全文获取类型
收费全文 | 35309篇 |
免费 | 2877篇 |
国内免费 | 366篇 |
专业分类
耳鼻咽喉 | 385篇 |
儿科学 | 978篇 |
妇产科学 | 954篇 |
基础医学 | 4498篇 |
口腔科学 | 588篇 |
临床医学 | 3683篇 |
内科学 | 7545篇 |
皮肤病学 | 828篇 |
神经病学 | 2370篇 |
特种医学 | 1311篇 |
外科学 | 4843篇 |
综合类 | 1162篇 |
一般理论 | 32篇 |
预防医学 | 1898篇 |
眼科学 | 1569篇 |
药学 | 2707篇 |
2篇 | |
中国医学 | 306篇 |
肿瘤学 | 2893篇 |
出版年
2023年 | 241篇 |
2022年 | 183篇 |
2021年 | 836篇 |
2020年 | 613篇 |
2019年 | 781篇 |
2018年 | 1001篇 |
2017年 | 763篇 |
2016年 | 868篇 |
2015年 | 1046篇 |
2014年 | 1375篇 |
2013年 | 1641篇 |
2012年 | 2346篇 |
2011年 | 2457篇 |
2010年 | 1408篇 |
2009年 | 1242篇 |
2008年 | 1915篇 |
2007年 | 2006篇 |
2006年 | 1998篇 |
2005年 | 1928篇 |
2004年 | 1704篇 |
2003年 | 1585篇 |
2002年 | 1419篇 |
2001年 | 1112篇 |
2000年 | 1050篇 |
1999年 | 890篇 |
1998年 | 343篇 |
1997年 | 250篇 |
1996年 | 234篇 |
1995年 | 215篇 |
1994年 | 208篇 |
1993年 | 209篇 |
1992年 | 457篇 |
1991年 | 444篇 |
1990年 | 426篇 |
1989年 | 425篇 |
1988年 | 363篇 |
1987年 | 391篇 |
1986年 | 336篇 |
1985年 | 299篇 |
1984年 | 215篇 |
1983年 | 157篇 |
1982年 | 99篇 |
1981年 | 93篇 |
1980年 | 100篇 |
1979年 | 142篇 |
1978年 | 92篇 |
1977年 | 84篇 |
1976年 | 83篇 |
1975年 | 77篇 |
1972年 | 69篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Anthonie W. A. Lensing Christoph Male Guy Young Dagmar Kubitza Gili Kenet M. Patricia Massicotte Anthony Chan Angelo C. Molinari Ulrike Nowak-Goettl Ákos F. Pap Ivet Adalbo William T. Smith Amy Mason Kirstin Thelen Scott D. Berkowitz Mark Crowther Stephan Schmidt Victoria Price Martin H. Prins Paul Monagle 《Thrombosis journal》2018,16(1):34
Background
Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20?mg once-daily.Methods
EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20?mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18?years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3?months with the option to continue treatment in 3-month increments, up to a total of 12?months. However, based on most common current practice, children younger than 2?years with catheter-related thrombosis will have a main treatment period of 1?month with the option to prolong treatment in 1-month increments, up to a total of 3?months.Conclusions
EINSTEIN-Jr will compare previously established 20?mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials.Trial registration
Clinicaltrials.gov NCT02234843, registered on 9 September 2014.992.
