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51.
A simple reproducible and versatile small animal model for hepatitis B virus (HBV) infection is still unavailable. We have generated a simple transient liver-targeted transgenic mouse. Hydrodynamics tail vein injection of a head-to-tail dimer of adw HBV genome (pHBVadwHTD) into immunocompetent mice generated HBsAg and HBeAg expression in both serum and hepatocytes, followed by seroconversion. The injection of pHBVadwHTD into SCID mice generated prolonged HBsAg and HBeAg antigenemia and HBV viremia. Our results demonstrate that hydrodynamic injection of naked DNA could support the generation of HBV particles. We used this model for the assessment of anti-viral agents. Administration of our human monoclonal antibodies, HBV-Ab17(XTL) and HBV-Ab19(XTL), as well as Lamivudine (3TC) treatment suppressed HBV viremia. The model presented herein supports long and stable expression of HBV and will enable determination of various biological questions related to HBV life cycle, mutants and could enhance the development of anti-viral reagents.  相似文献   
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A liquid chromatography-high resolution mass spectrometry (LC-HRMS) method was developed using three peptide drugs: salmon calcitonin, bivalirudin, and exenatide as model systems to assess the suitability of this approach for monitoring peptide drug product quality. Calcitonin and its related impurities displayed linear responses over the range from 0.1 to 10 μM (R2 values for calcitonin salmon, Glu14-calcitonin, and acetyl-calcitonin were 0.995, 0.996, and 0.993, respectively). Intra-assay precision in terms of relative standard deviation (%RSD) was less than 10% at all tested concentrations. The accuracy of the method was greater than 85% as measured by spiking 0.1, 0.3, and 1% of Glu14-calcitonin and acetyl-calcitonin into a stock calcitonin solution. Limits of detection for calcitonin, Glu14-calcitonin, and acetyl-calcitonin were 0.02, 0.03, and 0.04 μM, respectively, indicating that an impurity present at less than 0.1% (0.1 μM) of the drug product API concentration (107 μM) could be detected. Method validation studies analyzing bivalirudin and exenatide drug products exhibited similar results to calcitonin salmon in regard to high selectivity, sensitivity, precision, and linearity. Added benefits of using LC-HRMS-based methods are the ability to also determine amino acid composition, confirm peptide sequence, and quantify impurities, even when they are co-eluting, within a single experiment. LC-HRMS represents a promising approach for the quality control of peptides including the measurement of any peptide-related impurities. While the development work performed here is focus on peptide drug products, the principles could be adapted to peptide drug substance.KEY WORDS: High resolution mass spectrometry, impurity profiling, LC-HRMS, peptide drug  相似文献   
53.
Long QT syndrome     
The hereditary long QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity to syncope, polymorphous ventricular tachycardia (torsades de pointes), and sudden arrhythmic death. This inherited cardiac disorder constitutes an important cause of malignant ventricular arrhythmias and sudden cardiac death in young individuals with normal cardiac morphology. Risk assessment in affected LQTS patients relies upon a constellation of electrocardiographic, clinical, and genetic factors. Administration of beta-blockers is the mainstay therapy in affected patients, and primary prevention with an implantable cardioverter defibrillator or left cervicothoracic sympathetic denervation are therapeutic options in patients who remain symptomatic despite beta-blocker therapy. Accumulating data from the International LQTS Registry have recently facilitated a comprehensive analysis of risk factors for aborted cardiac arrest or sudden cardiac death in pre-specified age groups, including the childhood, adolescence, adulthood, and post-40 periods. These analyses have consistently indicated that the phenotypic expression of LQTS is time dependent and age specific, warranting continuous risk assessment in affected patients. Furthermore, the biophysical function, type, and location of the ion-channel mutation are currently emerging as important determinants of outcome in genotyped patients. These new data may be used to improve risk stratification and for the development of gene-specific therapies that may reduce the risk of life-threatening cardiac events in patients with this inherited cardiac disorder.  相似文献   
54.
BACKGROUND AND AIMS: Protein malnutrition in patients with chronic liver disease contributes to bone and muscle weakness and compromises immune function and survival. In contrast, high-protein diets may induce or exacerbate hepatic encephalopathy. The aim of the present study was to test whether increased amounts of protein, balanced by dietary carbohydrate in a 1:5 ratio, may be given to chronic liver disease patients in order to minimize postprandial increases in plasma amino acid (AA) concentrations. METHODS: Eight patients with chronic liver disease were studied. Each received, in a randomized order, three different diets of 2510 kJ of either high protein (37:50:28, carbohydrate:protein:fat), high carbohydrate (126:10:6) or a balanced 5:1 carbohydrate:protein diet (105:21:11). All patients were followed for plasma AA, glucose and insulin levels, as well as for cognitive and behavioral changes. RESULTS: Following the high protein diet, AA concentrations were significantly increased. In contrast, after the balanced diet, AA levels were practically constant enabled. All diets was well tolerated and no cognitive or behavioral changes appeared. CONCLUSION: The administration of a balanced 5:1 carbohydrate:protein diet may enable patients with chronic liver disease to tolerate increased amounts of dietary protein, without altering plasma amino acid concentrations.  相似文献   
