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51.
Chk1 and Akt signaling facilitate survival of cells treated with nucleoside analogues. Activation of Chk1 in response to cytarabine (ara-C) induced an S-phase checkpoint characterized by the inhibition of Cdk2, cell cycle arrest, no change in constitutively active Akt, or low-stress kinase signaling in ML-1 cells. However, inhibition of Chk1 by UCN-01 in S-phase-arrested cells resulted in an abrogation of the checkpoint, inhibition of Akt, activation of JNK, and a rapid induction of apoptosis. Similarly, primary acute myelogenous leukemia (AML) blasts exposed to ara-C and UCN-01 demonstrated a selective loss in cloning potential when compared with normal progenitors. Therefore, we evaluated a pilot clinical trial of ara-C in combination with UCN-01 in patients with relapsed AML. Blasts from some patients demonstrated a previously activated Chk1-Cdk2 DNA damage response pathway that decreased during therapy. Constitutively phosphorylated Akt kinase declined on addition of UCN-01 to the ara-C infusion, an action accompanied by an activation of JNK and reduction in absolute AML blast counts. Thus, use of UCN-01 in combination with ara-C decreases Chk1 phosphorylation, inhibits the Akt survival pathway, and activates JNK during the course of therapy, offering a rationale for the cytotoxic action of this combination during AML treatment. (Blood. 2006;107:2517-2524) 相似文献
52.
Gandhi MK Wills MR Okecha G Day EK Hicks R Marcus RE Sissons JG Carmichael AJ 《Blood》2003,102(9):3427-3438
To investigate the mechanisms of human T-cell reconstitution following allogeneic hemopoietic stem cell transplantation (alloSCT), we analyzed the clonal composition of human cytomegalovirus (HCMV)-specific or Epstein-Barr virus (EBV)-specific CD8+ T cells in 10 alloSC transplant recipients and their donors. All virus-specific CD8+ T-cell clones isolated from recipients after alloSCT contained DNA of donor origin. In all 6 D+/R+ sibling alloSCTs from seropositive donors into seropositive recipients, donor virus-specific clones transferred in the allograft underwent early expansion and were maintained long term in the recipient. In contrast, in 2 of 3 HCMV D+/R- alloSC transplant recipients in whom there was no detectable HCMV infection, donor HCMV-specific clones were undetectable, whereas donor EBV-specific clones were maintained in the same EBV-seropositive recipients, suggesting that transferred clones require antigen for their maintenance. Following D-/R+ transplantation from 3 seronegative donors into seropositive recipients, a delayed primary virus-specific CD8+ T-cell response was observed, in which the T cells contained donor DNA, suggesting that new antigen-specific T cells arose in the recipient from donor-derived progenitors. In 2 of 4 HCMV D+/R+ sibling allograft recipients the clonal composition underwent diversification as compared with their donors, with delayed persistent expansion of HCMV-specific clones that were undetectable in the donor or in the recipient during the early months after transplantation; this diversification may represent expansion of new clones generated from donor-derived progenitors. We conclude that, following alloSCT, late diversification of the HCMV-specific CD8+ T-cell clonal repertoire can occur in response to persistent viral antigen. 相似文献
53.
Parson SH Ribchester RR Davie N Gandhi NP Malik RQ Gillingwater TH Thomson D 《Journal of neuroscience research》2004,76(1):64-75
Progressive \"dying back\" neurodegenerative diseases are debilitating due to loss of connectivity after nerve terminal and axonal withdrawal, which impairs peripheral nerve function and leads ultimately to neuronal cell death. The mutant mouse (Wallerian degeneration slow; Wld(s)) provides an accessible model system to understand orthograde and retrograde degeneration, because in these mice axotomy induces slow, progressive withdrawal of nerve terminals from motor endplates. Axon degeneration itself is about 10 times slower than in wild-type mice. We describe an organ culture paradigm that permits direct observation of the progressive changes in morphology of neuromuscular junctions in Wld(s) mutant mice. Normal nerve terminal and motor endplate morphology were maintained at most Wld(s) neuromuscular junctions for up to 72 hr in vitro. At others, synaptic boutons were removed from postsynaptic junctional folds in piecemeal fashion, as observed in adults in vivo. By contrast, nerve terminals degenerated rapidly and synchronously in wild-type muscle cultures, resembling Wallerian degeneration in vivo. These observations confirm that in Wld(s) mice, axotomy triggers a mechanism of nerve-terminal withdrawal that seems qualitatively different from that in wild-type animals. The piecemeal dismantling of presynaptic terminals resembles that occurring during neonatal synapse elimination. Organ cultures of neonatal Wld(s) muscle maintained for 1-2 days in vitro also showed no evidence of synaptic terminal degeneration, but elimination of polyneuronal innervation progressed in vitro at approximately the same rate as in vivo. Taken together, the data suggest that both natural and axotomy-induced forms of synapse withdrawal may be accessible to continuous observation and analysis, in organ-cultures of Wld(S) mouse muscles. This offers several advantages over repeated visualization of synaptic remodeling that has thus far been possible only in vivo. 相似文献
54.
