全文获取类型
收费全文 | 957篇 |
免费 | 90篇 |
专业分类
耳鼻咽喉 | 3篇 |
儿科学 | 73篇 |
妇产科学 | 23篇 |
基础医学 | 153篇 |
口腔科学 | 27篇 |
临床医学 | 114篇 |
内科学 | 142篇 |
皮肤病学 | 7篇 |
神经病学 | 134篇 |
特种医学 | 28篇 |
外科学 | 68篇 |
综合类 | 1篇 |
预防医学 | 108篇 |
眼科学 | 10篇 |
药学 | 70篇 |
中国医学 | 1篇 |
肿瘤学 | 85篇 |
出版年
2024年 | 3篇 |
2023年 | 10篇 |
2022年 | 16篇 |
2021年 | 23篇 |
2020年 | 20篇 |
2019年 | 23篇 |
2018年 | 45篇 |
2017年 | 24篇 |
2016年 | 32篇 |
2015年 | 33篇 |
2014年 | 41篇 |
2013年 | 61篇 |
2012年 | 70篇 |
2011年 | 86篇 |
2010年 | 39篇 |
2009年 | 32篇 |
2008年 | 77篇 |
2007年 | 64篇 |
2006年 | 61篇 |
2005年 | 64篇 |
2004年 | 58篇 |
2003年 | 46篇 |
2002年 | 51篇 |
2001年 | 7篇 |
2000年 | 6篇 |
1999年 | 4篇 |
1998年 | 6篇 |
1997年 | 7篇 |
1996年 | 6篇 |
1995年 | 9篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1991年 | 4篇 |
1988年 | 1篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 3篇 |
排序方式: 共有1047条查询结果,搜索用时 31 毫秒
21.
Tiina A. Jokela Antti Lindgren Kirsi Rilla Edward Maytin Vincent C. Hascall Raija H. Tammi 《Connective tissue research》2013,54(3-4):115-119
Hyaluronan attached to cell surface can form at least two very different structures; a pericellular coat close to plasma membrane and hyaluronan chains coalesced into “cables” that can span several cell lengths. The hyaluronan in cables, induced by many inflammatory agents, can bind leukocytes, whereas that in the pericellular coat does not contribute to leukocyte binding. Therefore, this structural change seems to have a major role in inflammation. In the present study we checked whether cells of squamous epithelium, like epidermal keratinocytes, can form hyaluronan cables and bind leukocytes. In addition, we checked whether hyaluronan synthesis is affected during the induction of cables. Control keratinocytes expressed pericellular hyaluronan as small patches on plasma membrane. But when treated with inflammatory agents or stressful conditions (tunicamycin, interleukin-1β, tumor necrosis factor-α, and high glucose concentration), hyaluronan organization changed into cable-like structures that avidly bound monocytes. Simultaneously, the total amount of secreted hyaluronan was slightly decreased, and the expression levels of hyaluronan synthases (Has1–3) and CD44 were not significantly changed. The results show that epidermal keratinocytes can form cables and bind leukocytes under inflammatory provocation and that these effects are not dependent on stimulation of hyaluronan secretion. 相似文献
22.
Minna Koskenvuo Alexis Dumoulin Irmeli Lautenschlager Eeva Auvinen Laura Mannonen Veli-Jukka Anttila Kirsi Jahnukainen Ulla M. Saarinen-Pihkala Hans H. Hirsch 《Journal of clinical virology》2013,56(1):77-81
BackgroundBK polyomavirus-associated hemorrhagic cystitis (BK-PyVHC) is a significant complication of allogenic hematopoietic stem cell transplantation (HSCT), but risk factors and treatment are currently unresolved. BK-PyVHC typically presents with clinical cystitis, macrohematuria, and increasing urine and blood BKV loads.ObjectivesCharacterization of children undergoing allogeneic HSCT with BK-PyVHC and their clinical and antibody response to cidofovir treatment.Study designBy prospective screening of urine and plasma in 50 pediatric allogenic HSCT performed between 2008 and 2010, we identified 6 (12%) children with BK-PyVHC. Cidofovir was administered intravenously to 5 patients and intravesically to 4 patients (3 double treatments).ResultsDecreasing BKV viremia of > 2 log10 copies/mL and clinical resolution was seen in 4 patients over 5–12 weeks. Responses occurred only in patients mounting BKV-specific IgM and IgG responses. Epidemic curve plots, BKV genotyping and contact tracing provided evidence of transmission between 2 BKV-seronegative patients, but ruled out transmission among the remaining four patientsConclusionsThe data suggest that BK-PyVHC may be the result of nosocomial transmission in children with low/undetectable BKV antibodies and raises urgent questions about appropriate infection control measures and the role of cidofovir. 相似文献
23.
