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991.
Patrycja Kleczkowska Engin Bojnik Anna Leśniak Piotr Kosson Isabelle Van den Eynde Steven Ballet Sandor Benyhe Dirk Tourwé Andrzej W. Lipkowski 《Pharmacological reports : PR》2013,65(4):836-846
BackgroundRecently, we presented a novel compound (PK20, Dmt-D-Lys-Phe-Phe-Lys-Lys-Pro-Phe-Tle-Leu-OH) that targets single entity opioid and neurotensin pharmacophores. This endomorphin-2-like opioid peptide was introduced as a highly active analgesic because it elicited a strong dose- and time-dependent antinociceptive response when administered centrally and peripherally. Its pain-relieving activity was observed as rapidly as 5 min after drug injection. Such promising results led us to perform further studies, such as determining the resistance to enzymatic degradation, which resulted in obtaining a very stable opioid pharmacore PK20 metabolite.MethodsThe synthesis of PK20 and its N-terminal tetrapeptide fragment has been accomplished using solid phase peptide chemistry. The biological stability of peptides has been measured in human serum and analyzed by HPLC/MS. Peptides were pharmacologically characterized in in vitro MOP and DOP receptor binding as well as [35S]GTPγS receptor binding assays. Antinociceptive properties of compounds were measured by in vivo assays in C57Bl6 mice after intravenous or intrathecal applications.ResultsDmt-D-Lys-Phe-Phe-OH (PK20M), an N-terminal tetrapeptide metabolite of the opioid-neurotensin hybrid peptide PK20, is characterized by a long duration of action, as demonstrated by a preserved, long-lasting analgesic effect even 2 h post-injection (average % MPE = 69.33). In rat brain membranes, PK20M efficiently displaced both the MOP and DOP receptor selective radioprobes [3H]DAMGO and [3H]DIDI (pKi of 9.52 and 7.86, respectively) and potently stimulated [35S]GTPγS binding, proving full agonism at both receptor types. In the [35S]GTPγS assay, which measured the agonist-mediated G protein activation, PK20M together with PK20 and Met-enkephalin were potent stimulators of the regulatory G proteins. The relative affinities of PK20M for the μ and δ receptor subtypes revealed μ-receptor selectivity.ConclusionThe novel MOP receptor selective metabolite has been shown to possess opioid subtype receptor selectivity, high potency, and effective analgesic activities as measured in various bioassays. 相似文献
992.
Bartosz Pomierny Andrzej Starek Weronika Krzyżanowska Beata Starek-Świechowicz Irena Smaga Lucyna Pomierny-Chamioło Magdalena Regulska Bogusława Budziszewska 《Pharmacological reports : PR》2013,65(5):1415-1421
BackgroundEthylene glycol ethers (EGEs) are widely used as mixtures in various industrial processes and in many household products. 2-Methoxyethanol and 2-ethoxyethanol primarily exert gonadotoxic effect, while 2-butoxyethanol and 2-isopropoxyethanol have potent hemolytic activity. EGEs can cross the blood-brain barrier, but their potential neurodegenerative action in vivo has not been investigated, yet. In the present work, we examined potential adverse effects of EGEs on some selected brain structures.MethodsA mixture of two compounds: one with stronger hydrophilic properties (2-methoxyethanol or 2-ethoxyethanol) and the second more lipophilic (2-butoxyethanol or 2-isopropoxyethanol) were administered sc for 4 weeks. Total antioxidant capacity, lipid peroxidation and caspase-3 activity were determined in the frontal cortex and hippocampus.ResultsIt has been found that 4-week administration of a mixture of two EGEs, with various intensity, decreased total antioxidant capacity, enhanced lipid peroxidation and increased caspase-3 activity in the frontal cortex and hippocampus of Wistar rat.ConclusionThe obtained results suggested that EGEs exerted adverse effects on the CNS cells and may contribute in pathogenesis of neurodegenerative disorders. 相似文献
993.