Kayla R. Lee Abdul Wakeel Papia Chakraborty Chandler S. Foote Lauren Kajiura Joyce C. Barrozo Andrea C. Chan Alexey V. Bazarov Ryan Spitler Peter M. Kutny Jim M. Denegre Rob A. Taft Joachim Seemann Bradley W. Rice Christopher H. Contag Brian K. Rutt Caleb B. BellIII 《Molecular imaging and biology》2018,20(1):55-64
Purpose
The purposes of this study are to characterize magneto-endosymbiont (ME) labeling of mammalian cells and to discern the subcellular fate of these living contrast agents. MEs are novel magnetic resonance imaging (MRI) contrast agents that are being used for cell tracking studies. Understanding the fate of MEs in host cells is valuable for designing in vivo cell tracking experiments.Procedures
The ME’s surface epitopes, contrast-producing paramagnetic magnetosomal iron, and genome were studied using immunocytochemistry (ICC), Fe and MRI contrast measurements, and quantitative polymerase chain reaction (qPCR), respectively. These assays, coupled with other common assays, enabled validation of ME cell labeling and dissection of ME subcellular processing.Results
The assays mentioned above provide qualitative and quantitative assessments of cell labeling, the subcellular localization and the fate of MEs. ICC results, with an ME-specific antibody, qualitatively shows homogenous labeling with MEs. The ferrozine assay shows that MEs have an average of 7 fg Fe/ME, ~30 % of which contributes to MRI contrast and ME-labeled MDA-MB-231 (MDA-231) cells generally have 2.4 pg Fe/cell, implying ~350 MEs/cell. Adjusting the concentration of Fe in the ME growth media reduces the concentration of non-MRI contrast-producing Fe. Results from the qPCR assay, which quantifies ME genomes in labeled cells, shows that processing of MEs begins within 24 h in MDA-231 cells. ICC results suggest this intracellular digestion of MEs occurs by the lysosomal degradation pathway. MEs coated with listeriolysin O (LLO) are able to escape the primary phagosome, but subsequently co-localize with LC3, an autophagy-associated molecule, and are processed for digestion. In embryos, where autophagy is transiently suppressed, MEs show an increased capacity for survival and even replication. Finally, transmission electron microscopy (TEM) of ME-labeled MDA-231 cells confirms that the magnetosomes (the MRI contrast-producing particles) remain intact and enable in vivo cell tracking.Conclusions
MEs are used to label mammalian cells for the purpose of cell tracking in vivo, with MRI. Various assays described herein (ICC, ferrozine, and qPCR) allow qualitative and quantitative assessments of labeling efficiency and provide a detailed understanding of subcellular processing of MEs. In some cell types, MEs are digested, but the MRI-producing particles remain. Coating with LLO allows MEs to escape the primary phagosome, enhances retention slightly, and confirms that MEs are ultimately processed by autophagy. Numerous intracellular bacteria and all endosymbiotically derived organelles have evolved molecular mechanisms to avoid intracellular clearance, and identification of the specific processes involved in ME clearance provides a framework on which to develop MEs with enhanced retention in mammalian cells.993.
Louise Y. Sun Jack V. Tu Heather Sherrard Norvinda Rodger Thais Coutinho Michele Turek Elizabeth Chan Heather Tulloch Lisa McDonnell Lisa M. Mielniczuk 《Journal of cardiac failure》2018,24(9):568-574
Background
Differences in outcomes have previously been reported between urban and rural settings across a multitude of chronic diseases. Whether these discrepancies have changed over time, and how sex may influence these findings is unknown for patients with ambulatory heart failure (HF). We examined the temporal incidence and mortality trends by geography in these patients.Methods and Results
We conducted a retrospective cohort study of 36,175 eastern Ontario residents who were diagnosed with HF in an outpatient setting from 1994 to 2013. The primary outcome was 1-year mortality. We examined temporal changes in mortality risk factors with the use of multivariable Cox proportional hazard models. The incidence of HF decreased in women and men across both rural and urban settings. Age-standardized mortality rates also decreased over time in both sexes but remained greater in rural men compared with rural women.Conclusions
The incidence of HF in the ambulatory setting was greater for men than women and greater in rural than urban areas, but mortality rates remained higher in rural men compared with rural women. Further research should focus on ways to reduce this gap in the outcomes of men and women with HF. 相似文献994.
995.
Occurrence of matrix metalloproteinases and tissue inhibitors of metalloproteinases in tuberculous pleuritis 总被引:1,自引:0,他引:1
Hoheisel G Sack U Hui DS Huse K Chan KS Chan KK Hartwig K Schuster E Scholz GH Schauer J 《Tuberculosis (Edinburgh, Scotland)》2001,81(3):203-209
OBJECTIVE: Matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) have been found in high concentrations in pleural effusions. Because MMP and TIMP may play a part in the causation of the fibrosis seen in tuberculous (TB) pleuritis their occurrence was examined. DESIGN: Pleural effusion fluid and plasma concentrations of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, TIMP-1 and TIMP-2 were determined by ELISA in 21 patients with TB pleuritis. To adjust for the total protein content, respective ratios were calculated. Activities of MMP-2 and MMP-9 were measured by gelatine zymography and the MMP-9/MMP-2 ratios calculated. Pleural effusions and plasma of 15 patients with congestive heat failure (CHF) and plasma of 15 healthy persons (CON) served as controls. RESULTS: Immunoreactive pleural fluid concentrations of MMP-1, MMP-2, MMP-8, and MMP-9 were higher in TB compared to CHF, but plasma concentrations were not different between the groups. TB pleural fluid concentrations of MMP-1, MMP-2, TIMP-1, and TIMP-2 were higher compared to TB plasma. MMP-3 was found in trace amounts only. The MMP-9/total protein ratios in pleural fluid were higher in TB compared to CHF (0.4492+/-0.1633 vs 0.0364+/-0.0145, P<0.005) but the TIMP-1 ratios were lower (139.0+/-28.7 vs 517.8+/-183.7, P<0.0005). In TB pleural fluid vs TB plasma, the respective MMP-1, MMP-2, TIMP-1, and TIMP-2 ratios were increased (0.46+/-0.10 vs 0.17+/-0.02; 25.2+/-2.8 vs 4.2+/-0.9; 139.0+/-28.7 vs 27.8+/-8.2; 0.67+/-0.13 vs 0.18+/-0.04, P<0.0005 each). Gelatine zymography demonstrated MMP-2 and MMP-9 bands of different brightness in TB effusions but in CHF effusions the MMP-9 band was barely visible. The MMP-9/MMP-2 effusion ratios were therefore higher in TB compared to CHF (0.46+/-0.15 vs 0.05+/-0.04, P<0.0005). CONCLUSION: Compartmentalized MMP-1, MMP-2, TIMP-1, and TIMP-2 and, compared to CHF, a surplus of MMP-1, MMP-2, MMP-8, and MMP-9 in the pleural space obviously contribute to the fibrotic reactions in TB pleuritis. 相似文献
996.
