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排序方式: 共有1423条查询结果,搜索用时 15 毫秒
81.
Våbenø J Lejon T Nielsen CU Steffansen B Chen W Ouyang H Borchardt RT Luthman K 《Journal of medicinal chemistry》2004,47(4):1060-1069
A series of five Phe-Gly dipeptidomimetics containing different amide bond replacements have been synthesized in a facile way from the readily available unsaturated ketoester 1, and their affinities for the di-/tripeptide transporters hPEPT1 (Caco-2 cells) and rPEPT2 (SKPT cells) were tested. The compounds contained the amide bond isosteres ketomethylene (2a), (R)- and (S)-hydroxyethylidene (3a and 4a), and (R)- and (S)-hydroxyethylene (5a and 6a) to provide information on the conformational and stereochemical requirements for hPEPT1 and rPEPT2 affinity. The affinity studies showed that for rPEPT2 there is no significant difference in affinity between the ketomethylene isostere 2a and the natural substrate Phe-Gly (K(i) values of 18.8 and 14.6 microM, respectively). Also the affinities for hPEPT1 are in the same range (K(i) values of 0.40 and 0.20 mM, respectively). This corroborates earlier findings that the amide bond as such is not essential for binding to PEPTX, but the results also reveal possible differences in the binding of ketomethylene isosteres to hPEPT1 and rPEPT2. The trans-hydroxyethylidene and hydroxyethylene isosteres proved to be poor substrates for PEPTX. These results provide new information about the importance of flexibility and of the stereochemistry at the C(4)-position for this class of compounds. Furthermore, the intracellular uptake of 2a-4a in Caco-2 cells was investigated, showing a 3-fold reduction of the uptake of 2a in the presence of the competetive inhibitor Gly-Pro, indicating contribution from an active transport component. No active uptake of 3a and 4a was observed. Transepithelial transport studies also indicated active transport of 2a across Caco-2 monolayers. 相似文献
82.
Teriparatide (biosynthetic human parathyroid hormone 1-34): a new paradigm in the treatment of osteoporosis 总被引:7,自引:0,他引:7
Brixen KT Christensen PM Ejersted C Langdahl BL 《Basic & clinical pharmacology & toxicology》2004,94(6):260-270
The ideal treatment of osteoporosis should preferably prevent fractures through normalization of bone mass and bone micro-architecture. Biosynthetic human parathyroid hormone 1-34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2-3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 microg/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecules targeted at the parathyroid hormone receptor may be envisaged. 相似文献
83.
Drøjdahl N Fenger C Nielsen HH Owens T Finsen B 《Journal of neuroscience research》2004,75(2):203-217
The inflammatory cytokine tumour necrosis factor (TNF) can both induce oligodendrocyte and myelin pathology and promote proliferation of oligodendrocyte progenitor cells and remyelination. We have compared the response of the oligodendrocyte lineage to anterograde axonal (Wallerian) and terminal degeneration and lesion-induced axonal sprouting in the hippocampal dentate gyrus in TNF-transgenic mice with the response in genetically normal mice. Transectioning of the entorhino-dentate perforant path axonal projection increased hippocampal TNF mRNA expression in both types of mice, but to significantly larger levels in the TNF-transgenics. At 5 days after axonal transection, numbers of oligodendrocytes and myelin basic protein (MBP) mRNA expression in the denervated dentate gyrus in TNF-transgenic mice had increased to the same extent as in nontransgenic littermates. At this time, transgenics showed a tendency towards a greater increase in the number of juxtaposed, potentially proliferating oligodendrocytes. Noteworthy, at day 5 we also observed upregulation of MBP mRNA expression in adjacent hippocampal subregions with lesion-induced axonal sprouting, which were devoid of axonal degeneration, raising the possibility that sprouting axons provide trophic stimuli to the oligodendrocyte lineage. Twenty-eight days after lesioning, oligodendrocyte numbers and MBP mRNA expression were reduced to near normal levels. However, oligodendrocyte densities in the TNF-transgenic mice were significantly lower than in nontransgenics. We conclude that the early response of the oligodendrocyte lineage to axonal lesioning and lesion-induced axonal sprouting appears unaffected by the supranormal TNF levels in the TNF-transgenic mice. TNF may, however, have long-term inhibitory effects on the oligodendrocyte response to axonal lesioning. 相似文献
84.
