全文获取类型
收费全文 | 2090篇 |
免费 | 153篇 |
国内免费 | 10篇 |
专业分类
耳鼻咽喉 | 10篇 |
儿科学 | 33篇 |
妇产科学 | 76篇 |
基础医学 | 247篇 |
口腔科学 | 49篇 |
临床医学 | 180篇 |
内科学 | 467篇 |
皮肤病学 | 27篇 |
神经病学 | 202篇 |
特种医学 | 75篇 |
外科学 | 278篇 |
综合类 | 41篇 |
一般理论 | 2篇 |
预防医学 | 213篇 |
眼科学 | 106篇 |
药学 | 172篇 |
中国医学 | 13篇 |
肿瘤学 | 62篇 |
出版年
2023年 | 7篇 |
2022年 | 7篇 |
2021年 | 36篇 |
2020年 | 20篇 |
2019年 | 33篇 |
2018年 | 31篇 |
2017年 | 31篇 |
2016年 | 42篇 |
2015年 | 30篇 |
2014年 | 46篇 |
2013年 | 94篇 |
2012年 | 146篇 |
2011年 | 168篇 |
2010年 | 97篇 |
2009年 | 98篇 |
2008年 | 145篇 |
2007年 | 149篇 |
2006年 | 146篇 |
2005年 | 144篇 |
2004年 | 145篇 |
2003年 | 122篇 |
2002年 | 122篇 |
2001年 | 18篇 |
2000年 | 27篇 |
1999年 | 30篇 |
1998年 | 28篇 |
1997年 | 17篇 |
1996年 | 22篇 |
1995年 | 17篇 |
1994年 | 7篇 |
1993年 | 5篇 |
1992年 | 7篇 |
1991年 | 13篇 |
1990年 | 10篇 |
1989年 | 11篇 |
1988年 | 9篇 |
1987年 | 20篇 |
1986年 | 8篇 |
1985年 | 16篇 |
1984年 | 7篇 |
1983年 | 7篇 |
1982年 | 18篇 |
1981年 | 10篇 |
1980年 | 13篇 |
1979年 | 7篇 |
1978年 | 8篇 |
1977年 | 9篇 |
1976年 | 5篇 |
1974年 | 5篇 |
1946年 | 4篇 |
排序方式: 共有2253条查询结果,搜索用时 140 毫秒
21.
22.
CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid beta-peptide 总被引:2,自引:0,他引:2
Townsend KP Town T Mori T Lue LF Shytle D Sanberg PR Morgan D Fernandez F Flavell RA Tan J 《European journal of immunology》2005,35(3):901-910
Although deposition of amyloid beta-peptide (Abeta) as Abeta plaques involves activation of microglia-mediated inflammatory responses, activated microglia ultimately fail to clear Abeta plaques in the brains of either Alzheimer's disease (AD) patients or AD mouse models. Mounting evidence suggests that chronic microglia-mediated immune response during Abeta deposition etiologically contributes to AD pathogenesis by promoting Abeta plaque formation. However, the mechanisms that govern microglia response in the context of cerebral Abeta/beta-amyloid pathology are not well understood. We show that ligation of CD40 by CD40L modulates Abeta-induced innate immune responses in microglia, including decreased microglia phagocytosis of exogenous Abeta(1-42) and increased production of pro-inflammatory cytokines. CD40 ligation in the presence of Abeta(1-42) leads to adaptive activation of microglia, as evidenced by increased co-localization of MHC class II with Abeta. To assess their antigen-presenting cell (APC) function, cultured microglia were pulsed with Abeta(1-42) in the presence of CD40L and co-cultured with CD4(+) T cells. Under these conditions, microglia stimulate T cell-derived IFN-gamma and IL-2 production, suggesting that CD40 signaling promotes the APC phenotype. These data provide a mechanistic explanation for our previous work showing decreased microgliosis associated with diminished cerebral Abeta/beta-amyloid pathology when blocking CD40 signaling in transgenic Alzheimer's mice. 相似文献
23.
24.