Mollica L Preston RJ Chion AC Lees SJ Collins P Lewis S Lane DA 《British journal of haematology》2006,132(4):487-493
Immunoglobulin G (IgG) anti-thrombin autoantibodies (ATA) were purified from the plasma of a patient referred for haematological investigation because of bleeding for 24 h following a dental extraction. The ATA did not inhibit the catalytic activity of thrombin against a chromogenic substrate, suggesting that they did not interact with the active site of thrombin. The ATA did, however, prolong the time required to generate thrombin in plasma, suggesting that they inhibited factor V and factor VIII activation. Surface plasmon resonance (SPR) was used to demonstrate that ATA bound to thrombin with high affinity. Competition of thrombin-ATA binding, using known thrombin exosite I and II ligands (hirudin, thrombomodulin and heparin), demonstrated that ATA bound to both thrombin exosites. Thrombin residues that are important for ATA binding were identified using a library of 53 recombinant thrombin variants encompassing alanine substitutions of 78 surface-exposed residues. They were H66, R68, R70 and Y71 in exosite I, and R89, R93, E94, R98, R245 and K248 in exosite II. ATA bound predominantly to exosite II. They did not bind to prothrombin, illustrating the cryptic nature of both exosites exposed and presented as potential antigens following prothrombin conversion to thrombin. 相似文献
997.
Construction and selection of recombinant plasmids containing full-length complementary DNAs corresponding to rat insulins I and II. 总被引:8,自引:11,他引:8 下载免费PDF全文
S J Chan B E Noyes K L Agarwal D F Steiner 《Proceedings of the National Academy of Sciences of the United States of America》1979,76(10):5036-5040
We have used a synthetic deoxydecanucleotide to generate an insulin-specific cDNA probe suitable for selecting transformants that contain nearly full-length cDNAs corresponding to the mRNAs coding for rat insulins I and II. Double-stranded cDNA was synthesized from x-ray-induced rat insulinoma poly(A)-RNA, inserted in pBR322 plasmid DNA by the homopolymeric tailing technique, and cloned in Escherichia coli chi 1776. Colony hybridization with oligonucleotide-primed cDNA yielded 16 positive clones of which 7 corresponded to rat insulin I mRNA and 9 to rat insulin II mRNA. Restriction endonuclease maps of representative clones of each group indicated that these contained the complete coding sequences, as was confirmed by nucleotide sequence analysis of the 5' region of the cloned DNA for rat insulin II. Nucleotide sequence analysis also established the amino acid sequence of the prepeptide of rat preproinsulin II. Comparison of the amino acid sequence of the prepeptides of rat preproinsulin I and II shows that three conservative amino acid substitutions have occurred in this region of the molecule. 相似文献
998.
Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes 总被引:2,自引:0,他引:2
Aims/hypothesis Although insulin resistance induces compensatory increases in beta cell mass and function to maintain normoglycaemia, it is
not clear whether insulin resistance can precipitate beta cell dysfunction and hyperglycaemia without a pre-existing beta
cell susceptibility. We therefore examined the beta cell phenotype in the MKR mouse, a model in which expression of a dominant-negative
IGF 1 receptor (IGF1R) in skeletal muscle leads to systemic insulin resistance and diabetes.
Materials and methods Circulating glucose, insulin and glucagon concentrations were measured. Insulin sensitivity, glucose tolerance and insulin
release in vivo were assessed by i.p. insulin and glucose tolerance tests. Beta cell function was assessed via insulin secretion
from isolated islets and the glucose gradient in the perfused pancreas. Beta cell morphology was examined via immunohistochemistry.
