全文获取类型
收费全文 | 1923篇 |
免费 | 115篇 |
国内免费 | 21篇 |
专业分类
耳鼻咽喉 | 8篇 |
儿科学 | 51篇 |
妇产科学 | 30篇 |
基础医学 | 211篇 |
口腔科学 | 180篇 |
临床医学 | 124篇 |
内科学 | 361篇 |
皮肤病学 | 49篇 |
神经病学 | 86篇 |
特种医学 | 127篇 |
外科学 | 193篇 |
综合类 | 15篇 |
预防医学 | 274篇 |
眼科学 | 10篇 |
药学 | 218篇 |
中国医学 | 41篇 |
肿瘤学 | 81篇 |
出版年
2023年 | 14篇 |
2022年 | 24篇 |
2021年 | 44篇 |
2020年 | 33篇 |
2019年 | 50篇 |
2018年 | 61篇 |
2017年 | 54篇 |
2016年 | 57篇 |
2015年 | 65篇 |
2014年 | 91篇 |
2013年 | 104篇 |
2012年 | 122篇 |
2011年 | 129篇 |
2010年 | 101篇 |
2009年 | 76篇 |
2008年 | 114篇 |
2007年 | 104篇 |
2006年 | 94篇 |
2005年 | 72篇 |
2004年 | 78篇 |
2003年 | 62篇 |
2002年 | 43篇 |
2001年 | 32篇 |
2000年 | 20篇 |
1999年 | 30篇 |
1998年 | 36篇 |
1997年 | 34篇 |
1996年 | 32篇 |
1995年 | 26篇 |
1994年 | 28篇 |
1993年 | 20篇 |
1992年 | 14篇 |
1991年 | 11篇 |
1990年 | 12篇 |
1989年 | 20篇 |
1988年 | 20篇 |
1987年 | 11篇 |
1986年 | 19篇 |
1985年 | 16篇 |
1984年 | 9篇 |
1983年 | 9篇 |
1982年 | 13篇 |
1981年 | 9篇 |
1980年 | 5篇 |
1978年 | 4篇 |
1975年 | 6篇 |
1970年 | 5篇 |
1967年 | 3篇 |
1966年 | 4篇 |
1964年 | 3篇 |
排序方式: 共有2059条查询结果,搜索用时 15 毫秒
1.
2.
3.
4.
5.
V Bongertz M L Guimar?es M F Soares-da-Costa V G Veloso F I Bastos C L Szwarcwald M Derrico P R Telles J H Pilloto E C Jo?o Filho M G Morgado 《Journal of clinical virology》1999,12(1):27-36
BACKGROUND: Antibody binding assays carried out by our group have consistently indicated a higher reactivity of sera from male HIV-1 infected individuals. This study was carried out in order to analyze the importance of gender, route of transmission, disease progression and HIV-1 genotype in seroreactivity assays. STUDY DESIGN: Specificity of antibody binding was studied in plasma of 247 HIV-1 seropositive individuals belonging to patient groups of pregnant women, injecting drug users (IDUs) and recent seroconvertors, resident in Rio de Janeiro, RJ. Recognition of synthetic peptides corresponding to antigenically important epitopes in the envelope of HIV-1 (gp41 immunodominant epitope, V3 loop, V2 loop and gp41 735-752 epitope) was determined. RESULTS: The immunodominant gp41 peptide (amino acids 594-613, HIV-1 MN sequence) was recognized by 85% of all plasma tested. Reactivity with the gp41 735-752 peptide and gp120 V2 loop peptides was low but quite variable, being generally more often specific to a Brazilian V2 peptide used than to the HIV-1 MN derived V2 peptide. The overall recognition of the different V3 peptides tested varied from 41 to 76%. Patients with more advanced disease showed a more frequent reactivity with the peptides studied than did asymptomatic patients. Statistically significant differences in peptide recognition were observed by multiple logistic analyses comparing plasma derived from individuals infected by blood or sexual HIV transmission, adjusting for disease progression and gender. Plasma from individuals infected by sexual transmission showed lower peptide recognition than did plasma from individuals infected through HIV positive blood. Association attempts between seroreactivity and genotype indicated that plasma derived from patients infected with HIV-1 of the F subtype showed highest recognition of heterologous V3 peptides, as well as a slightly more frequent recognition of the non-V3 peptides tested. Recognition of homologous peptides was generally higher than recognition of heterologous peptides. Differences were most pronounced between the prototypical HIV-1 B subtype and the Brazilian B" variant of this subtype but almost non-existent between the HIV-1 B and F subtypes. CONCLUSIONS: Individual gender was shown to be a confounder when investigating the relationships of peptide reaction to HIV-1 route of transmission through multivariate statistical methods: patients infected by blood transmission (IDU) present higher frequency of peptide recognition than individuals infected by sexual HIV-1 transmission. Plasma from individuals infected with the B" variant (GWG) of B subtype HIV-1 showed lower heterologous peptide recognition than that from HIV-1 B (GPG) or F infected individuals. 相似文献
6.
