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71.
Glucocorticoid hormone resistance during primate evolution: receptor-mediated mechanisms. 总被引:5,自引:1,他引:5 下载免费PDF全文
G P Chrousos D Renquist D Brandon C Eil M Pugeat R Vigersky G B Cutler Jr D L Loriaux M B Lipsett 《Proceedings of the National Academy of Sciences of the United States of America》1982,79(6):2036-2040
The concentrations of total and protein-unbound plasma cortisol of New World monkeys are higher than those of Old World primates and prosimians. The urinary free-cortisol excretion also is increased markedly. However, there is no physiologic evidence of increased cortisol effect. These findings suggest end-organ resistance to glucocorticoids. This was confirmed by showing that the hypothalamic-pituitary adrenal axis is resistant to suppression by dexamethasone. To study this phenomenon, glucocorticoid receptors were examined in circulating mononuclear leukocytes and cultured skin fibroblasts from both New and Old World species. The receptor content is the same in all species, but the New World monkeys have a markedly decreased binding affinity for dexamethasone. Thus, the resistance of these species to the action of cortisol is due to the decreased binding affinity of the glucocorticoid receptor. This presumed mutation must have occurred after the bifurcation of Old and New World primates (approximately 60 x 10(6) yr ago) and before the diversion of the New World primates from each other (approximately 15 x 10(6) yr ago). 相似文献
72.
Alloimmunization to platelets in heavily transfused patients with sickle cell disease 总被引:2,自引:0,他引:2
Bone marrow transplantation (BMT) is now an option for some patients with sickle cell disease (SCD). Many SCD patients are multiply transfused with red blood cells (RBCs), and may be immunized to alloantigens other than erythrocyte antigens. Because platelet refractoriness is a significant complication during BMT, we wished to determine the prevalence of alloimmunization to platelets in transfused SCD patients. Sera collected from 47 transfused and 14 untransfused SCD patients were screened for HLA and platelet-specific antibodies. Transfusion and RBC antibody histories were reviewed. A subset of the patients were rescreened 1 year later. Eighty-five percent of patients with at least 50 RBC transfusions (22 of 26), 48% of patients with less than 50 transfusions (10 of 21), and none of 14 untransfused patients demonstrated platelet alloimmunization (P < .05). Platelet alloimmunization was more prevalent than RBC alloimmunization (20% to 30%). Half of the platelet reactivity was chloroquine-elutable. Eighteen of 22 patients (82%) on chronic RBC transfusion remained platelet-alloimmunized 11 to 22 months after initial testing. In summary, 85% of heavily transfused SCD patients are alloimmunized to HLA and/or platelet-specific antigens. These patients may be refractory to platelet transfusion, a condition that would increase their risk during BMT. Leukodepletion in the transfusion support of SCD patients should be considered to prevent platelet alloimmunization. 相似文献
73.
74.
J McClelland B Halperin J Cutler P Kudenchuk J Kron J McAnulty 《The American journal of cardiology》1990,65(20):1351-1357
Although sudden cardiac deaths and ischemic cardiac events clearly occur in a circadian pattern, such a pattern has not been shown for primary arrhythmic events. Because primary arrhythmic events are thought to play an important role in sudden cardiac death, a large series of ventricular stimulation studies was analyzed to determine whether circadian variation in ventricular electrical instability exists. If such a circadian variation could be shown, it could have implications for the conduct and interpretation of electrophysiologic testing and the etiology of circadian variation in sudden cardiac death. Results of 2 drug-free ventricular stimulation studies performed 4 to 28 hours apart in each of 162 patients with coronary artery disease were analyzed. Rate and duration of induced arrhythmia, number of extrastimuli required to induce arrhythmia and changes in these factors between the 2 tests in each patient were analyzed. Comparisons were made by half-day, by hour and in a temporally continuous manner to eliminate errors associated with any single method. No significant circadian variation was found in any electrophysiologic measure of ventricular electrical instability despite adequate statistical power. These findings show that the time of day during which ventricular stimulation tests are performed does not affect test results, and therefore does not need to be controlled during electrophysiologic studies. If these findings are parallel to those in ambulatory patients with coronary artery disease, then circadian changes in ventricular electrical instability may not play as important a role in the circadian pattern of sudden cardiac death as had been previously thought. 相似文献
75.