MKR mice were fed a high-fat diet containing sucrose (HFSD) to test metabolic capacity and beta cell function.
Results Insulin-resistant MKR mice developed hyperglycaemia and a loss of insulin responsiveness in vivo. Basal insulin secretion
from the perfused pancreas was elevated, with no response to glucose. Despite the demand on insulin secretion, MKR mice had
increased pancreatic insulin content and beta cell mass mediated through hyperplasia and hypertrophy. The HFSD worsened hyperglycaemia
in MKR mice but, despite increased food intake in these mice, failed to induce the obesity observed in wild-type mice.
Conclusions/interpretation Our studies demonstrate that insulin resistance of sufficient severity can impair glucose-stimulated insulin secretion, thereby
undermining beta cell compensation and leading to hyperglycaemia. Moreover, because insulin stores were intact, the secretory
defects reflect an early stage of beta cell dysfunction.
Electronic supplementary material Electronic supplementary material is available for this article at
Asghar and Chan contributed equally to this work.
An erratum to this article can be found at 相似文献
999.
Mitochondrial DNA A3243G mutation in patients with early- or late-onset type 2 diabetes mellitus in Hong Kong Chinese 总被引:6,自引:0,他引:6
Ng MC Yeung VT Chow CC Li JK Smith PR Mijovic CH Critchley JA Barnett AH Cockram CS Chan JC 《Clinical endocrinology》2000,52(5):557-564
BACKGROUND: AND OBJECTIVES: The mitochondrial DNA A to G mutation at nucleotide 3243 (mt3243) is associated with a subtype of diabetes characterized by maternal transmission and deafness. We have previously reported a 2.7% prevalence of this mutation in a cohort of young patients with either type 1 or type 2 diabetes. In this study, we aimed to confirm this finding by examining for the prevalence of this mutation in a large-scale study. SUBJECTS AND METHODS: Nine hundred and six unrelated Chinese patients with type 2 diabetes and 213 nondiabetic controls were studied. The presence of mt3243 mutation was determined by polymerase chain reaction amplification and ApaI digestion. RESULTS: This mutation was found in four of 133 (3.0%) patients with early onset (= 40 years) diabetes who also had a positive maternal family history, and in one of 348 (0.3%) patients with late-onset (> 40 years) diabetes and no family history. Basal pancreatic beta-cell function, as assessed by fasting plasma C-peptide, was variable amongst mutation carriers, and did not correlate with the level of heteroplasmy of mutation. CONCLUSIONS: In agreement with most studies, our results suggest that despite the high prevalence of positive maternal family history of diabetes amongst our type 2 diabetic patients, mt3243 mutation was not a major cause of diabetes in either early- or late-onset diabetic patients in Hong Kong. The role of other genetic, environmental and intrauterine factors needs further investigation. 相似文献
1000.
Cho KH Jeong MH Ahn Y Kim YJ Chae SC Hong TJ Seong IW Chae JK Kim CJ Cho MC Seung KB Park SJ;Korea Acute Myocardial Infarction Registry Investigators 《The American journal of cardiology》2010,106(8):1061-1068
The relation between low-density lipoprotein (LDL) cholesterol levels and clinical outcomes after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) has not been described. A total of 9,571 eligible patients (mean age 62.6 ± 12.5 years, 6,967 men) who underwent PCI with a final diagnosis of AMI from the Korea Acute Myocardial Infarction Registry (KAMIR) were divided into 5 groups according to LDL cholesterol level: < 70, 70 to 99, 100 to 129, 130 to 159, and ≥ 160 mg/dl. Clinical outcomes in hospital and 1 and 12 months after PCI in patients with AMI were examined. Age and co-morbidities decreased as LDL cholesterol increased. Patients with higher LDL cholesterol levels had favorable hemodynamic status and laboratory findings. Lifesaving medications, including lipid-lowering drugs, were underused in patients with lower LDL cholesterol levels. Clinical outcomes in hospital and 1 and 12 months after PCI showed better results as LDL cholesterol increased, except for patients with LDL cholesterol levels ≥ 160 mg/dl. In a Cox proportional-hazards model, LDL cholesterol level was not an independent predictor of mortality at 12 months, after adjusting for clinical characteristics including demographics and biologic data. In conclusion, the cholesterol paradox in patients with AMI is related to confounding by baseline characteristics associated with survival. More intensive treatment including lipid-lowering therapy for AMI in patients with lower LDL cholesterol level may result in better clinical outcomes. 相似文献