Karina R B Bastos Renato Barboza Luiz Sardinha Momtchilo Russo José M Alvarez Maria Regina D'Império Lima 《Journal of interferon & cytokine research》2007,27(5):399-410
Besides the established role of interleukin-12 (IL-12) and IL-18 on interferon-gamma (IFN-gamma) production by natural killer (NK), T, and B cells, the effects of these cytokines on macrophages are largely unknown. Here, we investigated the role of IL-12/IL-18 on nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) production by CD11b(+) adherent peritoneal cells, focusing on the involvement of endogenously produced IFN-gamma. C57BL/6 cells released substantial amounts of NO when stimulated with IFN-gamma or lipopolysaccharide (LPS), but failed to respond to IL-12 or IL-18 or both. However, IL-12/IL-18 pretreatment was able to program these cells to release 6-8-fold more NO and TNF-alpha in response to LPS or Trypanosoma cruzi stimulation, with NO levels directly correlating with macrophage resistance to intracellular parasite growth. Analysis of IL-12/IL-18-primed cells from mice deficient in IFN-gamma, IFNGR, and IFN regulatory factor-1 (IRF-1) revealed that these molecules were essential for LPS-induced NO release, but TNF-alpha production was IFN-gamma independent. Conversely, the myeloid differentiation factor 88 (MyD88)-dependent pathway was indispensable for IL-12/IL-18-programmed LPS-induced TNF-alpha production, but not for NO release. Contaminant T and NK cells largely modulated the IL-12/IL-18 programming of LPS-induced NO response through IFN-gamma secretion. Nevertheless, a small population of IFN-gamma(+) cells with a macrophage phenotype was also identified, particularly in the peritoneum of chronically T. cruzi-infected mice, reinforcing the notion that macrophages can be an alternative source of IFN-gamma. Taken together, our data contribute to elucidate the molecular basis of the IL-12/IL-18 autocrine pathway of macrophage activation, showing that endogenous IFN-gamma plays an important role in programming the NO response, whereas the TNF-alpha response occurs through an IFN-gamma-independent pathway. 相似文献
7.
Predominance of null mutations in ataxia-telangiectasia 总被引:15,自引:4,他引:15
Gilad S; Khosravi R; Shkedy D; Uziel T; Ziv Y; Savitsky K; Rotman G; Smith S; Chessa L; Jorgensen TJ; Harnik R; Frydman M; Sanal O; Portnoi S; Goldwicz Z; Jaspers NG; Gatti RA; Lenoir G; Lavin MF; Tatsumi K; Wegner RD; Shiloh Y; Bar-Shira A 《Human molecular genetics》1996,5(4):433-439
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving
cerebellar degeneration, immunodeficiency, chromosomal instability,
radiosensitivity and cancer predisposition. The responsible gene, ATM, was
recently identified by positional cloning and found to encode a putative
350 kDa protein with a Pl 3-kinase-like domain, presumably involved in
mediating cell cycle arrest in response to radiation-induced DNA damage.
The nature and location of A-T mutations should provide insight into the
function of the ATM protein and the molecular basis of this pleiotropic
disease. Of 44 A-T mutations identified by us to date, 39 (89%) are
expected to inactivate the ATM protein by truncating it, by abolishing
correct initiation or termination of translation, or by deleting large
segments. Additional mutations are four smaller in-frame deletions and
insertions, and one substitution of a highly conserved amino acid at the Pl
3-kinase domain. The emerging profile of mutations causing A-T is thus
dominated by those expected to completely inactivate the ATM protein. ATM
mutations with milder effects may result in phenotypes related, but not
identical, to A-T.
