全文获取类型
收费全文 | 8377篇 |
免费 | 621篇 |
国内免费 | 29篇 |
专业分类
耳鼻咽喉 | 31篇 |
儿科学 | 260篇 |
妇产科学 | 297篇 |
基础医学 | 1033篇 |
口腔科学 | 104篇 |
临床医学 | 1489篇 |
内科学 | 1248篇 |
皮肤病学 | 174篇 |
神经病学 | 870篇 |
特种医学 | 216篇 |
外科学 | 899篇 |
综合类 | 159篇 |
一般理论 | 39篇 |
预防医学 | 964篇 |
眼科学 | 173篇 |
药学 | 507篇 |
中国医学 | 4篇 |
肿瘤学 | 560篇 |
出版年
2023年 | 45篇 |
2022年 | 91篇 |
2021年 | 178篇 |
2020年 | 100篇 |
2019年 | 186篇 |
2018年 | 209篇 |
2017年 | 157篇 |
2016年 | 155篇 |
2015年 | 202篇 |
2014年 | 288篇 |
2013年 | 384篇 |
2012年 | 517篇 |
2011年 | 566篇 |
2010年 | 326篇 |
2009年 | 289篇 |
2008年 | 423篇 |
2007年 | 520篇 |
2006年 | 486篇 |
2005年 | 490篇 |
2004年 | 461篇 |
2003年 | 419篇 |
2002年 | 418篇 |
2001年 | 130篇 |
2000年 | 107篇 |
1999年 | 124篇 |
1998年 | 135篇 |
1997年 | 115篇 |
1996年 | 84篇 |
1995年 | 76篇 |
1994年 | 64篇 |
1993年 | 59篇 |
1992年 | 84篇 |
1991年 | 92篇 |
1990年 | 81篇 |
1989年 | 73篇 |
1988年 | 62篇 |
1987年 | 65篇 |
1986年 | 75篇 |
1985年 | 77篇 |
1984年 | 64篇 |
1983年 | 58篇 |
1982年 | 47篇 |
1981年 | 43篇 |
1980年 | 43篇 |
1979年 | 42篇 |
1978年 | 36篇 |
1977年 | 28篇 |
1976年 | 24篇 |
1975年 | 27篇 |
1974年 | 22篇 |
排序方式: 共有9027条查询结果,搜索用时 15 毫秒
91.
Malignant melanoma: analysis by DNA flow cytometry 总被引:2,自引:0,他引:2
The DNA content of 14 primary and 111 secondary melanomas was determined by flow cytometry. Aneuploidy was detected in 67% of samples. The frequency with which aneuploid cells were found was similar in primary and metastatic melanomas and, in the metastatic group, for melanotic and amelanotic tumours. Aneuploid diversity was marked with a wide variation in DNA content between tumours. Serial biopsies were performed in 14 patients, and in 10 there was discordance in DNA profiles between first and subsequent biopsies. Tumour biopsies taken from different sites at the same time also showed discordance in 3 of 5 cases. These features highlight the degree of cellular heterogeneity in malignant melanoma. 相似文献
92.
Taurine reduces high glucose induced leukocyte–endothelial interactions via down-regulation of ICAM-1
下载免费PDF全文
![点击此处可从《Journal of anatomy》网站下载免费的PDF全文](/ch/ext_images/free.gif)
R. G. Casey G. Chen M. Joyce C. J. Kelly D. J. Bouchier-Hayes 《Journal of anatomy》2002,200(5):523-534
Taurine is a semiessential amino acid and naturally occurring antioxidant. One of its main roles is to protect tissues against attack by chlorinated oxidants particularly hypochlorous acid (HOCl). It is found in high concentrations in neutrophils and previous studies showed it possesses potent antimicrobial properties and attenuates high glucose induced endothelial cell apoptosis. In humans taurine has been shown to up-regulate constitutive nitric oxide synthase (cNOS), a known cytoprotector.
No reported studies to date have looked at the possible therapeutic role of taurine in preventing diabetic endothelial dysfunction. We therefore hypothesised that taurine would attenuate the microvascular changes associated with hyperglycaemia in an animal model through alteration of leucocyte–endothelial interactions.
