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41.
Jesús Ruiz-Cabello Kirsten Berghmans Ofer Kaplan Marc E. Lippman Robert Clarke Jack S. Cohen 《Breast cancer research and treatment》1995,33(3):209-217
Many breast tumors appear to progress from estrogen-dependent growth to a more malignant phenotype characterized by estrogen-independent growth, antiestrogen resistance, and a high metastatic potential. Utilizing31P NMR spectroscopy on human breast cancer cells growingin vitro, we have investigated the effects of 17-estradiol and tamoxifen on the metabolic/bioenergetic spectra of a series of human breast cancer cells that vary in their estrogen and antiestrogen responsiveness. A comparison of baseline spectra associates higher levels of phosphodiesters and UDP-glucosides (e.g. UDP-glucose, UDP-N-acetylglucosamine), and lower phosphocholine/glycerylphosphocholine and phosphocholine/phosphoethanolamine ratios, with the acquisition of estrogen-independent growth in estrogen receptor expressing cells. No metabolic changes are clearly associated with the metastatic phenotype. Whilst estrogen treatment produces no consistently significant spectral changes in any of the cell lines, the estrogen-independent and estrogen-responsive MCF7/MIII cell line responds to tamoxifen treatment by significantly increasing all spectral resonances 30%-40% above baseline values. This may reflect a tamoxifen-induced change to a more differentiated or apoptotic phenotype, or an attempt by the cells to reverse the inhibitory effects of the drug. The ability to detect metabolic changes in response to tamoxifen by NMR spectroscopy may provide a novel means to identify those tumors that are responsive to antiestrogen therapy.Abbreviations CCS-IMEM
steroid-deprived Improved Minimal Essential Medium
- E2
17-estradiol
- ER
estrogen receptor
- Pi
inorganic phosphate
- GPE
glyceryl-phosphoethanolamine
- GPC
glyceryl-phosphocholine
- PC
phosphocholine
- PE
phosphoethanolamine
- PDE
phosphodiesters
- PME
phosphomonoesters
- TAM
tamoxifen (trans-1-(4--dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene)
- UDPG
uridine diphosphoglycoside 相似文献
42.
María Eugenia Romero-Abal Iván Mendoza Jesús Bulux Noel W. Solomons 《European journal of epidemiology》1995,11(2):133-139
Plasma retinol and -carotene levels were measured in 502 preschool Guatemalan children from five rural hamlets. Their ages ranged from 6 to 78 months (mean: 42.9±19.2 months); 45% males and 55% females. The mean retinol value in the whole group was 0.9±0.4 µmol/1 (range: 0.1 to 8.4 µmol/1). There was no significant difference between sexes in retinol mean values nor in the incidence of retinol values less than 0.7 µmol/1 (22% in males, 18% in females). When grouped by age and community, significant low retinol mean values were found in two hamlets in the youngest age group (12 to 23 months) as compared to the other age-groups (p<0.05). In the other two hamlets, there were no significant differences among retinol means by age-group. The highest prevalence of deficient retinol values by age-group was in the 12 to 23 months group (40%), and decreased as age increased. The mean value for -carotene in the whole group was 0.13±0.18 µmol/1 (range: 0.01 to 2.23 µmol/1). There were no significant differences in -carotene means between sexes in the whole group. Stratifying the -carotene data by age-groups and community, values were significantly higher in the 48–59 months and 72–83 months groups, as compared with the other age groups in two of the communities (p<0.05). Significant differences across communities for -carotene were found only in the 12 to 23 months group. 相似文献
43.
BACKGROUND: Tentorial dural arteriovenous fistulas (AVFs) are uncommon lesions usually treated surgically using a subtemporal exposure with division of the tentorium. This exposure requires significant retraction of the temporal lobe and has the possibility of significant arterialized venous bleeding if a draining vein is accidentally cut during division of the tentorium. Skull base surgical techniques may provide alternate approaches for the surgical treatment of tentorial dural AVFs. METHODS: A tentorial dural arteriovenous fistula supplied by the tentorial artery and drained by the petrosal vein was exposed and obliterated using the petrosal (subtemporal-presigmoid) approach. RESULTS: The petrosal approach allowed the exposure and division of the superior petrosal sinus and tentorium with direct visualization of the supratentorial and the infratentorial compartments, avoiding accidental damage to the draining veins. The dural fistula was easily obliterated after its venous drainage was interrupted and the tentorial artery occluded. CONCLUSIONS: Tentorial dural AVFs can be safely treated with interruption of the venous drainage. The exposure can be enhanced with a petrosal approach, decreasing the possibility of uncontrolled bleeding during the procedure. 相似文献
44.
Rationale: Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the
ratio EPS liability/antiamphetamine efficacy [“therapeutic index” (TI)] has fit well with clinical results. Objectives: 1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D1 antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT2 serotonergic/DA D1 and D2 antagonist) and DOD 647 (DA D1 and D2 antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to
gain more insight as to clozapine’s neuropharmacology. Methods: Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing
doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine
producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI.
