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11.
R W Lambert J A Martin G J Thomas I B Duncan M J Hall E P Heimer 《Journal of medicinal chemistry》1989,32(2):367-374
Phosphonoacetic acid (PAA, 1) was coupled with various acyclonucleosides, 2'-deoxyuridines, cytidines, and arabinosyluracils, with 2,4,6-triisopropylbenzenesulfonyl chloride (TPS) or dicyclohexylcarbodiimide (DCCI) as condensing agents, to give a range of phosphonate esters. The carboxylic ester linkage of PAA to the 5'-position of 5-bromo-2'-deoxyuridine (BUdR, 3) was achieved via the mixed anhydride formed from (diethylphosphono)acetic acid and trifluoroacetic anhydride. Phosphonoformic acid (PFA, 2) was coupled with BUdR by using the DCCI method to give the phosphonate ester. Of these compounds only phosphonate esters in the 2'-deoxyuridine series showed significant activity against herpes simplex virus types 1 and 2. The BUdR-PAA derivative and the BUdR-PFA derivative were highly active, especially the latter, which was more active than the parent nucleoside BUdR against the type 2 virus. The active compounds may exert their effects by extracellular or intracellular hydrolysis to the corresponding antiviral agents, but an intrinsic component of antiviral activity may also be involved. 相似文献
12.
Conventional teaching states that the spiral of Tillaux marks the location of the ora serrata. On literature review, no source for this was found. This study explores this anatomic relationship. In 20 cadaver eyes, narrow-gauge needles were placed penetrating the center of each rectus muscle insertion, and distance to the ora was measured. Insertions ranged from 2.25 mm posterior to 2.25 mm anterior to the ora, with 90% within 1 mm of it. In ten eyes, distance from the edge of insertion also was measured. Results indicate that the centers of rectus insertions, especially the lateral rectus, approximately overlie the ora, with the edges of the insertions more posterior and variable. 相似文献
13.
Typhoid fever remains an underestimated important health problem in many developing countries, causing more than 600,000 deaths annually in the world. Because of the reactogenicity of the parenteral, killed whole-cell vaccine, research has been oriented towards vaccination orally using live organisms and purified antigen. Live vaccine Ty21a, given by the oral route, has been extensively tested in several studies in developing countries. Its liquid formulation was the most effective, providing more than 60% protection after 7 years of follow-up. A Vi polysaccharide vaccine has been elaborated and provided more than 65% protection; after 3 years of follow-up the Vi antibody level was still at a high level. These two vaccines are therefore candidates for use in public health control programmes. Before such use, however, they need further evaluation for safety and protective efficacy when administered to the EPI-targeted age groups. The question of whether typhoid fever vaccines interfere with the response to simultaneously administered measles vaccine must also be studied. New live vaccines, given by the oral route in one dose, have been constructed through genetic engineering. The first results are promising, but they must be improved before use in a large-scale study. These strains could be used as live vector to deliver foreign antigens to the intestinal mucosa. 相似文献
14.
Lambert H.M. Janssen Anneloes L. van Til Frans B. van Duijneveldt 《Journal of electroanalytical chemistry (Lausanne, Switzerland)》1992,342(2):161-178
The reduction of the quinone moiety, which is found in many anti-cancer agents, is still a poorly understood process. It is commonly assumed that the reduction of a quinone by the uptake of two electrons and two protons leads to the active hydroquinone form. For a better understanding of these reactions electrochemical data, obtained for a series of substituted benzoquinones, were analyzed. In addition quantum chemical calculations on the STO-3G level were performed to obtain data for the one- and two-electron reduction.From the electrochemical experiments, thermodynamic data can be obtained which show that the unfavourable free energy of electron uptake is overcome by the favourable binding of protons. Both reactions are influenced by the electronic properties of the substituents, as demonstrated by Hammett-type relationships between the free energy of these reactions and the sigma-para character of these substituents. In these relationships the reaction constant of the electron uptake process has an absolute value which is five times higher than that of the proton uptake.Quantum chemical calculations yielded energy values for the one-electron uptake, as expressed by U(LUMO), and for the total reduction process. Most of the results from these calculations are in accord with the thermodynamic study. The calculations also revealed a conformational change to take place upon reduction of NH2 and N(CH2)2 substituted benzoquinones, which might be important for chemical and biological activity. 相似文献
15.