Previous studies have found that the primary change in the brain of chronic alcoholics is a selective loss of white matter in cerebral hemispheres. It is unknown whether the loss of white matter is due to alcohol-induced degeneration of axons in white matter, and this hypothesis has never been tested. We used a newly developed stereological method to investigate whether the length and diameter of myelinated fibres change in the subcortical white matter of male alcoholic subjects. We found no significant differences between control and alcoholic subjects with respect to the total volume, total length, and mean diameter of myelinated fibres in white matter. Our results do not find any support for the hypothesis that chronic alcoholic subjects may suffer from a degeneration of axons (myelinated fibres) in white matter in cerebral hemispheres. 相似文献
85.
A role for interferon-gamma in focal cerebral ischemia in mice 总被引:6,自引:0,他引:6
Lambertsen KL Gregersen R Meldgaard M Clausen BH Heibøl EK Ladeby R Knudsen J Frandsen A Owens T Finsen B 《Journal of neuropathology and experimental neurology》2004,63(9):942-955
The pro-inflammatory cytokine interferon-gamma (IFNgamma) has traditionally been associated with inflammatory CNS disease and more recently with ischemia-induced pathology. Using a murine model of focal cerebral ischemia, we found no evidence for induction of IFNgamma mRNA after permanent middle cerebral artery occlusion. In addition, we found that mice deficient in IFNgamma or IFNgamma receptors developed neocortical infarcts similar in size to those in wild type. In contrast, MBP promoter-IFNgamma-transgenic mice consistently developed significantly larger infarcts than non-transgenic mice. Because IFNgamma is a potent activator of microglia-macrophages, we investigated the involvement of microglial-macrophage-derived TNF in the larger infarcts. Numbers of TNF mRNA-expressing microglia-macrophages and levels of TNF mRNA and TNF in IFNgamma-transgenic and non-transgenic mice were similar. Furthermore, the ischemic brain damage in IFN-gamma-transgenic mice was unaffected by recombinant soluble TNF receptor I. Taken together, the data argues against a role for IFNgamma in cerebral ischemia under normal conditions. However, when present, IFNgamma significantly exacerbates ischemia-induced brain damage by mechanisms that appear to be independent of TNF or synergistic neurotoxic interactions of IFNgamma and TNF Irrespective of the mechanism(s) involved, this enhancing effect of IFNgamma on ischemia-induced neurotoxicity may need to be considered in diseases where immune IFNgamma is involved, such as multiple sclerosis. 相似文献
86.
Age-related inflammatory cytokines and disease 总被引:7,自引:0,他引:7
Aging is associated with chronic low-grade increases in circulating levels of inflammatory markers. A wide range of environmental factors, including smoking, infections, and obesity, genetic factors, and the declining function of sex hormones may contribute to systemic low-grade inflammatory activity in older individuals. Age-associated disease may exacerbate this phenomenon. The multifunctional cytokines TNF-alpha and IL-6 have been associated with morbidity and mortality in the elderly. Evidence supports the direct role of TNF-alpha in the pathogeneses of atherosclerosis, type 2 DM, and AD in older individuals. Age-related increases in systemic levels of TNF-alpha could provide a unifying basis for these disorders. Furthermore, TNF-alpha induces a catabolic state that causes frailty. Circulating levels of IL-6 seem to be a strong risk factor for frailty in the elderly, which could reflect its association with increased production of TNF-alpha. IL-6 also may be a risk factor for thromboembolic complications. In healthy, elderly populations, high circulating levels of TNF-alpha and IL-6 predict mortality, independent of comorbidity, indicating that TNF-alpha and IL-6 cause morbidity and mortality. In cohorts of frail, older individuals, TNF-alpha and IL-6 also act as disease markers. Circulating levels of TNF-alpha seem to be the best predictor of mortality in frail, elderly populations with a high mortality rate, whereas IL-6 seems to be the strongest risk marker in healthy, elderly populations. This finding could reflect that in relatively healthy old populations the increase in circulating levels of IL-6 represent a systemic response to local proinflammatory activities; however, when age-related inflammatory diseases progress, levels of TNF-alpha increase in the circulation and become gradually a stronger risk marker than IL-6. In conclusion low-grade elevations in levels of circulating cytokines are strong independent risk factors of morbidity and mortality in the elderly, and lifestyle factors and comorbidities may modulate these levels. Exercise and dietary interventions may be possible strategies to decrease inflammatory activity and improve the health status of the elderly. 相似文献
87.