Results: Excepting clozapine and DOD 647, all drugs induced dystonia. At 2–4 mg/kg, clozapine caused uncoordinated movements, myoclonic
jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD
647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3–5 versus 4 for clozapine
and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic
doses.
Received: 31 October 1997/Final version: 9 November 1998 相似文献
45.
Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. 总被引:2,自引:0,他引:2
Irene D Román M Dolores Fernández-Moreno Jesús A Fueyo Marcelo G Roma Roger Coleman 《Toxicological sciences》2003,71(2):276-281
Isolated rat hepatocyte couplets were used to perform the comparative study of two widely used immunosuppressors, cyclosporin A (CsA) and tacrolimus (FK506) on hepatocanalicular function. We assessed canalicular function by counting the percentage of couplets that were able to accumulate the fluorescent cholephile, cholyl-lysyl-fluorescein (CLF), into the canalicular vacuole between the two cells, i.e., canalicular vacuole accumulation (CVA) of CLF. Compared to controls (DMSO-treated cells), CsA, in the approximate range of concentrations used therapeutically, caused inhibition of CVA of CLF, disorganization of the bile salt export pump (Bsep) localization at canalicular level resulting in its relocation into the cell, and disruption of the pericanalicular F-actin cytoskeleton. In contrast, FK506, at both approximately therapeutic and supratherapeutic concentrations, had no deleterious effect upon CVA of CLF, upon the localization of the bile salt transporter at the canalicular membrane, or on the organization of the pericanalicular F-actin cytoskeleton. These results point to transporter and cytoskeletal disorganization as contributors or determinants of CsA-induced cholestasis at canalicular level, whereas FK506 does not appear to produce these cholestasis-determining responses even at supratherapeutic concentrations. 相似文献
46.
Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation. 总被引:5,自引:0,他引:5
Marcel Ferrer-Alcón Romano La Harpe José Guimón Jesús A García-Sevilla 《Neuropsychopharmacology》2003,28(5):947-955
Neuronal cyclin-dependent kinase-5 (Cdk5) and its neuron-specific activator p35 play a major role in regulating the cytoskeleton dynamics. Since opioid addiction was associated with hyperphosphorylation of neurofilament (NF) in postmortem human brains, this study was undertaken to assess the status of the cdk5/p35 complex and its relation with NF-H phosphorylation in brains of chronic opioid abusers. Decreased immunodensities of cdk5 (18%) and p35 (26-44%) were found in the prefrontal cortex of opioid addicts compared with matched controls. In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac and mu-calpain were found unaltered. Acute treatment of rats with morphine (30 mg/kg, 2 h) increased the density of cdk5 (35%), but not that of p35, in the cerebral cortex. In contrast, chronic morphine (10-100 mg/kg for 5 days) induced marked decreases in cdk5 (40%) and p35 (47%) in rat brain. In brains of opioid addicts, the density of phosphorylated NF-H was increased (43%) as well as the ratio of phosphorylated to nonphosphorylated NF-H forms (two-fold). In these brains, phosphorylated NF-H significantly correlated with p35 (r=0.58) but not with cdk5 (r=0.03). The results suggest that opiate addiction is associated with downregulation of cdk5/p35 levels in the brain. This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in the development of neural plasticity associated with opiate addiction in humans. 相似文献
47.
Maibritt B Andersen Anders Fink-Jensen Linda Peacock Jes Gerlach Frank Bymaster Jens August Lundbaek Thomas Werge 《Neuropsychopharmacology》2003,28(6):1168-1175
Xanomeline is a muscarinic M(1)/M(4) preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects (EPS) at therapeutically relevant doses. In the present study, we examined whether the xanomeline-induced functional dopamine antagonism found in rodent studies could also be observed in nonhuman primates. In addition, we studied whether the lack of EPS observed in rodents also applies to primates. To this end, we investigated the effects of xanomeline on the behavior induced by D-amphetamine and (-)-apomorphine in drug-naive Cebus apella monkeys. Antipsychotic compounds antagonize amphetamine-induced motor unrest and stereotypies in this species. Xanomeline inhibited D-amphetamine-induced motor unrest, stereotypies and arousal as well as apomorphine-induced stereotypies and arousal in drug-naive Cebus apella monkeys. Xanomeline did not induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patients following xanomeline administration. Even when xanomeline was tested in EPS-sensitized Cebus apella monkeys, EPS were not observed at the dose range of xanomeline used in the D-amphetamine-apomorphine combination study (0.5-3 mg/kg). However, when xanomeline was tested at 4 mg/kg, moderate dystonia was seen in two out of three monkeys. It is concluded that xanomeline inhibits D-amphetamine- and (-)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis. 相似文献
48.
