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991.
Janet Martin Stephen M. Stribbling Grace K. Poon Richard H. J. Begent Mark Napier Surinder K. Sharma C. J. Springer 《Cancer chemotherapy and pharmacology》1997,40(3):189-201
Antibody-directed enzyme prodrug therapy (ADEPT) was administered to ten patients in a phase I clinical trial. The aim was
to measure plasma levels of the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-l-glutamic acid (CMDA) and the bifunctional alkylating drug (CJS11) released from it by the action of tumour-localised carboxypeptidase
G2 (CPG2) enzyme. New techniques were developed to extract the prodrug and drug from plasma by solid-phase adsorbtion and
elution and to measure CPG2 activity in plasma and tissue. All extracts were analysed by high-performance liquid chromatography
(HPLC) and liquid chromatography-mass spectrometry (LC-MS). CPG2 activity was found in metastatic tumour biopsies but not
in normal tissue, indicating that localisation had been successful. The clearing agent SB43-gal, given at 46.5 mg/m2, achieved the aim of clearing non-tumour-localised enzyme in the circulation, indicating that conversion of prodrug to drug
could take place only at the site of localised conjugate. Plasma prodrug did not always remain above its required threshold
of 3 μM for the “therapeutic window” of 120 min after dosing, but the presence of residual prodrug after the first administration
of each day indicated that this could be achieved during the remaining four doses over the following 8 h. Despite considerable
inter-patient prodrug plasma concentration variability, the elimination half-life of the prodrug was remarkably reproducible
at 18 ± 8 min. Rapid appearance of the drug in plasma indicated that successful conversion from the prodrug had taken place,
but also undesirable leakback from the site of localisation into the bloodstream. However, drug plasma levels fell rapidly
by at least 50% at between 10 and 60 min with a half-life of 36 ± 14 min. Analysis of the plasma extracts by LC/MS indicated
that this technique might be used to confirm qualitatively the presence of prodrug, drug and their metabolites.
Received: 21 July 1996 / Accepted: 20 January 1997 相似文献
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995.
Wei Yue Steven J. Santner Shigeru Masamura Ji-Ping Wang Laurence M. Demers Christopher Hamilton Richard J. Santen 《Breast cancer research and treatment》1998,49(1):S1-S7
Estradiol stimulates the growth of breast tumor cells in both pre- and post menopausal women. Following the menopause, the levels of estradiol in breast tumor tissues are similar to those from tumors obtained prior to cessation of ovarian function, even though plasma estrogen levels are 10–50 fold lower in post- than in premenopausal women. These observations suggested the possibility of enhanced estradiol uptake from plasma or in situ synthesis in post-menopausal women. We systematically studied these possibilities in a series of model systems. Initially we demonstrated a very high affinity estradiol binding site in tissues from castrated rats. Enhanced uptake occurred under conditions of low plasma estrogen levels when compared to animals with higher estradiol levels. In situ synthesis also occurred both through the sulfatase and aromatase pathways. In further studies, we compared uptake from plasma with in situ synthesis via aromatase in a nude mouse model. Under the conditions utilized, in situ synthesis resulted in much higher tissue estradiol levels and tumor growth rates than did uptake from plasma. During these studies we demonstrated that tumors deprived of estradiol developed mechanisms rendering them more sensitive to estrogen. This involved the ability of cells to adapt to estradiol deprivation to allow them to be responsive to four log lower amounts of estrogen than when studied under wild type conditions. In addition, cells adapted by increasing their level of aromatase and thus developing the capability to become more sensitive to estrogen precursors. Taken together, these studies demonstrate that breast cancer tissue is highly plastic and can adapt to conditions of estrogen deprivation via a variety of mechanisms. 相似文献
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997.
Ruan Sanbao Fuller Greg Levin Victor Bruner Janet M. Zhang Wei 《Journal of neuro-oncology》1998,37(3):223-228
The p21WAF1/Cip1 (p21) protein, a negative regulator of G1 checkpoint control, was overexpressed in the majority of human gliomas. To investigate whether p21 expression in brain metastases from various systemic origins is similar to that in gliomas and whether p21 expression is regulated differently in brain metastases and in corresponding primary tumors, we used immunohistochemical staining to examine the expression of p21 in paraffin-embedded sections prepared from primary colon and breast carcinomas and from metastatic brain tumors that originated from colon, breast, lung, and kidney cancers and from melanoma. Our results showed that 56% (28 of 50) of the brain metastases samples have more than 1% p21-positive staining cells compared with 87% of primary gliomas reported previously. Among the samples analyzed, p21 expression in brain metastases from breast carcinomas was much higher than in primary breast carcinomas. In contrast, p21 expression in brain metastases from colon carcinomas was less than primary colon carcinomas. The results from this pilot study suggest that p21 expression is regulated differently in metastatic and primary tumors. 相似文献
998.
