全文获取类型
收费全文 | 312篇 |
免费 | 17篇 |
出版年
2022年 | 1篇 |
2019年 | 1篇 |
2018年 | 4篇 |
2017年 | 2篇 |
2016年 | 6篇 |
2015年 | 14篇 |
2014年 | 15篇 |
2013年 | 24篇 |
2012年 | 13篇 |
2011年 | 14篇 |
2010年 | 24篇 |
2009年 | 24篇 |
2008年 | 14篇 |
2007年 | 12篇 |
2006年 | 11篇 |
2005年 | 13篇 |
2004年 | 11篇 |
2003年 | 3篇 |
2002年 | 4篇 |
2001年 | 6篇 |
2000年 | 4篇 |
1999年 | 3篇 |
1998年 | 9篇 |
1997年 | 10篇 |
1996年 | 4篇 |
1995年 | 6篇 |
1994年 | 3篇 |
1993年 | 7篇 |
1991年 | 3篇 |
1989年 | 2篇 |
1988年 | 7篇 |
1986年 | 1篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 16篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 5篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1947年 | 1篇 |
1946年 | 1篇 |
1936年 | 1篇 |
1932年 | 1篇 |
1931年 | 2篇 |
排序方式: 共有329条查询结果,搜索用时 15 毫秒
301.
302.
Rieke Alten Hermann Gram Leo A Joosten Bvanden Wim Berg Joachim Sieper Siegfrid Wassenberg Gerd Burmester Piet van Riel Maria Diaz-Lorente Gerardus JM Bruin Thasia G Woodworth Christiane Rordorf Yannik Batard Andrew M Wright Thomas Jung 《Arthritis research & therapy》2008,10(3):1-9
Introduction
IL-1β is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production.Methods
ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1β, was generated to study the potent and long-lasting neutralization of IL-1β in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA).Results
The mouse IL-1 receptor cross-reacts with human IL-1β, and it was demonstrated that ACZ885 can completely suppress IL-1β-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study – the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study.Conclusion
ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted.Trial Registration
ClinicalTrials.gov identifier NCT00619905. 相似文献303.
Mankowski JL Queen SE Fernandez CS Tarwater PM Karper JM Adams RJ Kent SJ 《PloS one》2008,3(11):e3603
Human immunodeficiency virus (HIV) infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS) have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS) disease using a well-characterized simian immunodeficiency (SIV)/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis) was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5). Animals expressing the Mane-A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P<0.001). Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease. 相似文献
304.
305.
Marc Beyer Hongwei Wang Nina Peters Sandra Doths Cordula Koerner-Rettberg Peter JM Openshaw Jürgen Schwarze 《Respiratory research》2005,6(1):70
Background
The integrin CD11c is known as a marker for dendritic cells and has recently been described on T cells following lymphotropic choriomeningitis virus infection, a systemic infection affecting a multitude of organs. Here, we characterise CD11c bearing T cells in a murine model of localised pulmonary infection with respiratory syncytial virus (RSV).Methods
Mice were infected intranasally with RSV and expression of β2 integrins and T lymphocyte activation markers were monitored by flow cytometry. On day 8 post RSV infection CD11c+ CD8+ and CD11c- CD8+ T cells were assessed for cytokine production, cytotoxic activity and migration. Expression of CD11c mRNA in CD8+ T cells was assessed by quantitative PCR.Results
Following RSV infection CD11c+ CD8+ T cells were detectable in the lung from day 4 onwards and accounted for 45.9 ± 4.8% of CD8+ T cells on day 8 post infection, while only few such cells were present in mediastinal lymph nodes, spleen and blood. While CD11c was virtually absent from CD8+ T cells in the absence of RSV infection, its mRNA was expressed in CD8+ T cells of both naïve and RSV infected mice. CD11c+, but not CD11c-, CD8+ T cells showed signs of recent activation, including up-regulation of CD11a and expression of CD11b and CD69 and were recruited preferentially to the lung. In addition, CD11c+ CD8+ T cells were the major subset responsible for IFNγ production, induction of target cell apoptosis in vitro and reduction of viral titres in vivo.Conclusion
CD11c is a useful marker for detection and isolation of pulmonary antiviral cytotoxic T cells following RSV infection. It identifies a subset of activated, virus-specific, cytotoxic T cells that exhibit potent antiviral effects in vivo. 相似文献306.
