全文获取类型
收费全文 | 697篇 |
免费 | 25篇 |
国内免费 | 25篇 |
专业分类
耳鼻咽喉 | 4篇 |
儿科学 | 15篇 |
妇产科学 | 16篇 |
基础医学 | 254篇 |
口腔科学 | 7篇 |
临床医学 | 55篇 |
内科学 | 113篇 |
皮肤病学 | 2篇 |
神经病学 | 55篇 |
特种医学 | 46篇 |
外科学 | 30篇 |
综合类 | 53篇 |
预防医学 | 22篇 |
眼科学 | 2篇 |
药学 | 31篇 |
肿瘤学 | 42篇 |
出版年
2023年 | 5篇 |
2022年 | 11篇 |
2021年 | 16篇 |
2020年 | 14篇 |
2019年 | 17篇 |
2018年 | 13篇 |
2017年 | 21篇 |
2016年 | 23篇 |
2015年 | 29篇 |
2014年 | 21篇 |
2013年 | 52篇 |
2012年 | 30篇 |
2011年 | 62篇 |
2010年 | 34篇 |
2009年 | 60篇 |
2008年 | 72篇 |
2007年 | 71篇 |
2006年 | 56篇 |
2005年 | 32篇 |
2004年 | 33篇 |
2003年 | 13篇 |
2002年 | 10篇 |
2001年 | 11篇 |
2000年 | 4篇 |
1999年 | 5篇 |
1998年 | 7篇 |
1997年 | 5篇 |
1996年 | 3篇 |
1995年 | 5篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 3篇 |
1991年 | 2篇 |
1987年 | 1篇 |
1982年 | 1篇 |
排序方式: 共有747条查询结果,搜索用时 31 毫秒
191.
192.
Yue Fang Joyce B. J. van Meurs Pascal Arp Johannes P. T. van Leeuwen Albert Hofman Huibert A. P. Pols André G. Uitterlinden 《Calcified tissue international》2009,85(2):85-93
Osteoporosis is a bone disease leading to an increased fracture risk. It is considered a complex multifactorial genetic disorder
with interaction of environmental and genetic factors. As a candidate gene for osteoporosis, we studied vitamin D binding
protein (DBP, or group-specific component, Gc), which binds to and transports vitamin D to target tissues to maintain calcium
homeostasis through the vitamin D endocrine system. DBP can also be converted to DBP-macrophage activating factor (DBP-MAF),
which mediates bone resorption by directly activating osteoclasts. We summarized the genetic linkage structure of the DBP
gene. We genotyped two single-nucleotide polymorphisms (SNPs, rs7041 = Glu416Asp and rs4588 = Thr420Lys) in 6,181 elderly
Caucasians and investigated interactions of the DBP genotype with vitamin D receptor (VDR) genotype and dietary calcium intake
in relation to fracture risk. Haplotypes of the DBP SNPs correspond to protein variations referred to as Gc1s (haplotype 1),
Gc2 (haplotype 2), and Gc1f (haplotype3). In a subgroup of 1,312 subjects, DBP genotype was found to be associated with increased
and decreased serum 25-(OH)D3 for haplotype 1 (P = 3 × 10−4) and haplotype 2 (P = 3 × 10−6), respectively. Similar associations were observed for 1,25-(OH)2D3. The DBP genotype was not significantly associated with fracture risk in the entire study population. Yet, we observed interaction
between DBP and VDR haplotypes in determining fracture risk. In the DBP haplotype 1-carrier group, subjects of homozygous
VDR block 5-haplotype 1 had 33% increased fracture risk compared to noncarriers (P = 0.005). In a subgroup with dietary calcium intake <1.09 g/day, the hazard ratio (95% confidence interval) for fracture
risk of DBP hap1-homozygote versus noncarrier was 1.47 (1.06–2.05). All associations were independent of age and gender. Our
study demonstrated that the genetic effect of the DBP gene on fracture risk appears only in combination with other genetic
and environmental risk factors for bone metabolism. 相似文献
193.
