全文获取类型
收费全文 | 601篇 |
免费 | 35篇 |
国内免费 | 7篇 |
专业分类
耳鼻咽喉 | 3篇 |
儿科学 | 30篇 |
妇产科学 | 1篇 |
基础医学 | 56篇 |
口腔科学 | 43篇 |
临床医学 | 48篇 |
内科学 | 149篇 |
皮肤病学 | 17篇 |
神经病学 | 10篇 |
特种医学 | 100篇 |
外科学 | 60篇 |
综合类 | 24篇 |
预防医学 | 36篇 |
眼科学 | 4篇 |
药学 | 45篇 |
中国医学 | 1篇 |
肿瘤学 | 16篇 |
出版年
2021年 | 15篇 |
2020年 | 5篇 |
2019年 | 2篇 |
2018年 | 9篇 |
2017年 | 4篇 |
2016年 | 11篇 |
2015年 | 12篇 |
2014年 | 12篇 |
2013年 | 33篇 |
2012年 | 23篇 |
2011年 | 16篇 |
2010年 | 28篇 |
2009年 | 27篇 |
2008年 | 21篇 |
2007年 | 12篇 |
2006年 | 21篇 |
2005年 | 18篇 |
2004年 | 14篇 |
2003年 | 13篇 |
2002年 | 11篇 |
2001年 | 11篇 |
2000年 | 9篇 |
1999年 | 20篇 |
1998年 | 35篇 |
1997年 | 26篇 |
1996年 | 21篇 |
1995年 | 13篇 |
1994年 | 23篇 |
1993年 | 23篇 |
1992年 | 7篇 |
1991年 | 11篇 |
1990年 | 5篇 |
1989年 | 13篇 |
1988年 | 16篇 |
1987年 | 9篇 |
1986年 | 14篇 |
1985年 | 7篇 |
1984年 | 8篇 |
1983年 | 7篇 |
1982年 | 10篇 |
1981年 | 12篇 |
1980年 | 12篇 |
1978年 | 4篇 |
1977年 | 5篇 |
1976年 | 9篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1970年 | 1篇 |
1957年 | 1篇 |
1955年 | 1篇 |
排序方式: 共有643条查询结果,搜索用时 7 毫秒
131.
Biochemical, immunological, and in vivo functional characterization of B-domain-deleted factor VIII 总被引:12,自引:4,他引:12
Coagulation factor VIII (FVIII) is a cofactor in the intrinsic pathway of blood coagulation for which deficiency results in the bleeding disorder hemophilia A. FVIII contains a domain structure of A1-A2-B-A3- C1-C2 of which the B domain is dispensable for procoagulant activity in vitro. In this report, we compare the properties of B-domain-deleted FVIII (residues 760 through 1639, designated LA-VIII) to wildtype recombinant FVIII. In transfected Chinese hamster ovary (CHO) cells, LA- VIII was expressed at a 10- to 20-fold greater level compared with wildtype FVIII. The specific activity of purified LA-VIII was indistinguishable from wild-type recombinant FVIII and both exhibited similar thrombin activation coefficients. Wildtype recombinant-derived FVIII and LA-VIII also displayed similar timecourses of thrombin activation and heavy chain cleavage. However, compared with wildtype recombinant-derived FVIII, the light chain of LA-VIII was cleaved fivefold more rapidly by thrombin. Addition of purified von Willebrand factor (vWF) did not alter the kinetics of thrombin cleavage or activation of either wildtype recombinant-derived FVIII or LA-VIII. The immunogenicity of LA-VIII was compared with wildtype FVIII in a novel model of neonatal tolerance induction in mice. The results did not detect any immunologic differences between wildtype FVIII and LA-VIII, suggesting that LA-VIII does not contain significant new epitopes that are absent in wildtype FVIII. LA-VIII was tolerated well on infusion into FVIII-deficient dogs and was able to correct the cuticle bleeding time similar to wildtype recombinant factor VIII. In vivo, LA-VIII was bound to canine vWF and exhibited a half-life similar to wildtype recombinant FVIII. These studies support that B-domain-deleted FVIII may be efficacious in treatment of hemophilia A in humans. 相似文献
132.
133.
Use of a BamHI polymorphism in the factor IX gene for the determination of hemophilia B carrier status 总被引:8,自引:0,他引:8
A BamHI polymorphism has been identified in the human factor IX gene. This polymorphism, which occurs in approximately 6% of X chromosomes, has been used to determine the carrier status of a female in a family with a history of hemophilia B. This family was uninformative for the previously reported TaqI and Xmnl polymorphisms in the factor IX gene. 相似文献
134.
