全文获取类型
收费全文 | 572篇 |
免费 | 13篇 |
国内免费 | 4篇 |
专业分类
耳鼻咽喉 | 2篇 |
儿科学 | 13篇 |
妇产科学 | 7篇 |
基础医学 | 92篇 |
口腔科学 | 4篇 |
临床医学 | 57篇 |
内科学 | 120篇 |
皮肤病学 | 14篇 |
神经病学 | 36篇 |
特种医学 | 18篇 |
外科学 | 86篇 |
综合类 | 3篇 |
预防医学 | 41篇 |
眼科学 | 1篇 |
药学 | 48篇 |
中国医学 | 2篇 |
肿瘤学 | 45篇 |
出版年
2023年 | 9篇 |
2022年 | 12篇 |
2021年 | 29篇 |
2020年 | 15篇 |
2019年 | 13篇 |
2018年 | 28篇 |
2017年 | 11篇 |
2016年 | 23篇 |
2015年 | 28篇 |
2014年 | 32篇 |
2013年 | 46篇 |
2012年 | 55篇 |
2011年 | 63篇 |
2010年 | 22篇 |
2009年 | 28篇 |
2008年 | 38篇 |
2007年 | 25篇 |
2006年 | 24篇 |
2005年 | 25篇 |
2004年 | 21篇 |
2003年 | 17篇 |
2002年 | 20篇 |
2000年 | 1篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1997年 | 1篇 |
排序方式: 共有589条查询结果,搜索用时 31 毫秒
11.
12.
Benjamin Fournier Maud Tusseau Marine Villard Christophe Malcus Emilie Chopin Emmanuel Martin Debora Jorge Cordeiro Nicole Fabien Mathieu Fusaro Alexandra Gauthier Nathalie Garnier David Goncalves Sonia Lounis Christelle Lenoir Anne-Laure Mathieu Marion Moreews Magali Perret Capucine Picard Sylvain Latour 《The Journal of allergy and clinical immunology》2021,147(2):740-743.e9
13.
14.
Pietro Mesirca Isabelle Bidaud Fran?ois Briec Stéphane Evain Angelo G. Torrente Khai Le Quang Anne-Laure Leoni Matthias Baudot Laurine Marger Antony Chung You Chong Jo?l Nargeot Joerg Striessnig Kevin Wickman Flavien Charpentier Matteo E. Mangoni 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(7):E932-E941
Dysfunction of pacemaker activity in the sinoatrial node (SAN) underlies “sick sinus” syndrome (SSS), a common clinical condition characterized by abnormally low heart rate (bradycardia). If untreated, SSS carries potentially life-threatening symptoms, such as syncope and end-stage organ hypoperfusion. The only currently available therapy for SSS consists of electronic pacemaker implantation. Mice lacking L-type Cav1.3 Ca2+ channels (Cav1.3−/−) recapitulate several symptoms of SSS in humans, including bradycardia and atrioventricular (AV) dysfunction (heart block). Here, we tested whether genetic ablation or pharmacological inhibition of the muscarinic-gated K+ channel (IKACh) could rescue SSS and heart block in Cav1.3−/− mice. We found that genetic inactivation of IKACh abolished SSS symptoms in Cav1.3−/− mice without reducing the relative degree of heart rate regulation. Rescuing of SAN and AV dysfunction could be obtained also by pharmacological inhibition of IKACh either in Cav1.3−/− mice or following selective inhibition of Cav1.3-mediated L-type Ca2+ (ICa,L) current in vivo. Ablation of IKACh prevented dysfunction of SAN pacemaker activity by allowing net inward current to flow during the diastolic depolarization phase under cholinergic activation. Our data suggest that patients affected by SSS and heart block may benefit from IKACh suppression achieved by gene therapy or selective pharmacological inhibition.Pacemaker activity of the sinoatrial node (SAN) controls heart rate under physiological conditions. Abnormal generation of SAN automaticity underlies “sick sinus” syndrome (SSS), a pathological condition manifested when heart rate is not sufficient to meet the physiological requirements of the organism (1). Typical hallmarks of SSS include SAN bradycardia, chronotropic incompetence, SAN arrest, and/or exit block (1–3). SSS carries incapacitating symptoms, such as fatigue and syncope (1–3). A significant percentage of patients with SSS present also with tachycardia-bradycardia syndrome (3). SSS can also be associated with atrioventricular (AV) conduction block (heart block) (1–3). Although aging is a known intrinsic cause of SSS (4), this disease appears also in the absence of any associated cardiac pathology and displays a genetic legacy (1, 2). Heart disease or drug intake can induce acquired SSS (2). Symptomatic SSS requires the implantation of an electronic pacemaker. SSS accounts for about half of all pacemaker implantations in the United States (5, 6). The incidence of SSS has been forecasted to increase during the next 50 y, particularly in the elder population (7). Furthermore, it has been estimated that at least half of SSS patients will need to be electronically paced (7). Although pacemakers are continuously ameliorated, they remain costly and require lifelong follow-up. Moreover, the implantation of an electronic pacemaker remains difficult in pediatric patients (8). Development of alternative and complementary pharmacological or molecular therapies for SSS management could improve quality of life and limit the need for implantation of electronic pacemakers.Recently, the genetic bases of some inherited forms of SSS have been elucidated (recently reviewed in 1, 9) with the discovery of mutations in genes encoding for ion channels involved in cardiac automaticity (4, 9, 10). Notably, loss of function of L-type Cav1.3 Ca2+ channels is central in some inherited forms of SSS. For instance, loss of function in Cav1.3-mediated L-type Ca2+ (ICa,L) current causes the sinoatrial node dysfunction and deafness syndrome (SANDD) (10). Affected individuals with SANDD present with profound deafness, bradycardia, and dysfunction of AV conduction (10). Mutation in ankyrin-B causes SSS by reduced membrane targeting of Cav1.3 channels (11). The relevance of Cav1.3 channels to SSS is demonstrated also by work on the pathophysiology of congenital heart block, where down-regulation of Cav1.3 channels by maternal Abs causes heart block in infants (12). Additionally, recent data show that chronic iron overload induces acquired SSS via a reduction in Cav1.3-mediated ICa,L (13).In mice and humans, Cav1.3 channels are expressed in the SAN, atria, and the AV node but are absent in adult ventricular tissue (14, 15). Cav1.3-mediated ICa,L plays a major role in the generation of the diastolic depolarization in SAN and AV myocytes, thereby constituting important determinants of heart rate and AV conduction velocity (14, 16). The heart rate of mice lacking Cav1.3 channels (Cav1.3−/− mice) fairly recapitulates the hallmarks of SSS and associated symptoms, including bradycardia and tachycardia-bradycardia syndrome (17, 18). In addition, severe AV dysfunction is recorded in Cav1.3−/− mice to variable degrees. Typically, these mice show first- and second-degree AV block (16, 17, 19). Complete AV block with dissociated atrial and ventricular rhythms can also be observed in these animals. The phenotype of Cav1.3−/− mice thus constitutes a unique model for developing new therapeutic strategies against SSS (10).The muscarinic-gated K+ channel (IKACh) is involved in the negative chronotropic effect of the parasympathetic nervous system on heart rate (20, 21). Two subunits of the G-protein activated inwardly rectifying K+ channels (GIRK1 and GIRK4) of the GIRK/Kir3 subfamily assemble as heterotetramers to form cardiac IKACh channels (22). Indeed, both Girk1−/− and Girk4−/− mice lack cardiac IKACh (20, 21, 23). We recently showed that silencing of the hyperpolarization-activated current “funny” (If) channel in mice induces a complex arrhythmic profile that can be rescued by concurrent genetic ablation of Girk4 (24). In this study, we tested the effects of genetic ablation and pharmacological inhibition of IKACh on the Cav1.3−/− mouse model of SSS. We found that Girk4 ablation or pharmacological inhibition of IKACh rescues SSS and AV dysfunction in Cav1.3−/−. Thus, our study shows that IKACh targeting may be pursued as a therapeutic strategy for treatment of SSS and heart block. 相似文献
15.