Male Sprague Dawley rats were randomised into control, hyperglycaemia, and taurine + hyperglycaemia groups. Taurine was gavaged (200 mg/kg) for 5 d prior to the experiment. Hyperglycaemia was established by intravenous infusion of 50% glucose. Blood glucose reached a steady state of 3 times baseline at 30 min. Using intravital microscopy leukocyte rolling, adhesion and transendothelial migration was determined in mesenteric postcapillary venules for 3 h. Intracellular adhesion molecule-1 (ICAM-1) was immunohistochemically graded using a scoring system to determine the expression in mesenteric tissue.
Taurine pretreatment significantly attenuates leukocyte-endothelial adhesion and transendothelial migration following acute hyperglycaemia but not leukocyte rolling velocity. The mechanism by which taurine protects against these effects is in part by inhibition of ICAM-1 expression .
No reported studies to date have looked at the possible therapeutic role of taurine in preventing diabetic endothelial dysfunction. We therefore hypothesised that taurine would attenuate the microvascular changes associated with hyperglycaemia in an animal model through alteration of leucocyte–endothelial interactions.
Male Sprague Dawley rats were randomised into control, hyperglycaemia, and taurine + hyperglycaemia groups. Taurine was gavaged (200 mg/kg) for 5 d prior to the experiment. Hyperglycaemia was established by intravenous infusion of 50% glucose. Blood glucose reached a steady state of 3 times baseline at 30 min. Using intravital microscopy leukocyte rolling, adhesion and transendothelial migration was determined in mesenteric postcapillary venules for 3 h. Intracellular adhesion molecule-1 (ICAM-1) was immunohistochemically graded using a scoring system to determine the expression in mesenteric tissue.
Taurine pretreatment significantly attenuates leukocyte-endothelial adhesion and transendothelial migration following acute hyperglycaemia but not leukocyte rolling velocity. The mechanism by which taurine protects against these effects is in part by inhibition of ICAM-1 expression .
93.
Peiser L De Winther MP Makepeace K Hollinshead M Coull P Plested J Kodama T Moxon ER Gordon S 《Infection and immunity》2002,70(10):5346-5354
Macrophages (Mphi) play a key role in the pathogenesis of invasive meningococcal infections. The roles of two pattern recognition molecules, the Mphi scavenger receptor (SR-A) and Toll-like receptor 4 (TLR-4), have been investigated using bone marrow culture-derived Mphi (BMMphi). Surprisingly, a comparison of BMMphi from wild-type and SR-A knockout (SR-A(-/-)) mice showed that nonopsonic phagocytosis of meningococci was mediated almost exclusively via SR-A. Previous studies have demonstrated only a partial involvement of the receptor in the uptake of other bacteria, such as Escherichia coli. Interestingly, we also show that lipopolysaccharide (LPS) was not the ligand for the receptor on these organisms. Further study of the downstream events of SR-A-mediated ingestion of Neisseria meningitidis demonstrated that SR-A was not required for cytokine production. To determine the bacterial and host factors required to stimulate Mphi activation, we examined TLR-4-deficient Mphi from C3H/HeJ mice and LPS-deficient meningococci. TLR-4-deficient cells elaborated reduced amounts of tumor necrosis factor alpha, interleukin-12 (IL-12), and IL-10, even though ingestion via SR-A was unaffected in these cells. Similarly, although there was no change in SR-A-mediated ingestion of LPS-deficient meningococci, the mutant failed to stimulate a Mphi-dependent cytokine response. Thus, we show that Mphi SR-A mediates opsonin-independent uptake of N. meningitidis independently of lipid A and that this activity is uncoupled from the Mphi secretion of proinflammatory cytokines, which provides a basis for further investigation of the role of this receptor in meningococcal disease in humans. 相似文献
94.
95.