Mapping of monoclonal antibodies to human factor IX 总被引:2,自引:1,他引:2
Frazier D; Smith KJ; Cheung WF; Ware J; Lin SW; Thompson AR; Reisner H; Bajaj SP; Stafford DW 《Blood》1989,74(3):971-977
We used recombinant DNA techniques to map a panel of six monoclonal antibodies (MoAbs) to regions of the human factor IX molecule. A-2 maps to 17 amino acids at the amino terminus of the heavy chain of IXa; 2D5, an inhibitor of clotting, is defined to 36 amino acids of the first EGF- like domain of human factor IX. A-4, A-5, C10D, and FXC008 all map to a region of the heavy chain containing amino acids 180 through 310, suggesting an immunodominant site. FXC008 has been reported to interfere with binding of factor IXa to factor VIII:Ca. 相似文献
135.
Seroepidemiology of pertussis in Italy. 总被引:5,自引:0,他引:5
A Giammanco A Chiarini T Stroffolini D De Mattia M Chiaramonte M E Moschen I Mura G Rigo S Taormina A Sarzana 《Reviews of infectious diseases》1991,13(6):1216-1220
During 1988 and 1989 the prevalence of serum IgG antibodies to pertussis toxin in a sample of 3,875 unvaccinated, apparently healthy persons between the ages of 1 year to 19 years was estimated by enzyme-linked immunosorbent assay. The participants were recruited by means of systematic cluster sampling from public and private schools in five geographic areas of Italy. The overall prevalence of IgG antibodies was 80.8%, with a steady increase from 33.5% among 1- to 3-year-old children to 95% among 17- to 19-year-old individuals. The prevalence of natural immunity was 50% and 75% at the ages of 4 and 6 years, respectively. No gender-related difference in immunity was observed. For children greater than 10 years of age, the seroprevalence of pertussis antibodies was significantly higher in northern regions than in southern regions until the age of 17-19 years, when the pattern reversed. There was no association of a child's immune status with the father's number of years of schooling or with family size. For children aged 1-3 years, serologic studies showed that the history of pertussis reported by parents in questionnaires was highly specific (97.6%) in predicting antibody status, with positive and negative predictive values of 90.5% and 79.2%, respectively. However, 20.8% of children had antibodies to pertussis toxin even though they had no history of whooping cough. 相似文献
136.
Domen J; van der Lugt NM; Laird PW; Saris CJ; Clarke AR; Hooper ML; Berns A 《Blood》1993,82(5):1445-1452
The mouse Pim-1 gene encodes two cytoplasmic serine-threonine-specific protein kinases. The gene has been found to be activated (overexpressed) by retroviral insertion in hematopoietic tumors in mice. Transgenic mice that overexpress Pim-1 (E mu-Pim-1) have a low incidence of spontaneous T-cell lymphomas and an increased susceptibility to Moloney murine leukemia virus and N-ethyl-N- nitrosourea-induced lymphomas. Apart from a slight enlargement of the spleen, no abnormalities were found in prelymphomatous transgenic mice. Inactivation of the Pim-1 gene in the germline of mice resulted in mice with a surprisingly subtle phenotype. Therefore, we investigated whether subtle effects of the absence of Pim-1 could be made visible during in vitro culturing of hematopoietic cells. We found that bone marrow-derived mast cells (BMMC) lacking Pim-1 had a distinct growth disadvantage when grown on interleukin (IL)-3, but not when stimulated by the factors IL-4, IL-9, or Steel factor (SF). This indicates a role for Pim-1 as a modulator of the IL-3 signal transduction pathway. 相似文献
137.
Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy 总被引:36,自引:0,他引:36 下载免费PDF全文
Lang F Klingel K Wagner CA Stegen C Warntges S Friedrich B Lanzendorfer M Melzig J Moschen I Steuer S Waldegger S Sauter M Paulmichl M Gerke V Risler T Gamba G Capasso G Kandolf R Hebert SC Massry SG Broër S 《Proceedings of the National Academy of Sciences of the United States of America》2000,97(14):8157-8162
138.
The effects of recombinant human erythropoietin (Ep), granulocyte/macrophage (GM) and granulocyte (G) colony-stimulating factors (CSF), and interleukin-3 (IL-3) on erythroid burst and GM colony growth have been studied in fetal bovine serum (FBS)- supplemented and FBS-deprived culture. Sources of progenitor cells were nonadherent or nonadherent T-lymphocyte-depleted marrow or peripheral blood cells from normal humans. G-CSF, in concentrations up to 2.3 X 10(-10) mol/L, induced only the formation of neutrophil colonies. In contrast, GM-CSF and IL-3 both induced GM colonies and sustained the formation of erythroid bursts in the presence of Ep. However, the activities of these growth factors were affected by the culture conditions. IL-3 induction of GM colonies depended on the presence of FBS, whereas the degree of GM-CSF induction of GM colonies in FBS- deprived cultures depended on the method by which adherent cells were removed. GM-CSF increased colony numbers in a concentration-dependent manner only if the cells had been prepared by overnight adherence. Both GM-CSF and IL-3 exhibited erythroid burst-promoting activity in FBS- deprived cultures. However, some lineage restriction was evident because GM-CSF was two- to threefold more active than IL-3 in inducing GM colonies but IL-3 was two- to threefold more active in promoting erythroid burst growth. Furthermore, in FBS-deprived cultures, the number of both erythroid bursts and GM colonies reached the maximum only when Ep, GM-CSF, and IL-3 or GM-CSF, IL-3, and G-CSF, respectively, were added together. These results suggest that the colonies induced by IL-3, GM-CSF, and G-CSF are derived from different progenitors. 相似文献
139.
