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151.
Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis
Whereas in most cases a fatty liver remains free of inflammation, 10%-20% of patients who have fatty liver develop inflammation and fibrosis (nonalcoholic steatohepatitis [NASH]). Inflammation may precede steatosis in certain instances. Therefore, NASH could reflect a disease where inflammation is followed by steatosis. In contrast, NASH subsequent to simple steatosis may be the consequence of a failure of antilipotoxic protection. In both situations, many parallel hits derived from the gut and/or the adipose tissue may promote liver inflammation. Endoplasmic reticulum stress and related signaling networks, (adipo)cytokines, and innate immunity are emerging as central pathways that regulate key features of NASH. 相似文献
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A Bernardi ACCV Zilberstein E J?ger MM Campos FB Morrone JB Calixto AR Pohlmann SS Guterres AMO Battastini 《British journal of pharmacology》2009,158(4):1104-1111
Background and purpose:
The effects of systemic treatment with indomethacin-loaded nanocapsules (IndOH-NC) were compared with those of free indomethacin (IndOH) in rat models of acute and chronic oedema.Experimental approach:
The following models of inflammation were employed: carrageenan-induced acute oedema (measured between 30 min and 4 h), sub-chronic oedema induced by complete Freund''s adjuvant (CFA) (determined between 2 h and 72 h), and CFA-induced arthritis (oedema measured between 14 and 21 days).Key results:
IndOH or IndOH-NC produced equal inhibition of carrageenan-elicited oedema. However, IndOH-NC was more effective in both the sub-chronic (33 ± 4% inhibition) and the arthritis (35 ± 2% inhibition) model of oedema evoked by CFA, when compared with IndOH (21 ± 2% and 14 ± 3% inhibition respectively) (P < 0.01). In the CFA arthritis model, treatment with IndOH-NC markedly inhibited the serum levels of the pro-inflammatory cytokines tumour necrosis factor α and IL-6 (by 83 ± 8% and 84 ± 11% respectively), while the levels of the anti-inflammatory cytokine IL-10 were significantly increased (196 ± 55%). The indices of gastrointestinal damage in IndOH-NC-treated animals were significantly less that those after IndOH treatment (58 ± 16%, 72 ± 6% and 69 ± 2%, for duodenum, jejunum and ileum respectively).Conclusions and implications:
IndOH-NC produced an increased anti-inflammatory efficacy in long-term models of inflammation, allied to an improved gastrointestinal safety. This formulation might represent a promising alternative for treating chronic inflammatory diseases, with reduced undesirable effects.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009 相似文献155.
DJ Behm NV Aiyar AR Olzinski JJ McAtee MA Hilfiker JW Dodson SE Dowdell GZ Wang KB Goodman CA Sehon MR Harpel RN Willette MJ Neeb CA Leach SA Douglas 《British journal of pharmacology》2010,161(1):207-228
BACKGROUND AND PURPOSE
Recently identified antagonists of the urotensin–II (U-II) receptor (UT) are of limited utility for investigating the (patho)physiological role of U-II due to poor potency and limited selectivity and/or intrinsic activity.EXPERIMENTAL APPROACH
The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays.KEY RESULTS
GSK1440115 (pKi= 7.34–8.64 across species) and GSK1562590 (pKi= 9.14–9.66 across species) are high affinity ligands of mammalian recombinant (mouse, rat, cat, monkey, human) and native (SJRH30 cells) UT. Both compounds exhibited >100-fold selectivity for UT versus 87 distinct mammalian GPCR, enzyme, ion channel and neurotransmitter uptake targets. GSK1440115 showed competitive antagonism at UT in arteries from all species tested (pA2= 5.59–7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pKb= 8.93–10.12 across species), but a competitive antagonist in monkey arteries (pKb= 8.87–8.93). Likewise, GSK1562590 inhibited the hU-II-induced systemic pressor response in anaesthetized cats at a dose 10-fold lower than that of GSK1440115. The antagonistic effects of GSK1440115, but not GSK1562590, could be reversed by washout in rat isolated aorta. In ex vivo studies, GSK1562590 inhibited hU-II-induced contraction of rat aorta for at least 24 h following dosing. Dissociation of GSK1562590 binding was considerably slower at rat than monkey UT.CONCLUSIONS AND IMPLICATIONS
Whereas both GSK1440115 and GSK1562590 represent high-affinity/selective UT antagonists suitable for assessing the (patho)physiological role of U-II, only GSK1562590 exhibited sustained UT residence time and improved preclinical efficacy in vivo. 相似文献156.
