全文获取类型
收费全文 | 1111篇 |
免费 | 82篇 |
国内免费 | 10篇 |
专业分类
耳鼻咽喉 | 3篇 |
儿科学 | 57篇 |
妇产科学 | 17篇 |
基础医学 | 161篇 |
口腔科学 | 16篇 |
临床医学 | 112篇 |
内科学 | 194篇 |
皮肤病学 | 20篇 |
神经病学 | 135篇 |
特种医学 | 82篇 |
外科学 | 95篇 |
综合类 | 28篇 |
一般理论 | 1篇 |
预防医学 | 146篇 |
眼科学 | 43篇 |
药学 | 53篇 |
肿瘤学 | 40篇 |
出版年
2022年 | 12篇 |
2021年 | 15篇 |
2020年 | 16篇 |
2019年 | 19篇 |
2018年 | 23篇 |
2017年 | 16篇 |
2016年 | 26篇 |
2015年 | 30篇 |
2014年 | 40篇 |
2013年 | 47篇 |
2012年 | 62篇 |
2011年 | 52篇 |
2010年 | 35篇 |
2009年 | 26篇 |
2008年 | 35篇 |
2007年 | 41篇 |
2006年 | 37篇 |
2005年 | 47篇 |
2004年 | 38篇 |
2003年 | 29篇 |
2002年 | 28篇 |
2001年 | 18篇 |
2000年 | 32篇 |
1999年 | 27篇 |
1998年 | 31篇 |
1997年 | 24篇 |
1996年 | 32篇 |
1995年 | 26篇 |
1994年 | 22篇 |
1993年 | 16篇 |
1992年 | 21篇 |
1991年 | 21篇 |
1990年 | 16篇 |
1989年 | 19篇 |
1988年 | 19篇 |
1987年 | 12篇 |
1986年 | 13篇 |
1985年 | 18篇 |
1984年 | 10篇 |
1983年 | 8篇 |
1982年 | 11篇 |
1981年 | 9篇 |
1979年 | 11篇 |
1978年 | 8篇 |
1977年 | 12篇 |
1976年 | 7篇 |
1974年 | 10篇 |
1971年 | 8篇 |
1970年 | 10篇 |
1968年 | 7篇 |
排序方式: 共有1203条查询结果,搜索用时 15 毫秒
991.
Gwen Bergen Cora Peterson David Ederer Curtis Florence Tadesse Haileyesus Marcie-jo Kresnow Likang Xu 《MMWR. Morbidity and mortality weekly report》2014,63(40):894-900
Background
Motor vehicle crashes are a leading cause of death and injury in the United States. The purpose of this study was to describe the current health burden and medical and work loss costs of nonfatal crash injuries among vehicle occupants in the United States.Methods
CDC analyzed data on emergency department (ED) visits resulting from nonfatal crash injuries among vehicle occupants in 2012 using the National Electronic Injury Surveillance System – All Injury Program (NEISS-AIP) and the Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS). The number and rate of all ED visits for the treatment of crash injuries that resulted in the patient being released and the number and rate of hospitalizations for the treatment of crash injuries were estimated, as were the associated number of hospital days and lifetime medical and work loss costs.Results
In 2012, an estimated 2,519,471 ED visits resulted from nonfatal crash injuries, with an estimated lifetime medical cost of $18.4 billion (2012 U.S. dollars). Approximately 7.5% of these visits resulted in hospitalizations that required an estimated 1,057,465 hospital days in 2012.Conclusions
Nonfatal crash injuries occur frequently and result in substantial costs to individuals, employers, and society. For each motor vehicle crash death in 2012, eight persons were hospitalized, and 100 were treated and released from the ED.Implications for Public Health
Public health practices and laws, such as primary seat belt laws, child passenger restraint laws, ignition interlocks to prevent alcohol impaired driving, sobriety checkpoints, and graduated driver licensing systems have demonstrated effectiveness for reducing motor vehicle crashes and injuries. They might also substantially reduce associated ED visits, hospitalizations, and medical costs. 相似文献992.
