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实验性肌炎动物模型制作的研究 总被引:2,自引:0,他引:2
目的建立实验性肌炎动物模型,研究特发性炎性肌病的发病机制。方法将50只健康的雄性SD大鼠随机分成两组:模型组40只,对照组10只。兔骨骼肌制备肌匀浆。模型组用肌匀浆与弗氏完全佐剂完全乳化后皮下免疫注射1ml.对照组用生理盐水替代肌匀浆,每周免疫1次,连续免疫5次。前2周同时腹腔注射百日咳毒素1ml。分别于免疫注射后各周取大鼠的骨骼肌组织,观察其肌活检病理、免疫组织化学的改变,同时检测血清肌酶水平,并与人类炎性肌病比较。结果模型组肌酶升高与对照组间有显著差别。病理改变以骨骼肌多发性炎症为特点:横纹肌呈灶性分布的肌纤维变性、坏死,横纹消失;周围炎性细胞浸润;肌纤维粗细不等、染色不一。病理分级以2a级为主。单个核细胞浸润以CD8^+T细胞为主.主要定位于肌内膜。骨骼肌细胞膜上主要组织相容性复合体(MHC)-Ⅰ类分子表达增加。结论用异种动物骨骼肌匀浆免疫大鼠可诱导出炎性肌病动物模型,与人类炎性肌病在临床表现、组织病理和免疫组织化学方面有相似之处。 相似文献
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A. Reinert A. Kaske S. Mense 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》1998,121(2):174-180
The density of substance P (SP)-, calcitonin gene-related peptide (CGRP)- and vasoactive intestinal polypeptide (VIP)-immunoreactive
(ir) nerve endings was quantitatively evaluated in intact and inflamed gastrocnemius-soleus muscle of the rat. In persistently
inflamed muscle (12 days after a single injection of Freund’s adjuvant into the muscle), the density of SP-ir fibres was significantly
increased. CGRP- and VIP-ir fibres displayed an insignificant increase in density. The density of fibres ir for nerve growth
factor (NGF) and for growth-associated protein 43 (GAP-43/B-50), a marker for axonal sprouting, regeneration and synaptic
reorganisation, increased significantly in persistently inflamed muscle. The data are consistent with the established contribution
of NGF on the expression of SP and GAP-43 in afferent neurones under the influence of a persistent inflammation.
Received: 8 September 1997 / Accepted: 12 February 1998 相似文献
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Thomas Barba Romain Fort Vincent Cottin Steeve Provencher Isabelle Durieu Sabine Jardel Arnaud Hot Quitterie Reynaud Jean-Christophe Lega 《Autoimmunity reviews》2019,18(2):113-122
Objective
Interstitial lung disease (ILD) is the most severe complication of idiopathic inflammatory myositis (IIM), resulting in significant increase in morbidity and mortality and for which the best treatment remains controversial. We conducted a meta-analysis to evaluate the efficacy of therapies used for the management of IIM-related ILD.Methods
Studies were selected from MEDLINE up to July 2017. Two investigators independently extracted data on study design, patient characteristics, clinical features, treatment, follow-up and outcomes. Global survival rates and objectively confirmed lung function improvements were extracted as the main outcome for rapidly progressive IIM-related ILD (RP-ILD) and chronic forms of ILD (C-ILD), respectively, and pooled using the weighted mean proportion with fixed or random-effects models in case of significant heterogeneity (I2?>?50%).Results
Twenty-seven studies encompassing 553 patients (male: 30.5%, age: 53.5?±?5.5?years) were included in the meta-analysis. Globally, retrieved studies were of limited methodological quality (no controlled studies and only 2 prospective studies). Dermatomyositis (40%) and anti-tRNA synthetase syndrome (45%) were the most represented IIM subtypes. In C-ILD, functional improvement rates were 89.2% (95%CI 82.5–93.6; 7 studies, n?=?124) for corticosteroids alone, 80.7% (95%CI 49.6–94; 6 studies, n?=?38) for cyclosporine A, 64.1% (95%CI 46.3–78.7; 4 studies, n?=?32) for azathioprine, 86.2% (95%CI 61.5–96; 2 studies, n?=?23) for tacrolimus, 56.4% (95%CI 44–68.0; 8 studies, n?=?71) for cyclophosphamide, and 76.6% (95%CI 50.4–96.0; 2 studies, n?=?20) for rituximab. In RP-ILD, survival rates at 3?months were 51.7% (95%CI 24.2–78.1; 2 studies, n?=?11) for corticosteroids alone, 69.2% (95%CI 55.0–80.5; 8 studies, n?=?146) for cyclosporine A and 72.4% (95%CI 6.4–99.0, 2 studies, n?=?16) for cyclophosphamide.Conclusion
Despite aggressive immunosuppressive therapies, the short-term mortality of RP-ILD remains high. While immunosuppressive therapies are associated with significant functional improvements in most patients with C-ILD, substantial uncertainty remains about the best treatment strategy in the absence of good quality evidence. 相似文献6.