Alberto Falchetti Marco Di Stefano Francesca Marini Sergio Ortolani Massimo Fabio Ulivieri Simona Bergui Laura Masi Chiara Cepollaro Maurizio Benucci Ombretta Di Munno Maurizio Rossini Silvano Adami Antonio Del Puente Giancarlo Isaia Francesca Torricelli Maria Luisa Brandi 《Calcified tissue international》2009,84(1):20-37
Families affected by Paget’s disease of bone frequently harbor mutations in the SQSTM1/p62 gene. In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy, identifying 12 different
mutations, 5 of which are newly reported and 3, D335E, A381V, and Y383X, external to the UBA domain. Subjects with truncating mutations, E396X, showed a significantly younger age at clinical diagnosis, while the Y383X subjects had a higher average number of affected skeletal sites. All the mutants exhibited the CGTG-H2 haplotype. In two pairs and one triad of unrelated Italian PDB families from different Italian regions, we detected a
common SQSTM1/p62 mutation for each P392L, M404V, and G425R group. Since the CGTG-H2 haplotype frequency was also high in normal subjects, and genetic influence due to migratory fluxes of different ethnic
groups exists in the Italian population, to refine the search for a more geographically specific founder effect, we extended
the haplotype analysis in these families using polymorphic microsatellite repeat markers, within and flanking the SQSTM1/p62 locus, from chromosome 5q35, other than the exon 6 and 3′UTR polymorphisms. All mutant carriers from two of the three M404V families and from the G425R families exhibited common extended chromosome 5q35 haplotypes, IT01 and IT02, respectively, which may be reflecting influences of past migrations. This may be helpful in estimating the true rate of
de novo mutations. We confirm the data on the existence of both a mutational hotspot at the UBA domain of SQSTM1/p62 and a
founder effect in the PDB population. 相似文献
194.
Objectives The aims of this study were to characterize the population frequency of PEPT2 (SLC15A2) polymorphic variants in three Asian ethnic populations, namely Chinese, Malay and Asian Indian, and to investigate the associations
of ethnicity (Chinese vs. Asian Indian), PEPT2 haplotype and cephalexin pharmacokinetics in healthy Asian subjects.
Methods
PEPT2 polymorphisms were screened from a cohort of 96 Chinese, 96 Malay and 96 Asian Indian subjects. Cephalexin (1000 mg, orally)
pharmacokinetics was characterized in an additional 15 Chinese and 15 Asian Indian healthy subjects. These 30 subjects were
subsequently genotyped for their PEPT2 polymorphisms.
Results In total, ten common single nucleotide polymorphisms (SNPs) were detected in the three populations, forming two PEPT2 haplotypes. There were significant ethnic differences in PEPT2 haplotype distribution: the frequencies of the *1 and *2 alleles were 0.307 and 0.693 in the Chinese population, 0.495 and
0.505 in the Malay population and 0.729 and 0.271 in Asian Indian population, respectively. The C
max of cephalexin was significantly lower in the Chinese (29.80 ± 4.09 μg ml−1) population than in the Asian Indian one (33.29 ± 4.97 μg ml−1; P = 0.045). This difference could be explained by the higher average body weight of the Chinese population. There was no other
significant difference in cephalexin pharmacokinetics between either ethnic or PEPT2 genotype groups.
Conclusion
PEPT2 polymorphism distributions differ significantly between Chinese, Malay and Asian Indian populations. However, cephalexin
pharmacokinetics is not meaningfully different between Chinese and Asian Indians. The association between the PEPT2 haplotype and cephalexin pharmacokinetics could not be confirmed, and future studies under better controlled conditions are
needed. 相似文献
195.