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OBJECTIVES: The study was designed to assess the effect of elapsed time from coronary revascularization (CR) on the benefit of the implantable cardioverter-defibrillator (ICD) and the risk of sudden cardiac death (SCD) in patients with ischemic left ventricular dysfunction. BACKGROUND: The ICD improves survival in appropriately selected high-risk cardiac patients by 30% to 54%. However, in the Coronary Artery Bypass Graft (CABG)-Patch trial no evidence of improved survival was shown among a similar population of patients in whom an ICD was implanted prophylactically at the time of elective CABG. METHODS: The outcome by time from CR was analyzed in 951 patients in whom a revascularization procedure was performed before enrollment in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. RESULTS: The adjusted hazard ratio (HR) of ICD versus conventional therapy was 0.64 (p = 0.01) among patients enrolled more than six months after CR, whereas no survival benefit with ICD therapy was shown among patients enrolled six months or earlier after CR (HR = 1.19; p = 0.76). In the conventional therapy group, the risk of cardiac death increased significantly with increasing time from CR (p for trend = 0.009), corresponding mainly to a six-fold increase in the risk of SCD among patients enrolled more than six months after CR. CONCLUSIONS: In patients with ischemic left ventricular dysfunction, the efficacy of ICD therapy after CR is time dependent, with a significant life-saving benefit in patients receiving device implantation more than six months after CR. The lack of ICD benefit when implanted early after CR may be related to a relatively low risk of SCD during this time period.  相似文献   
58.
Endocannabinoids and liver disease--review.   总被引:4,自引:0,他引:4  
AIMS: Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease. METHODS: The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered. RESULTS: Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function. CONCLUSIONS: Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities.  相似文献   
59.
Introduction: Hereditary hemochromatosis (HH) is an autosomal recessive disorder that occurs in approximately 1 in 200–250 individuals. Mutations in the HFE gene lead to excess iron absorption. Excess iron in the form of non-transferrin-bound iron (NTBI) causes injury and is readily uptaken by cardiomyocytes, pancreatic islet cells, and hepatocytes. Symptoms greatly vary among patients and include fatigue, abdominal pain, arthralgias, impotence, decreased libido, diabetes, and heart failure. Untreated hemochromatosis can lead to chronic liver disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Many invasive and noninvasive diagnostic tests are available to aid in diagnosis and treatment. MRI has emerged as the reference standard imaging modality for the detection and quantification of hepatic iron deposition, as ultrasound (US) is unable to detect iron overload and computed tomography (CT) findings are nonspecific and influenced by multiple confounding variables. If caught and treated early, HH disease progression can significantly be altered.

Area covered: The data on Hemochromatosis, iron overload, and MRI were gathered by searching PubMed.

Expert commentary: MRI is a great tool for diagnosis and management of iron overload. It is safe, effective, and a standard protocol should be included in diagnostic algorithms of future treatment guidelines.  相似文献   

60.

Purpose of Review

The global emergence of antifungal resistance among Candida spp. and Aspergillus spp. will disproportionately affect transplantation recipients, who are prone to invasive fungal disease.

Recent Findings

Invasive candidiasis is increasingly caused by non-albicans Candida species with reduced susceptibility to first-line antifungals. Echinocandin resistance in Candida glabrata is increasing in some settings. Candida auris has rapidly emerged as a global concern due to multidrug resistance and efficient nosocomial spread in healthcare settings. Azole-resistant Aspergillus fumigatus is already an important concern in some European countries and is increasingly reported elsewhere, possibly driven by agricultural use of triazole fungicides.

Summary

Antifungal resistance is anticipated to expand among these and other common fungal pathogens. Culture-independent detection methods will become more important for rapid diagnosis and to guide empiric therapy. Antifungal stewardship is of critical importance to conserve our limited antifungal armamentarium for transplantation recipients and other vulnerable patients.
  相似文献   
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