Simone CS Wolfkamp Caroline Verseyden Esther WM Vogels Sander Meisner Kirsten Boonstra Charlotte P Peters Pieter CF Stokkers Anje A te Velde 《World journal of gastroenterology : WJG》2014,20(10):2664-2672
AIM:To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn’s disease(CD).METHODS:In this study,we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls.As both autophagy related like 1(ATG16L1)and immunityrelated guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleo-tide-binding ligomerization domain-containing protein2(NOD2)has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction.The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodo?Escherichia coli Bioparticles Phagocytosis kit for flowcytometry.RESULTS:In this study,we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity(ratio of mean fluorescence intensity)between the patient groups and the healthy controls.CD patients show a significantly higher phagocytic capacity(ratio mean percentage of phagocytic cells)compared to healthy controls(51.91%±2.85%vs 37.67%±7.06%,P=0.05).The extend of disease was not of influence.However,variants of ATG16L1(WT:2.03±0.19 vs homozygoot variant:4.38±0.37,P<0.009)as well as NOD2(C-ins)(heterozygous variant:42.08±2.94 vs homozygous variant:75.58±4.34(P=0.05)are associated with the phagocytic activity in patients with CD.CONCLUSION:Monocytes of CD patients show enhanced phagocytosis associated with the presence of ATG16L1 and NOD2 variants.This could be part of the pathophysiological mechanism resulting in the disease. 相似文献
76.
77.
Michael J. Cutler Bradley N. Plummer Xiaoping Wan Qi-An Sun Douglas Hess Haiyan Liu Isabelle Deschenes David S. Rosenbaum Jonathan S. Stamler Kenneth R. Laurita 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(44):18186-18191
Nitric oxide (NO) derived from the activity of neuronal nitric oxide synthase (NOS1) is involved in S-nitrosylation of key sarcoplasmic reticulum (SR) Ca2+ handling proteins. Deficient S-nitrosylation of the cardiac ryanodine receptor (RyR2) has a variable effect on SR Ca2+ leak/sparks in isolated myocytes, likely dependent on the underlying physiological state. It remains unknown, however, whether such molecular aberrancies are causally related to arrhythmogenesis in the intact heart. Here we show in the intact heart, reduced NOS1 activity increased Ca2+-mediated ventricular arrhythmias only in the setting of elevated myocardial [Ca2+]i. These arrhythmias arose from increased spontaneous SR Ca2+ release, resulting from a combination of decreased RyR2 S-nitrosylation (RyR2-SNO) and increased RyR2 oxidation (RyR-SOx) (i.e., increased reactive oxygen species (ROS) from xanthine oxidoreductase activity) and could be suppressed with xanthine oxidoreductase (XOR) inhibition (i.e., allopurinol) or nitric oxide donors (i.e., S-nitrosoglutathione, GSNO). Surprisingly, we found evidence of NOS1 down-regulation of RyR2 phosphorylation at the Ca2+/calmodulin-dependent protein kinase (CaMKII) site (S2814), suggesting molecular cross-talk between nitrosylation and phosphorylation of RyR2. Finally, we show that nitroso–redox imbalance due to decreased NOS1 activity sensitizes RyR2 to a severe arrhythmic phenotype by oxidative stress. Our findings suggest that nitroso–redox imbalance is an important mechanism of ventricular arrhythmias in the intact heart under disease conditions (i.e., elevated [Ca2+]i and oxidative stress), and that therapies restoring nitroso–redox balance in the heart could prevent sudden arrhythmic death.Nitric oxide (NO) is an important regulator of cardiac function via both the activation of cyclic guanosine monophosphate-dependent signaling pathways and direct posttranslational modification of protein thiols (S-nitrosylation) (1). NO derived from the activity of neuronal nitric oxide synthase (NOS1) is involved in S-nitrosylation of key sarcoplasmic reticulum (SR) Ca2+ handling proteins (2). In particular, nitrosylation of both skeletal and cardiac muscle ryanodine receptors (RyR1 and RyR2, respectively) alters their release properties, favoring activation (3, 4). Notably, an increase in RyR2 open probability can cause spontaneous SR Ca2+ release, which may cause arrhythmias. Recently, it was shown that decreased RyR2 S-nitrosylation (RyR2-SNO) through loss of NOS1, was associated with increased spontaneous SR Ca2+ release events in isolated cardiomyocytes, following rapid pacing (5). In a separate study, NOS1 deficiency was shown to decrease spontaneous SR Ca2+ sparks and the open probability of RyR2 under resting conditions in cardiomyocytes and lipid bilayers, respectively (6). These studies suggest that NOS1 