全文获取类型
收费全文 | 525篇 |
免费 | 40篇 |
国内免费 | 2篇 |
专业分类
耳鼻咽喉 | 1篇 |
儿科学 | 15篇 |
妇产科学 | 7篇 |
基础医学 | 170篇 |
口腔科学 | 2篇 |
临床医学 | 51篇 |
内科学 | 130篇 |
皮肤病学 | 5篇 |
神经病学 | 80篇 |
特种医学 | 11篇 |
外科学 | 38篇 |
综合类 | 2篇 |
预防医学 | 15篇 |
眼科学 | 1篇 |
药学 | 20篇 |
肿瘤学 | 19篇 |
出版年
2023年 | 1篇 |
2022年 | 4篇 |
2021年 | 4篇 |
2020年 | 5篇 |
2019年 | 11篇 |
2018年 | 22篇 |
2017年 | 16篇 |
2016年 | 11篇 |
2015年 | 10篇 |
2014年 | 13篇 |
2013年 | 23篇 |
2012年 | 35篇 |
2011年 | 44篇 |
2010年 | 19篇 |
2009年 | 15篇 |
2008年 | 36篇 |
2007年 | 29篇 |
2006年 | 27篇 |
2005年 | 18篇 |
2004年 | 30篇 |
2003年 | 21篇 |
2002年 | 23篇 |
2001年 | 25篇 |
2000年 | 21篇 |
1999年 | 21篇 |
1998年 | 8篇 |
1997年 | 4篇 |
1996年 | 7篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1992年 | 5篇 |
1991年 | 5篇 |
1990年 | 6篇 |
1989年 | 1篇 |
1988年 | 4篇 |
1987年 | 1篇 |
1986年 | 6篇 |
1985年 | 5篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1981年 | 1篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1977年 | 1篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1970年 | 1篇 |
1967年 | 1篇 |
排序方式: 共有567条查询结果,搜索用时 18 毫秒
1.
2.
3.
Parental origin of de novo MECP2 mutations in Rett syndrome 总被引:6,自引:0,他引:6
Girard M Couvert P Carrié A Tardieu M Chelly J Beldjord C Bienvenu T 《European journal of human genetics : EJHG》2001,9(3):231-236
Rett syndrome (RTT) is a neurodevelopmental disorder occurring almost exclusively in females as sporadic cases. Recently, DNA mutations in the MECP2 gene have been detected in approximately 70% of patients with RTT. To explain the sex-limited expression of RTT, it has been suggested that de novo X-linked mutations occur exclusively in male germ cells resulting therefore only in affected daughters. To test this hypothesis, we have analysed 19 families with RTT syndrome due to MECP2 molecular defects. In seven informative families we have found by DHPLC a nucleotide variant which could be used to differentiate between the maternal and the paternal allele. In each subject investigated from these families, we have amplified specifically each allele and sequenced allele-specific PCR products to identify the allele bearing the mutation as well as the parental origin of each X chromosome. This approach allowed us to determine the parental origin of de novo mutations in all informative families. In five cases, the de novo MECP2 mutations have a paternal origin and in the two other cases a maternal origin. In all transitions at CpG, the de novo mutation observed was of paternal origin. The high frequency of male germ-line transmission of the mutation (71% of RTT informative cases) is consistent with a predominant occurrence of the disease in females. 相似文献
4.
Monitoring of basophil activation using CD63 and CCR3 in allergy to muscle relaxant drugs 总被引:12,自引:0,他引:12
Monneret G Benoit Y Debard AL Gutowski MC Topenot I Bienvenu J 《Clinical immunology (Orlando, Fla.)》2002,102(2):192-199
Allergic or pseudoallergic reactions that occur during anesthesia have been increasing for the last few years. To date, the diagnosis of allergy to muscle relaxants remains difficult. In this respect, we developed a flow cytometric method for the study of drug-induced basophil degranulation using CD63 and CCR3. Fifty patients who developed clinical features evocative of allergic reactions immediately after induction of anesthesia were included and classified into two groups. Group 1 (n = 39) comprised true allergic patients, who developed typical signs of shock associated to positive skin testing. Group 2 (n = 11) consisted of patients whose clinical history was not typical and skin testing was negative or nonconclusive. Seventeen control subjects were also studied in this report. We compared data from flow cytometry to skin tests, specific IgE, and histamine release results. Flow cytometry showed a sensitivity of 54%, while that of specific IgE was similar, at 62%. Interestingly, when considering the sensitivity of IgE + CD63 for diagnosis, we reached a sensitivity value of 80%. Of 15 negative results for specific IgE, we found 7 positive CD63 tests, while histamine release gave positive results in only 2 cases. Furthermore, the CD63 protocol showed good specificity (100%). We conclude that our flow cytometry protocol is a promising tool in allergy diagnosis since it is specific and complementary to specific IgE detection. 相似文献
5.
