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31.
32.
Because of complexities in platelet serotonin uptake dynamics, we studied the influence of the time of day and year as well as the subject's age on uptake parameters. While the assay itself was quite reproducible, and the kinetic parameters of 5 HT uptake were stable over a few days, at a given time, within an individual, the variance was quite large when samples from different times of the day or year or from different individuals were compared. An inverse relationship between V
max (moles/cell number/time) and platelet number was found in data from a group of individuals, suggesting regulation of V
max not at the level of uptake capacity per cell, but in a manner that somehow takes into consideration the number of platelets in the subject's plasma. Indeed, expressing V
max in a new way (called total V
max), not based on V
max per cell or per 107 cells but for the total number of platelets in the volume of PRP used, greatly reduced the scatter in the between-individuals and across-time data. While V
max (moles/cell number/time) exhibited only a trend toward reduction with age, for example, the decline in total V
max with subject age was statistically significant. It is suggested that total V
max (moles/time) may be a more physiologically relevant expression for an uptake function than V
max (moles/time/cell number). 相似文献
33.
Glutamate transporters are vulnerable to oxidants resulting in reduced uptake function. We have studied the effects of beta-amyloid(25-35) (beta A(25-35)) on [(3)H]-glutamate uptake on cortical neuron or astrocyte cultures in comparison with a scrambled peptide (SCR) and dihydrokainic acid (DHK), a prototypic uptake inhibitor. beta A(25-35) was more potent than DHK in inhibiting glutamate uptake and the effects of both were more marked on astrocytes than on neurons. At 24 h, beta A(25-35) dose-dependently (0.5-15 microM) increased glutamate levels in media from neuron cultures. DHK only enhanced extracellular glutamate at the highest concentration tested (2500 microM). beta A(25-35) induced gradual neurotoxicity (0.1-50 microM) over time. Exposure to beta A(25-35) resulted in increased uptake in astrocytes (0.25-5 microM) and neurons (0.5-15 microM) surviving its toxic effects. However, exposure to DHK (2.5-2500 microM) did not induce neurotoxicity nor modulated uptake. These results indicate that, while inhibition of glutamate uptake may be involved in the neurotoxic effects of beta A(25-35), enhancement of uptake may be a survival mechanism following exposure to beta A(25-35). 相似文献
34.
Alain Segonzac Hans Schoemaker Christopher R. Lee Salomon Z. Langer 《Naunyn-Schmiedeberg's archives of pharmacology》1987,336(1):1-4
Summary 5-Methoxytryptoline (5-MeO-TLN, 6-methoxytetrahydro--carboline) inhibits with high affinity [3H]-imipramine binding to the serotonin transporter in platelets. To evaluate whether 5-MeO-TLN is a substrate for the serotonin transporter, the accumulation of [3H]-5-MeO-TLN into rabbit platelets was studied in vitro. At short incubation times (5 min), [3H]-5-MeO-TLN accumulation was temperature-sensitive, but not saturable over a concentration range from 0.06 mol/l to 10 mol/l Moreover, [3H]-5-MeO-TLN uptake was not affected by 100 mol/1 ouabain, its structural analogs tryptoline and 5-hydroxytryptoline, nor by the serotonin uptake inhibitors imipramine and citalopram. After longer incubation times (60 min), [3H]-5-MeO-TLN accumulation at O°C approached that seen at 37°C and temperature-sensitive [3H]-5-MeO-TLN uptake could no longer be observed. It is concluded that temperature-sensitive accumulation of [3H]-5-MeO-TLN is not mediated by the serotonin transporter and most likely represents a passive, diffusional process, the rate of which is temperature-dependent. The present studies thus confirm the hypothesis that 5-MeO-TLN affects [3H]-imipramine binding in platelets through a competitive mechanism and not via an allosteric interaction mediated through the substrate recognition site of the macromolecular complex of the serotonin transporter.
Send offprint requests to S. Z. Langer at the above address 相似文献
35.
目的通过回顾性研究甲状腺摄碘率(RAIU)与有效半衰期(EHL)对甲亢患者131I疗效的影响,探讨131I治疗甲亢的更有效方案。方法收集531例行131I治疗的Graves病患者资料,包括131I疗前的RAIU、EHL检查结果,及定期检测的F13、FT4、sTSH、TRAb等结果。根据RAIU高峰值、高峰时间、EHL不同分别进行分组,观察各组近期预后。结果RAIU高峰值越高,未愈比例越高。高峰值(100~91)%组痊愈比例最低,高峰值(70~51)%组甲减发生比例最高。高峰值出现的越早,未愈比例越高,甲减发生比例越低。EHL最长组痊愈比例最低,未愈比例最高;EHL小于4天组未愈比例也较高。结论RAIU高峰值高于90%或低于70%者,及高峰时间太短或EHL小于4d者,131I疗效较差,需调整131I治疗量。EHL长短与131I疗效不成正比,当EHL大于7d时,不宜因此而减少131I治疗用量。 相似文献
36.
