全文获取类型
收费全文 | 478篇 |
免费 | 13篇 |
国内免费 | 67篇 |
专业分类
耳鼻咽喉 | 1篇 |
儿科学 | 25篇 |
妇产科学 | 7篇 |
基础医学 | 48篇 |
口腔科学 | 9篇 |
临床医学 | 81篇 |
内科学 | 68篇 |
皮肤病学 | 13篇 |
神经病学 | 16篇 |
特种医学 | 137篇 |
外科学 | 16篇 |
综合类 | 24篇 |
预防医学 | 33篇 |
眼科学 | 1篇 |
药学 | 58篇 |
肿瘤学 | 21篇 |
出版年
2022年 | 3篇 |
2021年 | 7篇 |
2020年 | 2篇 |
2019年 | 2篇 |
2017年 | 2篇 |
2016年 | 6篇 |
2015年 | 7篇 |
2014年 | 7篇 |
2013年 | 12篇 |
2012年 | 6篇 |
2011年 | 6篇 |
2010年 | 23篇 |
2009年 | 24篇 |
2008年 | 11篇 |
2007年 | 56篇 |
2006年 | 14篇 |
2005年 | 9篇 |
2004年 | 8篇 |
2003年 | 11篇 |
2002年 | 5篇 |
2001年 | 4篇 |
2000年 | 7篇 |
1999年 | 7篇 |
1998年 | 23篇 |
1997年 | 33篇 |
1996年 | 25篇 |
1995年 | 22篇 |
1994年 | 21篇 |
1993年 | 19篇 |
1992年 | 10篇 |
1991年 | 9篇 |
1990年 | 12篇 |
1989年 | 15篇 |
1988年 | 21篇 |
1987年 | 13篇 |
1986年 | 9篇 |
1985年 | 14篇 |
1984年 | 5篇 |
1983年 | 5篇 |
1982年 | 10篇 |
1981年 | 6篇 |
1980年 | 9篇 |
1979年 | 2篇 |
1978年 | 6篇 |
1977年 | 9篇 |
1976年 | 7篇 |
1975年 | 8篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
排序方式: 共有558条查询结果,搜索用时 15 毫秒
11.
12.
Isolation and characterization of propagable cell lines (HUNC) from the androgen-sensitive Dunning R3327H rat prostatic adenocarcinoma 总被引:1,自引:0,他引:1
Presnell SC; Borchert KM; Glover WJ; Gregory CW; Mohler JL; Smith GJ 《Carcinogenesis》1998,19(4):585-590
The Dunning H rat prostate tumor (R3327H) is a widely used experimental
model of human prostatic adenocarcinoma (CaP). The Dunning H tumor has been
characterized as androgen-sensitive, androgen-receptor (AR) positive,
prostate-specific antigen and prostatic acid phosphatase (PAP) positive. To
date, the tumor has been maintained by serial passage in vivo because of
the lack of an in vitro cell line that retains the characteristics of the
in vivo tumor. The objective of the present study was to establish a
propagable cell line from R3327H adenocarcinoma that maintained androgen
sensitivity and expression of AR, PSA and PAP. Tissue harvested from an in
vivo R3327H tumor was dissociated with collagenase and placed into
Richter's improved media (with supplements). A cytokeratin-positive
epithelial cell line (HUNC- E) and a vimentin-positive stromal cell line
(HUNC-S) were generated from the primary culture, subcultured continuously
for >300 days, and passaged >50 times. Survival of the HUNC-E cell
line in vitro depended on several media supplements, including
nicotinamide, insulin, transferrin, selenium and epidermal growth factor
(EGF). HUNC-E cells expressed AR and produced PSA and PAP throughout the
culture period, as confirmed by immunocytochemistry and Western blot
analyses. Addition of 14 nM testosterone (T) or dihydrotestosterone (DHT)
to HUNC-E cells, stimulated DNA synthesis as well as anchorage-independent
growth and PSA production, which demonstrated the androgen-sensitive nature
of the cells in vitro. When HUNC-E and HUNC-S cells were combined in a 3:1
ratio and introduced subcutaneously into syngeneic male hosts, tumors
formed in 2/3 animals with an average latency of 7 months. RT-PCR and
immunocytochemical characterization of the HUNC cell lines revealed that
the cells expressed several growth factors and their cognate receptors,
including HGF, TGF-alpha and the TGF-betas, indicating the establishment of
potential autocrine loops in the neoplastic cells. The HUNC-E and HUNC-S
CaP cell lines, which retain the characteristics of the epithelial and
stromal components of the in vivo R3327H tumor, will allow a more thorough
and informative molecular and biological analysis of prostatic
adenocarcinoma.
相似文献
13.
