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91.
ZK 91296, a partial agonist at benzodiazepine receptors 总被引:2,自引:0,他引:2
Petersen Erling N. Jensen Leif H. Honoré Tage Braestrup Claus Kehr Wolfgang Stephens David N. Wachtel Helmuth Seidelman Dieter Schmiechen Ralph 《Psychopharmacology》1984,83(3):240-248
ZK 91296 (ethyl 5-benzyloxy-4-methoxymethyl--carboline-3-carboxylate) is a potent and selective ligand for benzodiazepine (BZ) receptors. Biochemical investigations indicate that ZK 91296 may be a partial agonist at BZ receptors. Such partial agonism may explain to some extent why ZK 91296 needs higher BZ receptor occupancy than diazepam for the same effect against chemical convulsants and for behavioural effects. The lack of sedatiye effects, and the very potent inhibition of reflex epilepsy, spontaneous epilepsy and DMCM-induced seizures suggest, furthermore, that ZK 91296 may possess pharmacological selectivity for a particular type of BZ receptor interaction, perhaps including topographic as well as receptor subtype differentiation. 相似文献
92.
93.
With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCRI). Subjects (104 with normal glucose tolerance [NGT], 57 with impaired glucose tolerance [IGT], and 207 with type 2 diabetes mellitus [T2DM]), divided in nonobese and obese groups, received a euglycemic insulin-clamp (40 mU/m2 ⋅ min) and an oral glucose tolerance test (OGTT) (75 g) on separate days. MCRI was calculated during the insulin-clamp performed with [3-3H]glucose and the OGTT and related to IR: peripheral (glucose uptake during the insulin clamp), hepatic (basal endogenous glucose production × fasting plasma insulin [FPI]), and adipocyte (fasting free fatty acid × FPI). MCRI during the insulin clamp was reduced in obese versus nonobese NGT (0.60 ± 0.03 vs. 0.73 ± 0.02 L/min ⋅ m2, P < 0.001), in nonobese IGT (0.62 ± 0.02, P < 0.004), and in nonobese T2DM (0.68 ± 0.02, P < 0.03). The MCRI during the insulin clamp was strongly and inversely correlated with IR (r = −0.52, P < 0.0001). During the OGTT, the MCRI was suppressed within 15–30 min in NGT and IGT subjects and remained suppressed. In contrast, suppression was minimal in T2DM. In conclusion, the development of IR in obese subjects is associated with a decline in MCRI that represents a compensatory response to maintain normal glucose tolerance but is impaired in individuals with T2DM. 相似文献
94.
Ralph F Jozefowicz Bruce M Koeppen Susan Case Robert Galbraith David Swanson Robert H Glew 《Academic medicine》2002,77(2):156-161
PURPOSE: Most medical schools test their students throughout the curriculum using in-house examinations written by the faculty who teach the courses. The authors assessed the quality of in-house examinations used in three U.S. medical schools. METHOD: In 1998, nine basic science examinations from the three schools were gathered and each question was subjected to quality assessment by three expert biomedical test developers, each of whom has had extensive experience in reviewing and evaluating questions for the United States Medical Licensing Examination (USMLE) Steps 1 and 2. Questions were rated on a five-point scale: 1 = tested recall only and was technically flawed to 5 = used a clinical or laboratory vignette, required reasoning to answer, and was free of technical flaws. Each rater made independent assessments, and the mean score for each question was calculated. Mean quality scores for National Board of Medical Examiners (NBME) who were trained question writers were compared with the mean scores for question writers without NBME training. The raters' quality assessments were made without knowledge of the test writers' training background or the study's hypothesis. RESULTS: A total of 555 questions were analyzed. The mean score for all questions was 2.39 +/- 1.21. The 92 questions written by NBME-trained question writers had a mean score of 4.24 +/- 0.85, and the 463 questions written by faculty without formal NBME training had a mean score of 2.03 +/- 0.90 (p <.01). CONCLUSIONS: The in-house examinations were of relatively low quality. The quality of examination questions can be significantly improved by providing question writers with formal training. 相似文献
95.