Tanner LM Näntö-Salonen K Rashed MS Kotilainen S Aalto M Venetoklis J Niinikoski H Huoponen K Simell O 《Metabolism: clinical and experimental》2008,57(4):549-554
The aim of the study was to investigate the prevalence and mechanisms of development of carnitine deficiency in patients with lysinuric protein intolerance (LPI). In our cohort of 37 Finnish patients with LPI, 8 (8-52 years of age) have been diagnosed with hypocarnitinemia. Their free and total serum carnitine levels, acyl carnitine profiles, renal function, diet, and medication were compared with the data from 8 age- and sex-matched patients with LPI not treated with carnitine supplementation. In patients with LPI, hypocarnitinemia was strongly associated with female sex, renal insufficiency, and the use of ammonia-scavenging drugs. Of the 8 hypocarnitinemic patients, 3 complained of muscle weakness, and their symptoms disappeared during carnitine supplementation. Oral lysine supplementation did not correct hypocarnitinemia in our patients. The patients with LPI are at considerable risk for carnitine deficiency. Supplementation of hypocarnitinemic LPI patients with oral L-carnitine improved serum total carnitine values, but the ratio of free and total carnitine remained subnormal in all supplemented patients except one. Furthermore, decreased ratio of free and total serum carnitine was common even in LPI patients with normal total serum carnitine concentration. 相似文献
24.
Maria Malm Kirsi Tamminen Suvi Lappalainen Hanni Uusi-Kerttula Timo Vesikari Vesna Blazevic 《Clinical and Vaccine Immunology : CVI》2015,22(6):656-663
Norovirus (NoV) genogroup I (GI) and GII are responsible for most human infections with NoV. Because of the high genetic variability of NoV, natural infection does not induce sufficient protective immunity to different genotypes or to variants of the same genotype and there is little or no cross-protection against different genogroups. NoV-derived virus-like particles (VLPs) are promising vaccine candidates that induce high levels of NoV-specific humoral and cellular immune responses. It is believed that a bivalent NoV vaccine consisting of a representative VLP from GI and GII is a minimum requirement for an effective vaccine. Here, we compared the abilities of monovalent immunizations with NoV GI.1-2001, GI.3-2002, GII.4-1999, and GII.4-2010 New Orleans VLPs to induce NoV type-specific and cross-reactive immune responses and protective blocking antibody responses in BALB/c mice. All of the VLPs induced comparable levels of type-specific serum IgG antibodies, as well as blocking antibodies to the VLPs used for immunization. However, the abilities of different VLP genotypes to induce cross-reactive IgG and cross-blocking antibodies varied remarkably. Our results confirm previous findings of a lack of cross-protective immune responses between GI and GII NoVs. These data support the rationale for including NoV GI.3 and GII.4-1999 VLPs in the bivalent vaccine formulation, which could be sufficient to induce protective immune responses across NoV genotypes in the two common genogroups in humans. 相似文献
25.
Objective
The aim of this systematic review was to describe the effects of health coaching on adult patients with chronic diseases.Methods
The reviewers searched electronic databases and performed a manual search for studies published from 2009 to 2013. The inclusion criteria covered health coaching for adults with chronic diseases by health care professionals. The studies were original, randomized controlled trials or quasi-experimental designs.Results
Thirteen studies were selected using the inclusion criteria. The results indicate that health coaching produces positive effects on patients’ physiological, behavioral and psychological conditions and on their social life. In particular, statistically significant results revealed better weight management, increased physical activity and improved physical and mental health status.Conclusion
Health coaching improves the management of chronic diseases. Further research into the cost-effectiveness of health coaching and its long-term effectiveness for chronic diseases is needed.Practice implications Health care professionals play key roles in promoting healthy behavior and motivating good care for adults with chronic diseases. Health coaching is an effective patient education method that can be used to motivate and take advantage of a patient's willingness to change their life style and to support the patient's home-based self-care. 相似文献26.
Anna Kallio Kirsi Sepponen Philippe Hermand Philippe Deno?l Fabrice Godfroid Merit Melin 《Infection and immunity》2014,82(4):1683-1691
Pneumococcal adherence to mucosal surfaces is a critical step in nasopharyngeal colonization, but so far few pneumococcal adhesins involved in the interaction with host cells have been identified. PhtA, PhtB, PhtD, and PhtE are conserved pneumococcal surface proteins that have proven promising as vaccine candidates. One suggested virulence function of Pht proteins is to mediate adherence at the respiratory mucosa. In this study, we assessed the role of Pht proteins in pneumococcal binding to respiratory epithelial cells. Pneumococci were incubated with human nasopharyngeal epithelial cells (Detroit-562) and lung epithelial cells (A549 and NCI-H292), and the proportion of bound bacteria was measured by plating viable counts. Strains R36A (unencapsulated), D39 (serotype 2), 43 (serotype 3), 4-CDC (serotype 4), and 2737 (serotype 19F) with one or more of the four homologous Pht proteins deleted were compared with their wild-type counterparts. Also, the effect of anti-PhtD antibodies on the adherence of strain 2737 to the respiratory epithelial cells was studied. Our results suggest that Pht proteins play a role in pneumococcal adhesion to the respiratory epithelium. We also found that antibody to PhtD is able to inhibit bacterial attachment to the cells, suggesting that antibodies against PhtD present at mucosal surfaces might protect from pneumococcal attachment and subsequent colonization. However, the relative significance of Pht proteins to the ability of pneumococci to bind in vitro to epithelial cells depends on the genetic background and the capsular serotype of the strain. 相似文献
27.
