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21.
Joseph A. Jakubowski Dominick J. Angiolillo Chunmei Zhou David S. Small Brian A. Moser Jurrien M. ten Berg Patricia B. Brown Stefan James Kenneth J. Winters David Erlinge 《Thrombosis research》2014
Introduction
Patients treated with clopidogrel who have higher body size exhibit greater platelet reactivity than patients with lower body size. In a retrospective analysis of the FEATHER trial, we examined the relationship between platelet response to thienopyridines clopidogrel 75 mg (Clop-75), prasugrel 5 mg (Pras-5), and prasugrel 10 mg (Pras-10) using 3 body size indices: body weight (BW), body mass index (BMI), and body surface area (BSA). Relationships were assessed as continuous variables and as 4 incremental body size groups.Materials and Methods
Aspirin-treated patients with stable coronary artery disease (N = 72) and a BW range of 45-134 kg received Clop-75, Pras-5, and Pras-10 in a 3-period, blinded, cross-over study. Platelet assays included maximum platelet aggregation (MPA) to 20 μM ADP by light transmission aggregometry, VerifyNow-P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). Exposure to active metabolites (AMs) was also assessed.Results
Body size was a determinant of AM exposure and residual platelet reactivity regardless of type and dose of thienopyridine. BW and BSA demonstrated marginally stronger correlations with platelet reactivity; VASP-PRI demonstrated a stronger correlation with the body size than the other tests. Correlation coefficients ranged from a high of 0.64 (BW vs. PRI on Pras-5) to a low of 0.34 (BMI vs. MPA on Pras-10), but all were statistically significant (p < 0.01).Conclusions
Using a comprehensive selection of body size indices, AM exposures, platelet function tests, and thienopyridine doses, we demonstrated a consistent inverse relationship between body size and response to clopidogrel and prasugrel. 相似文献22.
Albert Dahan Eveline van Dorp Terry Smith Ashraf Yassen 《European Journal of Pain》2008,12(4):403-411
Morphine‐6‐glucuronide (M6G) is morphine's active metabolite acting at the μ‐opioid receptor. Recent experimental human studies and 5 of 6 randomized clinical trials indicate that M6G causes adequate and long lasting pain relief comparable to morphine. There are various observations that M6G is associated with a reduction in the severity of side effects normally associated with opioid use, such as reduced postoperative nausea and vomiting (PONV) and reduced respiratory depression. The present drug profile provides a review of the pharmacological properties of M6G, the clinical evidence relating to its efficacy and safety, and discusses its future role in the treatment of postoperative pain. 相似文献
23.
24.
Jyh-Chin Yang Yu-Fan Yang Yow-Shieng Uang Chun-Jung Lin & Teh-Hong Wang 《British journal of clinical pharmacology》2009,67(5):503-510
AIMS
The aim was to explore the role of CYP2C19 polymorphism in short-term rabeprazole-based triple therapy against Helicobacter pylori infection.METHODS
Patients with H. pylori infection were tested for CYP2C19 genotype as poor metabolizers (PMs) or extensive metabolizers (EMs, homozygous EM or heterozygous EM) and given rabeprazole for 7 days. Antibiotics (clarithromycin and amoxicillin) were given on days 1–4, days 4–7, or days 1–7. A direct link model with an effect compartment was used in the population pharmacokinetic–pharmacodynamic analysis. The status of H. pylori infection was evaluated.RESULTS
Rabeprazole clearance was lower in CYP2C19 PMs than in EMs (with average values of 10.7 vs. 16.8 l h−1 in PMs and EMs, respectively), resulting in higher plasma levels in the former group. The values of EC50 and keo of gastrin response increased with multiple doses of rabeprazole. The keo values were lower in CYP2C19 PMs than in EMs on day 1 (0.012 vs. 0.017 × 10−4 l min−1), and higher than in EMs on day 4 (0.804 vs. 0.169 × 10−4 l min−1) of rabeprazole treatment. The predicted gastrin-time profile showed a higher response in CYP2C19 PMs than in EMs on days 4 and 7. Helicobacter pylori was eradicated in all CYP2C19 PMs except in one patient infected by a resistant strain. In contrast, in CYP2C19 EMs the eradication rates ranged from 58 to 85%.CONCLUSIONS
CYP2C19 genotypes play a role in H. pylori eradication therapy. Rabeprazole-based short-term triple therapy may be applicable in CYP2C19 PMs for H. pylori eradication. 相似文献25.