C Brassett J A Joyce N J Froggatt G Williams D Furniss S Walsh R Miller D G Evans E R Maher 《Journal of medical genetics》1996,33(12):981-985
Hereditary non-polyposis colorectal cancer syndrome (HNPCC) is often considered to be the most common form of inherited colorectal cancer, although its precise incidence is unknown. The clinical diagnosis of HNPCC relies on a combination of family history and young age of onset of colorectal cancer, but as many familial aggregations of colorectal cancer do not fulfil the strict diagnostic criteria, HNPCC might be underdiagnosed. The majority of HNPCC families have germline mutations in mismatch repair (MMR) genes, such as MSH2 or MLH1, so that HNPCC cancers characteristically exhibit DNA replication errors (RERs) at microsatellite loci. Although an RER positive phenotype in tumours can also result from somatic mutations in an MMR gene, the prevalence of RER + tumours should provide a maximum estimate of the incidence of germline MMR gene mutations in patients with early onset and familial colorectal cancer. We investigated colorectal cancers for RERs from (1) a population based study of 33 patients with colorectal cancer aged 45 years or less, (2) 65 kindreds with familial colorectal cancer which only partially fulfilled the criteria for the diagnosis of HNPCC, and (3) 18 cancers from 12 HNPCC kindreds. Seven of 33 patients (21%) with colorectal cancer aged 45 years or less had an RER + cancer, with only two of these having a clear family history of HNPCC. A greater proportion of RER + tumours (5/7) occurred proximal to the splenic flexure than RER - tumours (4/26; chi2 = 6.14, p < 0.025). RERs were detected in all 18 cancers from HNPCC patients but in only six of 65 non-HNPCC familial colorectal cancer kindreds (9%; chi2 = 52.2, p < 0.0005). These findings suggest that most cancers in patients diagnosed at 45 years of age or less and familial aggregations of colorectal cancer which do not fulfil HNPCC diagnostic criteria do not have germline mutations in MSH2 and MLH1. Hence population screening for germline mutations in these genes is unlikely to be an efficient strategy for identifying people at high risk of developing colorectal cancer. 相似文献
96.
David R. Milich Florian Schdel Darrell L. Peterson Joyce E. Jones Janice L. Hughes 《European journal of immunology》1995,25(6):1663-1672
Previous studies of hepatitis B e antigen (HBeAg)-expressing transgenic (Tg31e) mice have indicated that the degree of T cell tolerance was epitope specific. For example, T cells specific for residues 120–131 of HBeAg are profoundly tolerant, whereas a proportion of T cells specific for residues 129–140 escape tolerance induction in B10. S × B10-Tg31e mice. To understand the basis for differential tolerance towards two T cell sites on the same self antigen, we characterized T cell recognition of HBeAg by primary T cells and T cell hybridomas derived from HBeAg-Tg and non-Tg mice. The self-reactive T cells surviving in B10-Tg31e mice exhibited a unique fine specificity, albeit still focussed on HBeAg residues 129–140, which could be distinguished from the HBeAg-specific T cell repertoire in non-Tg B10 mice. Further, self-reactive T cells were comprised predominantly of Th2-type cells that preferentially evaded tolerance induction as compared to their Th1 counterparts. Because HBeAg may act as a tolerogen during the vertical transmission of chronic hepatitis B virus (HBV) infection, these results suggest that a predominance of HBeAg-specific Th2 cells expressing a limited repertoire may influence the initiation or the maintenance of the HBV chronic carrier state. 相似文献
97.
98.
Gerald Batist Raymond W. Klecker Jr. Hiremagalur N. Jayaram Jean F. Jenkins John Grygiel Daniel C. Ihde Joyce L. Eddy Robert L. Fine Ian G. Kerr Jerry M. Collins 《Investigational new drugs》1985,3(4):349-355
Summary Tiazofurin (2--D-ribofuranosylthiazole-4-carboxamide, TCAR) is a synthetic C-nucleoside that demonstrated significant in vivo activity against a variety of animal tumors as well as in vitro activity against human tumor-derived cell lines. Thirteen patients were treated with TCAR administered as a 5-day continuous infusion in this Phase I trial. Seventeen complete cycles were administered in three dose levels ranging from 550 to 1450 mg/M2. Dose-limiting toxicities were myelosuppression and neurotoxicity including severe lethargy. Other toxicities including superficial skin peeling, myalgias, and tearing were seen at all doses. One patient had chest pain on day 4 resulting in stopping the drug, however, there was no evidence of cardiac or pericardial disease. Uric acid levels rose within one day in the absence of allopurinol treatment. There were no treatment related deaths. HPLC measurement of drug levels demonstrated steady-state plasma levels during the infusion, and a half-life following the infusion of 7.7 ± 0.6 hours. Minor abnormalities in renal function were associated with dramatic changes in pharmacokinetics and toxicity. No clinical responses were observed in this trial.Abbreviations TCAR
Tiazofurin
- HPLC
High performance liquid chromatography
- IMPD
Inosine monophosphate dehydrogenase
- WBC
white blood cell
- CPK
creatine phosphokinase
- Css
steady-state concentration 相似文献
99.