Pre-trigeminal neuralgia 总被引:1,自引:0,他引:1
Eighteen patients who subsequently developed typical trigeminal neuralgia experienced a prodromal pain termed "pre-trigeminal neuralgia." These patients described their prodromal pain as a toothache or sinusitis-like pain lasting up to several hours, sometimes triggered by jaw movements or by drinking hot or cold liquids. Typical trigeminal neuralgia developed a few days to 12 years later, and in all cases affected the same division of the trigeminal nerve. Six additional patients experiencing what appeared to be pre-trigeminal neuralgia became pain-free when taking carbamazepine or baclofen. Recognition of pretrigeminal neuralgia makes it possible to relieve the pain with appropriate medications and avoid unnecessary irreversible dental procedures. 相似文献
25.
McGrady AV Andrasik F Davies T Striefel S Wickramasekera I Baskin SM Penzien DB Tietjen G 《Primary care companion to the Journal of clinical psychiatry》1999,1(4):96-102
BACKGROUND: Headaches account for a high percentage of office visits to primary care physicians, with migraine and tension-type headaches the most common. This article provides a summary of psychophysiologic therapies for migraine and tension-type headache and considers psychosocial factors relevant to headache. Psychophysiologic therapy of headache consists primarily of relaxation and biofeedback. METHOD: Representative controlled studies, meta-analysis, and reviews are utilized to assess the efficacy of biofeedback and relaxation for migraine and tension-type headache. RESULTS: Psychophysiologic therapy comprising biofeedback and relaxation can be provided in standard or limited therapist contact formulas to patients as sole therapy or concurrently with medical therapy. Effectiveness has been demonstrated for thermal biofeedback-and electromyograph biofeedback-assisted relaxation with minimal or no side effects. A typical treatment protocol is offered to exemplify the integration of psychophysiologic therapy into primary care practice. CONCLUSION: Psychophysiologic therapy represents an important adjunctive treatment for chronic benign headache that can be incorporated into primary care. 相似文献
26.
The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide
Kathleen M. Giacomini Sarah E. Swezey Kathleen Turner-Tamiyasu Terrence F. Blaschke 《Journal of pharmacokinetics and pharmacodynamics》1982,10(1):1-14
Disopyramide exhibits saturable binding to plasma proteins in the therapeutic plasma concentration range. Because of this property, controversy exists in the literature regarding the pharmacokinetic properties of the drug. The purposes of this study were to reassess the pharmacokinetic properties of disopyramide in humans, taking into consideration both total and unbound concentrations and to use disopyramide as a model compound to study the effect of drug binding on the renal clearance of both total and unbound drug. A single intravenous dose of disopyramide (1.5 mg/kg) was administered to eight normal volunteers. Blood and urine samples were collected for 36h. Total concentrations of disopyramide in plasma and urine were determined by high pressure liquid chromatography. Binding of disopyramide to plasma proteins was determined by equilibrium dialysis. In all subjects, the binding of disopyramide to plasma proteins was saturable, but there were considerable differences in binding between subjects. The volume of distribution, total body clearance, and renal clearances of both total and unbound drug were calculated. Because only the total body clearance and renal clearance of unbound compound are not dependent upon unbound fraction (), these are the only parameters which can be reported without qualification as to the concentration. The mean ± SD total body clearance of unbound drug in the eight subjects was 5.40± 2.80 ml/min/kg. About 50% of this was due to renal elimination. A statistically significant negative correlation of the renal clearance of total disopyramide with time was observed in seven of eight subjects, whereas a significant correlation between the renal clearance of unbound disopyramide and time was observed in only one subject. This suggests that the renal clearance of unbound disopyramide is independent of , while the renal clearance of total disopyramide is dependent upon . 相似文献
27.
1 BACKGROUNDTheincidenceofCPis 0 .7per 1 0 0 0livebirths[1 ] .Becausecerebralpalsyinfluencesthewaychildrendevelop,itoftenresultsindevelop mentaldisability .Today ,more peoplehavecerebralpalsythananyotherdevelopmentaldis ability ,includingDownsyndrome,epilepsy ,andautism .Accordingtoasurveyconductedin1 986,2 .6%ofthepopulationofPakistaniaredisabled (includingbothphysicalandmentaldis abilities) .Childrenbetween 0~1 4 yearsinageconstitute 40 %ofthedisabled populationinPakistan .Routineme… 相似文献
28.
