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31.
32.
Differential expression of orexin receptors 1 and 2 in the rat brain 总被引:22,自引:0,他引:22
Marcus JN Aschkenasi CJ Lee CE Chemelli RM Saper CB Yanagisawa M Elmquist JK 《The Journal of comparative neurology》2001,435(1):6-25
Orexins (hypocretins) are neuropeptides synthesized in the central nervous system exclusively by neurons of the lateral hypothalamus. Orexin-containing neurons have widespread projections and have been implicated in complex physiological functions including feeding behavior, sleep states, neuroendocrine function, and autonomic control. Two orexin receptors (OX(1)R and OX(2)R) have been identified, with distinct expression patterns throughout the brain, but a systematic examination of orexin receptor expression in the brain has not appeared. We used in situ hybridization histochemistry to examine the patterns of expression of mRNA for both orexin receptors throughout the brain. OX(1)R mRNA was observed in many brain regions including the prefrontal and infralimbic cortex, hippocampus, paraventricular thalamic nucleus, ventromedial hypothalamic nucleus, dorsal raphe nucleus, and locus coeruleus. OX(2)R mRNA was prominent in a complementary distribution including the cerebral cortex, septal nuclei, hippocampus, medial thalamic groups, raphe nuclei, and many hypothalamic nuclei including the tuberomammillary nucleus, dorsomedial nucleus, paraventricular nucleus, and ventral premammillary nucleus. The differential distribution of orexin receptors is consistent with the proposed multifaceted roles of orexin in regulating homeostasis and may explain the unique role of the OX(2)R receptor in regulating sleep state stability. 相似文献
33.
Wang WS; Fan FS; Hsieh RK; Chiou TJ; Lin JK; Lin TC; Yen CC; Liu JH; Hsu H; Chen PM 《Japanese journal of clinical oncology》1997,27(3):174-179
5-Fluorouracil in combination with leucovorin has been shown to be active
in therapeutic trials of metastatic colorectal carcinoma. In this study, we
administered these drugs to 72 patients with metastatic colorectal
carcinoma. Thirty-six of them without previous exposure to 5-fluorouracil
were treated with weekly bolus injections of 5-fluorouracil (425 mg/m2) and
leucovorin (25 mg/m2) supplemented with oral levamisole. Another 36
patients with or without prior 5-fluorouracil treatment received
5-fluorouracil 3,000 mg/m2 and leucovorin 300 mg/m2 in a 48-hour continuous
infusion every two weeks. Clinical efficacy and toxicity were assessed by
WHO criteria. Variables were tested for relations to response and survival
by univariate and multivariate analysis. The response rate was 19.4% in
weekly bolus arm and 13.9% in biweekly high-dose infusion arm (P = 0.527).
Median survivals in the two arms were 18.4 months (weekly) and 21 months
(biweekly) respectively (P = 0.708). Gastrointestinal side effects
including nausea, vomiting, diarrhea and mucositia were the major
toxicities of these regimens. By multivariate analysis, the only factor to
influence response rate was the site of metastases (P = 0.009). The only
factor to affect survival was performance status of the patient (P =
0.0001). We concluded that the two 5-fluorouracil based regimens are
well-tolerated and shown to have a response rate comparable with previous
reports of similar regimens in patients with metastatic colorectal cancer.
Only liver metastases seemed to have a better response to therapy.
Performance status is the most important prognostic factor in patients with
metastatic colorectal cancer.
相似文献
34.
Recent reports have demonstrated that the HIV-1 transactivator protein,tat, induces apoptosis in T-lymphocyte cell lines, as well as in peripheral blood mononuclear cells, and stimulates a cascade
of events resulting in up-regulation of the potent immunosuppressive cytokine, transforming growth factor-β (TGF-β). In this
study we evaluated the ability of TGF-β to mediatetat induced apoptosis in T-lymphocyte cell lines. T-cells treated exogenously with either TGF-β1 or a combination of tat and
pan-specific TGF-β neutralizing antibodies showed little change in the amount of apoptosis. When treated with pan-specific
TGF-β neutralizing antibodies, Jurkat cells that stably expresstat protein (Jurkat-tat) showed only a modest decrease in apoptosis, while CEM-TART cells (CEM T-cells expressing both HIV-1tat andrev) demonstrated little change in the amount of apoptosis. In conclusion, we have demonstrated that TGF-β does not play a significant
role in mediatingtat induced T-cell apoptosis. 相似文献
35.