Pediatric patients with acute lymphoblastic leukemia (ALL) are at an increased risk of thromboembolic events. Potential responsible mechanisms include the disease process itself, treatment with chemotherapeutic agents (particularly L-Asparaginase [ASP]), or a combination of the disease and treatment. We studied thrombin regulation in 26 consecutive children with ALL and 14 healthy age- matched controls by: (1) plasma concentrations of prothrombin; (2) plasma inhibition of 125I-alpha-thrombin; and (3) four biochemical markers of in vivo thrombin activation (thrombin complexed to its inhibitor antithrombin III [ATIII; TAT], prothrombin fragment 1.2 (F1.2), activated protein C complexed to the inhibitors alpha 1 antitrypsin [APCAT]), and protein C inhibitor (APC-PCI). Measurements were made at presentation before treatment, after treatment with ASP alone, and during combination chemotherapy with and without ASP. At presentation, the capacity to generate thrombin (reflected by plasma prothrombin concentrations) and the capacity to inhibit thrombin (125I- alpha-thrombin--inhibitor complex formation) were similar in children with ALL compared with that for healthy children. After ASP alone or as part of combination chemotherapy, prothrombin levels were preserved, whereas plasma inhibition of 125I-alpha-thrombin decreased significantly because of a decrease in plasma concentrations of inhibitors, most importantly ATIII. After combination chemotherapy without ASP, plasma concentrations of ATIII and the capacity to inhibit 125I-alpha-thrombin returned to normal values, whereas prothrombin levels increased above control values. Thrombin generation in vivo also differed from healthy controls. At presentation, plasma concentrations of three of four markers of in vivo thrombin activity (TAT, F1.2, APCAT, but not APC-PCI) were increased in children with ALL. Neither ASP alone nor combination chemotherapy with or without ASP significantly altered values of these three markers. In summary, although the in vitro capacity to generate thrombin was preserved, the in vitro capacity to inhibit 125I-alpha-thrombin decreased after ASP therapy. Evidence for increased endogenous thrombin generation was documented in children with ALL at presentation and throughout treatment. We speculate that poor regulation of this thrombin may contribute to thrombotic complications in children with ALL. 相似文献
140.
Adiponectin and its receptors in non-alcoholic steatohepatitis 总被引:30,自引:0,他引:30
Kaser S Moschen A Cayon A Kaser A Crespo J Pons-Romero F Ebenbichler CF Patsch JR Tilg H 《Gut》2005,54(1):117-121
BACKGROUND: Adiponectin, an adipocyte derived polypeptide, has been shown to alleviate steatosis and inflammation in mice with non-alcoholic fatty liver disease. AIM: In the present study, we wished to define liver expression of adiponectin and its receptors in morbidly obese patients undergoing bariatric surgery. Patients with non-alcoholic steatohepatitis (NASH) or simple steatosis were investigated to test whether dysregulation of this system might be involved in these disorders. PATIENTS AND METHODS: Liver mRNA expression of adiponectin and its recently cloned receptors RI and RII (adipoRI and adipoRII) were analysed by fluorescence based real time polymerase chain reaction in 13 patients with NASH and nine with simple steatosis. Adiponectin and adipoRII protein expression were assessed by immunohistochemistry in a subgroup of patients. RESULTS: Adiponectin and adipoRII mRNA expression were significantly reduced in liver biopsies of patients with NASH compared with simple steatosis while no difference was found in adipoRI mRNA expression. In NASH, adipoRII mRNA expression was negatively correlated with serum aspartate aminotransferase levels, serum alanine aminotransferase levels, and grade of fibrosis. Liver adiponectin protein expression was mainly found in endothelial cells of portal vessels and liver sinusoids whereas adipoRII expression was seen in hepatocytes only. Adiponectin and adipoRII staining were lower in biopsies of subjects with NASH compared with simple steatosis. CONCLUSION: Reduced hepatic expression of adiponectin and adipoRII might be of pathophysiological relevance in non-alcoholic fatty liver diseases. 相似文献