Serakinci N Østergaard M Larsen H Madsen B Pedersen B Koch J 《Cancer Genetics and Cytogenetics》2002,138(1):11-16
Bone marrow samples from a pancytopenia/leukemia patient were routinely analyzed at first and second admission. At the first presentation, the karyotype was normal, whereas 17 months later several chromosome aberrations were recognized including presumed additions to the short arms of chromosomes 1 and 16 in all cells, and numerous other aberrations in subpopulations of cells. From the predominance of aberrations at chromosome ends, we suspected insufficient telomere maintenance as an underlying mechanism behind the karyotype changes, in particular as an interstitial deletion in the region harboring the gene for the RNA component (hTERC) of the telomerase enzyme was also noticed; however, while molecular cytogenetic investigation confirmed the terminal aberrations, we found the malignant cells positive for telomerase activity and the presence of an hTERC gene on both chromosomes 3. A presumed chromosome 1 addition turned out to reflect an amplification of a tandemly repeated sequence element. Labeling of multiple tandem repeat sequences in situ by a novel multicolor primed in situ hybridization showed no evidence of instability of other repeated DNA elements. 相似文献
88.
Bente K Schaadt Helle W Hendel Peter Gimsing Viggo J?nsson Heidi Pedersen Birger Hesse 《Journal of nuclear medicine》2003,44(2):177-183
Changes in the amount and distribution of amyloid lesions have been difficult to monitor because they can usually be demonstrated only by evident symptoms or from a biopsy. The recent progress in the treatment of amyloidosis stresses the need for an early diagnosis and the need for noninvasive monitoring during the course of treatment. To validate (99m)Tc-aprotinin scintigraphy, we studied 23 consecutive patients with known or suspected amyloidosis. METHODS: (99m)Tc-Aprotinin (500-700 MBq) was injected intravenously and whole-body scans, regional images, and SPECT tomograms were obtained 90 min after tracer injection. RESULTS: Focal accumulations of (99m)Tc-aprotinin were seen in different organs of 22 patients with a total of 90 lesions, of which 20 were confirmed by biopsy or autopsy. Scintigraphy revealed "silent" amyloid deposits in at least 5 patients who later developed clinical symptoms. Physiologic uptake or excretion in liver and kidneys could not be differentiated from pathologic lesions in those organs. CONCLUSION: (99m)Tc-Aprotinin scintigraphy appears to be a fairly sensitive and specific diagnostic modality in patients with suspected amyloidosis. The technique is noninvasive, and it entails a minimal stress to the patient and is useful for detection of a wide range of lesions. 相似文献
89.
90.
Bruunsgaard H Poulsen HE Pedersen BK Nyyssönen K Kaikkonen J Salonen JT 《The Journal of nutrition》2003,133(4):1170-1173
Inflammatory and oxidative stresses play a pivotal role in atherogenesis. Vitamin E and vitamin C are the two most important dietary antioxidants; moreover, vitamin E has anti-inflammatory effects. Combined supplementations with vitamin E and vitamin C twice daily for 3 y reduced lipid peroxidation and retarded the progression of common carotid atherosclerosis in healthy men in the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. To further elucidate the underlying mechanisms that retarded the progression of atherosclerosis in the ASAP study, we investigated the effect of a combined intake of vitamin E and vitamin C on inflammatory markers in vivo. Circulating levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and C reactive protein (CRP) were measured in 45- to 69-y-old men from the ASAP study with cholesterol >5.0 mmol/L before and after treatment with either placebo (n = 52) or a combined supplementation with 91 mg (136 IU) alpha-tocopherol and 250 mg of slow-release vitamin C twice a day (n = 55) for 3 y. Antioxidant treatment for 36 mo had no effect on circulating levels of TNF-alpha, IL-6 or CRP. In conclusion, long-term combined supplementations with alpha-tocopherol and vitamin C in reasonable doses have no detectable systemic anti-inflammatory effects in a healthy population of men with slight hypercholesterolemia and no overt signs of inflammation. 相似文献