In order to enhance the immune efficacy of DNA vaccination, experiments were conducted to investigate the regulating effects of Bacillus Calmette-Guerin (BCG)-DNA as an adjuvant on immune responses of mice against foot-and-mouth disease (FMD), Aujeszky's disease (AID) and classical swine fever (CSF). BCG-DNA was purified from BCG by ion-exchange chromatography. Three DNA vaccines (pVSG, pVgD and pVE2) against the respective infection were constructed, and BCGDNA was coimmunized to mice by muscle injection. The results showed that titres of specific immunoglobulin (Ig)G to the vaccines mounted remarkably in the sera of the adjuvant covaccinated mice (P〈0.01). Antibody isotype IgG2a and IgG1 also increased, respectively, in mice coimmunized with BCG-DNA compared with those of the control groups (P〈0.01). Cellular immune cytokine interferon-gamma and cytotoxic T lymphocytes were detected in coimmunized BCG-DNA groups (P〈0. 05). Whereas interleukin-4, humoral immune cytokine, was not significant (P〉 0. 05). These results suggest that codelivery of BCG-DNA with DNA vaccines against FMD, AjD and CSF can enhance the induction of antigen-specific, especially, cell-mediated immunity. 相似文献
14.
目的:应用功能磁共振成像观察脑卒中后及康复过程中,在相应脑内运动功能区激活的变化情况,探讨不同运动模式下皮质功能再塑的表现。方法:选取2003-02/10大庆油田总医院康复科住院的皮质下脑梗死患者8例,在发病后1周始进行连续两个月的康复。在康复前、康复1,2个月时运用Brunnstrom分级、Caroll上肢功能量表(0 ̄100分,评分越高功能越好)对其手功能进行评价,并采用GEMR/iHiSpeed1.5超导磁共振扫描机进行磁共振成像功能激发检查。患者用病手执行简单运动(快速连续的拇指与其他各指的对指动作)、随意运动(用病手摸不同形状的木块),获得脑功能激发图像,观察脑内相关功能区的激活情况。结果:8例受试者均进入结果分析。①康复后所有患者Brunnstrom分级和Caroll上肢功能评分均较康复前有明显改善。②病手简单运动时脑内相关功能区的激活情况:8例受试者7例在损伤后早期手指不能对指,所以没有激活;M1,SMA,PMA脑区和小脑呈现单侧激活-双侧激活-单侧激活的变化过程;随着运动功能恢复,脑内激活数目随时间呈下降趋势,几乎接近正常人脑功能表现。③病手随意运动时脑内相关功能区的激活情况:实验中发现引起的运动相关功能区的激发情况变化多样,规律性较差,但其中5例受试者表现出损伤后激发数目明显减少,许多对运动起决定性支配作用的功能区亦不激活;随着运动功能恢复,激发区数目呈上升趋势,同损伤后简单运动的激活表现。结论:①脑卒中后病手经过康复治疗简单运动恢复较好,康复治疗2个月后脑内运动功能相关区域激活的规律已同正常人。②脑卒中后病手随意运动恢复较困难,康复治疗后不如简单运动恢复好,脑内相关运动功能区激活无明显的规律性。随着运动功能的恢复,脑内相应的运动功能区激活增多。 相似文献
15.
目的:一些理论质疑富血小板血浆对骨前体细胞成骨分化的作用,本实验拟验证富血小板血浆对体外培养的人骨髓间充质干细胞成骨分化的抑制效应。方法:实验于2005-05/11在南方医科大学组织工程试验室(省级)完成。①实验方法:抽取6名健康志愿者髂前上棘骨髓5mL进行体外细胞培养扩增,静脉血10mL以二次离心法制得富血小板血浆。诱导骨髓间充质干细胞时富血小板血浆与骨髓间充质干细胞均来自同一个体。②碱性磷酸酶染色:取第4代骨髓间充质干细胞,分为两组:富血小板血浆组加入富血小板血浆使终浓度为100g/L,单纯血清培养组仅加入等量胎牛血清。培养后第7天进行碱性磷酸酶染色,阳性细胞为胞质中呈现黑色颗粒或块状沉淀。③矿化结节染色:取第4代骨髓间充质干细胞,分组同上。培养后第19天以0.1%茜素红-TrisHcl(pH8.3)37℃下放置30min,矿盐沉积染色阳性为红色。④Cbfa1基因表达:取第4代骨髓间充质干细胞,分组同上。培养后第3,7,12,16天RT-PCR法检测骨髓间充质干细胞Cbfa1基因的表达。⑤形态学观察:实验过程中使用相差显微镜观察各组细胞生长情况及形态学变化。结果:①骨髓间充质干细胞碱性磷酸酶染色结果:培养后第7天,富血小板血浆组碱性磷酸酶阳性细胞数量较单纯血清培养组明显减少,且阳性细胞内灰黑色颗粒也明显减少,为弱阳性。②骨髓间充质干细胞矿化结节染色结果:培养后第19天,单纯血清培养组可见细胞表面有较多的矿盐沉积,但未形成明显的矿化结节。富血小板血浆组细胞表面只有稀少的矿盐沉积。③骨髓间充质干细胞cbfa1mRNA的表达:培养后第3,7,12,16天,随着培养时间的延长单纯血清培养组与富血小板血浆组cbfa1基因表达量均逐渐增高,同一时间点两组间cbfa1基因的表达基本相似。④骨髓间充质干细胞形态学变化:富血小板血浆组骨髓间充质干细胞增殖旺盛,细胞达到单层汇合的时间较单纯血清培养组明显缩短。单纯血清培养组细胞在完全汇合后开始出现聚合现象(14~16d),但趋向性不明显,未完全形成团簇;富血小板血浆组细胞在完全汇合后未出现聚合现象,细胞密集生长。培养初期两组细胞以梭形为主,多角形细胞较少,培养至14~16d单纯血清培养组多角形细胞较富血小板血浆组增多。结论:富血小板血浆可抑制人骨髓间充质干细胞碱性磷酸酶的分泌与矿盐沉积,对人骨髓间充质干细胞成骨分化的直接效应是抑制其分化。 相似文献
16.