Nicolas L Monneret G Debard AL Blesius A Gutowski MC Salles G Bienvenu J 《Clinical immunology (Orlando, Fla.)》2001,98(3):358-363
The aim of our study was to compare CD3 expression on gammadelta T cells and alphabeta T cells in human patients. The antigen density of TCR and CD3 on both subsets was assessed by a quantitative method in eight patients. In parallel, we developed and validated a reliable direct tricolor staining protocol that we tested on samples from hospitalized and healthy individuals (n = 60). Our results demonstrate that human gammadelta T cells constitutively express approximately twofold more of the TCR/CD3 complex than alphabeta T cells. We suggest that this enhanced expression of the TCR/CD3 complex could contribute to the higher reactivity of gammadelta T cells compared to alphabeta T cells. These clinical laboratory results confirm the fundamental data described elsewhere. gammadelta T cells deserve further clinical investigations to understand their precise role in human immunity. 相似文献
6.
Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study 总被引:3,自引:0,他引:3
Aknin-Seifer IE Touraine RL Lejeune H Jimenez C Chouteau J Siffroi JP McElreavey K Bienvenu T Patrat C Levy R 《Human reproduction (Oxford, England)》2005,20(3):736-740
BACKGROUND: Recent data emphasized the implication of polymerase gamma (POLG) CAG repeats in infertility, making it a very attractive gene for study. A comparison of POLG CAG repeats in infertile and fertile men showed a clear association between the absence of the usual 10-CAG allele and male infertility, excluding azoospermia. It has also been suggested that the POLG gene polymorphism should be considered as a possible contributing factor in unexplained couple infertility where semen parameters are normal. In this study, we investigated the POLG CAG repeats, in a well-defined population of patients with severe male factor infertility. METHODS: We conducted a large study of POLG CAG repeats in 433 infertile and 91 fertile, normozoospermic and healthy males. In all subjects, phenotypic data, including semen parameters, hormonal status and clinical profiles, were available. RESULTS: Thirteen 'homozygous mutants' (3%) were found among the 433 idiopathic infertile patients. The follow-up of the 13 'homozygous mutant' resulted in pregnancy for more than half of the couples, through assisted reproductive techniques or even spontaneously. In addition, one 'homozygous mutant' was identified in 91 fertile men (1.1%) CONCLUSION: Under our conditions, our study does not confirm any relationship between the polymorphic CAG repeat in the POLG gene and male infertility. 相似文献
7.
Cystic fibrosis screening: a fetus with hyperechogenic bowel may be the index case. 总被引:1,自引:1,他引:1 下载免费PDF全文
F Muller M Dommergues B Simon-Bouy C Ferec J F Oury M C Aubry R Bessis E Vuillard E Denamur T Bienvenu J L Serre 《Journal of medical genetics》1998,35(8):657-660
BACKGROUND: The potential of hyperechogenic fetal bowel to act as a hallmark for prenatal cystic fibrosis screening in the general population is controversial. METHODS: Our goal was to evaluate the incidence of cystic fibrosis in 209 fetuses with hyperechogenic bowel diagnosed at routine ultrasonography and with no family history of cystic fibrosis. The diagnosis of cystic fibrosis was based on prenatal screening for the eight mutations most frequently observed in France (deltaF508, deltaI507, 1717-1G-->A, G542X, G551D, R553X, W1282X, N1303K) and at postnatal follow up. RESULTS: The overall incidence of cystic fibrosis was 7/209 (3.3%) which is 84 times the estimated risk of CF in the general population (112500). Of these seven cases, six were diagnosed prenatally based on DNA analysis (deltaF508/deltaF508, n=5; deltaF508/G542X, n=1). One case in which only one mutation had been recognised was diagnosed clinically after birth (deltaF508/unidentified mutation). Of the seven cases, none was diagnosed at 16-19 weeks, four at 16-24 weeks, and three after this. The incidence of heterozygous fetuses (15/209, 7%) was not significantly higher than the 5% expected in the general population. The mutations involved in these heterozygous cases were deltaF508 (n=13), G542X (n=1), and G551D (n=1). CONCLUSIONS: Screening for cystic fibrosis should be offered to families in which fetal hyperechogenic bowel is diagnosed at routine ultrasonography. This underlines the need to review genetic counselling in this situation where the fetus is the index case for a genetic disease. 相似文献
8.