Do local anaesthetics interact with dihydropyridine binding sites on neuronal L-type Ca2+ channels? 总被引:1,自引:0,他引:1
Hirota K.; Browne T.; Appadu B. L.; Lambert D. G. 《British journal of anaesthesia》1997,78(2):185-188
We have examined the interaction of procaine, prilocaine, lignocaine,
bupivacaine, amylocaine and R(+) and S(-) ropivacaine with L-type
voltage-sensitive Ca2+ channels in rat cerebrocortical membranes. Membranes
were prepared in Tris HCl 50 mmol litre-1, pH 7.4, by homogenization and
centrifugation. Binding assays were performed in 1- ml volumes of Tris HCl
50 mmol litre-1, pH 7.4, for 90 min at room temperature using approximately
200 micrograms of protein. Non-specific binding was defined in the presence
of nifedipine 10(-5) mol litre-1, and bound and free radioactivity were
separated by vacuum filtration. The effects of local anaesthetics were
determined by displacement of [3H]PN200-110 (approximately 0.2 nmol
litre-1), a radiolabelled 1,4- dihydropyridine (DHP) L-channel antagonist.
The concentration of displacer producing 50% displacement was corrected for
the competing mass of [3H]PN200-110 to yield the affinity constant, K50.
All local anaesthetics displaced [3H]PN200-110 in a dose-dependent manner
with a rank order potency of (K50, mmol litre-1) bupivacaine (0.48),
amylocaine (0.74), lignocaine (1.09), prilocaine (2.06) and procaine
(2.09). Ropivacaine enantiomers did not show stereo-selective displacement,
with K50 values of 0.99 and 0.92 mmol litre-1 for R(+) and S(-)
ropivacaine, respectively. There was a significant correlation between pK50
and p (octanol:buffer partition coefficient) (r2 = 0.872, P = 0.020), pK50
and p (local anaesthetic potency) (r2 = 0.816, P = 0.036), pK50 and p
(relative conduction blocking potency) (r2 = 0.843, P = 0.028) and between
pK50 and p (IC50 for inhibition of cardiac output) (r2 = 0.897, P = 0.015).
These data suggest that DHP binding sites may be involved in both the
mechanism of local anaesthesia and the cardiotoxicity of these agents.
相似文献
16.
H Angus-Leppan GA Lambert J Michalicek 《Cephalalgia : an international journal of headache》1997,17(6):625-630
Co-existence of facial and occipital pain may occur in occipital neuralgia, migraine and cluster headache; suggesting convergence of trigeminal and cervical afferents. Such convergence has been shown in humans and other animals, but the site and extent of this are uncertain. In anaesthetized adult cats, the superior sagittal sinus and occipital nerve were stimulated electrically, and extracellular recordings made in the dorsolateral area of the upper cervical cord using glass-coated tungsten electrodes. Of 49 units in 10 cats, 33 (67%) had input from the superior sagittal sinus and the occipital nerve. Thirteen (27%) had superior sagittal sinus input and 3 (6%) had occipital nerve input. Convergent receptive fields were identified mechanically in 7 units. These experiments in cats show convergent input from occipital nerve and superior sagittal sinus on dorsolateral area units in two-thirds of cases studied. This experimental site of trigeminocervical convergence may relate to referral of pain in occipital neuralgia and other headaches. 相似文献
17.
Leonore C Dijkgraaf Gustavo Zardeneta Fabian W Cordewener Robert S b Liem John P Schmitz Lambert G m de Bont Stephen B Milam 《Journal of oral and maxillofacial surgery》2003,61(1):101-111
PURPOSE: Adhesion formation in osteoarthritis (OA) of the temporomandibular joint (TMJ) typically results in a sustained limitation of joint movement. We propose the hypothesis that free-radical-mediated crosslinking of proteins underlies this adhesion formation in affected joints. Free radicals may cause oxidative modification of proteins, creating an opportunity for the formation of intramolecular and intermolecular crosslinks via covalent bonds. This may stabilize protein aggregates, rendering them more resistant to degradation. In this study, the free-radical-mediated crosslinking of model proteins (fibrinogen and fibronectin) was investigated to test our hypothesis that free radicals contribute to adhesion formation via this mechanism in OA of the TMJ. MATERIALS AND METHODS: Physiological clot formation of fibrinogen by thrombin and free-radical-induced crosslinking of fibrinogen and of fibronectin were analyzed using spectrophotometric turbidity measurements, light-scattering techniques, polyacrylamide gel electrophoresis (PAGE), and rotary shadowing. RESULTS: Fibrinogen was shown to aggregate after free radical treatment, as detected using turbidity measurements and light-scattering techniques. Using PAGE, fibrinogen as well as fibronectin was shown to degrade under low oxidative stress. Under high oxidative stress, however, fragments from both proteins were found to be covalently crosslinked, resulting in high-molecular-weight protein aggregates. The aggregation was shown to be at random with rotary shadowing. CONCLUSION: The study shows that high oxidative stress contributes to the formation of crosslinked proteins that may serve as an initial scaffolding for the development of adhesions frequently seen in OA of the TMJ. 相似文献
18.