The reliability of proton spectroscopic imaging in evaluating fatty infiltration of the liver was investigated in 35 subjects (12 healthy volunteers and 23 patients with fatty livers). With this modified spin-echo technique, fatty liver could be separated from normal liver both visually and quantitatively. On the opposed image, normal liver had an intermediate signal intensity, greater than that of muscle, whereas fatty liver had a lower signal intensity, equal to or less than that of muscle. In normal livers, the lipid signal fraction was less than 10%, while in fatty livers it was greater than 10% and usually exceeded 20%. With this technique, nonuniform fatty infiltration of the liver can be differentiated from hepatic metastases, and the technique may prove useful in the differentiation of some hepatic disorders. 相似文献
36.
Dai H Chen Y Elmquist WF 《The Journal of pharmacology and experimental therapeutics》2005,315(1):222-229
Pemetrexed disodium is a novel antifolate that exhibits potent inhibitory effects on multiple enzymes in folate metabolism. Phase II/III clinical trials have shown that pemetrexed is effective against various solid tumors. Like methotrexate, pemetrexed may be useful in treatment of primary and secondary brain tumors. In this study, we examined the central nervous system (CNS) distribution of pemetrexed and the interaction with an organic anion transport inhibitor indomethacin. Male Wistar rats were administered pemetrexed by either single intravenous bolus or constant intravenous infusion. Unbound pemetrexed in blood and brain was measured by simultaneous arterial blood and frontal cortex microdialysis sampling. In the i.v. bolus experiments, indomethacin was administered by i.v. bolus (10 mg/kg) followed by i.v. infusion (0.1 mg/kg/h) in a crossover manner. In the infusion experiments, the same dose of indomethacin was administered after a steady state was reached for pemetrexed. CNS distributional kinetics was analyzed by compartmental and noncompartmental methods. Both bolus and infusion studies showed that pemetrexed has a limited CNS distribution. The mean area under concentration-time curve (AUC)(brain)/AUC(plasma) ratio of unbound pemetrexed was 0.078 +/- 0.038 in the i.v. bolus study. The pemetrexed steady-state brain-to-plasma unbound concentration ratio after i.v. infusion was 0.106 +/- 0.054. The distributional clearance into the brain was approximately 10% of the clearance out of the brain in both the compartmental and noncompartmental analyses. Indomethacin had no effect on either the brain-to-plasma AUC ratio or the steady-state brain-to-plasma concentration ratio. The distribution of pemetrexed into the brain is limited, and an efflux clearance process, such as an efflux transporter, may be involved. 相似文献
37.
Thoracic wall involvement by Hodgkin disease and non-Hodgkin lymphoma: CT evaluation 总被引:6,自引:0,他引:6
Thoracic computed tomographic (CT) scans of 250 patients with newly diagnosed or recurrent lymphoma revealed thoracic wall involvement in 24 patients (11 with Hodgkin disease, 13 with non-Hodgkin lymphoma). Thoracic wall involvement occurred without contiguous mediastinal or parenchymal involvement in 17 patients. Of these, 13 patients had masses beneath the pectoralis muscles or within the breast, and four had masses arising from the ribs. Five additional patients had mediastinal masses with thymic involvement and parasternal extension through the thoracic wall. Pulmonary parenchymal lymphoma with thoracic wall invasion was noted in the remaining two patients. In five of nine patients receiving radiation therapy, treatment plans were modified by CT demonstration of thoracic wall lymphoma. 相似文献
38.