Gaëlle Dzangué-Tchoupou Kuberaka Mariampillai Loïs Bolko Damien Amelin Wladimir Mauhin Aurélien Corneau Catherine Blanc Yves Allenbach Olivier Benveniste 《Autoimmunity reviews》2019,18(4):325-333
Background
Myositis is a heterogeneous group of muscular auto-immune diseases with clinical and pathological criteria that allow the classification of patients into different sub-groups. Inclusion body myositis is the most frequent myositis above fifty years of age. Diagnosing inclusion body myositis requires expertise and is challenging. Little is known concerning the pathogenic mechanisms of this disease in which conventional suppressive-immune therapies are inefficacious.Objectives
Our aim was to deepen our understanding of the immune mechanisms involved in inclusion body myositis and identify specific biomarkers.Methods
Using a panel of thirty-six markers and mass cytometry, we performed deep immune profiling of peripheral blood cells from inclusion body myositis patients and healthy donors, divided into two cohorts: test and validation cohorts. Potential biomarkers were compared to myositis controls (anti-Jo1-, anti-3-hydroxyl-3-methylglutaryl CoA reductase-, and anti-signal recognition particle-positive patients).Results
Unsupervised analyses revealed substantial changes only within CD8+ cells. We observed an increase in the frequency of CD8+ cells that expressed high levels of T-bet, and containing mainly both effector and terminally differentiated memory cells. The senescent marker CD57 was overexpressed in CD8+T-bet+ cells of inclusion body myositis patients. As expected, senescent CD8+T-bet+ CD57+ cells of both patients and healthy donors were CD28nullCD27nullCD127null. Surprisingly, non-senescent CD8+T-bet+ CD57- cells in inclusion body myositis patients expressed lower levels of CD28, CD27, and CD127, and expressed higher levels of CD38 and HLA-DR compared to healthy donors. Using classification and regression trees alongside receiver operating characteristics curves, we identified and validated a frequency of CD8+T-bet+ cells >51.5% as a diagnostic biomarker specific to inclusion body myositis, compared to myositis control patients, with a sensitivity of 94.4%, a specificity of 88.5%, and an area under the curve of 0.97.Conclusion
Using a panel of thirty-six markers by mass cytometry, we identify an activated cell population (CD8+T-bet+ CD57- CD28lowCD27lowCD127low CD38+ HLA-DR+) which could play a role in the physiopathology of inclusion body myositis, and identify CD8+T-bet+ cells as a predominant biomarker of this disease. 相似文献7.