Jarogniew J. Łuszczki Andrzej Prystupa Marta Andres-Mach Ewa Marzęda Magdalena Florek-Łuszczki 《Pharmacological reports : PR》2013,65(5):1407-1414
BackgroundThe aim of this study was to determine the effect of ivabradine (a hyperpolarization activated cyclic nucleotide-gated channel (HCN) blocker) on the threshold for maximal electroshock (MEST)-induced tonic seizures in mice.MethodsElectroconvulsionswere produced inmice bymeans of a current (sine-wave, 50Hz,maximum500V, strength from3–10mA, ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint).ResultsIvabradine administered intraperitoneally (ip), 60 min before the MEST test, at doses of 5 and 10 mg/kg, did not alter the threshold for maximal electroconvulsions in mice. In contrast, ivabradine at doses of 15 and 20 mg/kg significantly elevated the threshold for maximal electroconvulsions in mice (p < 0.05 and p < 0.001, respectively). Linear regression analysis of ivabradine doses and their corresponding threshold increases allowed determination of the threshold increasing doses by 20 and 50% (TID20 and TID50 values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID20 and TID50 values for ivabradine were 8.70 and 18.29 mg/kg, respectively.ConclusionsBased on this preclinical study, one can ascertain that ivabradine dose-dependently increased the threshold for MEST-induced seizures, suggesting the antiseizure activity of the compound in this seizure model in mice. 相似文献
994.
Andrzej ?yluk Katarzyna Paszkowska-Szczur Satish Gupta Rodney J Scott Jan Lubiński Tadeusz D?bniak 《Hereditary cancer in clinical practice》2014,12(1):6
The object of this study was the investigation of the risk of occurrence of malignant neoplasms in 508 patients with Dupuytren’s disease (DD) and in 2157 of their 1st degree relatives. In the first stage of the study, we evaluated the tumour spectrum as well as the age of the patient at diagnosis of cancers in DD families along with the observed and expected frequencies of malignancies. In the second stage of the study, we examined the distribution of 20 common mutations/polymorphisms in 12 known cancer susceptibility genes among DD patients and 508 matched healthy controls. No such study has been published to date. Results. No significant differences were noted between malignancies diagnosed among members of DD families and the general population. Molecular examination of 20 mutations/polymorphisms in 12 cancer susceptibility genes in Dupuytren’s patients and controls showed a statistically significant association of one mutation with Dupuytren disease: D312M in XPD (OR = 1.75, p = 0.004). We observed a tendency toward changed frequencies of occurrence of central nervous system tumors, laryngeal cancer and non-melanoma skin cancers in DD families. The results of our study indicate a lack of a strong association between Dupuytren disease and familial cancer risk. 相似文献
995.
996.
Anna Pryczynicz Katarzyna Guzińska-Ustymowicz Katarzyna Niewiarowska Dariusz Cepowicz Andrzej Kemona 《Tumour biology》2014,35(7):6587-6592
E-cadherin, a transmembrane adhesion molecule, and phosphatase of regenerating liver 3 (PRL-3) protein, a member of the family of tyrosine phosphatases, seem to be responsible for cancer cell migration. Therefore, the study objective was to determine a correlation between PRL-3 and E-cadherin, to assess their expression in neoplastic tissue and normal mucosa of the stomach, to analyze their effect on cancer advancement, and to evaluate their potential as prognostic markers in gastric cancer. The expressions of PRL-3 and E-cadherin were assessed immunohistochemically in 71 patients with gastric cancer. Positive expression of PRL-3 was observed in 42.2 % of gastric cancer cases, whereas E-cadherin expression was abnormal in 38 % of cases. The study revealed that the positive PRL-3 expression and abnormal E-cadherin expression were associated with mucinous gastric carcinoma and lymph node involvement. The former was also related to the infiltrating type of tumor and abnormal E-cadherin expression. The expression of PRL-3, but not of E-cadherin, was associated with shorter survival of patients. PRL-3 and E-cadherin exhibit interactions in gastric cancer and are involved in the formation of lymph node metastases. The PRL-3 protein can be an independent predictive factor of overall survival in gastric cancer patients. 相似文献
997.