28.
29.
Johanna I. Kiiski Liisa M. Pelttari Sofia Khan Edda S. Freysteinsdottir Inga Reynisdottir Steven N. Hart Hermela Shimelis Sara Vilske Anne Kallioniemi Johanna Schleutker Arto Leminen Ralf Bützow Carl Blomqvist Rosa B. Barkardottir Fergus J. Couch Kristiina Aittom?ki Heli Nevanlinna 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(42):15172-15177
Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26–2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81–6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.Breast cancer is the most common cancer affecting women worldwide. It is also the principal cause of death from cancer among women globally, accounting for 14% of all cancer deaths (1). The etiology of breast cancer is multifactorial, and the risk depends on various factors like age, family history, and reproductive, hormonal, or dietary factors. The majority of breast cancers are sporadic, but approximately 15% of cases show familial aggregation (2, 3). Since the identification of the first breast and ovarian cancer susceptibility genes breast cancer 1 and 2 (BRCA1 and BRCA2, respectively) by linkage analysis and positional cloning, several breast cancer susceptibility genes and alleles with different levels of risk and prevalence in the population have been recognized. BRCA1 and BRCA2 mutation carriers have more than 10-fold increased risk of breast cancer compared with women in the general population, and mutations in TP53, PTEN, STK11, and CDH1 have also been associated with a high lifetime risk of breast cancer in the context of rare inherited cancer syndromes (4). In addition, rare variants in genes such as checkpoint kinase 2 (CHEK2), ataxia telangiectasia mutated (ATM), and BRCA1 interacting helicase BRIP1, that confer a two- to fourfold increased risk, and in partner and localizer of BRCA2 (PALB2), with even higher risk estimates, have been found with candidate gene approaches (5, 6), and an increasing number of common low-risk loci with modest odds ratios (ORs; as much as 1.26-fold increased risk for heterozygous carriers) have been identified by genome-wide association studies (7).However, the major portion of hereditary breast cancer still remains unexplained, and many susceptibility loci are yet to be found. Exome sequencing combined with genotyping of the identified variants in case-control analysis is an effective method to recognize novel risk alleles, based on the assumption that disease-causing variants are rare and often accumulate in the protein-coding areas of the genome (8–10).Since the discovery that proteins encoded by the BRCA1 and BRCA2 breast/ovarian cancer susceptibility genes are directly involved in homologous recombination repair of DNA double-strand breaks, it has been evident that other genes involved in DNA repair are attractive breast cancer susceptibility candidates (4). Biallelic mutations in ATM gene cause rare ataxia telangiectasia disease and are associated with an increased risk for breast cancer as a result of improper DNA damage response (11). Fanconi anemia (FA) is a rare genetic disorder caused by biallelic mutations in FA genes that also participate in DNA repair. At least 15 FA genes have been identified (12). Patients with heterozygous mutations in certain FA genes have an elevated risk for various cancers, and monoallelic mutations in at least four of these genes [BRCA2, BRIP1, PALB2, and RAD51 paralog C (RAD51C)] are associated with an increased risk of breast or ovarian cancer (12, 13). Recurrent founder mutations in several cancer susceptibility genes, including the BRCA2, PALB2, and RAD51C FA genes, have been identified in the Finnish population (14–16). The PALB2 and RAD51C founder mutations have been detected at 2% frequency in Finnish breast or ovarian cancer families (15–17), whereas, in other populations, mutations in these genes are rare and often unique for each family. Founder effects in the isolated populations such as Finland or Iceland may enrich certain mutations and thus explain a significant proportion of all mutations in certain genes (18, 19). This provides an advantage in the search for novel susceptibility genes and alleles.In this study, we used exome sequencing to uncover previously unidentified recurrent breast or ovarian cancer predisposing variants in the Finnish population with a focus on DNA repair genes. Selected variants were further genotyped in a large case-control sample set. Our investigation revealed an association of a nonsense mutation (rs147021911) in an FA complementation gene, FANCM, with breast cancer, especially with triple-negative (TN) breast cancer (TNBC). 相似文献
30.
White adipose tissue is one of the largest organs of the body. It plays a key role in whole‐body energy status and metabolism; it not only stores excess energy but also secretes various hormones and metabolites to regulate body energy balance. Healthy adipose tissue capable of expanding is needed for metabolic well‐being and to prevent accumulation of triglycerides to other organs. Mitochondria govern several important functions in the adipose tissue. We review the derangements of mitochondrial function in white adipose tissue in the obese state. Downregulation of mitochondrial function or biogenesis in the white adipose tissue is a central driver for obesity‐associated metabolic diseases. Mitochondrial functions compromised in obesity include oxidative functions and renewal and enlargement of the adipose tissue through recruitment and differentiation of adipocyte progenitor cells. These changes adversely affect whole‐body metabolic health. Dysfunction of the white adipose tissue mitochondria in obesity has long‐term consequences for the metabolism of adipose tissue and the whole body. Understanding the pathways behind mitochondrial dysfunction may help reveal targets for pharmacological or nutritional interventions that enhance mitochondrial biogenesis or function in adipose tissue. 相似文献