Opstelten W Van Wijck AJ Van Essen GA Buskens E Bak AA Kalkman CJ Verheij TJ Moons KG 《BMC anesthesiology》2004,4(1):2-7
BACKGROUND: Postherpetic neuralgia (PHN) is by far the most common complication of herpes zoster (HZ) and one of the most intractable pain disorders. Since PHN is seen most often in the elderly, the number of patients with this disorder is expected to increase in our ageing society. PHN may last for months to years and has a high impact on the quality of life. The results of PHN treatment are rather disappointing. Epidural injection of local anaesthetics and steroids in the acute phase of HZ is a promising therapy for the prevention of PHN. Since randomised trials on the effectiveness of this intervention are lacking, the PINE (Prevention by epidural Injection of postherpetic Neuralgia in the Elderly) study was set up. The PINE study compares the effectiveness and cost-effectiveness of a single epidural injection of local anaesthetics and steroids during the acute phase of HZ with that of care-as-usual (i.e. antivirals and analgesics) in preventing PHN in elderly patients. METHODS / DESIGN: The PINE study is an open, multicenter clinical trial in which 550 elderly (age >/= 50 yr.) patients who consult their general practitioner in the acute phase of HZ (rash < 7 days) are randomised to one of the treatment groups. The primary clinical endpoint is the presence of HZ-related pain one month after the onset of the rash. Secondary endpoints include duration and severity of pain, re-interventions aiming to treat the existing pain, side effects, quality of life, and cost-effectiveness. CONCLUSION: The PINE study is aimed to quantify the (cost-) effectiveness of a single epidural injection during the acute phase of HZ on the prevention of PHN. 相似文献
307.
Lall AB Ventura DS Bechara EJ de Souza JM Colepicolo-Neto P Viviani VR 《Journal of insect physiology》2000,46(7):1137-1141
The presence of two spectral mechanisms, near-ultraviolet and green (lambda(max)=545nm), is strongly suggested by electroretinographic visual spectral sensitivity curves obtained under dark and red chromatic adaptation conditions in the compound eyes of the click beetle Pyrophorus punctatissimus. The bioluminescence emission of the dorsal prothoracic lanterns is deep green (lambda(max)=543nm) and that of the ventral abdominal lantern is lime green (lambda(max)=556nm) in colour in P. punctatissimus. A broad green visual receptor would detect both deep green and lime green bioluminescent optical signals. 相似文献
308.
There are few effective or efficient established methods for monitoring cryptic herpetofauna. Footprint tracking tunnels are routinely used to index small mammal populations, but also have potential for monitoring herpetofauna. We evaluated the utility of tracking tunnels for identification of New Zealand lizards using captive- and wild-sourced animals (four skink and eight gecko species). All skink prints that we obtained were indistinct or obscure, but we obtained relatively clear, measurable prints for all gecko species. We found that identification to species level was possible for the two gecko species for which we had a large sample—Naultinus gemmeus and Woodworthia ‘Otago large’—using linear discriminant analysis (the best model correctly assigned 96.1% of individuals). Our findings suggest that footprints from tracking tunnels may be used to distinguish between species of geckos. Additional research is needed to assess the ability to further discriminate intra- and inter-genera lizard footprints from tracking tunnels, and the utility of the technique for surveying and monitoring lizard populations. 相似文献
309.
Polymerase chain reaction (PCR) gut analysis was conducted on specimens of the introduced spider Tenuiphantes tenuis collected from dairy pasture in Canterbury, New Zealand. PCR primers were specifically designed to amplify a fragment of the mitochondrial gene cytochrome c oxidase subunit 1 (COI) from Listronotus bonariensis and revealed that this major pasture pest species is consumed in the field by T. tenuis. The field predation rate of L. bonariensis by T. tenuis was estimated from our PCR results together with published data on the degradation of DNA and the density of T. tenuis in Canterbury pastures. We found that T. tenuis is a potentially significant predator of L. bonariensis in New Zealand pastures. 相似文献
310.
Sabine JM de Brouwer Henri?t van Middendorp Floris W Kraaimaat Timothy RDJ Radstake Irma Joosten A Rogier T Donders Agnes Eijsbouts Saskia Spillekom-van Koulil Piet LCM van Riel Andrea WM Evers 《Arthritis research & therapy》2013,15(6):R200