Payam Sajedi Lydia Chelala Joel Nunez-Gonalez Carolyn Cronin Steven Kittner Jiachen Zhuo Yang Zhang Dheeraj Gandhi Prashant Raghavan 《Journal of neuroradiology. Journal de neuroradiologie》2019,46(2):136-140
Background and purpose
Carotid webs are intraluminal filling defects at the carotid bulb which are considered rare, though possibly underappreciated entities with recent studies demonstrating a likely casual association with ischemic stroke. The purpose of the study is to describe our recent experience with clinical and imaging manifestations of carotid webs.Materials and methods
A retrospective review of CTA neck studies in all adult patients presenting to our institution during the 19-month study interval was performed to determine the presence of carotid webs. Subsequent chart review of these patients with webs was performed to assess their clinical history and to obtain demographic detail.Results
A total of 14 patients were identified with carotid webs in the study population. The mean age of patients with webs was 42.1?years (range: 28–54), consisting mostly of African Americans (86%) and females (64%). Ten (71%) of web patients had a history of ischemic stroke, each ipsilateral to the side of web, and at least four of these patients had recurrent ischemic stroke.Conclusion
We provide one of the largest sample sizes of webs gathered in a single study. Given its association with ischemic stroke, carotid webs should be assessed for in all patients presenting with ischemic stroke, especially younger African Americans. 相似文献55.
56.
Sanjiv K. Gandhi 《Journal of interventional cardiac electrophysiology》2007,20(3):119-125
Atrial reentrant tachycardias are a common source of morbidity in children with significant structural heart disease, especially
following cardiac surgery. Preexisting atrial geometry combined with the hemodynamic effect of a congenital cardiac defect
and electrophysiological alterations caused by surgical lesions can create large anatomic-functional barriers to conduction,
allowing reentrant wavefronts to flourish. Elucidation of the genesis of reentrant arrhythmias in children has led to catheterization
and surgical therapies. The primary goals of these procedures are to restore synchronous atrioventricular conduction and eliminate
hemodynamically significant residual physiologic lesions. Debilitating arrhythmias may be cured, and patients have an improvement
in functional class. 相似文献
57.
Xiang Ling Fong Warren Low Andrea Hsiu Ling Leung Ying Ying Gandhi Mihir Xin Xiaohui Uy Elenore Judy B. Hamilton Louise Thumboo Julian 《Clinical rheumatology》2022,41(4):1095-1103
Clinical Rheumatology - To address the diagnostic delay in axial spondyloarthritis (axSpA), we have cross-culturally adapted the Hamilton axSpA questionnaire, a self-administered screening... 相似文献
58.
59.
Harry Sokol Sophie Georgin-Lavialle Danielle Canioni Stéphane Barete Gandhi Damaj Erinn Soucie Julie Bruneau Marie-Olivia Chandesris Felipe Suarez Jean-Marie Launay Achille Aouba Catherine Grandpeix-Guyodo Fanny Lanternier Bernard Grosbois Christian de Gennes Pascal Cathébras Olivier Fain Nadia Hoyeau-Idrissi Patrice Dubreuil Olivier Lortholary Laurent Beaugerie Brigitte Ranque Olivier Hermine 《The Journal of allergy and clinical immunology》2013
60.
Kinsella Paul M. Smibert Olivia C. Whitlam John B. Steven Mark Masia Ricard Gandhi Ronak G. Kotton Camille N. Holmes Natasha E. 《European journal of clinical microbiology & infectious diseases》2021,40(12):2627-2631
European Journal of Clinical Microbiology & Infectious Diseases - Malakoplakia is a chronic granulomatous disease associated with incomplete clearance of bacterial pathogens. A multimodal... 相似文献