Howard B. Moss M.D George L. Panzak R.N. M.S. Ralph E. Tarter Ph.D. 《Archives of sexual behavior》1993,22(1):1-12
The effects of anabolic steroid use on male sexual behavior were assessed using a structured clinical interview administered to male body builders currently using steroids, and to two comparison groups (body builders with a past but not current history of steroid use, and a group of natural body builders who had never used steroids). Current anabolic steroid users had a significantly higher coital and orgasmic frequency than did comparison athletes. They also reported a significantly higher incidence of erectile difficulties during the past month. Beliefs concerning the sexually stimulating effects of steroids did not correlate with the frequencies of specific sexual behaviors. The data support the contention that anabolic steroids, as androgenic compounds, enhance sexual desire. 相似文献
96.
U. Borgmann W. P. Norwood K. M. Ralph 《Archives of environmental contamination and toxicology》1990,19(4):558-564
The addition of 100 (g/L of Aroclor® 1242 (A1242) or 2,5,2,5-tetrachlorobiphenyl (TeCB) during 10 week chronic toxicity tests withHyalella azteca resulted in complete mortality. There were no effects on survival, growth, or reproduction after addition of 30 g/L. Toxic effects were observed at tissue levels of between 30 and 180 g/g on a wet weight basis, and tissue levels appear to be a better indicator of toxicity than levels in water. No toxic effects were observed after additions of up to 2,700 g/L of the coplanar congener 3,4,3,4-TeCB.H. azteca has the ability to avoid accumulating in excess of 140 g/g 3,4,3,4-TeCB. The amount taken up was proportional to the amount added in water up to 100 g/L, but was constant at higher additions, possibly accounting for its relatively low toxicity. The low toxicity of the coplanar congener, as compared to the non-coplanar 2,5,2,5-TeCB, is in direct contrast to the high toxicity of coplanar PCB congeners to mammals and may be associated with slower rates of aromatic hydrocarbon metabolism in amphipods. Polychlorinated biphenyl levels measured in amphipods from Lake Ontario are approximately 100-fold below levels associated with toxicity inH. azteca, but are above levels which, through biomagnification up the food chain, lead to salmonid residues in excess of 2 g/g, a tolerance limit for human consumption. 相似文献
97.
A series of multilamellar liposome dispersions was prepared from lipids of soy phosphatidylcholine or hydrogenated soy phosphatidylcholine containing from 0 to 30 mol% of either cholesterol, steary-lamine, or dipalmitoyl phosphatidylglycerol. The liposome dispersions were aerosolized with a Collison nebulizer for 80 min at an output flow rate of 4.7 liters of air/min. The effects of nebulization on the vesicles were determined by monitoring the release of encapsulated 5,6-carboxyfluorescein (CF) from dispersions containing 200 µg of total CF, of which 93.1 ± 2.4% (N = 18) was initially encapsulated. In all experiments CF was released from the liposomes while being aerosolized, and this ranged from a mean of 12.7 ± 3.8 to 60.9 ± 1.9% of the encapsulated CF, depending upon the lipid composition. The lipid concentration in the dispersions did not affect the rate or percentage release of CF over a range of 0.5 to 50 mg per nebulized dispersion. If liposomes are to be used as drug carriers in an inhalation aerosol a lipid composition should be employed which will minimize the release of encapsulated drug caused by nebulization. 相似文献
98.
To determine the effects on the pulmonary barrier of several surface active agents, a series of metered dose inhalers (MDIs) was prepared and used to dose aerosolized surfactant to the airways of isolated perfused rat lungs. The MDIs contained a range of concentrations, from 0.1 to 5.0% (w/w), of either oleic acid, oleyl alcohol, or Span 85, which released 45 µg (0.1%, w/w) to 1660 µg (5.0%, w/w) of surfactant per actuation. The permeability of the pulmonary barrier was assessed by the rate of transfer of disodium fluorescein dosed as 100 µl of aqueous solution (1 mg/ml) after administering the surfactants. Some 12.1 ± 4.7% of the recovered surfactant, per dose, was assessed to reach the pulmonary regions of the lung. All surfactants tested caused an increase in fluorescein transfer rates. A single actuation from the MDI containing 5% (w/w) oleic acid produced gross edema in all lungs tested within 40 min and the first-order half-lives of absorption were reduced almost threefold, from 12.9 ± 2.5 min for controls to 4.5 ± 0.8 min. Differences in absorption were noted between the acid and the alcohol, which is consistent with the hypothesis that both the hydrocarbon chain and the polar head group have roles in the altered permeability to fluorescein. The absorption of fluorescein when dosed from the MDI containing 5% (w/w) Span 85 was increased but all surfactants dosed from the lowest concentration MDI of 0.1% (w/w) did not alter absorption rates of the dye relative to those of controls. Results are discussed in light of current interest in absorption enhancement and the presence of surfactants in currently marketed MDIs. 相似文献
99.