Kim HB Lee YC Lee SY Jung J Jin HS Kim JH Kim BS Kang MJ Jang SO Kim J Kimm K Shin ES Lee SG Hong SJ 《Journal of human genetics》2006,51(12):1055-1062
Interleukin (IL)-13, which is essential for IgE synthesis, mediates its effects by binding with a receptor composed of IL-4Rα and IL-13Rα1. We investigated the effects of IL-13 and IL-13Rα1 polymorphisms in Korean children with asthma, and whether these have been associated with IgE production. We enrolled 358 atopic asthmatic, 111 non-atopic asthmatic, and 146 non-atopic healthy children. IL-13 and IL-13Rα1 genotypes were identified using the PCR-RFLP method. There was an association between the asthma susceptibility and homozygosity for risk allele of IL-13 G+2044A. In children with atopic asthma, risk alleles in IL-13 (A−1512C and C−1112T) and IL-13Rα1 (A+1398G) showed increased total IgE (P=0.012, 0.015 and 0.017, respectively). Three-loci haplotype analysis for IL-13 showed that the haplotype composed of −1512C, −1112T and +2044A was associated with higher total IgE than other tested haplotypes in children with atopic asthma (P=0.003). The gene–gene interaction between risk alleles of each IL-13 promoter polymorphism and IL-13Rα1 polymorphism was associated with higher total IgE in children with atopic asthma (P=0.002, 0.010). These findings indicate that the IL-13 G+2044A is associated with asthma development and the IL-13 and IL-13Rα1 polymorphisms may interact to enhance IgE production.Hyo-Bin Kim, and Yong-Chul Lee contributed equally to this work. This work was supported by grants from the Asan Institute for Life Science (2005-091) and the National Research Laboratory Program, Korea Science and Engineering Foundation and by Korea Research Foundation Grants funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2005-201-E00014), Republic of Korea. 相似文献
196.
HDL-associated paraoxonase1 (PON1) is believed to be an important anti-oxidative enzyme in the retardation of atherosclerosis. In this study, we determined haplotypes of three SNPs within the PON1 gene promoter to elucidate association of functional sites with coronary artery disease (CAD). We applied a direct haplotyping procedure through ARMS (Amplification Refractory Mutation System) and RFLP (Restriction Fragment Length Polymorphism) analysis techniques. The haplotypes of the G(− 907)C, A(− 162)G and C(− 107)T polymorphisms within the 5' region of the PON1 gene were determined in 99 patients and 66 controls who were evaluated angiographically for the presence and extent of stenosis in coronary arteries. The genotype and haplotype distributions had significant differences between patient subgroups (One-, Two- and Three-vessel disease) but not between the patient and control groups. Multivariate analyses suggested decreased arylesterase activity is the most important independent factor in the CAD severity. The increase of high activity variants [G(− 907) and C(− 107)] within the two-allelic haplotypes was reversely associated with the extent of stenosis in coronary arteries. However, we could not determine the independent involvement each of the C(− 107)T and G(− 907)C polymorphisms on the extent of stenosis. We found no significant association between the A(− 162)G polymorphism and the extent of stenosis in vessels. The study indicated the association of polymorphic variations within the PON1 gene promoter haplotypes with the serum arlyesterase activity. The arlyesterase activity was also associated with the extent of stenosis in coronary arteries but not with primary development of atherosclerosis. 相似文献
197.
Tadić A Baskaya O Victor A Lieb K Höppner W Dahmen N 《Journal of psychiatric research》2008,43(2):155-163
Borderline personality disorder (BPD) is a serious psychiatric disorder affecting about 1-2% of the general population. Key features of BPD are emotional instability, strong impulsivity, repeated self-injurious behavior (SIB) and dissociation. In the etiology of BPD and its predominant symptoms, genetic factors have been suggested. The voltage-gated sodium channel Nav1.7 is expressed in sensory neurons and in the hippocampus, a key region of the limbic system probably dysfunctional in BPD and dissociative disorders. The alpha-subunit of Nav1.7 is encoded by the SCN9A gene on chromosome 2 and variations of SCN9A can lead to complete inability to sense pain. The aim of the present study was to test for associations between SCN9A gene variants and BPD as well as BPD-related phenotypes. We genotyped ten tagging single nucleotide polymorphisms (SNPs) within the SCN9A gene in 161 well-defined Caucasian BPD patients and 156 healthy controls. We found no globally significant association of SCN9A markers with BPD at level 5%. However, in the female and in the male subsample, different SCN9A markers and individual haplotypes showed uncorrected p-values < 0.05. In addition, p-values < 0.05 were observed in the analysis of associations between SCN9A markers and dissociative symptoms. Although our results were largely negative, replication studies in an independent sample are warranted to follow up on the potential role of SCN9A gene variants in BPD and dissociative symptoms, paying special attention to a possible gender different etiology. 相似文献
198.