Sibille M Deigat N Durieu I Guillaumont M Morel D Bienvenu J Massignon D Durand DV 《European journal of clinical pharmacology》1999,55(1):13-19
Objective: Laboratory data are key evaluation procedures for Phase I clinical pharmacology for two reasons. Firstly, laboratory data
are used within the screening process to exclude subjects with asymptomatic diseases, which could result in increased danger
to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluation and
in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory
adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common variation and a significant
abnormality, which is considered to be a LAE. This report presents laboratory data distribution, reference values and reference
changes and, based on previously published new methods, suggests inclusion limits at screening and laboratory adverse event
limits for analysis during study implementation.
Subjects and methods: Nine hundred and twenty-seven young healthy male volunteers were recruited in one centre (Association de Recherche Thérapeutique).
A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed
in the same conditions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting
2.5% and 97.5% of the distribution of data. Reference changes were also defined as the 2.5–97.5% interval of distribution
of the variations between the end of treatment and baseline. Inclusion limit and LAE limit methods of determination used had
been specified in previous articles.
Results: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion
limits and LAE limits are presented in tables with number of subjects, mean, median, standard deviation, minimal and maximal
values and the 2.5–97.5% interval for each laboratory parameter.
Conclusion: The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the
real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits,
or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy
volunteers and to analyse LAEs during Phase I studies.
Received: 30 July 1998 / Accepted in revised form: 25 November 1998 相似文献
9.
P Chauvet J G Bienvenu J F Théorêt J G Latour Y Merhi 《Journal of cardiovascular pharmacology》1999,34(4):597-603
The selectin family of cell-adhesion molecules contributes to the interactions of leukocytes and platelets at the site of vascular injury. Such interactions enhance inflammatory reactions and thrombus formation during the arterial response to injury. In this study, we investigated the effects of a selectin inhibitor (Fucoidan) on platelet and neutrophil interactions after arterial injury produced by angioplasty in pigs. [51Cr]-platelet deposition and [111In]-neutrophil adhesion were quantified on intact, mildly, and deeply injured carotid arterial segments, produced by balloon dilation in control (saline, n = 7) and Fucoidan-treated (i.v.; 1 mg/kg, n = 6; 5 mg/kg, n = 5) pigs. In the control group, platelet deposition (x10(6)/cm2) was influenced by the severity of injury and increased significantly (p < 0.05) from 0.06+/-0.06 on intact endothelium to 3.8+/-0.6 and 33.6+/-4.9 on mildly and deeply injured segments, respectively. Fucoidan, 1 mg/kg, had no significant effect, although doses of 5 mg/kg reduced platelet deposition by 73% on deeply injured segments. The level of neutrophil adhesion (x10(3)/cm2) was also influenced by the severity of injury: it increased in the control group from 8.8+/-2.5 on intact endothelium to 226.6+/-45.5 and 397.4+/-61.3 on mildly and deeply injured arterial segments, respectively (p < 0.05). Again, 1 mg/kg Fucoidan had no effect, although doses of 5 mg/kg reduced neutrophil adhesion by 92% and by 84% on mildly and deeply injured segments, respectively. The effects of Fucoidan were associated with a 51% decrease in the vasoconstrictive response at the site of arterial injury. However, Fucoidan had no significant effect on either platelet aggregation or activated clotting time (ACT). In the in vitro perfusion experiments, Fucoidan inhibited both isolated platelet, and neutrophil, adhesion to damaged arterial surfaces. This inhibition was more pronounced in experiments using mixed cell preparations, indicating that Fucoidan interferes with platelet and neutrophil interactions. These results highlight the importance of selectins in the acute physiopathologic reactions related to platelet-neutrophil interactions after arterial injury. 相似文献
10.
Bienvenu B Thervet E Bedrossian J Scieux C Mazeron MC Thouvenot D Legendre C 《Transplantation》2000,69(1):182-184
The emergence of a resistant strain is a theoretical threat after extensive use of antiviral drugs. We report the emergence of a ganciclovir-resistant cytomegalovirus (CMV) strain in a kidney transplant recipient during oral ganciclovir maintenance treatment. The patient was treated by oral ganciclovir for 2 months after successful treatment of CMV primary infection by intravenous ganciclovir. He developed a new episode of CMV infection with no clinical response to intravenous ganciclovir. The CMV isolate exhibited both phenotypic and genotypic resistance to ganciclovir. The CMV isolate was constituted of a mixture of strains, with and without a mutation at codon 460 of the UL97 gene. The clinical condition improved when mycophenolate mofetil (MMF) was discontinued, and a short course of intravenous globulin was added to ganciclovir. The emergence of the CMV strain could be secondary to more potent immunosuppression provide by MMF or subtherapeutic level obtained during oral ganciclovir treatment. We believe that ganciclovir resistance must be part of the differential diagnosis when a patient relapses or fails to respond to ganciclovir treatment. 相似文献