (TE) from nonobese diabetic (NOD) embryos was grafted into non autoimmune prone newborn C57BL/6 athymic mice. The results show that NOD TE selects host T cell repertoires that establish autoimmunity in otherwise nondiabetic animals. Thus, such chimeras regularly show CD4 and CD8 T cell-mediated insulitis and sialitis, in contrast with syngeneic or allogeneic chimeras produced with TE from nonautoimmune strains. This is the first demonstration that autoimmunity to pancreatic β cells and salivary glands can be established by the sole alteration of the thymic environment involved in T cell selection, regardless of the nature and presentation of both major histocompatibility complex and tissue-specific antigens on the target organ. These data indicate that T cell repertoire selection by the NOD thymic epithelium is sufficient to induce specific autoimmune characteristics in the context of an otherwise normal host. 相似文献
87.
Dvorak AM; Tepper RI; Weller PF; Morgan ES; Estrella P; Monahan-Earley RA; Galli SJ 《Blood》1994,83(12):3600-3612
We used light and electron microscopy to analyze the eyelid inflammation that develops in transgenic mice that overexpress interleukin-4 (IL-4; Tepper et al, Cell 62:457, 1990). Analysis of alkaline Giemsa-stained plastic sections examined by light microscopy (Dvorak et al, J Exp Med 132:558, 1970), as well as by routine transmission electron microscopy, indicated that the mast cells in the inflammatory eyelid lesions were undergoing piecemeal degranulation, a form of secretion in which the cells' cytoplasmic granules exhibit characteristic morphologic changes that are thought to be associated with the prolonged, vesicle-mediated release of the granules' constituents. Moreover, by using a newly reported enzyme affinity-gold method, which stains histamine based on binding to diamine oxidase-gold (Dvorak et al, J Histochem Cytochem 41:787, 1993), we show that these activated mast cells had released much of their histamine content. The eyelid lesions also exhibited increased numbers of mast cells; interstitial fibrosis, particularly around cutaneous nerves and blood vessels; activated fibroblasts; focal axonal damage; venules with endothelial cells containing numerous vesiculo-vacuolar organelles; and infiltrates of neutrophils and eosinophils. Our findings illustrate that overexpression of the IL-4 gene in vivo can result in eyelid lesions associated with piecemeal degranulation of mast cells, as well as tissue fibrosis and a variety of other pathologic changes. These results also represent the first direct morphologic evidence for histamine secretion by mast cells in vivo. 相似文献
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89.
Mariline Santos Angela Reis Rego Joao Lino Miguel Coutinho Cecília Almeida Sousa 《中华耳科学杂志(英文版)》2021,16(1):18-21
Objective:To assess hyperacusis after stapedotomy and its possible influencing factors.Study design:Prospective,interventional,and longitudinal study.Setting:A tertiary referral center.Patients:Fifty consecutive patients(35 females,mean age=46.8 years).Intervention:All patients underwent stapedotomy.The validated Portuguese version of the“Hyperacusis Questionnaire”(HQ)was administered before and two weeks and one month after surgery.Results:No hyperacusis was reported by any patient before surgery.At two weeks after surgery,all patients experienced hyperacusis,with a mean HQ at 16.88±6.54(range 4e25).One month after surgery,hyperacusis had already resolved in most patients.Gender,preoperative presentation or surgeon had no influence on HQ scores(p>0.05).Patients with previous contralateral stapedotomy showed lower HQ scores(p=0.001).Audiological parameters improvement measured at one month after surgery(PTA,SRT and contralateral SRT)were associated with HQ higher scores.Conclusion:This study confirms that hyperacusis is a common complaint after stapedotomy that usually resolves in one month after surgery.The HQ highest scores were registered among patients with the highest audiological gain after surgery.This suggests that hyperacusis may be a positive prognostic factor for audiological success after stapedotomy. 相似文献
90.
Jorge Canena João Coimbra Diana Carvalho Catarina Rodrigues Mário Silva Mariana Costa David Horta António Mateus Dias Isabel Seves Gonçalo Ramos Leonel Ricardo António Pereira Coutinho Carlos Romão Pedro Mota Veiga 《Digestive diseases and sciences》2014,59(11):2779-2789