In vivo microdialysis was used to examine the effect ofl-3,4-dihydroxyphenylalanine (l-DOPA) administration upon dopamine (DA) in extracellular fluid both in intact striatum and in striatum of rats treated with the catecholaminergic neurotoxin 6-hydroxydopamine (6-HDA). Basal extracellular levels of DA were not significantly altered by 6-HDA unless the DA content of striatal tissue was reduced to less than 20% of control. Peripheral aromatic amino acid decar☐ylase (AADC) inhibition (RO4−4602, 50 mg/kg i.p.) followed byl-DOPA treatment (100 mg/kg i.p.) elevated extracellular DA in striatum of control rats from37 ± 5to68 ± 11pg/sample(n = 7); values corrected for recovery of the dialysis probe). In animals with severe bilateral depletions of DA in striatal tissue(mean depletion 87%; n = 6),l-DOPA increased extracellular DA in striatum from8 ± 3to266 ± 60pg/sample. In animals with large unilateral depletions of DA in striatal tissue(mean depletion 96%; n= 6), the increase in extracellular DA in striatum afterl-DOPA was greater on the lesion side(from7 ± 4to245 ± 67pg/sample) than on the intact side(from28 ± 11to61 ± 8pg/sample). Animals with unilateral DA depletions showed contralateral circling behavior afterl-DOPA. Increases in extracellular DA approaching the magnitude of those occuring in DA-depleted striata were observed when intact animals were treated with nomifensine(5mg/kg i.p.; n = 5), an inhibitor of high-affinity DA uptake, in addition tol-DOPA. 相似文献
37.
The role of solvents in drug transport has not been properly addressed in the literature, despite its well known influence on drug permeation. Previously we have conducted thermodynamic and kinetic analyses to probe the molecular mechanisms of alcohol enhanced permeation. In the present study, the influence of temperature on the partitioning of methyl paraben into silicone membranes is investigated. In line with previous membrane transport studies of methyl paraben in silicone membranes, butanol and heptanol are used as representative alcohols. The results show higher amounts of methyl paraben extracted from the silicone membrane following equilibration with butanol, at all experimental temperatures. This was in line with alcohol uptake data. In fact, a linear correlation (r2 ∼0.97) was found between the amount of methyl paraben in the silicone membrane and the corresponding alcohol uptake. Calculated “specific” vehicle-membrane partition coefficients for both alcohols were approximately one, suggesting that the effective concentrations of methyl paraben inside and outside the membrane were the same. Thermodynamic analysis of the alcohol-membrane partition coefficients as a function of temperature showed no apparent trend for butanol, with an associated enthalpy change of approximately zero. Conversely, there was a positive trend in the van’t Hoff plot for methyl paraben in heptanol, indicative of an exothermic process. Moreover, the partitioning trends of methyl paraben in silicone membranes obtained from membrane transport and equilibrium experiments were not the same. This reflects the fundamental differences between the calculated vehicle-membrane partition coefficients in the two studies. Finally, the findings from membrane transport and equilibrium experiments support a model of alcohol enhanced permeation where high solvent sorption promotes high solute concentrations in the overall volume of the membrane (i.e. K), thus leading to modified solute transport (i.e. increased flux). The same model also accounts for changes in membrane diffusivity (i.e. D) related to the properties of the imbibed alcohol. 相似文献
38.
Detergent-insoluble EAAC1/EAAT3 aberrantly accumulates in hippocampal neurons of Alzheimer's disease patients 总被引:1,自引:0,他引:1
Duerson K Woltjer RL Mookherjee P Leverenz JB Montine TJ Bird TD Pow DV Rauen T Cook DG 《Brain pathology (Zurich, Switzerland)》2009,19(2):267-278
Disturbed glutamate homeostasis may contribute to the pathological processes involved in Alzheimer's disease (AD). Once glutamate is released from synapses or from other intracellular sources, it is rapidly cleared by glutamate transporters. EAAC1 (also called EAAT3 or SLC1A1) is the primary glutamate transporter in forebrain neurons. In addition to transporting glutamate, EAAC1 plays other roles in regulating GABA synthesis, reducing oxidative stress in neurons, and is important in supporting neuron viability. Currently, little is known about EAAC1 in AD. To address whether EAAC1 is disturbed in AD, immunohistochemistry was performed on tissue from hippocampus and frontal cortex of AD and normal control subjects matched for age and gender. While EAAC1 immunostaining in cortex appeared comparable to controls, in the hippocampus, EAAC1 aberrantly accumulated in the cell bodies and proximal neuritic processes of CA2-CA3 pyramidal neurons in AD patients. Biochemical analyses showed that Triton X-100-insoluble EAAC1 was significantly increased in the hippocampus of AD patients compared to both controls and Parkinson's disease patients. These findings suggest that aberrant glutamate transporter expression is associated with AD-related neuropathology and that intracellular accumulation of detergent-insoluble EAAC1 is a feature of the complex biochemical lesions in AD that include altered protein solubility. 相似文献
39.
Conflicting reports exist concerning the effect aspartame (APM, l-aspartyl-l-phenylalanine methyl ester) has upon brain biogenic amines. In the following study, in vivo voltammetry was utilized to measure evoked extracellular dopamine (DA) levels in the striatum of rats in order to assess APM's effect. Time-course experiments revealed a significant decline in evoked extracellular DA levels within 1 h of a single systemic dose (500 mg/kg i.p.) when compared to vehicle-injected controls. The effect was frequency dependent and showed a significant decrease utilizing high frequency stimulation parameters (50 and 60 Hz). In order to further determine APM's potential to alter evoked extracellular DA levels, extended stimulation periods were employed to deplete releasable stores both before and after APM administration in intact and 6-OHDA partially lesioned animals. The extended stimulation periods were applied at 60 Hz for 2,5,10 and 20 s durations. APM decreased DA levels under these conditions in both intact and 6-OHDA partially lesioned animals by an average of 34% and 51%, respectively. Kinetic analysis performed on frequency series indicated that the diminished DA levels corresponded to a significant reduction in DA release. These findings suggest that APM has a relatively potent effect of decreasing evoked extracellular DA levels when administered systemically under the conditions specified. 相似文献
40.
Budygin EA Oleson EB Mathews TA Läck AK Diaz MR McCool BA Jones SR 《Psychopharmacology》2007,193(4):495-501