Phosphodiesterase type 5A inhibition with sildenafil improves cardiac function in heart failure. In addition, sildenafil in animal models of myocardial infarction has direct cardioprotective and antiarrhythmic effects. Sildenafil reduces L-type calcium current (Ica-L) and attenuates adrenergically driven inotropism, but effects on calcium handling are largely undetermined.Isolated adult rat ventricular myocytes were voltage clamped and calcium fluorescence measured with the indicator fura-2. Cells were paced at 0·5 Hz with depolarisations from ?60 mV to +10 mV. Sarcoplasmic reticulum (SR) content was determined by application of caffeine (10–20 mmol/L) and integration of inward sodium-calcium exchanger current. Rate constants for calcium extrusion from the cell (Kcaff) and calcium uptake into the SR (KSERCA) were determined by fitting first order exponentials to decay phases of the respective calcium transients. Following the initial control protocol, a therapeutically relevant dose of sidenafil (1 μM) was applied. Differences were determined with student's paired t tests.Sildenafil reduced SR content by 26·5% (n=9, p<0·01). To a lesser extent, sildenafil also reduced calcium transient amplitude (by ?13·6%, n=9, p<0·05); this was not accompanied by a reduction in KSERCA (–2.3% with sildenafil, p=0·97, n=5). Peak and integrated Ica-L were also reduced with sildenafil (–9·1% and ?6·0%, respectively, n=9, p<0·05). The effect on Ica-L was also seen in adult dog ventricular myocytes (reducing peak and integrated Ica-L by 15·9% and 26·4%, respectively, p<0·05 and p<0·01, n=6, 23°C). These effects cannot be attributed to run-down effects.Sildenafil substantially reduced SR content with no reduction in KSERCA, and thus may be mediated through ryanodine receptor modulation. Such reduction in SR load may reduce proarrhythmic SR calcium release, indicating a novel mechanism through which sildenafil exerts an antiarrhythmic effect. Acute reductions in calcium transient amplitude and Ica-L with sildenafil indicate acute negative inotropic effects and may contribute to our understanding of its cardioprotective effects in the setting of hyperadrenergic drive in heart failure.FundingBritish Heart Foundation. 相似文献
993.
Robert S. Jansen Asl? Kü?ükosmano?lu Marcel de Haas Sunny Sapthu Jon Andoni Otero Ilse E. M. Hegman Arthur A. B. Bergen Theo G. M. F. Gorgels P. Borst Koen van de Wetering 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(50):20206-20211
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes, and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding ATP-binding cassette sub-family C member 6 (ABCC6), an ATP-dependent efflux transporter present mainly in the liver. Abcc6−/− mice have been instrumental in demonstrating that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver. Why absence of this factor results in PXE has remained a mystery. Here we report that medium from HEK293 cells overexpressing either human or rat ABCC6 potently inhibits mineralization in vitro, whereas medium from HEK293 control cells does not. Untargeted metabolomics revealed that cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. Extracellularly, ectonucleotidases hydrolyze the excreted nucleoside triphosphates to nucleoside monophosphates and inorganic pyrophosphate (PPi), a strong inhibitor of mineralization that plays a pivotal role in several mineralization disorders similar to PXE. The in vivo relevance of our data are demonstrated in Abcc6−/− mice, which had plasma PPi levels <40% of those found in WT mice. This study provides insight into how ABCC6 affects PXE. Our data indicate that the factor that normally prevents PXE is PPi, which is provided to the circulation in the form of nucleoside triphosphates via an as-yet unidentified but ABCC6-dependent mechanism.Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by late-onset and progressive ectopic mineralization of skin, eyes, and arteries (1). This prototypical connective tissue disease affects ∼1 in 50,000 persons worldwide, for whom there is no effective therapy (2). Along with relatively benign (but stigmatizing) skin lesions, PXE causes progressive loss of vision and cardiovascular complications (2). The severity of these symptoms is highly variable among patients, even within families (3).In 2000, multiple research groups reported that PXE is caused by inactivating mutations in the ATP-binding cassette sub-family C member 6 (ABCC6) gene (4–7). ABCC6, also known as multidrug resistance-associated protein 6 (MRP6), is a member of the C branch of the superfamily of ATP-binding cassette (ABC)-transporters, which use the energy provided by the hydrolysis of ATP to transport substrates across a membrane (8). ABCC6 expression is high in the liver, lower in the kidney, and very low or absent in other tissues, including affected skin, eyes, and arteries (5, 9). In the liver, ABCC6 is present in the sinusoidal (basolateral) membrane of hepatocytes, facing the central circulation (10–12).Abcc6−/− mice faithfully recapitulate most of the symptoms of PXE and have been indispensable for showing that PXE is a metabolic disease (13–16). Abcc6−/− muzzle skin that mineralizes in Abcc6−/− mice does not mineralize when grafted onto WT mice, and muzzle skin of WT mice mineralizes only when grafted onto Abcc6−/− mice (17). Moreover, surgically joining the systemic circulation of Abcc6−/− mice with that of WT mice halts mineralization in Abcc6−/− mice (18). Thus, PXE is caused not by a lack of functional ABCC6 in the affected tissues, but rather by the absence of a factor that is normally provided to the circulation by an ABCC6-dependent mechanism. The nature of this factor has remained elusive.In vitro vesicular uptake experiments have confirmed that ABCC6, like its close homolog ABCC1, is an efflux transporter, transporting a handful of glutathione-conjugates and the cyclic peptide BQ-123 (10, 19, 20). The short list of identified ABCC6 substrates does not include any compound obviously relevant for PXE, and the only substrate shared by human ABCC6 (hABCC6) and rat ABCC6 (rABCC6) is not an endogenous compound, but rather the synthetic cyclic peptide BQ-123. Based on the clinical similarities of PXE to other diseases, vitamin K conjugates (21) and adenosine (22) have been proposed as substrates, but none of these are actually transported (23, 24).Thus, despite all efforts, the mechanism by which ABCC6 prevents ectopic mineralization remains a mystery, and no attractive new hypotheses about the nature of the physiological ABCC6 substrate have been proposed. In the present study, we used untargeted metabolomics to screen for ABCC6-dependent factors that inhibit mineralization, to shed more light on the mechanism by which ABCC6 prevents pathological mineralization. 相似文献
994.
Helderman-van den Enden AT van den Bergen JC Breuning MH Verschuuren JJ Tibben A Bakker E Ginjaar HB 《Clinical genetics》2011,79(3):236-242
Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease. After identification of the mutation in the index patient, family members can be reliably investigated. Carriers should be informed about their risk of having offspring with the disease and about their own risk for cardiomyopathy for which regular cardiac surveillance is recommended. In a small country like the Netherlands with well-organized genetic services, one would expect that most DMD families are adequately informed about the above mentioned risks for carriers. We have investigated whether women at risk had been tested at a molecular level. In the national Duchenne/Becker database 311 DMD and 99 Becker muscular dystrophy (BMD) patients had been registered up to 1 July 2009. These patients were asked to give information about the number of sisters and maternal aunts of the DMD/BMD patient and anything that was known about their genetic status and that of the mother. This information was compared with the information known at the genetic laboratory. Thirty-five of 104 adult sisters/maternal aunts of DMD patients with a 50% risk of being a carrier and 45 of 148 adult women with a 4.3% risk because of germ line mosaicism for DMD had not been tested by DNA analysis. Our study indicates that about one third of the potential carriers have not been tested. Given the possible far-reaching clinical consequences of being a carrier, further studies are needed to investigate the reasons why potential female carriers have not been tested. 相似文献
995.
996.