Ralph Bültmann Bernd Driessen Jorge Gonçalves Klaus Starke 《Naunyn-Schmiedeberg's archives of pharmacology》1995,351(5):555-560
The effect of Evans blue on nucleotide breakdown, nucleotide-evoked contractions and electrically evoked contractions, overflow of ATP and overflow of tritium (after labelling with [3H]-noradrenaline) was studied in rat vas deferens. Pieces of vas deferens degraded 83 to 85% of added ATP, ADP and 2-methylthio ATP (all 100 M) over 30 min. Evans blue (100 M) reduced this degradation to 22 to 26%. Nucleotides elicited contraction with potency declining in the order , \-methylene ATP > 2-methylthio ATP > ATP > ADP. Evans blue (100 M) shifted the concentration-response curve of , \-methylene ATP to the right and increased the maximum. Concentration-response curves of ATP, ADP and 2-methylthio ATP, in contrast, were shifted to the left and responses were much potentiated. In the presence of Evans blue, the rank order of potency was ATP > 2-methylthio ATP > , \-methylene ATP > ADP. Electrical field stimulation (100 pulses at 10 Hz) elicited contraction and an overflow of tritium and ATP. Evans blue (100 M) did not alter the contraction and the evoked overflow of tritium but increased 24-fold the evoked overflow of ATP. The results indicate that Evans blue may serve as an — albeit impure — ecto-nucleotidase inhibitor in functional experiments. Such experiments demonstrate that the low potency of ATP (and also ADP and 2-methylthio ATP) in eliciting contraction, and the small size of the overflow of ATP upon sympathetic nerve stimulation, are due to rapid breakdown. 相似文献
100.
Niven Ralph W. Whitcomb K. Lane Shaner Linda Ip Anna Y. Kinstler Olaf B. 《Pharmaceutical research》1995,12(9):1343-1349
Purpose. The objective of this study was to highlight differences in the pulmonary absorption of a monoPEGylated rhG-CSF and rhG-CSF after intratracheal instillation and aerosol delivery.
Methods. Male Sprague Dawley rats (250 g) were anesthetized and intratracheally instilled (IT) with protein solution or were endotracheally intubated and administered aerosol for 20 min via a Harvard small animal ventilator. A DeVilbiss Aerosonic nebulizer containing 5 ml of protein solution at 3 mg/ml was used to generate aerosol. The volume of protein solution deposited in the lung lobes was estimated to be 13 µl after delivery of Tc-99m HSA solutions. The PEGylated proteins consisted of a 6 kDa (P6) or 12 kDa PEG (PI2) linked to the N-terminus of rhG-CSF. rhG-CSF also was administered IT in buffers at pH 4 and pH 7 and in dosing volumes ranging from 100 to 400 µl. Blood samples were removed at intervals after dosing and the total white blood cell counts (WBC) were determined. Plasma was assayed for proteins by an enzyme immuno assay.
Results. The plasma protein concentration v. time profiles were strikingly different for aerosol v. IT delivery. The C
max values for rhG-CSF and P12 after aerosol delivery were greater than found after IT (Aerosol: 598 ± 135 (ng/ml) rhG-CSF; 182 ± 14 P12 v. IT: 105 ± 12 rhG-CSF; 65.9 ± 5 P12). Similarly, Tmax was reached much earlier after aerosol administration (Aerosol: 21.7 ± 4.8 (min) rhG-CSF; 168 ± 31 P12 v. IT: 100 ± 17 rhG-CSF; 310 ± 121 P12). Estimated bioavailabilities (Flung %) were significantly greater via aerosol delivery than those obtained after IT (Aerosol: 66 ± 14 rhG-CSF; 12.3 ± 1.9 P12 v. IT: 11.9 ± 1.5 rhG-CSF; 1.6 ± 0.1 P12). An increase in circulating WBC counts was induced by all proteins delivered to the lungs. The rate and extent of absorption of rhG-CSF was not influenced by the pH employed nor the instilled volume.
Conclusions. Estimates of bioavailability are dependent upon the technique employed to administer drug to the lungs. Aerosol administration provides a better estimate of the systemic absorption of macromolecules. 相似文献