Obesity and obesity-related disorders play an important role in clinical medicine. Adipose tissue, with its soluble mediators called adipocytokines, has emerged as a major endocrine organ. These adipocytokines comprise many mediators such as adiponectin, PBEF (pre-B-cell-enhancing factor)/visfatin, leptin, resistin, retinol-binding protein-4 and others. They play major roles in key aspects of metabolism, such as insulin resistance, fatty acid oxidation, inflammation and immunity. Adiponectin, a prototypic adipocytokine, is of importance in the regulation of insulin resistance, as circulating levels are decreased in obesity and diseases associated with insulin resistance. Besides its major role in regulation of insulin sensitivity, recent evidence suggests potent anti-inflammatory functions for adiponectin. These effects are paralleled by other immune-regulatory properties, such as regulation of endothelial cell function. The in vitro effects of adiponectin have been corroborated by several studies demonstrating potent in vivo anti-inflammatory effects. Many other adipocytokines, such as PBEF/visfatin, leptin, resistin or retinol binding protein-4, are involved in the physiology and pathophysiology of adipocytes, adipose tissue and related diseases. PBEF/visfatin, another recently characterized adipocytokine, has been linked to several inflammatory disease states beyond insulin resistance, such as acute lung injury or inflammatory bowel diseases. It has been recognized for many decades that obesity is accompanied by an increase in cancer and potentially some immune-mediated diseases. Understanding this new exciting world of adipocytokines will be of importance in the development of novel therapies for obesity-associated diseases. 相似文献
157.
致编辑:葛兰素史克对最近美国糖尿病学会和欧洲糖尿病研究学会共识声明中不推荐2型糖尿病使用罗格列酮治疗的建议[1]表示遗憾,因为这有悖于科学证据. 相似文献
158.
RA Vicente VR Leite e Silva AR Baby MVR Velasco V Bedin 《Journal of the European Academy of Dermatology and Venereology》2009,23(4):410-414
Background Excess of terminal hair can be defined as excessive hair that appears in male-like pattern in women. Some experts consider this condition as a result of an atypical relationship between levels of circulating androgens and sensitivity of androgen receptors in hair follicles to circulating androgens.
Aims The aim of this research work was to evaluate the efficacy of a topical treatment for suppressing terminal hair growth of a cream containing 6.0% of the Stryphnodendron adstringens bark extract.
Study design and subjects Study was randomized, double-blind and placebo-controlled. Subjects with excess of terminal hair were randomized to placebo and to the active treatment (cream with 6.0% of the extract). Evaluation was performed before and after 6 months, and subjects were photographed in each time. Clinical examination was carried out with the same physicians and in accordance with the Ferriman-Gallwey (FG) score.
Results Benefits of the cream containing S. adstringens bark extract was observed in 60.98% ( P < 0.001) of the subjects. FG score changed from 4 to 3 in the placebo group compared to 4–2 in the active. The cream suppressed the terminal hair growth and diminished the number of terminal hair. Subjects also described the reduction of skin hyperpigmentation, folliculitis and acne. Adverse events were not verified by physicians or patients.
Conclusions The cream with 6.0% of the S. adstringens bark extract was effective on the reduction and on the reversion of the terminal hair excess, being considered a new promissory product for such finality . 相似文献
Aims The aim of this research work was to evaluate the efficacy of a topical treatment for suppressing terminal hair growth of a cream containing 6.0% of the Stryphnodendron adstringens bark extract.
Study design and subjects Study was randomized, double-blind and placebo-controlled. Subjects with excess of terminal hair were randomized to placebo and to the active treatment (cream with 6.0% of the extract). Evaluation was performed before and after 6 months, and subjects were photographed in each time. Clinical examination was carried out with the same physicians and in accordance with the Ferriman-Gallwey (FG) score.
Results Benefits of the cream containing S. adstringens bark extract was observed in 60.98% ( P < 0.001) of the subjects. FG score changed from 4 to 3 in the placebo group compared to 4–2 in the active. The cream suppressed the terminal hair growth and diminished the number of terminal hair. Subjects also described the reduction of skin hyperpigmentation, folliculitis and acne. Adverse events were not verified by physicians or patients.
Conclusions The cream with 6.0% of the S. adstringens bark extract was effective on the reduction and on the reversion of the terminal hair excess, being considered a new promissory product for such finality . 相似文献
159.
TR Villa AR Correa Moutran LA Sobirai Diaz MM Pereira Pinto FA Carvalho AA Gabbai & D de Souza Carvalho 《Cephalalgia : an international journal of headache》2009,29(6):631-634
The aim of this study was to evaluate the visual attention of children with migraine and compare it with a control group. Thirty migrainous children and 30 controls without headache were subjected to a visual attention assessment with Trail Making Tests (TMT) A/B, Letter Cancellation Test, and the Brazilian computerized test Visual Attention Test, third edition. The migraine group was evaluated after 2 days without headache. The migraine group had an inferior performance compared with the control group on TMT A ( P = 0.03) and B ( P = 0.001), and more errors on tasks 1 ( P = 0.032) and 2 ( P = 0.015) of the Visual Attention Test, presenting difficulty with selective and alternate attention. Attention is a neurological function that depends on structures such as the brainstem, cerebral cortex and the limbic system and on neurotransmitters such as dopamine and noradrenaline. The neurochemical aspects involved in the physiopathology of migraine and attention mechanisms probably predispose these children to visual attention deficits. 相似文献
160.