Goodman S; Xiao X; Donahue RE; Moulton A; Miller J; Walsh C; Young NS; Samulski RJ; Nienhuis AW 《Blood》1994,84(5):1492-1500
Recombinant adeno-associated viruses (rAAV) containing only the inverted terminal repeats (ITR) from the wild-type virus are capable of stable integration into the host cell genome, and expression of inserted genes in cultured cells. We have now defined the ability of rAAV to introduce genes into primary hematopoietic progenitors. A vector was constructed containing the coding sequences for beta- galactosidase (beta-gal), including a nuclear localization signal, under the control of a strong viral promotor. Infectious vector particles were prepared by cotransfection of the vector plasmid with a second plasmid that contained the coding sequences for AAV proteins into adenovirus-infected human embryonic kidney cells. These vector preparations transferred and expressed the beta-gal gene in human K562 erythroleukemia and Detroit 6 cells. Positive immunoselection yielded a population of enriched CD34+ cells that were transduced with the rAAV beta-gal vector. Nuclear localized enzyme expression was documented in 60% to 70% of infected cells. Progenitor-derived colonies that developed after 2 weeks in clonogenic cultures were shown to have viral- associated DNA at an estimated copy number of 1 to 2 per cell using a semiquantitative polymerase chain reaction (PCR) method. Integration of AAV into hematopoietic progenitors was documented using wild-type virus, as its genome may integrate at a preferred site on chromosome 19. Our data suggest that rAAV will transfer and express genes in primitive hematopoietic progenitors with high frequency, and support the development of this vector system for therapeutic gene transfer. 相似文献
997.
998.
Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c-kit receptor 总被引:10,自引:5,他引:5
Mouse pluripotent hematopoietic stem cells (PHSC) were fractionated based on size and density using counterflow centrifugal elutriation (CCE). These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage-specific markers (Lin-) followed by positive sorting for c-kit expression. The cells were characterized for their functional and biochemical properties. We defined a subpopulation of c-kit-positive cells that expressed high numbers of c-kit receptors (c-kitBR). One hundred c-kitBR cells from either low- or higher-density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1-W/Wv (W/Wv) recipients, whereas no PHSC were found in cells with low (c-kitDULL) or no (c-kitNEG) c-kit expression. Lin- c-kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 (Rho). The PHSC were concentrated in Lin- c-kitBR RhoDULL cells and the number of Lin- c-kitBR RhoBR cells correlated directly with the number of day 12 colony-forming unit- spleen (CFU-S12) in each fraction. We were not able to enrich further for PHSC using monoclonal antibodies to the cell-surface markers AA4.1 or CD4, which have been used by others to isolate PHSC. The small, low- density Lin- c-kitBR subset contained PHSC and few CFU-S12. This enabled us to assay PHSC for expression of the flk-2 gene, which encodes a tyrosine kinase receptor present on fetal liver PHSC. Purified RNA from the low-density Lin- c-kitBR subset did not contain flk-2 mRNA. We suggest that AA4.1, CD4 and flk-2 are expressed as stage- specific markers on PHSC in cell cycle. 相似文献
999.
1000.
This paper outlines the detail of the case study method used in a project commissioned by the English National Board for Nursing, Midwifery and Health Visiting (ENB) to investigate the changing educational needs of community nurses with regard to needs assessment and quality of care in the context of the NHS and Community Care Act, 1990. It explains the methodological procedures and analytic processes which led to integration of data across the whole study, focusing on the role of a prior theoretical framework in case study design.Recently qualified practitioners (health visitors and district nurses) were observed during a regular shift (N=134 visits), concentrating on their practice of assessing needs, and on liaison and collaboration within teams and across sectors. They were interviewed after the observation period (N=33 practitioners), to determine the extent of formality they attached to each assessment, and elicit information about aspects which may be embedded in everyday practice as well as those recorded for explicit requirements.The preliminary analysis resulted in the modification of a model for assessing service quality, and identified various points where a 'policy-practice gap' might arise between policies and practice in both the health service and education. The practicalities of operationalising a multiple case study design into research are highlighted, and the mechanism for 'generalising to theory' illustrated. 相似文献