Dennis A Chakkalakal Jerzy R Novak Edward D Fritz Teresa J Mollner Daniel L McVicker Kevin L Garvin Michael H McGuire Terrence M Donohue 《Alcohol》2005,36(3):201-214
Alcohol abuse is associated with increases in both the incidence of fractures and complications in fracture healing. The purpose of this study was to determine the dose-dependent effects of ethanol on bone repair in a rat model. Three-month-old male Wistar rats were continuously fed liquid diets containing ethanol as either 36% or 26% of total calories or control diets for 6 weeks. Then, a bone repair model was created in all rats. Bone healing and liver metabolism were evaluated 7 weeks after bone injury. For each dose, there were three ethanol-feeding groups receiving (1) ethanol for 13 weeks, (2) control diet for 13 weeks (pair-fed), and (3) ethanol before bone injury and control diet (pair-fed) after injury. Another group was fed ethanol (36%) before injury and given control diet ad libitum after injury. There were also two nutritional controls consuming control diet and standard rat chow ad libitum for 13 weeks. Abnormal liver metabolism was evident at the higher ethanol dose - increases in cytochrome P4502E1 specific activity (5-fold; P < .01), triglyceride content (4-fold; P < .02), and liver weight (25%; P = .05) - compared with pair-fed controls. The higher dose of ethanol resulted in deficient bone repair when compared with rats receiving ethanol-free control diet by pair-feeding: 26% less (P = .02) rigidity of the repaired bone, 41% less (P = .02) intrinsic stiffness, 24% less intrinsic strength (P = .05), and 14% less (P = .001) ash density of the repair tissue. The reduced food consumption of ethanol-fed rats compared with that in the nutritional controls did not contribute to this deficiency. Furthermore, removal of ethanol (as 36% of calories) from the diet after bone injury completely restored normal bone healing and nearly normalized the liver metabolism. The lower ethanol dose (26% of calories) had a minimal effect on liver metabolism and bone repair. We conclude that ethanol (as 36% of calories) in the rat diet, especially during the postinjury period, was solely responsible for the observed inhibition of bone repair. 相似文献
29.
PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. 总被引:30,自引:0,他引:30
Christopher L Corless Arin Schroeder Diana Griffith Ajia Town Laura McGreevey Patina Harrell Sharon Shiraga Troy Bainbridge Jason Morich Michael C Heinrich 《Journal of clinical oncology》2005,23(23):5357-5364
PURPOSE: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. MATERIALS AND METHODS: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. RESULTS: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. CONCLUSION: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors. 相似文献
30.
C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are endogenous inhibitors of the Src-family protein tyrosine kinases (SFKs). Since constitutive activation of SFKs contributes to cancer formation and progression, to prevent excessive activation of SFKs, their activity in normal cells is kept at the basal level by CSK and CHK. CSK and CHK inactivate SFKs by specifically phosphorylating a consensus tyrosine (called YT) near their C-termini. Upon phosphorylation, the phospho-YT engages in intramolecular interactions that lock the SFK molecule in an inactive conformation. SFKs are anchored to the plasma membrane, while CSK and CHK are localized predominantly in the cytosol. To inhibit SFKs, CSK and CHK need to translocate to the plasma membrane. Recruitment of CSK and CHK to the plasma membrane is mediated by the binding of their SH2, SH3 and/or kinase domains to specific transmembrane proteins, G-proteins and adaptor proteins located near the plasma membrane. For CSK, membrane recruitment often accompanies activation. CSK and CHK employ two types of direct interactions with SFKs to achieve efficient YT phosphorylation: (i) short-range interactions involving binding of the active sites of CSK and CHK to specific residues near YT, (ii) long-range non-catalytic interactions involving binding of SFKs to motifs located distally from the active sites of CSK and CHK. The interactions between CSK and SFKs are transient in nature. Unlike CSK, CHK binds tightly to SFKs to form stable protein complexes. The binding is non-catalytic as it is independent of YT. More importantly, the tight binding alone is sufficient to completely inhibit SFKs. This non-catalytic inhibitory binding represents a novel mechanism employed by CHK to inhibit SFKs. Given that SFKs are implicated in cancer development, compounds mimicking the non-catalytic inhibitory mechanism of CHK are potential anti-cancer therapeutics. 相似文献