Jean Reignier Michael Darmon Romain Sonneville Anne-Laure Borel Maité Garrouste-Orgeas Stéphane Ruckly Bertrand Souweine Anne-Sylvie Dumenil Hakim Haouache Christophe Adrie Laurent Argaud Lilia Soufir Guillaume Marcotte Virginie Laurent Dany Goldgran-Toledano Christophe Clec’h Carole Schwebel Elie Azoulay Jean-François Timsit 《Intensive care medicine》2015,41(5):875-886
16.
Jorian Prudhomme Céline Toty Ozge Erisoz Kasap Nil Rahola Baptiste Vergnes Carla Maia Lenea Campino Maria Antoniou Maribel Jimenez Ricardo Molina Arnaud Cannet Bulent Alten Denis Sereno Anne-Laure Bañuls 《Acta tropica》2015
The population structure of Phlebotomus ariasi, a proven vector of Leishmania infantum in the Mediterranean area, is still poorly understood. Previously, only two microsatellite loci had been developed to study the population genetics of this species. Herein we use these loci and determined fourteen novel microsatellite loci, useful for the characterization of P. ariasi populations. These loci were tested on three populations of P. ariasi, two from France and one from Portugal. In addition, the usefulness of these markers was also evaluated on seven other sandfly species. 相似文献
17.
Kennedy Kassaza Patrick Orikiriza Augusto Llosa Joel Bazira Dan Nyehangane Anne-Laure Page Yap Boum II 《Journal of clinical microbiology》2014,52(7):2671-2673
We compared Mycobacterium tuberculosis sputum culture recovery and contamination rates between Lowenstein-Jensen medium (LJ) containing the following decontaminants and LJ alone: (i) PANTA (n = 299), (ii) Selectatab-MB (n = 299), and (iii) penicillin G (n = 234). The contamination rate for LJ alone was approximately 31%, versus 5.0% for PANTA-containing, 2% for Selectatab-containing, and 9% for penicillin-containing media (P < 0.001). M. tuberculosis isolation rates were 9.8%, 17%, 18%, and 12% for standard LJ, PANTA, Selectatab, and penicillin cultures, respectively. 相似文献
18.
Dubessy AL Ursu R Maillet D Augier A Le Guilloux J Carpentier AF Belin C 《Age and ageing》2012,41(2):275-277
A 75-year-old patient was evaluated for dementia. His past medical history included an ischaemic cardiomyopathy treated with aspirin daily. His neurological examination showed mild ataxia syndrome and central deafness. The neuropsychological examination did not suggest Alzheimer's disease. No specific aetiology was found from biological investigations, but MRI scans revealed a superficial siderosis, which was further confirmed with CSF exams. This case highlights the interest of MRI with echo-gradient-T2 weighted sequences in patients investigated for memory disorders. Once the diagnosis is known, specific preventive measures have to be taken: searching for a treatable source of bleeding and the interruption of antiplatelet aggregation or anticoagulant treatments. 相似文献
19.
20.
Chantal Loirat Fadi Fakhouri Gema Ariceta Nesrin Besbas Martin Bitzan Anna Bjerre Rosanna Coppo Francesco Emma Sally Johnson Diana Karpman Daniel Landau Craig B Langman Anne-Laure Lapeyraque Christoph Licht Carla Nester Carmine Pecoraro Magdalena Riedl Nicole C. A. J. van de Kar Johan Van de Walle Marina Vivarelli Véronique Frémeaux-Bacchi for HUS International 《Pediatric nephrology (Berlin, Germany)》2016,31(1):15-39