Yaqub M van Berckel BN Schuitemaker A Hinz R Turkheimer FE Tomasi G Lammertsma AA Boellaard R 《Journal of cerebral blood flow and metabolism》2012,32(8):1600-1608
Performance of two supervised cluster analysis (SVCA) algorithms for extracting reference tissue curves was evaluated to improve quantification of dynamic (R)-[11C]PK11195 brain positron emission tomography (PET) studies. Reference tissues were extracted from images using both a manually defined cerebellum and SVCA algorithms based on either four (SVCA4) or six (SVCA6) kinetic classes. Data from controls, mild cognitive impairment patients, and patients with Alzheimer''s disease were analyzed using various kinetic models including plasma input, the simplified reference tissue model (RPM) and RPM with vascular correction (RPMVb). In all subject groups, SVCA-based reference tissue curves showed lower blood volume fractions (Vb) and volume of distributions than those based on cerebellum time-activity curve. Probably resulting from the presence of specific signal from the vessel walls that contains in normal condition a significant concentration of the 18 kDa translocation protein. Best contrast between subject groups was seen using SVCA4-based reference tissues as the result of a lower number of kinetic classes and the prior removal of extracerebral tissues. In addition, incorporation of Vb in RPM improved both parametric images and binding potential contrast between groups. Incorporation of Vb within RPM, together with SVCA4, appears to be the method of choice for analyzing cerebral (R)-[11C]PK11195 neurodegeneration studies. 相似文献
26.
Imaging of activated microglia with PET and [11C]PK 11195 in corticobasal degeneration. 总被引:3,自引:0,他引:3
Karsten Henkel Jochen Karitzky Michaela Schmid Irina Mader Gerhard Glatting Jürgen W Unger Bernd Neumaier Albert C Ludolph Sven N Reske G Bernhard Landwehrmeyer 《Movement disorders》2004,19(7):817-821
Positron emission tomography (PET) using [(11)C]PK 11195, a ligand for peripheral benzodiazepine receptor binding sites, offers the opportunity to image activated microglia in vivo. This tool may therefore be used to display the occurrence of microglial activation in the course of neurodegeneration. A patient with the clinical diagnosis of corticobasal degeneration (CBD) and left-sided symptoms was studied using fluorodeoxyglucose (FDG) and [(11)C]PK 11195 PET. We found a marked right hemispheric hypometabolism and asymmetric microglial activation in corresponding areas of the basal ganglia and right temporal and parietal cortex. [(11)C]PK 11195 PET suggests involvement of microglial activation in the pathogenesis of CBD. 相似文献
27.
《Placenta》2017
Gestational hypercholesterolemia has been recognized as a risk factor of some pregnancy complications. We supposed that maternal hypercholesterolemia modified the lipid profile of the fetus. Thirty pregnant women with hypercholesterolemia and matched controls were recruited and cord blood was sampled. Lipidomic analysis was used to evaluate the lipid profile change between the two groups. The results showed that the content of diacylglycerophosphocholines (PC) was significantly high in cord blood from hypercholesterolemic pregnant women. PC (16:0/20:4) and PC (18:0/20:4) were selected as the most important lipid species in cord plasma and their contents were positively related to the total cholesterol and high-density lipoprotein cholesterol levels in cord blood. The contents of these two PCs were significantly higher in the hypercholesterolemic group than in the control group. These results suggested that gestational hypercholesterolemia might program the phospholipid metabolism in offspring. 相似文献
28.
