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101.
Soundararajan Krishnaswamy Su X Duan Lisa L Von Moltke David J Greenblatt Michael H Court 《Drug metabolism and disposition》2003,31(1):133-139
Investigation of human UDP-glucuronosyltransferase (UGT) isoforms has been limited by a lack of specific substrate probes. In this study serotonin was evaluated for use as a probe substrate for human UGT1A6 using recombinant human UGTs and tissue microsomes. Of the 10 commercially available recombinant UGT isoforms, only UGT1A6 catalyzed serotonin glucuronidation. Serotonin-UGT activity at 40 mM serotonin concentration varied more than 40-fold among human livers (n = 54), ranging from 0.77 to 32.9 nmol/min/mg of protein with a median activity of 7.1 nmol/min/mg of protein. Serotonin-UGT activity kinetics of representative human liver microsomes (n = 7) and pooled human kidney, intestinal and lung microsomes and recombinant human UGT1A6 typically followed one enzyme Michaelis-Menten kinetics. Serotonin glucuronidation activity in these human liver microsomes had widely varying V(max) values ranging from 0.62 to 51.3 nmol/min/mg of protein but very similar apparent K(m) values ranging from 5.2 to 8.8 mM. Pooled human kidney, intestine, and lung microsomes had V(max) values (mean +/- standard error of the estimates) of 8.8 +/- 0.4, 0.22 +/- 0.00, and 0.03 +/- 0.00 nmol/min/mg of protein (respectively) and apparent K(m) values of 6.5 +/- 0.9, 12.4 +/- 2.0, and 4.9 +/- 3.3 mM (respectively). In comparison, recombinant UGT1A6 had a V(max) of 4.5 +/- 0.1 nmol/min/mg of protein and an apparent K(m) of 5.0 +/- 0.4 mM. A highly significant correlation was found between immunoreactive UGT1A6 protein content and serotonin-UGT activity measured at 4 mM serotonin concentration in human liver microsomes (R(s) = 0.769; P < 0.001) (n = 52). In conclusion, these results indicate that serotonin is a highly selective in vitro probe substrate for human UGT1A6. 相似文献
102.
103.
Adhikary A Bothe E Jain V Von Sonntag C 《International journal of radiation biology》2000,76(9):1157-1166
PURPOSE: The DNA-minor-groove-ligands bisbenzimidazoles Hoechst 33258 and 33342 have been reported to protect against radiation-induced DNA-strand breakage. In order to elucidate the mechanisms of protection by these DNA-binding compounds, pulse radiolysis studies on the reactions of the OH radical, the solvated electron and the H atom with Hoechst as well as OH-radical-induced nucleotide radical quenching by free Hoechst (model level) was investigated. MATERIALS AND METHODS: The pulse radiolysis of Hoechst 33258 and 33342 was studied in N2O and N2O/O2-(4:1)-saturated aqueous solutions in the absence and presence of azide and bromide ions and nucleotides. RESULTS: In a fully scavenged system (3 x 10(-2) mol x dm(-3) t-butanol, N2O/O2-saturated), a transient is formed which in the presence of phosphate buffer is no longer observed. This is assigned metastable quinonoid forms of Hoechst (lambdamax(Hoechst) = 340; lambdamax(transient) = 370 nm) which is generated in protonation/ deprotonation reactions by H+/OH- formed during the pulse. To prevent their formation 10(-3) mol x dm(-3) phosphate buffer was added in all other experiments. The transient spectra formed upon OH-radical attack (k=9 x 10(9) dm3 x mol(-1) x s(-1)) indicate that a major part of the primary OH-adduct radicals undergo rapid transformation (k approximately 5 x 10(5) x s(-1)), attributed to water elimination yielding an N-centered radical. This intermediate, also generated by N3. (k = 4 x 10(9) dm3 mol(-1) x s(-1)), subsequently complexes with a Hoechst molecule [k = 8 x 10(8) dm3 x mol(-1) x s(-1) epsilon(440 nm) = 1.4 x 10(4) dm3 mol(-1) x cm(-1)]. The N-centered radical does not react with O2 (k < 5 x 10(5) dm3 mol(-1) x s(-1)), but reacts readily with the superoxide radical (k= 1.0 x 10(9) dm3 x mol(-1) x s(-1)). Hoechst reacts with the peroxyl radicals derived from uridine (k approximately 5 x 10(6) dm3 x mol(-1) x s(-1)) or 5'-UMP (k approximately 1 x 10(7) dm3 mol(-1) x (s-1)), but not with the less oxidizing (e.g. methylperoxyl radical) yielding intermediates whose spectral properties are similar to those of the N-centered radical. However, they decay at a much lower rate (2k approximately 1 x 10(8) dm3 mol(-1) x s(-1)) than the N-centered radicals generated by N3. (2k= 1.1 x 10(9) dm3 x mol(-1) s(-1)), and it has been suggested that these peroxyl radicals form adducts rather than undergoing electron transfer. The H atom (k= 7 x 10(9) dm3 x mol(-1) x s(-1)) and the solvated electron (k= 2.3 x 10(10) dm3 x mol(-1) x s(-1)) yield, albeit noticeably different, H-adduct radicals which also strongly absorb in the 440 nm region. The reduction potential of Hoechst 33258 has been determined electrochemically at 0.84-0.90 V vs. NHE at pH 6.8. CONCLUSION: Hoechst reacts fast only with strongly oxidizing radicals by electron transfer (e.g. with the adenine-and guanine-derived heteroatom-centered radicals), but also more slowly with nucleo-base-derived peroxyl radicals, here albeit via addition. This may have important implications with regard to its protection owing to DNA-radical quenching under oxic vs. anoxic conditions. 相似文献
104.