Linkage exclusion and mutational analysis of the noggin gene in patients with fibrodysplasia ossificans progressiva (FOP) 总被引:1,自引:0,他引:1
Xu MQ Feldman G Le Merrer M Shugart YY Glaser DL Urtizberea JA Fardeau M Connor JM Triffitt J Smith R Shore EM Kaplan FS 《Clinical genetics》2000,58(4):291-298
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling genetic disorder characterized by congenital malformation of the great toes and by progressive heterotopic endochondral ossification in predictable anatomical patterns. Although elevated levels of bone morphogenetic protein 4 (BMP4) occur in lymphoblastoid cells and in lesional cells of patients with FOP, mutations have not been identified in the BMP4 gene, suggesting that the mutation in FOP may reside in a BMP4-interacting factor or in another component of the BMP4 pathway. A powerful antagonist of BMP4 is the secreted polypeptide noggin. A recent case report described a heterozygous 42-bp deletion in the protein-coding region of the noggin gene in a patient with FOP. In order to determine if noggin mutations are a widespread finding in FOP, we examined 31 families with 1 or more FOP patients. Linkage analysis with an array of highly polymorphic microsatellite markers closely linked to the noggin gene was performed in four classically-affected multigenerational FOP families and excluded linkage of the noggin locus to FOP (the multipoint lod score was -2 or less throughout the entire range of markers). We sequenced the noggin gene in affected members of all four families, as well as in 18 patients with sporadic FOP, and failed to detect any mutations. Single-strand conformation polymorphism (SSCP) analysis of 4 of these patients plus an additional 9 patients also failed to reveal any mutations. Among the samples analyzed by SSCP and DNA sequencing was an independently obtained DNA sample from the identical FOP patient previously described with the 42-bp noggin deletion; no mutation was detected. Examination of the DNA sequences of 20 cloned noggin PCR products, undertaken to evaluate the possibility of a somatic mutation in the noggin gene which could be carried by a small subset of white blood cells, also failed to detect the presence of the reported 42-bp deletion. We conclude that mutations in the coding region of noggin are not associated with FOP. 相似文献
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Gunnar Buyse Jonathon Silberstein Nathalie Goemans Paul Casaer 《European journal of pediatrics》1995,154(9):694-699
Fibrodysplasia ossificans progressiva (FOP), a rare autosomal dominant disorder, is characterized by symmetrical congenital skeletal abnormalities and progressive heterotopic ossification of the connective tissues. At present, more than 300 years after the first report by Patin in 1648 in which he described the woman who turned to wood, its pathogenesis remains largely unknown and its therapy is limited to symptom-modifying trials. However, significant progress has been recently made and new data on the molecular organization and regulation of normal and disordered bone induction are likely to lead to a more specific therapy. FOP is believed to be a genetic disorder characterized by a disturbed expression of the endochondral osteogenesis programme, and the remarkable clues from the fly reported by Kaplan et al. [8] in 1990 suggest a gain-of-function mutation in the genetic regulation of bone morphogenetic proteins. 相似文献
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特发性炎症性肌病是一组具有临床表现异质性的自身免疫性疾病,以骨骼肌无力和肌肉炎症病变为特征.临床分型包括皮肌炎、多发性肌炎、散发的包涵体肌炎、免疫介导的坏死性肌病和抗合成酶抗体综合征等[1-3].在儿童期,皮肌炎为最常见的临床类型,约占80%[4].特发性炎症性肌病为临床罕见病,年发病率约为每年每百万人1 ~ 19例[5].美国儿童皮肌炎的发病率约为每年每百万人2.5~4.1例[6],国内尚未见流行病学资料.特发性炎症性肌病的治疗一直非常具有临床挑战性,尤其是一线治疗药物失败的病例[7].近年来,对难治性病例的精准治疗成为特发性炎症性肌病领域的研究重点[8].自20世纪初期开始,利妥昔单抗在国外就被尝试用于难治性特发性炎症性肌病的治疗,但关于利妥昔单抗的应用剂量和疗程,目前尚无统一认识[9],国内也尚未见相关临床研究报道.本文分享了3例传统药物治疗反应欠佳、经长疗程(2年7个月至3年2个月)利妥昔单抗联合治疗后获得临床缓解的特发性炎症性肌病患者的治疗过程,以期为该疾病的治疗提供参考.本观察研究开始前获北京大学第一医院生物医学研究伦理委员会审查批准(批准号:2021科研263). 相似文献