deficiency has a variable effect on RyR2 function, likely dependent on the underlying physiological state (i.e., rapid heart rate versus quiescence). It remains unknown, however, whether these changes create a substrate for arrhythmogenesis in the intact heart.It is increasingly evident that activities of nitric oxide and reactive oxygen species (ROS) are tightly coupled in cardiomyocytes producing nitroso–redox balance. Elevated ROS production (oxidative stress) is a hallmark of several cardiovascular diseases associated with increased risk of fatal ventricular arrhythmias [e.g., myocardial infarction (MI) and heart failure]. Burger et al. (7) recently demonstrated an increased incidence of ventricular arrhythmias following MI in NOS1-deficient mice. These data suggest that a nitroso–redox imbalance may be arrhythmogenic in the setting of MI. However, the molecular basis of the increased arrhythmogenesis is not known.In the current study, we found that decreased NOS1 activity increased Ca2+-mediated ventricular arrhythmias only in the setting of elevated myocardial [Ca2+]i. These arrhythmias arose from increased spontaneous SR Ca2+ release resulting from a combination of decreased RyR2-SNO and increased RyR2 oxidation (RyR2-SOx) [i.e., increased ROS from xanthine oxidoreductase (XOR) activity] and could be suppressed with xanthine oxidoreductase inhibition (i.e., allopurinol) or nitric oxide donors (i.e., GSNO). Notably, we found evidence of NOS1 regulation of RyR2 phosphorylation at the Ca2+/calmodulin-dependent protein kinase (CaMKII) site (S2814), suggesting molecular cross-talk between the nitrosylation and phosphorylation states of RyR2. Finally, we show that nitroso–redox imbalance due to decreased NOS1 activity sensitizes RyR2 to a severe arrhythmic phenotype under oxidative stress. 相似文献
78.
Only 30% of patients who require an allogeneic hematopoietic cell transplant will have a HLA matched sibling donor. Many patients, particularly those patients with diverse racial and ethnic backgrounds, may not be able to identify a suitably matched unrelated donor. Over 25,000 umbilical cord blood transplant procedures have been performed in the last 25 years. Considerable challenges exist in defining the appropriate conditioning regimen and graft vs host disease prophylaxis, surmounting issues of cell dose and delayed engraftment, and improving immune recovery. In this review, we discuss strategies to improve umbilical cord blood transplant outcomes, focusing on cord blood unit selection, expansion, and homing efficiency. 相似文献
79.
Steven D Targum Celine Houser Joanne Northcutt Jessica A Little Andrew J Cutler David P Walling 《Annals of general psychiatry》2013,12(1):1-6
Background
The clinical global impression of severity (CGI-S) scale is a frequently used rating instrument for the assessment of global severity of illness in Central Nervous System (CNS) trials. Although scoring guidelines have been proposed to anchor these scores, the collection of sufficient documentation to support the derived score is not part of any standardized interview procedure. It is self evident that the absence of a standardized, documentary format can affect inter-rater reliability and may adversely affect the accuracy of the resulting data.Method
We developed a structured interview guide for global impressions (SIGGI) and evaluated the instrument in a 2-visit study of ambulatory patients with Major Depressive Disorder (MDD) or schizophrenia. Blinded, site-independent raters listened to audio recorded SIGGI interviews administered by site-based CGI raters. We compared SIGGI-derived CGI-S scores between the two separate site-based raters and the site-independent raters.Results
We found significant intraclass correlations (p = 0.001) on all SIGGI-derived CGI-S scores between two separate site-based CGI raters with each other (r = 0.768) and with a blinded, site-independent rater (r = 0.748 and r = 0.706 respectively) and significant Pearson’s correlations between CGI-S scores with all MADRS validity comparisons for MDD and PANSS comparisons for schizophrenia (p- 0.001 in all cases). Compared to site-based raters, the site-independent raters gave identical “dual” CGI-S scores to 67.6% and 68.2% of subjects at visit 1 and 77.1% at visit 2.Conclusion
We suggest that the SIGGI may improve the inter-rater reliability and scoring precision of the CGI-S and have broad applicability in CNS clinical trials. 相似文献80.
Agustín Estrada-Peña Sally Cutler Aleksandar Potkonjak Muriel Vassier-Tussaut Wim Van Bortel Hervé Zeller Natalia Fernández-Ruiz Andrei Daniel Mihalca 《International journal of health geographics》2018,17(1):41