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101.
Filho SB Gargioni C Silva Pinto PL Chiodelli SG Gurgel Vellosa SA da Silva RM da Silveira MA 《International journal of pharmaceutics》2002,233(1-2):35-41
Oxamniquine derivatives were synthesized and evaluated as novel schistosomicide agents. Oxamniquine (1,2,3,4-tetrahydro-2-[[(1-methylethyl)amino]methyl]-7-nitro-6-quinolinemethanol) was submitted to the Mannich reaction, using formaldehyde, paraformaldehyde and acetaldehyde as reagents, and gave three unexpected products: two of them were cyclized on the alkylamine side chain and another etherified on the aminequinolinemethanol group. The three compounds were biologically evaluated using mice infected with Schistosoma mansoni and showed promising activities, but had higher toxicities. For studies on structure-activity relationships, results demonstrate that the side alkylamine group can be modified with preserved activity, but that this modification is associated with increased toxicity. 相似文献
102.
Fiege M Wappler F Weisshorn R Ulrich Gerbershagen M Steinfath M Schulte Am Esch J 《Anesthesiology》2002,97(2):345-350
BACKGROUND: More than 20 mutations in the gene encoding for the ryanodine receptor (RYR1), a Ca2+ release channel of the skeletal muscle sarcoplasmic reticulum, have been found to be associated with malignant hyperthermia (MH). This study was designed to investigate the effects of different mutations in the RYR1 gene on contracture development in in vitro contracture tests (IVCT) with halothane, caffeine, and ryanodine. METHODS: Ninety-three MH-susceptible (MHS) patients, diagnosed by the standard IVCT with halothane and caffeine, were included in this prospective study. Surplus muscle specimens were used for an IVCT with 1 microm ryanodine. The contracture course during the ryanodine IVCT was described by the attainment of different time points: onset time of contracture and times when contracture reached 2 mN or 10 mN. In addition, all patients were screened for mutations of the RYR1 gene. RESULTS: In 36 patients, four different mutations of the RYR1 gene (C487-T, G1021-A, C1840-T, G7300-A) were found. The IVCT threshold concentrations of halothane and caffeine were lower in patients with the C487-T mutation compared with patients without a detected mutation in the RYR1 gene. In the IVCT with ryanodine, contracture levels of 2 mN and 10 mN were reached earlier in muscle specimens from patients with C487-T, C1840-T, and G7300-A mutations compared with specimens from patients with the G1021-A mutation and patients without detected mutation in the RYR1 gene. CONCLUSIONS: The differences between the groups in the halothane and caffeine IVCT threshold concentrations and in the time course of contracture development in the ryanodine IVCT underline the hypothesis that certain mutations in the RYR1 gene could make the ryanodine receptor more sensitive to specific ligands. This may be an explanation for varying clinical symptoms of MH crisis in humans. 相似文献
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This work synthesizes the authors' views on the damages to the development of human capital in health services, which are caused by the disregard to the human spiritual dimension. New administration paradigms related to the development of spirituality are pointed out. Considering that the spiritual dimension has a systemic nature and that, by means of ethics and esthetics, it harmonizes all of man's dimensions in his relationships with others, the authors aim at approaching the spiritual value as fundamental for the re-humanization of the managing nurse's job. They recommend the integration of the spiritual dimension to the daily work of such professional as a determinant factor for a new performance as well as an inductor for nurses' better personal and professional life quality. 相似文献
107.