Molecular characterization of in vivo mutation at the human hypoxanthine phosphoribosyltransferase (hprt) locus has revealed a broad spectrum of mutation, both with regard to germ-line mutation in Lesch-Nyhan and gout patients, and somatic mutation in 6-thioguanine resistant T-lymphocytes from healthy individuals. The pattern of missense mutation shows a non-random distribution with a preferential location to codons for amino acids which are identical in human and the two parasites Schistosoma mansoni and Plasmodium falciparum. Although these 'evolutionary conserved' amino acids account for only 32% of the amino acids in the human hprt protein, they are involved in 76% of the missense mutations at the hprt locus in human T-lymphocytes, 67% in Lesch-Nyhan patients (with severe hprt-deficiency), but only 43% in gout patients (with partial hprt deficiency). This observation supports the notion that evolutionary conserved amino acids constitute functionally important sites in the hprt enzyme, and missense mutations affecting these amino acids will often lead to complete loss of enzyme activity. Substitutions of 'non-conserved' amino acids cause less severe hprt-deficiency (as seen in the gout patients), or may even escape clinical diagnosis. These considerations are important for the understanding of structure-activity relationships in the hprt protein, possible differences between hprt mutational spectra in germ-line and somatic cells, and the mutational spectra induced by specific exogeneous mutagens. 相似文献
19.
An electrophysiological investigation of the properties of a murine recombinant 5-HT3 receptor stably expressed in HEK 293 cells. 总被引:2,自引:2,他引:0 下载免费PDF全文
1. The pharmacological and biophysical properties of a recombinant 5-HT3 receptor have been studied by use of patch-clamp techniques applied to HEK 293 cells stably transfected with the murine 5-HT3 R-A cDNA. 2. At a holding potential of -60 mV, 77% of cells investigated responded to ionophoretically applied 5-HT with an inward current. Such currents were unaffected by methysergide (1 microM), or ketanserin (1 microM), but were antagonized in a concentration-dependent and reversible manner by the selective 5-HT3 receptor antagonist, ondansetron (IC50 = 440 pM) and the non-selective antagonists (+)-tubocurarine (IC50 = 1.8 nM) and metoclopramide (IC50 50 nM). 3. The 5-HT-induced current reversed in sign (E5-HT) at approximately -2mV and exhibited inward rectification. The influence of extra- and intracellular ion substitutions upon E5-HT indicates the 5-HT-evoked current to be mainly mediated by a mixed monovalent cation conductance. 4. Calcium and magnesium (0.1-10 nM) produced a concentration-dependent, voltage-independent, inhibition of the 5-HT-induced response. Zinc (0.3-300 microM) exerted a biphasic effect with low concentrations enhancing, and high concentrations depressing, the 5-HT-evoked current. 5. Fluctuation analysis of inward currents evoked by a low (1 microM) concentration of 5-HT suggests the current to be mediated by the opening of channels with a conductance of 420 fS. 6. The pharmacological and biophysical properties of the 5-HT3 R-A are similar to those previously described for 5-HT3 receptors native to murine neuroblastoma cell lines, with the exception that the function of the recombinant receptor was enhanced by low concentrations of zinc. This observation suggests that the properties of the native receptor are not completely represented by the 5-HT3 R-A subunit alone. 相似文献
20.
Single dose ciprofloxacin for the eradication of pharyngeal carriage of Neisseria meningitidis 总被引:4,自引:0,他引:4
Single dose oral ciprofloxacin was given to all personnel in a naval training establishment as part of the management of an outbreak of meningococcal meningitis. Two thousand one hundred personnel received the drug and Neisseria meningitidis was eradicated from the pharynx of 97% of 570 who were swabbed two to four days later. In a cohort of 277 personnel who were followed for up to nine weeks, pharyngeal carriage was eliminated from 93% of 104 carriers. The overall prevalence of carriage fell from 19% to less than 1.5% as a result of the use of ciprofloxacin. Few side effects were encountered, compliance was good and meningococci resistant to the antibiotic were not found after therapy. A single oral dose of ciprofloxacin 500 mg eliminates pharyngeal carriage of N. meningitidis effectively and has few adverse reactions. 相似文献