Schuitemaker A van der Doef TF Boellaard R van der Flier WM Yaqub M Windhorst AD Barkhof F Jonker C Kloet RW Lammertsma AA Scheltens P van Berckel BN 《Neurobiology of aging》2012,33(6):1067-1072
Healthy brain aging is characterized by neuronal loss and decline of cognitive function. Neuronal loss is closely associated with microglial activation and postmortem studies have indeed suggested that activated microglia may be present in the aging brain. Microglial activation can be quantified in vivo using (R)-[(11)C]PK11195 and positron emission tomography. The purpose of this study was to measure specific binding of (R)-[(11)C]PK11195 in healthy subjects over a wide age range. Thirty-five healthy subjects (age range 19-79 years) were included. In all subjects 60-minute dynamic (R)-[(11)C]PK11195 scans were acquired. Specific binding of (R)-[(11)C]PK11195 was calculated using receptor parametric mapping in combination with supervised cluster analysis to extract the reference tissue input function. Increased binding of (R)-[(11)C]PK11195 with aging was found in frontal lobe, anterior and posterior cingulate cortex, medial inferior temporal lobe, insula, hippocampus, entorhinal cortex, thalamus, parietal and occipital lobes, and cerebellum. This indicates that activated microglia appear in several cortical and subcortical areas during healthy aging, suggesting widespread neuronal loss. 相似文献
29.
Brian J. Werth Nathaniel K. Ashford Kelsi Penewit Adam Waalkes Elizabeth A. Holmes Dylan H. Ross Tianwei Shen Kelly M. Hines Stephen J. Salipante Libin Xu 《Clinical microbiology and infection》2021,27(6):910.e1-910.e8
ObjectivesDalbavancin is a lipoglycopeptide active against methicillin-resistant Staphylococcus aureus (MRSA). Its long half-life (8.5–16 days) allows for once-weekly or single-dose treatments but could prolong the mutant selection window, promoting resistance and cross-resistance to related antimicrobials such as vancomycin. The objective of this study was to evaluate the capacity of post-distributional pharmacokinetic exposures of dalbavancin to select for resistance and cross-resistance in MRSA.MethodsWe simulated average, post-distributional exposures of single-dose (1500 mg) dalbavancin (fCmax 9.9 μg/mL, β-elimination t1/2 204 h) in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model for 28 days (672 h) against five MRSA strains and one methicillin-susceptible strain (MSSA). Samples were collected at least daily, and surviving colonies were enumerated and screened for resistance on drug-free and dalbavancin-supplemented medium respectively. Isolates from resistance screening plates were subjected to whole-genome sequencing (WGS) and susceptibly testing against dalbavancin, vancomycin, daptomycin, and six β-lactams with varying penicillin-binding protein (PBP) affinities.ResultsDalbavancin was bactericidal against most strains for days 1–4 before regrowth of less susceptible subpopulations occurred. Isolates with eight-fold increases in dalbavancin MIC were detected as early as day 4 but increased 64–128-fold in all models by day 28. Vancomycin and daptomycin MICs increased 4–16-fold, exceeding the susceptibly breakpoints for both antibiotics; β-lactam MICs generally decreased by two-to eight-fold, suggesting a dalbavancin–β-lactam seesaw effect, but increased by eight-fold or more in certain isolates. Resistant isolates carried mutations in a variety of genes, most commonly walKR, apt, stp1, and atl.ConclusionsIn our in vitro system, post-distributional dalbavancin exposures selected for stable mutants with reduced susceptibility to dalbavancin, vancomycin, and daptomycin, and generally increased susceptibility to β-lactams in all strains of MRSA tested. The clinical significance of these findings remains unclear, but created an opportunity to genotype a unique collection of dalbavancin-resistant strains for the first time. Mutations involved genes previously associated with vancomycin intermediate susceptibility and daptomycin non-susceptibility, most commonly walKR-associated genes. 相似文献
30.
The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging 总被引:1,自引:0,他引:1
Microglia constitute the primary resident immune surveillance cell in the brain and are thought to play a significant role in the pathogenesis of several neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and HIV-associated dementia. Measuring microglial activation in vivo in patients suffering from these diseases may help chart progression of neuroinflammation as well as assess efficacy of therapies designed to modulate neuroinflammation. Recent studies suggest that activated microglia in the CNS may be detected in vivo using positron emission tomography (PET) utilizing pharmacological ligands of the mitochondrial peripheral benzodiazepine receptor (PBR (recently renamed as Translocator protein (18 kDa)). Beginning with the molecular characterization of PBR and regulation in activated microglia, we examine the rationale behind using PBR ligands to image microglia with PET. Current evidence suggests these findings might be applied to the development of clinical assessments of microglial activation in neurological disorders. 相似文献