Dietary factors and the risk of squamous cell esophageal cancer among black and white men in the United States 总被引:4,自引:0,他引:4
Linda Morris Brown Christine A. Swanson Gloria Gridley G. Marie Swanson Debra T. Silverman Raymond S. Greenberg Richard B. Hayes Janet B. Schoenberg Linda M. Pottern Ann G. Schwartz Jonathan M. Liff Robert Hoover Joseph F. Fraumeni 《Cancer causes & control : CCC》1998,9(5):467-474
Objectives: To investigate dietary factors for squamous cell esophageal cancer and whether these factors may contribute to the five-fold higher incidence of this cancer in the black versus white population of the United States.Methods: Data from a food frequency questionnaire were analyzed for 114 white men and 219 black men with squamous cell esophageal cancer, and 681 white and 557 black male controls from three areas of the United States who participated in a population-based case-control study of esophageal cancer.Results: Protective effects were associated with intake of raw fruits and vegetables (odds ratio for high versus low consumers=0.3 in both white and black men) and use of vitamin supplements (especially vitamin C; odds ratio for high versus low consumers=0.4 in both races), with the frequency of consumption of raw fruits and vegetables and vitamin supplements being greater for white than black controls. In addition, elevated risks were associated with high versus low intake of red meat (OR=2.7 for blacks and 1.5 for whites) and processed meat (OR=1.6 for blacks and 1.7 for whites), with the levels of consumption being greater for black than white controls.Conclusions: In the United States, these dietary factors may contribute in part to the much higher incidence of squamous cell esophageal cancer among black compared to white men. 相似文献
999.
Plasma from pre-eclamptic women and functional change in myometrial resistance arteries 总被引:1,自引:0,他引:1
Janet R. Ashworth Specialist Registrar Averil Y. Warren Chief Technician Ian R. Johnson Professor Philip N. Baker Senior Lecturer 《BJOG : an international journal of obstetrics and gynaecology》1998,105(4):459-461
This study assesses the ability of plasma from women with pre-eclampsia to induce altered endothelial function in myometrial resistance vessels from normotensive women. Vessels from normotensive pregnant women (n= 7) were incubated with plasma from other pregnant women who were normotensive (n= 6)or had pre-eclampsia (n= 7). A wire myograph was used to test the endothelium-dependent relaxatory response to bradykinin of preconstricted vessels. The relaxation in vessels incubated with plasma from women with pre-eclampsia was markedly less than in vessels incubated with plasma from normotensive pregnant women ( P = 0.039 ). This supports the theory that a plasma-borne factor contributes to the endothelial changes seen in pre-eclampsia. 相似文献
1000.
OBJECTIVE: To test a quality improvement approach called COPE (Client-Oriented, Provider-Efficient services), for use in strengthening health systems and supporting Integrated Management of Child Health (IMCI) efforts. DESIGN: Pre- and post-intervention observations of client/provider interactions, facility audits, staff and client surveys, and focus groups to evaluate differences between eight COPE intervention and eight matched non-intervention facilities after a 15-month intervention in 2001. SETTING: Primary care clinics in Guinea and Kenya. STUDY PARTICIPANTS: Health care providers and child caregivers. INTERVENTIONS: Over 15 months, the intervention supported four COPE exercises at each intervention site, supported supervisor training in quality management, and organized minimal training in topics selected by site staff as areas where training was needed. MAIN OUTCOME MEASURES: Differences in staff's and child caregiver's knowledge, attitudes, and practices; differences in the quality of services provided. RESULTS: On almost every quality indicator (over 65 indicators), whether reported by staff, observed by evaluators, or reported by clients, the intervention sites performed statistically significantly better than control sites. INTERVENTION: sites were cleaner and more pleasant, with more respect and information for clients, and more privacy. Staff had better personal communication skills, better diagnostic skills, and prescribing practices and gave better home care instructions to carers. Clients in intervention sites were more informed and more satisfied, and their children had better immunization coverage than those in control sites. CONCLUSION: COPE is a simple process, yet our study confirms that it can have a very dramatic effect on the quality of services. This study demonstrated how all areas of quality can be addressed by empowering health care providers to take action by using COPE. We suggest that COPE can complement Integrated Management of Childhood Illness (IMCI) training and can help to achieve better health for children. 相似文献