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11.
Background We studied the relationship between the augmentative effects of leucovorin (LV) on 5-fluorouracil (5-FU) and the inhibition rate of thymidylate synthase (TS) activity in Colon 26 murine colon carcinoma cells and L1210 murine leukemia cells. Methods In cytotoxic and TS inhibition studies, cells were exposed for 24 hours to varied concentrations of 5-FU alone or in combination with 1 or 10 μmol/L LV. Cytotoxicity was determined by colony forming efficiency or trypan blue dye exclusion, and TS inhibition rate was determined by [6-3H]-5-FdUMP binding assay. A growth inhibition curve was constructed for longer exposures. Results For tumor cell growth inhibition and cytotoxicity, the augmentative effect was observed when the lower 5-FU concentrations (0.1 μg/mL) were used. There was no difference in the effects between the low (1 μmol/L) and high (10 μmol/L) LV doses. Normally, TS enzyme levels rise acutely when cells are exposed to 5-FU. Both cell lines displayed an increase in TS after exposure to 5-FU. This exposure to 5-FU resulted in the maintenance of free enzyme. LV was able to increase the ternary complex and TS inhibition rate with little induction of TS, however, the inhibition rate was not dependent on doses of LV. Conclusions It was concluded that the augmentative effect of LV at a concentration of 0.1 μg/mL 5-FU occurred at the clinically achievable levels of 1 μmol/L of LV, and there was no difference in the effect between the low and high doses. TS was inhibited effectively by 5-FU and the addition of LV, without a marked induction of TS.  相似文献   
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Some mixed hyperplastic adenomatous polyps (MHAPs) contain dysplastic lesions or even carcinomas. These polyps are considered to be different from ordinary hyperplastic polyps and may have a preneoplastic potential. We investigated APC and K- ras mutations in MHAPs of the colon and rectum, and also in colorectal adenomas and hyperplastic polyps to identify molecular differences between MHAPs, adenomas and hyperplastic polyps, using direct sequencing of mutation cluster regions (MCR) in APC and K- ras . No APC mutations were identified in 12 MHAPs and 8 hyperplastic polyps, whereas 10 of 27 (37.0%) adenomas showed somatic mutations. K- ras mutations were identified in one of 12 (8.3%) MHAPs, one of 8 (12.5%) hyperplastic polyps, and 10 of 27 (37.0%) adenomas. p53 mutation was found in a carcinoma arising in an MHAP. Mutations other than APC mutations may play a role in the development of MHAPs.  相似文献   
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Long-term toluene abuse causes a variety of psychiatric symptoms. However, little is known about abnormalities at the neurochemical level in the living human brain after long-term exposure to toluene. To detect neurochemical changes in the basal ganglia of subjects with a history of long-term toluene use, proton magnetic resonance spectroscopy (1H MRS) was performed in 12 abstinent toluene users and 13 healthy comparisons with no history of drug abuse. N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr + PCr), choline-containing compounds (Cho), and myo-inositol (MI) levels were measured in the left and right basal ganglia. The Cho/Cr + PCr ratio, a marker of membrane metabolism, was significantly increased in the basal ganglia of toluene users in comparison to that of the control subjects. Furthermore, the increase in the Cho/Cr + PCr ratio was significantly correlated with the severity of residual psychiatric symptoms. These findings suggest that long-term toluene use causes membrane disturbance in the basal ganglia, which is associated with residual psychiatric symptoms that persist even after long-term abstinence from toluene use.  相似文献   
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Diabetes mellitus is known to exacerbate cerebral ischemic injury. In the present study, we investigated antiapoptotic and anti-inflammatory effects of oral supplementation of ascorbic acid (AA) on cerebral injury caused by middle cerebral artery occlusion and reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. We also evaluated the effects of AA on expression of sodium-dependent vitamin C transporter 2 (SVCT2) and glucose transporter 1 (GLUT1) after MCAO/Re in the brain. The diabetic state markedly aggravated MCAO/Re-induced cerebral damage, as assessed by infarct volume and edema. Pretreatment with AA (100 mg/kg, p.o.) for two weeks significantly suppressed the exacerbation of damage in the brain of diabetic rats. AA also suppressed the production of superoxide radical, activation of caspase-3, and expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) in the ischemic penumbra. Immunohistochemical staining revealed that expression of SVCT2 was upregulated primarily in neurons and capillary endothelial cells after MCAO/Re in the nondiabetic cortex, accompanied by an increase in total AA (AA + dehydroascorbic acid) in the tissue, and that these responses were suppressed in the diabetic rats. AA supplementation to the diabetic rats restored these responses to the levels of the nondiabetic rats. Furthermore, AA markedly upregulated the basal expression of GLUT1 in endothelial cells of nondiabetic and diabetic cortex, which did not affect total AA levels in the cortex. These results suggest that daily intake of AA attenuates the exacerbation of cerebral ischemic injury in a diabetic state, which may be attributed to anti-apoptotic and anti-inflammatory effects via the improvement of augmented oxidative stress in the brain. AA supplementation may protect endothelial function against the exacerbated ischemic oxidative injury in the diabetic state and improve AA transport through SVCT2 in the cortex.  相似文献   
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The Epstein-Barr virus (EBV) infection is known to result in infectious mononucleosis, hemophagocytic syndrome, chronic active EBV infection, and lymphoma. Among them, hemophagocytic syndrome sometimes causes thrombocytopenia, which is often life threatening because of its hemorrhagic complications such as gastrointestinal bleeding and pulmonary alveolar hemorrhage. A young adult case of critical hemophagocytic syndrome after primary EBV infection is presented. Chemotherapy was performed using methyl prednisolone succinate, prednisolone, cyclosporin A, and 20 mg/kg of cyclophosphamide. The patient received intensive care, including plasma exchange for hepatic failure, extracorporeal membrane oxygenation for acute respiratory failure, and splenectomy for hemophagocytosis; however, the patient died of multiple organ failure, including fulminant hepatic failure. The pathologic examination of the resected specimen demonstrated infiltrated macrophages containing many phagocytosed erythrocytes. Further immunopathologic examination of these cells showed that the histiocyte markers were positive, whereas the T-cell marker was negative. In view of these findings, definite diagnosis of EBV-related hemophagocytic lymphohistiocytosis could not be made at that time. The immunohistologic examinations on the liver necropsy specimen provided the evidences suggesting the morbid activation of the hepatic stellate macrophage by EBV-infected T/NK cells and subsequent apoptosis induction of the liver cells through the Fas ligand pathway.  相似文献   
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