A haplotype analysis of CYP2E1 polymorphisms in relation to alcoholic phenotypes in Mexican Americans 总被引:1,自引:0,他引:1
Background: Studies regarding the association between the 4 polymorphisms of CYP2E1 (CYP2E1*1D, *5B, *6, and *1B) and alcoholism are inconsistent and inconclusive. The purpose of the present study was to clarify previously discordant studies by haplotype analysis in the Mexican American population. Methods: The 4 polymorphisms of CYP2E1 were studied in 334 alcoholics and 365 controls. Genotype, allele, and haplotype frequency comparisons between alcoholics and controls were assessed. Patterns of linkage disequilibrium (LD) at CYP2E1 were determined. Reconstructed haplotypes were tested for associations with clinical phenotypes (age onset of drinking, Maxdrinks, and smoking status). Results: No significant associations between the 4 polymorphisms of CYP2E1 and alcoholism were revealed by single allele tests. High LD was found between the CYP2E1 c2 and C alleles in Mexican Americans. Eleven haplotypes were present in the 699 participants. The 6 main haplotypes with frequencies higher than 1% made up 97% of the total halpotypes. The frequency of subjects carrying H6 (1C‐c2‐C‐A2) was significantly higher in alcoholics than in controls (p = 0.0001). In contrast, the frequencies of H7 (1C‐c2‐C‐A1) and H10 (1C‐c2‐D‐A1) were significantly lower in alcoholics than in controls (p = 0.0072 for H7 and p = 0.0407 for H10). The frequency of H6 was significantly higher in alcoholics who had late onset of drinking than in nonalcoholic controls. Furthermore, the frequencies of H6 haplotype were also consistently higher in groups who had high number of maximum drinks (9 to 32 drinks) than in controls. When smokers are excluded, the frequencies of H6, H7, and H9 (1C‐c2‐D‐A2) showed statistically significant differences between alcoholics and controls (p < 0.05). Moreover, the association between H6 and alcoholism become more robust when smokers are excluded. Furthermore, the frequency of H1 (1C‐c1‐D‐A2) in alcoholic‐smokers was much higher than in alcoholic‐nonsmokers (p = 0.0028). In contrast, alcoholic‐smokers carried less H2 (1C‐c1‐D‐A1) in comparison with alcoholic‐nonsmokers (p = 0.0417). The H3 (1D‐c2‐C‐A2) frequency in alcoholic‐smokers was much lower than in alcoholic‐nonsmokers (p = 0.0042) and control‐smokers (p = 0.0363). Conclusions: Our data demonstrate that carrying haplotype H6 might enhance susceptibility to developing alcoholism, but possessing the H7 or H10 haplotype appears to decrease this susceptibility. The H6, H7, and H9 haplotypes may play certain roles in different clinical phenotypes in Mexican American alcoholics. In addition, our data suggest that the H1, H2, and H3 haplotypes are associated with alcohol drinking and smoking. These results support that haplotype analysis is much more informative than single allele analysis. Our findings clearly indicate the importance of H6 haplotype in alcohol drinking in Mexican Americans. 相似文献
199.
Tao R Li C Zheng Y Qin W Zhang J Li X Xu Y Shi YY Feng G He L 《Schizophrenia Research》2007,90(1-3):108-114
The Sialyltransferase 8B gene (SIAT8B) is located at 15q26, a susceptibility region for both schizophrenia and bipolar disorder. The protein encoded by this gene has an important role in neural development and sialic acid synthesis on the neural cell adhesion molecule (NCAM). Previous research had indicated that the promoter region of SIAT8B is associated with schizophrenia in the Japanese population. To take this further we carried out an association study based on 643 unrelated schizophrenics and 527 unrelated healthy subjects, all Han Chinese, recruited from Shanghai. Although our results differed from those of the Japanese research, rs3759915, also located in the promoter region of SIAT8B, showed nominally significant association with schizophrenia (P = 0.0036). Moreover, haplotypes constructed from rs3759915 and another two SNPs reported in the Japanese study (rs3759914 and rs3759916, also located in promoter region of SIAT8B) which located in the same LD block were significantly associated with schizophrenia (global P = 0.0000050). Our findings indicate that SIAT8B may be a candidate susceptibility gene for schizophrenia in the Chinese Han population and may also provide further support for the potential importance of polysaccharide-synthesizing genes in the etiology of schizophrenia. 相似文献