Clinical features and serum antinuclear antibodies in 230 Danish patients with systemic sclerosis 总被引:5,自引:2,他引:5
Jacobsen S; Halberg P; Ullman S; Van Venrooij WJ; Hoier-Madsen M; Wiik A; Petersen J 《Rheumatology (Oxford, England)》1998,37(1):39-45
The objective was to investigate the relationship between the presence of
different types of antinuclear antibodies (ANA) in patients with systemic
sclerosis (SSc) and the presence of clinical features. Sera from 230
patients with SSc were tested for the presence of ANA, including
anticentromere antibodies (ab), antitopoisomerase I ab, anti- U1 RNP ab and
antinucleolar ab, including anti-Th RNP, anti-U3 RNP and anti-U17 RNP.
Clinical features were registered prospectively in a clinical database.
Eighty-two per cent of the patients were women. The median age was 58 yr
(45-67, quartiles) and median age at disease onset was 44 (30-55) yr. ANA
were found in 86% of the patients (anticentromere: 34%; antitopoisomerase
I: 14%; anti-U1 RNP: 6.5%; antinucleolar total: 16%; anti-Th RNP: 2.2%;
anti-U3 RNP: 3.5%; anti- U17 RNP: 0%). Anticentromere ab were found to be
related to a high prevalence of calcinosis, telangiectasia, digital ulcers,
acrosclerosis, primary biliary cirrhosis, isolated reduction of pulmonary
diffusing capacity, and a low prevalence of radiological evidence of
pulmonary fibrosis. Antitopoisomerase I ab were associated with a high
prevalence of digital joint deformity, distal osteolysis, radiological
signs of pulmonary fibrosis, a low prevalence of calcinosis and late onset
of disease. Anti-U1 RNP ab were related to a high prevalence of arthritis
and myositis, a low prevalence of calcinosis, and early disease onset. The
presence of antinucleolar ab, including anti-U3 RNP and anti-Th RNP, was
not significantly related to any particular clinical features in this
study; possibly due to the small number of patients with these ab. The
presence of anticentromere, antitopoisomerase I and anti-U1 RNP ab in the
serum was also found to have previously described clinical correlations in
a group of Danish SSc patients.
相似文献
17.
Jacqueline AM Smith DL Patil OT Daniels Y-S Ding J-D Gallezot S Henry KHS Kim S Kshirsagar WJ Martin GP Obedencio E Stangeland PR Tsuruda W Williams RE Carson ST Patil 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2015,18(2)
Background:
Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.Methods:
We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.Results:
TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC50 of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [11C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [11C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.Conclusions:
These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation. 相似文献18.
Dal Canto Elisa Remmelzwaal Sharon van Ballegooijen Adriana Johanne Handoko M. Louis Heymans Stephane van Empel Vanessa Paulus Walter J. Nijpels Giel Elders Petra Beulens Joline WJ 《Heart failure reviews》2022,27(1):207-218
Heart Failure Reviews - This study aimed to evaluate the diagnostic performance of echocardiographic markers of heart failure with preserved ejection fraction (HFpEF) and left ventricular diastolic... 相似文献
19.
KA Hodgkinson SP Connors N Merner A Haywood T‐L Young WJ McKenna B Gallagher F Curtis AS Bassett PS Parfrey 《Clinical genetics》2013,83(4):321-331
To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1–2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex‐influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre‐symptomatic diagnosis has the greatest clinical utility. 相似文献
20.
Connor WJ Bevington Ju-Chieh Cheng Ivan S Klyuzhin Mariya V Cherkasova Catharine A Winstanley Vesna Sossi 《Journal of cerebral blood flow and metabolism》2021,41(1):116
Current methods using a single PET scan to detect voxel-level transient dopamine release—using F-test (significance) and cluster size thresholding—have limited detection sensitivity for clusters of release small in size and/or having low release levels. Specifically, simulations show that voxels with release near the peripheries of such clusters are often rejected—becoming false negatives and ultimately distorting the F-distribution of rejected voxels. We suggest a Monte Carlo method that incorporates these two observations into a cost function, allowing erroneously rejected voxels to be accepted under specified criteria. In simulations, the proposed method improves detection sensitivity by up to 50% while preserving the cluster size threshold, or up to 180% when optimizing for sensitivity. A further parametric-based voxelwise thresholding is then suggested to better estimate the release dynamics in detected clusters. We apply the Monte Carlo method to a pilot scan from a human gambling study, where additional parametrically unique clusters are detected as compared to the current best methods—results consistent with our simulations. 相似文献