Inconsistent effects of all-trans retinoic acid on different clones of chemically transformed rat liver epithelial cells 总被引:1,自引:0,他引:1
Tsao Ming-Sound; Blaisdell Joyce; Chou Barbara B.; Earp H.Shelton; Grisham Joe W. 《Carcinogenesis》1987,8(4):497-501
The effects of all-trans retinoic acid (RA) on the growth andbiochemical properties of five clonal strains of neoplasticallytransformed rat liver epithelial cells were studied. These cellstrains were derived clonally from a single line of normal diploidrat liver epithelial cells that had been transformed by treatmentwith N-methyl-N'-nitro-N-nitrosoguanidine. The results showthat RA induces inconsistent alterations in selected phenotypicproperties of these five different cell strains. Retinoic acideither depressed, enhanced or produced no effect on the colony-formingability in soft agar, on the activity of -glutamyl transpeptidase,on the amount of cell-associated fibronectin, and on the bindingcapacity of 125I-epidermal growth factor (EGF). The only consistentcorrelation observed among cell strains was between the cellularability to grow in soft agar and the amount of cell-associatedfibronectin. Enhancement of anchorage-independent growth byretinoic acid was not mediated through changes in the numberof EGF receptors. Our data demonstrate that the responses toretinoic acid of clonal subpopulations of chemically transformedrat liver epithelial cells are inconsistent, even when the clonalsubpopulations are derived from a common precursor. 相似文献
100.
Biochemical and morphologic studies of heterogeneous lobe responses in hepatocarcinogenesis 总被引:1,自引:1,他引:0
Richardson Frank C.; Boucheron Joyce A.; Dyroff Martin C.; Popp James A.; Swenberg James A. 《Carcinogenesis》1986,7(2):247-251
Experiments have demonstrated interlobe differences in the incidenceof diethylnitrosamine (DEN)-induced hepatocellular carcinoma(HCCA), with a 100% incidence in the left and right median lobesand a 30% incidence in the right anterior lobe 20 weeks afterexposure began. These tumor data provide a model to test thehypothesis that chemically induced neoplasia can be qualitativelyand quantitatively related to promutagenic DNA damage and concurrentcell replication. Experiments were performed to measure O4-ethyldeoxythymidine(O4-EtdT) (a major pro-mutagenic lesion in hepatic DNA of ratsexposed to DEN), N7-ethylguanine, cell replication and hepatocyteinitiation using the induction of growthselected -glutamyl transferase-positive(GGT+) foci in the left and right median and right anteriorhepatic lobes following 0, 3, 7, 14 or 28 days of DEN administration.Results demonstrated that O4-EtdT concentrations were consistentlyhigher in the left and right median versus the right anteriorhepatic lobes, while cell replication was transiently higherin the right median and right anterior lobes. Likewise, highnumbers of GGT+ foci were observed in the left and right medianlobes in DEN-exposed rats subjected to a Cayama-Farber growthselection protocol. Following administration of [14C]DEN, thedistribution of radioactivity showed a marked left lobe preferencein 4-week-old rats that had no prior exposure to DEN and in8-week-old rats exposed to DEN for 4 weeks. This study suggeststhat interlobe differences in hepatocyte initiation and theincidence of HCCA may be due in part to differences in cellreplication and in DNA alkylation resulting from differentialDEN distribution and/or metabolism. 相似文献