New insights into impairment of mucosal defense in portal hypertensive gastric mucosa 总被引:5,自引:0,他引:5
Morimasa Tomikawa M.D. Yasunori Akiba M.D. Jonathan D. Kaunitz M.D. Hirofumi Kawanaka M.D. Keizo Sugimachi M.D. I. James Sarfeh M.D. Andrzej S. Tarnawski M.D. D.Sc. 《Journal of gastrointestinal surgery》2000,4(5):458-463
Portal hypertension (PHT) increases susceptibility of the gastric mucosa to injury. The aim of this study was to investigate
whether PHT affects rat gastric mucosal defense mechanisms in vivo at the preepithelial, epithelial, and/or post-epithelial
levels. PHT was produced in rats by staged portal vein ligation and sham-operated (SO) rats served as controls. The gastric
mucosa was exposed, chambered, and continuously superfused with buffers under in vivo microscopy. We measured gastric mucosal
gel layer thickness, surface epithelial cell intracellular pH (pH1), mucosal blood flow, and mucosal/serosal oxygenation. In PHT rats, gastric mucosal gel layer thickness was significantly
reduced (88 ±16 μm in PHT rats vs. 135 ±25 μm in SO rats; P <0.0001), and the surface epithelial cell pH1 was significantly decreased (6.80 ± 0.11 in PHT rats vs. 7.09 ± 0.21 in SO rats; P <0.01). Although total gastric mucosal blood flow was significantly increased in PHT rats by 72 % (P <0.05), the oxygenation of the gastric mucosal surface was decreased by 42 % (P <0.05) compared with SO rats. PHT impairs
pre-epithelial (mucosal gel layer thickness), epithelial (pH1), and post-epithelial (maldistribution of blood flow) components of the gastric mucosal barrier. These findings can explain
the increased susceptibility of portal hypertensive gastric mucosa to injury.
Supported by Veterans Affairs Medical Research Service Merit Review Awards (J.D.K., I.J.S., and AS.T.) and a REAP award.
Presented at the Fortieth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Fla., May 16–19, 1999. 相似文献
998.
Artur Dziewierz Krzysztof Ciszowski Tomasz Gawlikowski Tomasz Rakowski Paweł Kleczyński Andrzej Surdacki Dariusz Dudek 《The Journal of emergency medicine》2013
Background
ST-segment elevation myocardial infarction (STEMI) due to coronary artery occlusion in the setting of acute carbon monoxide (CO) poisoning is a very rare presentation.Objective
Our aim was to report on the use of primary angioplasty in a patient with STEMI in the setting of CO poisoning.Case Report
A 36-year-old man with retrosternal chest pain was admitted after exposure to CO. The initial electrocardiogram (ECG) showed ST depression in I, aVL, and V3−V4 with slight ST elevation in II, III, aVF leads. Toxic carboxyhemoglobin level of 22% and troponin I of 2.19 μg/L were confirmed. After oxygen therapy the chest pain diminished, but after about 15 h it returned. The repeat ECG revealed normalization of previous ST depression with persistent ST elevation in II, III, aVF leads. The troponin I concentration was 5.94 μg/L. An echocardiogram demonstrated an apex hypokinesia involving the adjacent segments of the anterior and lateral wall. On the coronary angiogram, an acute occlusion of the distal left anterior descending coronary artery was confirmed. Primary percutaneous coronary intervention (PCI) of the infarct-related artery was performed. After PCI, the patient was symptom free and had partial ST-segment elevation resolution. The patient was discharged home after 7 days, with persistent ST-T changes and mild hypokinesia of the apex suggesting myocardial injury.Conclusions
Patients with toxic CO exposure who have symptoms of STEMI should be carefully evaluated with serial ECG, cardiac necrosis marker measurements, and an echocardiogram. When there is evidence of myocardial injury, a wider use of coronary angiography can identify patients who could benefit from PCI. 相似文献999.