E Wayne Holden Elizabeth Grossman Hoang Thanh Nguyen Margaret J Gunter Becky Grebosky Ann Von Worley Leila Nelson Scott Robinson David J Thurman 《Disease management》2005,8(1):1-14
The goal of this study was to develop an algorithm for detecting epilepsy cases in managed care organizations (MCOs). A data set of potential epilepsy cases was constructed from an MCO's administrative data system for all health plan members continuously enrolled in the MCO for at least 1 year within the study period of July 1, 1996 through June 30, 1998. Epilepsy status was determined using medical record review for a sample of 617 cases. The best algorithm for detecting epilepsy cases was developed by examining combinations of diagnosis, diagnostic procedures, and medication use. The best algorithm derived in the exploratory phase was then applied to a new set of data from the same MCO covering the period of July 1, 1998 through June 30, 2000. A stratified sample based on ethnicity and age was drawn from the preliminary algorithm-identified epilepsy cases and non-cases. Medical record review was completed for 644 cases to determine the accuracy of the algorithm. Data from both phases were combined to permit refinement of logistic regression models and to provide more stable estimates of the parameters. The best model used diagnoses and antiepileptic drugs as predictors and had a positive predictive value of 84% (sensitivity 82%, specificity 94%). The best model correctly classified 90% of the cases. A stable algorithm that can be used to identify epilepsy patients within MCOs was developed. Implications for use of the algorithm in other health care settings are discussed. 相似文献
105.
106.
Monodeep Biswas Pranjal Kumar Boruah Lear Von Koch 《Indian Journal of Critical Care Medicine》2012,16(3):157-159
Accidental malposition of a chest tube in the pulmonary artery is a potentially fatal complication. Here we describe a 66 year-old obese woman with prior cardiac transplantation, intubated for respiratory failure and felt to have a large left pleural effusion. A chest tube was inserted using a trocar tube, and resulted in near-exsanguinating hemorrhage immediately, with development of hypovolemic shock. Prompt clamping of the tube proved life-saving, and CT scan confirmed placement of the tube in the main pulmonary artery. Initial stabilization, followed by a planned surgical approach, resulted in successful removal of the tube. 相似文献
107.
108.
S. Krishnaswamy S. X. Duan L. L. Von Moltke D. J. Greenblatt J. L. Sudmeier W. W. Bachovchin 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(2):169-180
1. The main purpose was to develop a high-performance liquid chromatography (HPLC)-based method to assay serotonin glucuronidation activity using liver microsomal fractions. Application of this method was then demonstrated by determining serotonin UDP-glucuronosyltransferase (UGT) enzyme kinetics using human liver microsomes and recombinant human UGT1A6. Interspecies differences were also evaluated using liver microsomes from 10 different mammalian species. 2. Incubation of liver microsomes with serotonin, UDP-glucuronic acid and magnesium resulted in the formation of a single product peak using HPLC with fluorescence and ultraviolet absorbance detection. This peak was confirmed as serotonin glucuronide based on sensitivity to β-glucuronidase and by obtaining the expected mass of 352 with positive-ion mass spectrometry. 3. Following a preparative HPLC isolation, the structure of this metabolite was established as serotonin-5- O -glucuronide by 1 H-NMR spectroscopy. 4. Enzyme kinetic studies showed apparent K m and V max of 8.8 ±0.3 mM and 43.4 ±0.4 nmoles min <1 mg <1 protein, respectively, for human liver microsomes, and 5.9 ±0.2 mM and 15.8 ±0.2 nmoles min <1 mg <1, respectively, for recombinant UGT1A6. 5. The order of serotonin-UGT activities in animal liver microsomes was rat > mouse > human > cow > pig > horse > dog > rabbit > monkey > ferret. Cat livers showed no serotonin-UGT activity. Heterozygous and homozygous mutant Gunn rat livers had 40 and 13%, respectively, of the activity of the normal Wistar rat, indicating a significant contribution by a rat UGT1A isoform to serotonin glucuronidation. 6. This assay provides a novel sensitive and specific technique for the measurement of serotonin-UGT activity in vitro. 相似文献
109.
Georgios Dimitrakakis Ulrich Otto Von Oppell Subramaniam Balachandran Agamemnon Pericleous Richard Anderson 《The International journal of angiology》2013,22(4):239-242
Coronary artery perforation is a known complication of percutaneous coronary intervention and potentially life threatening. Normally, these perforations are small and localized. We report the successful surgical management of a coronary artery perforation following stent insertion with extrusion of an 8-cm endarterectomy length of the circumflex coronary artery with a brief review of the recent literature. 相似文献
110.