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排序方式: 共有7295条查询结果,搜索用时 15 毫秒
991.
Menon D Karyekar CS Fasano A Lu R Eddington ND 《International journal of pharmaceutics》2005,306(1-2):122-131
OBJECTIVE: The objective of this study was to evaluate the ability of DeltaG, the 12 kDa active fragment of ZOT, to increase the brain distribution of MTX and paclitaxel, two commonly used anticancer agents with poor distribution into the brain. METHODS: As part of dose estimation of DeltaG, [14C]-sucrose (40 microCi/kg), a hydrophilic paracellular marker, was co-administered with DeltaG (0, 400 and 800 microg/kg) with and without protease inhibitors to male Sprague-Dawley rats (n=3 per group) via an intracarotid cannula. MTX (50 mg/kg) and [3H]-paclitaxel (120 microCi/kg) were co-administered with the effective doses of DeltaG determined from the above study via the intracarotid cannula. Animals were euthanized by carbon dioxide asphyxiation at the specified time periods and brain and plasma samples were analyzed for the respective drug. RESULTS: The brain distribution of [14C]-sucrose was significantly enhanced at both doses of DeltaG. A fold enhancement in the B/P ratios of 1.88 and 2.68 was observed at the 400 and 800 microg/kg doses respectively, when the protein was protected from metabolic degradation with PIs. DeltaG significantly increased the brain distribution of MTX at each of the doses administered, with over a seven-fold increase at the 600 microg/kg dose. [3H]-paclitaxel brain AUC(0-60 min) was significantly higher in the presence of DeltaG (800 microg/kg with PIs) with a 2.5-fold enhancement in brain exposure. CONCLUSIONS: DeltaG significantly enhances the brain distribution of MTX (hydrophilic) and paclitaxel (lipophilic) and has the potential to be further developed as adjunct therapy to increase delivery of poorly permeable chemotherapeutic and other CNS targeted compounds. 相似文献
992.
Lund BW Piu F Gauthier NK Eeg A Currier E Sherbukhin V Brann MR Hacksell U Olsson R 《Journal of medicinal chemistry》2005,48(24):7517-7519
4'-Octyl-4-biphenylcarboxylic acid (1g, AC-55649) was identified as a highly isoform-selective agonist at the human RARbeta2 receptor in a functional intact cell-based screening assay. The subsequent hit to lead optimization transformed the lipophilic, poorly soluble hit into a more potent and orally available compound (2, AC-261066) with retained beta2 selectivity and greatly improved physiochemical properties. Being an isoform-selective RARbeta2 receptor agonist that discriminates between nuclear receptor isoforms having identical ligand binding domains, 2 will be useful as a pharmacological research tool but also a valuable starting point for drug development. 相似文献
993.
Ciallella JR Saporito M Lund S Leist M Hasseldam H McGann N Smith CS Bozyczko-Coyne D Flood DG 《European journal of pharmacology》2005,520(1-3):179-187
Oxidative stress and low-grade inflammation are hallmarks of diabetes mellitus. We explored protective, blood pressure-independent effects of the angiotensin II type 1 (AT1) receptor antagonist candesartan and the selective β1-adrenoceptor antagonist metoprolol. Diabetes mellitus was induced in 8-week-old Sprague–Dawley rats after injection of streptozotocin. Diabetic rats were randomized to treatment with candesartan or metoprolol in sub-antihypertensive doses or to placebo treatment. In the quadriceps, musculature markers of oxidative stress and inflammation were determined. Function of the inherent vascular bed was measured in vivo in the autoperfused hindlimb. Increases in NAD(P)H activity, expression of its cytosolic subunit p22phox and of endothelial NO synthase e(NOS) displayed enhanced oxidative stress. Upregulated intercellular (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and of inducible NOS (iNOS) revealed inflammatory processes. Diabetes was associated with severe impairment of endothelium-dependent and -independent vasodilatation. Candesartan, but not metoprolol, reduced NAD(P)H activity, attenuated diabetes-induced over-expression of p22phox and eNOS mRNA as well as ICAM-1, VCAM-1, iNOS and eNOS immunoreactivity and led to a substantial improvement of endothelium-dependent vasodilatation (+ 46.3% vs. placebo treatment; P < 0.05). Angiotensin AT1 receptor antagonism, but not β1-adrenoceptor antagonism, ameliorates diabetes-generated oxidative stress, indicating a pivotal role of the renin–angiotensin system in the development of diabetic complications. 相似文献
994.
As prescribers of opioid pharmacotherapies, general practitioners (GPs) are pivotal to the sustainability of opioid pharmacotherapy treatment services. The goal of this study was to examine the nature and sustainability of the Australian GP prescriber workforce in order to inform future programmes and policy development in this area. Data were collected from four Australian states: South Australia, Queensland, Victoria and New South Wales. Key features of the available data were: a heavy client load carried by a small number of prescribers, a high proportion of trained but inactive prescribers, and a high proportion (one-third to two-thirds) of medical practitioners who undertake training but do not take up prescribing, i.e. a high attrition rate. Available data indicate significant shortfalls in the number of prescribers available in each state to service this patient population. Across all states a relatively small number of prescribers were providing services for the majority of methadone clients. In order to achieve sustainable, high quality prescriber service provision, workforce development strategies are needed which focus on recruitment of new prescribers, and the support and retention of existing and inactive prescribers. Establishment of systematic and detailed data collection systems should also be considered a priority. [Hotham E, Roche A, Skinner N, Dolman B. The GP pharmacotherapy prescribing workforce: examining sustainability from a systems perspective. Drug Alcohol Rev 2005;24:393-400] 相似文献
995.