Anna Kociemba Ma?gorzta Pyda Katarzyna Katulska Magdalena ?anocha Andrzej Siniawski Magdalena Janus Stefan Grajek 《Journal of cardiovascular magnetic resonance》2013,15(1):90
Background
Recent studies, performed with the use of a commercially available diffusion weighted imaging (DWI) sequence, showed that they are sensitive to the increase of water content in the myocardium and may be used as an alternative to the standard T2-weighted sequences. The aim of this study was to compare two methods of myocardial edema imaging: DWI and T2-TIRM.Methods
The study included 91 acute and post STEMI patients. We applied a qualitative and quantitative image analysis. The qualitative analysis consisted of evaluation of the quality of blood suppression, presence of artifacts and occurrence of high signal (edema) areas. On the basis of edema detection in AMI and control (post STEMI) group, the sensitivity and specificity of TIRM and DWI were determined. Two contrast to noise ratios (CNR) were calculated: CNR1 - the contrast between edema and healthy myocardium and CNR2 - the contrast between edema and intraventricular blood pool. The area of edema was measured for both TIRM and DWI sequences and compared with the infarct size in LGE images.Results
Edema occurred more frequently in the DWI sequence. A major difference was observed in the inferior wall, where an edema-high signal was observed in 46% in T2-TIRM, whereas in the DWI sequence in 85%. An analysis of the image quality parameters showed that the use of DWI sequence allows complete blood signal suppression in the left ventricular cavity and reduces the occurrence of motion artifacts. However, it is connected with a higher incidence of magnetic susceptibility artifacts and image distortion. An analysis of the CNRs showed that CNR1 in T2-TIRM sequence depends on the infarct location and has the lowest value for the inferior wall. The area of edema measured on DWI images was significantly larger than in T2-TIRM.Conclusions
DWI is a new technique for edema detection in patients with acute myocardial infarction which may be recommended for the diagnosis of acute injuries, especially in patients with slow-flow artifacts in TIRM images. 相似文献1000.
Robert P. Ostrowski Zdzisawa Kowalska Sawomir Jauszewski Andrzej Kapuciski 《Drug development research》2005,64(3):137-144
In previous studies, bosentan was found to decrease plasma leptin concentrations after myocardial infarction (MI) in rats and had decreased mortality. The present study was undertaken to examine the effect of bosentan on leptin and endothelin‐1 (ET‐1) concentrations in plasma and ET‐1 concentrations in the hippocampus after cardiac arrest (CA) in rats. Studies were performed in 72 rats divided into treated and untreated animals in the following experimental groups: control, 3 min, 10 min, 1 h, 24 h, and 7 days after CA. Bosentan was given daily 2 h before CA or decapitation, 7 days, by gavage at a dose of 100 mg/kg. Plasma leptin concentration decreased in the early period after CA, and being elevated in 24 h, normalized 1 week later. Bosentan kept plasma leptin concentration at the control level in the postischemic period. Plasma ET‐1 concentration significantly increased during the postischemic period. Bosentan produced the elevation of plasma ET‐1 concentration in the preischemic period and kept the level of ET‐1 at control values after CA. Concentration of ET‐1 in the hippocampus was significantly lower 24 h after CA and was elevated after 1 week. The most dramatic effect of bosentan on ET‐1 concentration was in the hippocampus, where it significantly decreased during the entire postischemic recovery period. We postulate an important effect of bosentan on concentration of ET‐1 and leptin in plasma and ET‐1 in the brain after global cerebral ischemia caused by CA. Drug Dev Res 64:137–144, 2005. © 2005 Wiley‐Liss, Inc. 相似文献