相似文献
8.
9.
High throughput parallel analysis of hundreds of patient samples for more than 100 mutations in multiple disease genes 总被引:5,自引:0,他引:5
Shuber AP; Michalowsky LA; Nass GS; Skoletsky J; Hire LM; Kotsopoulos SK; Phipps MF; Barberio DM; Klinger KW 《Human molecular genetics》1997,6(3):337-347
As more mutations are identified in genes of known sequence, there is a
crucial need in the areas of medical genetics and genome analysis for
rapid, accurate and cost-effective methods of mutation detection. We have
developed a multiplex allele-specific diagnostic assay (MASDA) for analysis
of large numbers of samples (> 500) simultaneously for a large number of
known mutations (> 100) in a single assay. MASDA utilizes
oligonucleotide hybridization to interrogate DNA sequences. Multiplex DNA
samples are immobilized on a solid support and a single hybridization is
performed with a pool of allele-specific oligonucleotide (ASO) probes. Any
probes complementary to specific mutations present in a given sample are in
effect affinity purified from the pool by the target DNA. Sequence-specific
band patterns (fingerprints), generated by chemical or enzymatic sequencing
of the bound ASO(s), easily identify the specific mutation(s). Using this
design, in a single diagnostic assay, we tested samples for 66 cystic
fibrosis (CF) mutations, 14 beta-thalassemia mutations, two sickle cell
anemia (SCA) mutations, three Tay-Sachs mutations, eight Gaucher mutations,
four mutations in Canavan disease, four mutations in Fanconi anemia, and
five mutations in BRCA1. Each mutation was correctly identified. Finally,
in a blinded study of 106 of these mutations in > 500 patients, all
mutations were properly identified. There were no false positives or false
negatives. The MASDA assay is capable of detecting point mutations as well
as small insertion or deletion mutations. This technology is amenable to
automation and is suitable for immediate utilization for high-throughput
genetic diagnostics in clinical and research laboratories.
相似文献
10.
Karina R B Bastos Renato Barboza Rosa M Elias Luiz R Sardinha Marcos G Grisotto Cláudio R F Marinho Gustavo P Amarante-Mendes José M Alvarez Maria Regina D'Império Lima 《Journal of interferon & cytokine research》2002,22(12):1191-1199
Aiming to clarify the role of endogenous interleukin-12 (IL-12) in protective immunity against blood stages of Plasmodium chabaudi chabaudi (AS), we evaluated the course of infection in IL-12p40 gene knockout (IL-12p40KO) and wild-type (WT) C57BL/6 mice, focusing (1) on the ability of T cells to develop adequate type 1 responses and (2) on the potentiality of macrophages to respond to parasites, interferon-gamma (IFN-gamma), or both. We observed that IL-12p40KO mice develop significantly higher parasitemias during the acute infection, although mice from both groups clear the parasites within a month and similarly eliminate a secondary challenge. Thus, fully protective immunity to P. c. chabaudi can be generated in the absence of IL-12. However, this cytokine may promote parasite control during the early phase of infection. The increased acute parasitemia of IL-12p40KO mice was associated with both impaired IFN-gamma and nitric oxide (NO) response by spleen cells. Because stimulation with recombinant IFN-gamma (rIFN-gamma) failed to improve the NO response in IL-12p40KO macrophages, we investigated whether these cells have an intrinsic defect. Analysis of peritoneal macrophages revealed that IL-12p40KO cells produce higher levels of transforming growth factor-beta1 (TGF-beta1) compared with WT cells and respond to infected erythrocytes or rIFN-gamma by releasing little NO. Moreover, IL-12p40KO macrophages had a severely impaired ability to internalize opsonized infected erythrocytes, suggesting that the low effector profile assumed by these cells may compromise antibody-mediated immunity. Taken together, our results support the idea that the absence of IL-12p40 not only affects IFN-gamma production but also has deep consequences in macrophage effector functions that may contribute to exacerbation of the early phase of P. c. chabaudi malaria. 相似文献