Seabury CM Honeycutt RL Rooney AP Halbert ND Derr JN 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(42):15142-15147
Amino acid replacements encoded by the prion protein gene (PRNP) have been associated with transmissible and hereditary spongiform encephalopathies in mammalian species. However, an association between bovine spongiform encephalopathy (BSE) and bovine PRNP exon 3 has not been detected. Moreover, little is currently known regarding the mechanisms of evolution influencing the bovine PRNP gene. Therefore, in this study we evaluated the patterns of nucleotide variation associated with PRNP exon 3 for 36 breeds of domestic cattle and representative samples for 10 additional species of Bovinae. The results of our study indicate that strong purifying selection has intensely constrained PRNP over the long-term evolutionary history of the subfamily Bovinae, especially in regions considered to be of functional, structural, and pathogenic importance in humans as well as other mammals. The driving force behind this intense level of purifying selection remains to be explained. 相似文献
996.
Roschnik N Parawan A Baylon MA Chua T Hall A 《Tropical medicine & international health : TM & IH》2004,9(8):904-909
OBJECTIVES: To examine the effectiveness of weekly iron supplements given for 10 weeks by teachers to children in rural schools in the Philippines. METHODS: Forty-nine rural primary schools took part in the study and were randomly assigned to two groups: children in 25 schools received a weekly tablet providing 108 mg iron while children in 24 schools acted as controls. All children were dewormed before the start of the iron supplementation. The haemoglobin concentration of a systematic sample of one in three children in two classes in each school was estimated before and 5-17 weeks after the end of the iron supplementation. RESULTS: A total of 1510 children aged 7-12 years were studied at both surveys. The mean haemoglobin concentration of children in the intervention group did not change significantly; in the untreated group it fell by 3.8 g/l and the prevalence of anaemia rose from 14.3% to 25.6%. The difference between study groups was significantly larger amongst the younger children (7-8 years), and was observed in both anaemic and non-anaemic children. CONCLUSION: Even where anaemia is only a mild public health problem, weekly iron supplements given by teachers may prevent a fall in the haemoglobin concentration, and can benefit both anaemic and non-anaemic children. 相似文献
997.
998.
999.
Sharma AK Bury MI Fuller NJ Rozkiewicz DI Hota PV Kollhoff DM Webber MJ Tapaskar N Meisner JW Lariviere PJ Destefano S Wang D Ameer GA Cheng EY 《Journal of biomedical materials research. Part A》2012,100(3):561-570
The ultimate success of in vivo organ formation utilizing ex vivo expanded "starter" tissues relies heavily upon the level of vascularization provided by either endogenous or artificial induction of angiogenic or vasculogenic events. To facilitate proangiogenic outcomes and promote tissue growth, an elastomeric scaffold previously shown to be instrumental in the urinary bladder regenerative process was modified to release proangiogenic growth factors. Carboxylic acid groups on poly(1,8-octanediol-co-citrate) films (POCfs) were modified with heparan sulfate creating a heparan binding POCf (HBPOCf). Release of proangiogenic growth factors vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and insulin-like growth factor 1 (IGF-1) from HBPOCfs demonstrated an approximate threefold increase over controls during a 30-day time course in vitro. Atomic force microscopy demonstrated significant topological differences between films. Subcutaneous implantation of POCf alone, HBPOCf, POCf-VEGF, and HBPOCf-VEGF within the dorsa of nude rats yielded increased vascular growth in HBPOCf-VEGF constructs. Vessel quantification studies revealed that POCfs alone contained 41.1 ± 4.1 vessels/mm2, while HBPOCf, POCf-VEGF, and HBPOCF-VEGF contained 41.7 ± 2.6, 76.3 ± 9.4, and 167.72 ± 15.3 vessels/mm2, respectively. Presence of increased vessel growth was demonstrated by CD31 and vWF immunostaining in HBPOCf-VEGF implanted areas. Data demonstrate that elastomeric POCfs can be chemically modified and possess the ability to promote angiogenesis in vivo. 相似文献
1000.
Susanne Kumpulainen Natalie Mrachacz-Kersting Jussi Peltonen Michael Voigt Janne Avela 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2012,221(3):241-249
Changes in the excitability of the cortical projections to muscles in the upper and lower limbs can be induced in the intact human by paired associative stimulation (PAS). An interstimulus interval (ISI) of 25 ms between peripheral nerve and transcranial magnetic stimuli has been found to be effective when targeting hand muscles. The optimal ISI to induce plasticity changes in the cortical projections to lower limbs is still not well established. The purpose of this study was twofold: first, to investigate the effect of PAS with four different ISIs based on the individual latency of the sensory evoked potential (SEP plus 6, 12, 18 and 24 ms) and second, to evaluate the repeatability of the established optimal ISI. Transcranial magnetic stimulation was used to measure changes in the motor evoked potentials (MEPs) of the soleus (SOL) muscle before and after the PAS interventions. Significant increases in the amplitude of SOL MEPs (88 %) were attained with an ISI of SEP latency plus 18 ms (P32 + 18 ms). The PAS effect was long-lasting, input-specific and supraspinal in origin. The intraclass correlation coefficient to test the repeatability of the PAS intervention with the optimal ISI was 0.85. The results show that the excitability of cortical projections to the soleus muscle can be repeatedly increased after PAS with an optimal ISI of SEP plus 18 ms. 相似文献