Galanin and its receptors in neurological disorders 总被引:2,自引:0,他引:2
Galanin is a highly inducible neuropeptide, showing distinct up-regulation after pathological disturbance within the nervous
system. Significant increase in galanin expression is observed after peripheral nerve injury, in the basal forebrain in Alzheimer’s
disease (AD), during neuronal development, and after stimulation with estrogen, while seizure activity deplete galanin in
the hippocampus. A wide distribution of galanin and its receptors is seen in the nervous system, often in co-localization
with classical neurotransmitters and other neuromodulators. Galanin acts predominantly as an inhibitory, hyperpolarizing neuromodulator
on neurotransmitter and glucose-induced insulin release and stimulates growth hormone and prolactin secretion. Galanin has
been implicated in several higher order physiological functions including cognition, feeding, nociception, mood regulation,
and neuroendocrine modulation. The effects of galanin are mediated via three G protein-coupled receptors with different functional
coupling. Moderate to low pharmacological effects are seen by galanin under physiological conditions, in contrast to its dramatic
effects on the nervous system after neuronal disturbance. This pathophysiological heavy function of the galaninergic system
renders it an interest for disorders such as AD, depression, and epilepsy in terms of side effects. Some properties of the
galaninergic system are of particular importance in the context of neurodegeneration. Galanin is highly inducible, 10- to
100-fold, upon nerve injury, whereas most neuropeptides are induced 1.5- to 2-fold. Galanin is strongly neurotrophic during
development as well as subsequent to injury. Whereas other neurotrophic neuropeptides like VIP and PACAP activate cAMP synthesis,
galanin suppresses its synthesis, yet it is a strong neurotrophic as well as neuroprotective agent. As we delineate which
galanin receptor subtype mediates neuroprotective and neurotrophic effects and which mediates synaptic inhibition, pharmacological
use of receptor-selective galaninergic ligands for treatment in neurodegenerative diseases are coming closer. 相似文献
39.
Plasma membrane localization of multidrug resistance-associated protein homologs in brain capillary endothelial cells 总被引:5,自引:0,他引:5
Zhang Y Schuetz JD Elmquist WF Miller DW 《The Journal of pharmacology and experimental therapeutics》2004,311(2):449-455
Several multidrug resistance-associated protein (MRP) homologs are expressed in brain microvessel endothelial cells forming the blood-brain barrier (BBB). The influence of these MRP transporters on BBB permeability will be dependent on their localization within the brain microvessel endothelial cells. Using two different and complementary approaches, the localization of various MPR homologs (MRP1, MRP4, and MRP5) was examined in primary cultured bovine brain microvessel endothelial cells (BBMECs). The first approach involved centrifugal separation of apical and basolateral plasma membranes of cultured BBMECs. The membrane fractions were then subjected to Western blot analysis for MRPs. The second approach used confocal laser scanning microscopy to determine membrane localization of MRPs in BBMECs. Results show a predominantly apical plasma membrane distribution for MRP1 and MRP5, and an almost equal distribution of MRP4 on the apical and basolateral plasma membrane of BBMECs. These studies provide the first demonstration of the localization of MRP1, MRP4, and MRP5 homologs in brain microvessel endothelial cells. The present studies also indicate that the localization of MRPs in the endothelial cells forming the BBB is different from that observed in polarized epithelial cells and thus may contribute to the reduced entry and enhanced elimination of organic anions and nucleotides in the brain. 相似文献
40.
Kilk K Elmquist A Saar K Pooga M Land T Bartfai T Soomets U Langel U 《Neuropeptides》2004,38(5):316-324
In this work, we have targeted positions 18-38 of the human galanin receptor type 1 (GalR1) mRNA coding sequence with different peptide nucleic acid (PNA) oligomers. This region has previously been shown to be a good antisense region and therefore we aimed to identify the subregions and/or thermodynamic parameters determining the antisense efficacy. Nine different PNA oligomers were conjugated to a cell-penetrating peptide, transportan, to enhance their cellular uptake. Concentration-dependent down-regulation of GalR1 protein expression in human melanoma cell line Bowes was measured by radioligand binding assay. No reduction of GalR1 mRNA level was observed upon PNA treatment, thus, the effect was concluded to be translational arrest. Judging from the EC50 values, antisense PNA oligomers targeting regions 24-38 (EC50=70 nM) or 27-38 (EC50=80 nM) were the most potent suppressors of protein expression. No parameter predicted by M-fold algorithm was found to correlate with the measured antisense activities. Presence of some subregions was found not to increase antisense efficiency of PNA. Presence of a short unpaired triplet between nucleotides 33 and 35 in the target region was, on the other hand, found to be the most critical for efficient GalR1 down-regulation. Thus, the results are of high impact in designing antisense oligomers. Specific results of this study demonstrate 20-fold more efficient antisense down-regulation of GalR1 as achieved before. 相似文献