Marta Ruiz Hiroya Kobayashi Juan José Lasarte Jesús Prieto Francisco Borrás-Cuesta Esteban Celis Pablo Sarobe 《Clinical cancer research》2004,10(8):2860-2867
PURPOSE: The purpose of this research was to identify promiscuous T-helper cell determinants (THd) from carcinoembryonic antigen (CEA) to be used to prime T-cell help for cancer therapy. CEA was selected because this antigen is expressed in an important variety of carcinomas. EXPERIMENTAL DESIGN: Potential promiscuous THd from CEA were predicted using available computer algorithms. Predicted peptides were synthesized and tested in binding experiments to different HLA-DR molecules. Binder peptides were then used to prime T-cell responses both in vitro and in vivo. RESULTS: Twenty 15-mer peptides from CEA were predicted to bind to different HLA-DR molecules. The promiscuous character of these peptides was demonstrated in binding experiments. Fifteen of 20 peptides tested were able to bind to HLA-DR4, but only CEA (625-639) was shown to be presented after processing of recombinant CEA. CEA (625-639) was also found to be presented by HLA-DR53. Moreover, immunization of HLA-DR4 transgenic mice with CEA (625-639) in conjunction with class I epitope OVA (257-264), induced a CTL response specific of OVA (257-264). CONCLUSIONS: CEA (625-639) might be a relevant promiscuous THd peptide for cancer therapy. 相似文献
49.
Lilia Suárez María-Belén Vidriales José García-Lara?a Guillermo Sanz María-José Moreno Antonio López Susana Barrena Rafael Martínez Mar Tormo Luis Palomera Esperanza Lavilla Ma Consuelo López-Berges María de Santiago M Encarnación Pérez de Equiza Jesús F San Miguel Alberto Orfao 《Clinical cancer research》2004,10(22):7599-7606
Myelodysplastic syndromes and acute myeloid leukemia (AML) are heterogeneous disorders in which conflicting results in apoptosis and multidrug resistance (MDR) have been reported. We have evaluated by multiparameter flow cytometry the expression of apoptosis- (APO2.7, bcl-2, and bax) and MDR-related proteins [P-glycoprotein (P-gp), multidrug resistance protein (MRP), and lung resistance protein (LRP)] specifically on bone marrow (BM) CD34+ cells, and their major CD32-/dim and CD32+ subsets, in de novo AML (n=90), high-risk myelodysplastic syndrome (n=9), and low-risk myelodysplastic syndrome (n=21) patients at diagnosis, and compared with normal BM CD34+ cells (n=6). CD34+ myeloid cells from AML and high-risk myelodysplastic syndrome patients displayed higher expression of bcl-2 (P <0.0001) and lower reactivity for APO2.7 (P=0.002) compared with low-risk myelodysplastic syndrome and normal controls. Similar results applied to the two predefined CD34+ myeloid cell subsets. No significant differences were found in the expression of P-gp, MRP, and LRP between low-risk myelodysplastic syndrome patients and normal BM, but decreased expression of MRP (P <0.03) in AML and high-risk myelodysplastic syndromes and P-gp (P=0.008) in high-risk myelodysplastic syndromes were detected. Hierarchical clustering analysis showed that low-risk myelodysplastic syndrome patients were clustered next to normal BM samples, whereas high-risk myelodysplastic syndromes were clustered together and mixed with the de novo AML patients. In summary, increased resistance to chemotherapy of CD34+ cells from both AML and high-risk myelodysplastic syndromes would be explained more appropriately in terms of an increased antiapoptotic phenotype rather than a MDR phenotype. In low-risk myelodysplastic syndromes abnormally high apoptotic rates would be restricted to the CD34- cell compartments. 相似文献
50.
Lorenzo Alonso Carrión Francisco Jesús González Sánchez Emilio Alba Conejo Esperanza Torres Sánchez 《Clinical & translational oncology》2004,6(8):462-467
Advanced stage ovarian cancer has a high rate of recurrence even after surgery followed by chemotherapy combining carboplatin
and a taxane. New strategies are currently under way to combat this situation and one of the most promising ones is based
on the knowledge that angiogenesis, the mechanism of formation of new blood vessels coupled with the degradation of the extracellular
matrix for metalloproteinases, could be crucial in the development of this tumor. The principal molecule implicated in angiogenesis
process of ovarian cancer is the vascular endothelial growth factor (VEGF). Several studies are now in progress to clarify
its role as a diagnostic tool or its therapeutic implication. Presently, there is no indication for the use of VEGF in a preliminary
diagnosis seeing that an increase in levels can be seen in both benign and malignant ovarian conditions. VEGF is also responsible
for an increase in vascular permeability and is directly related to symptoms such as ascites and pleural effusion, both of
which are frequent in ovarian cancer. Several papers have analised the role of VEGF as a prognostic factor and some of them
do confirm VEGF as an independent prognostic factor in ovarian cancer. VEGF and the metalloproteinase system coupled with
angiogenesis are currently being evaluated as therapeutic targets but no positive results have yet to be seen in this field.
相似文献