Lansiaux A Tanious F Mishal Z Dassonneville L Kumar A Stephens CE Hu Q Wilson WD Boykin DW Bailly C 《Cancer research》2002,62(24):7219-7229
Diphenylfuran diamidines represent an important class of DNA minor groove binders of high therapeutic interest as antiparasitic or antitumor agents depending on the compounds structures. To exert their cytotoxic action, the compounds must first get into the cell and reach the nuclear compartment where the main target, DNA, is located. The forces that drive the drugs into cell nuclei, as well as the influence of the molecular structures on the cell distribution, are not known. To address these issues, we took advantage of the fluorescence of the molecules to analyze their intracellular distribution profiles in tumor cells of different origins (B16 melanoma, MCF7 mammary adenocarcinoma, A549 lung carcinoma, HT29 colon carcinoma, LNCaP, and PC3 prostatic carcinoma) by epifluorescence and confocal microscopy. A homogeneous series of synthetic bis-substituted alkyl or phenyl amidine and reverse amidine derivatives of furamidine was used to dissect the molecular mechanisms that control the distribution of the drugs into the cytoplasm or the nucleus of the cells. The amidine (DB75) and the various N-alkyl derivatives were found to accumulate selectively in the cell nuclei. This is also the case for a guanidine derivative but not for the phenyl-substituted compound DB569, which essentially localizes in cytoplasmic granules. Similar cytoplasmic patterns were observed with a reverse amidine analogue and a pyridine-substituted compound indicating that the presence of aromatic rings on the terminal side chain is the limiting factor that restricts the uptake of the compounds in the nuclear compartment. The use of different organelle-selective fluorescent probes, such as JC-1 and chloromethyl-X-rosamine, both specific to mitochondria and neutral red considered as a lysosome-selective probe, suggests that DB569 preferentially accumulates in mitochondria. Competition experiments with the antitumor drug daunomycin reveal that the diphenylfurans are attracted into the nuclei by the DNA. The DNA minor groove-drug interactions provide the driving force that permits massive accumulation of the fluorescent molecules in the nuclei. The DNA binding properties of the diphenylfuran derivatives were investigated by DNase I footprinting and surface plasmon resonance biosensor experiments to measure sequence selectivity and binding affinities, respectively. Furamidine and its phenyl-substituted analogue that accumulate in the cell nuclei and mitochondria, respectively, share a common selectivity for AT sites and bind equally tightly to these sites. Therefore, it is possible to modulate the intracellular distribution of the furamidine derivatives without affecting their DNA binding and sequence recognition properties. The introduction of aromatic substituents on diphenylfuran diamidines represents a novel strategy to control the intracellular compartmentalization of these DNA binding agents and directs them to mitochondria. This drug design strategy may prove useful to trigger drug-induced apoptosis. 相似文献
108.
Sleep and epilepsy share some common mechanisms. The objective of the present investigation was to study the macrostructure of sleep in patients with idiopathic epilepsies, focal and generalized, comparing these two groups to each other and to a control group of 12 individuals without epilepsy. A total of 35 polysomnographies were performed, 12 of them in the control group, 10 in patients with idiopathic generalized epilepsies, and 13 in patients with idiopathic focal epilepsies. Antiepileptic medications were maintained for ethical reasons. The group with idiopathic focal epilepsy showed an increase in the total recording time (p = 0.04) and the group with idiopathic generalized epilepsy had a reduction of phase 4 NREM sleep. The efficiency of total sleep period and of total sleep time was also lower in the group with idiopathic generalized epilepsy (p = 0.03 in both cases). We concluded that the group with idiopathic generalized epilepsy presents sleep of poorer quality, whereas the group with idiopathic focal epilepsy presents a tendency toward an excessive somnolence. 相似文献
109.
Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. 总被引:7,自引:0,他引:7
110.
Mucinous carcinomas of the colorectum have distinct molecular genetic characteristics 总被引:2,自引:0,他引:2
Song GA Deng G Bell I Kakar S Sleisenger MH Kim YS 《International journal of oncology》2005,26(3):745-750
We compared the frequency of CpG island methylation phenotype (CIMP), inactivation of APC, p53 and DCC genes and K-ras and BRAF mutations in 39 mucinous carcinomas (MC) and 34 non-mucinous carcinomas (NMC) of the colorectum with different microsatellite instability (MSI) status. The higher incidence of MSI (36% vs. 18%) was observed in MC compared with NMC. APC inactivation and K-ras mutations occurred more frequently in NMC (APC, 88%, p<0.001; K-ras, 58%, p=0.01) than in MC (APC, 24%; K-ras, 28%) regardless of MSI status. BRAF mutation occurred at a higher frequency in MC (18%, p=0.01) than in NMC (0%). However, with respect to inactivation of p53 and DCC, MSI status did matter and in both NMC and MC, more frequent inactivation of p53 and DCC was observed in MSS tumors than in MSI tumors. MSS tumors of NMC had a higher frequency of p53 (58% by IHC, p=0.03 and 83% by LOH, p=0.02) and DCC inactivation (83%, p=0.02) compared to MSI tumors of NMC (p53, 33% by IHC and 20% by LOH; DCC, 20%). MSS tumors of MC also showed a higher frequency of p53 and DCC inactivation (p53, 45% by IHC, p=0.02 and 53% by LOH, p=0.005; DCC, 82%, p=0.001) compared to MSI tumors of MC (p53, 0% by IHC and 0% for LOH; DCC, 17%). MC showed a higher frequency of CIMP compared with NMC (41% vs. 11%, p=0.01). These results indicate that mucinous carcinomas of the colorectum exhibit distinct molecular genetic characteristics and may arise from distinct pathogenic pathways. 相似文献