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202.
INTRODUCTION: Straightforward studies compared adeno-associated virus (AAV) serotypes to determine the most appropriate one for robust expression in the CNS. AAV9 was efficient when directly injected into the brain, but more surprisingly, AAV9 produced global expression in the brain and spinal cord after a peripheral, systemic route of administration to neonatal mice. AREAS COVERED: Topics include AAV9 gene delivery from intraparenchymal, intravenous, intrathecal and intrauterine routes of administration, and related preclinical studies and disease models. Systemic AAV9 gene transfer yields remarkably consistent neuronal expression, though only in early development. AAV9 is versatile to study neuropathological proteins: microtubule-associated protein tau and transactive response DNA-binding protein 43 kDa (TDP-43). EXPERT OPINION: AAV9 will be more widely used based on current data, although other natural serotypes and recombineered vectors may also support or improve upon wide-scale expression. A peripheral-to-central gene delivery that can affect the entire CNS without having to inject the CNS is promising for basic functional experiments, and potentially for gene therapy. Systemic or intra-cerebrospinal fluid routes of AAV9 administration should be considered for spinal muscular atrophy, lysosomal storage diseases and amyotrophic lateral sclerosis, if more neuronal expression can be achieved in adults, or if glial expression can be exploited. 相似文献
203.
Dayton RD Wang DB Cain CD Schrott LM Ramirez JJ King MA Klein RL 《Experimental neurology》2012,233(2):807-814
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease that involves cognitive decline and dementia. To model the hippocampal neurodegeneration and memory-related behavioral impairment that occurs in FTLD and other tau and TDP-43 proteinopathy diseases, we used an adeno-associated virus serotype 9 (AAV9) vector to induce bilateral expression of either microtubule-associated protein tau or transactive response DNA binding protein 43 kDa (TDP-43) in adult rat dorsal hippocampus. Human wild-type forms of tau or TDP-43 were expressed. The vectors/doses were designed for moderate expression levels within neurons. Rats were evaluated for acquisition and retention in the Morris water task over 12 weeks after gene transfer. Neither vector altered acquisition performance compared to controls. In measurements of retention, there was impairment in the TDP-43 group. Histological examination revealed specific loss of dentate gyrus granule cells and concomitant gliosis proximal to the injection site in the TDP-43 group, with shrinkage of the dorsal hippocampus. Despite specific tau pathology, the tau gene transfer surprisingly did not cause obvious neuronal loss or behavioral impairment. The data demonstrate that TDP-43 produced mild behavioral impairment and hippocampal neurodegeneration in rats, whereas tau did not. The models could be of value for studying mechanisms of FTLD and other diseases with tau and TDP-43 pathology in the hippocampus including Alzheimer's disease, with relevance to early stage mild impairment. 相似文献
204.
The national guidelines for the diagnosis and management of asthma published in April of 1997 emphasized patient education in asthma management. It is unclear how often patient education is included in asthma management clinics. We sought to determine how often education programs are available by surveying teaching hospitals with training programs in pulmonary and critical care medicine. Using this survey, we also determined the reason programs are not offered and whether computer resources are outinely available to utilize computer-delivered patient educational materials. We sent mail questionnaires to 163 training programs in the United States. We had a response rate of 72% (117 of 163). Of the 117 programs responding, 75 (64%) reported having a formal asthma patient education program. Most (72%) were in university teaching hospitals. A majority of respondents (84%) believed that compensation for their efforts was inadequate, and those hospitals with no formal asthma education program reported that financial cost and time requirements were the primary reasons for not having such a program. Despite the fact that many programs did not have a patient education component, 96% (72 of 75) of respondents with an educational program viewed patient education as an effective patient self-management tool. Of all programs surveyed, 85% reported they would use a high-quality computer-based asthma education program if one was available. Implementation of such a program is feasible, with 69% of programs surveyed having a personal computer in their clinic and 60% having Internet access. We conclude that most training directors believe that patient asthma education is important and effective; however, cost and time issues remain barriers to its implementation. Computer-based educational programs delivered over the Internet are feasible, could address some of these limitations, and are acceptable to most programs. 相似文献
205.
Steven J Frucht Yvette Bordelon William H Houghton Dayton Reardan 《Movement disorders》2005,20(10):1330-1337
Sodium oxybate is currently approved in the United States exclusively for the treatment of cataplexy in narcoleptic patients. In a prior article published in this journal, we reported a patient with severe posthypoxic myoclonus whose myoclonus improved with ethanol and also with treatment with sodium oxybate. We extend this preliminary observation to five other patients with ethanol-responsive movement disorders in an open-label, dose-titration, add-on, 8-week trial. All five patients (one with severe alcohol-responsive posthypoxic myoclonus, two with epsilon-sarcoglycan-linked myoclonus-dystonia, and two with essential tremor) experienced improvement from baseline of 50% or greater as measured by blinded videotape review. Tolerability was satisfactory, with dose-dependent sedation as the most common side effect. Further studies of this drug in hyperkinetic movement disorders are warranted. 相似文献
206.
Intragenic cis-acting art gene-responsive sequences of the human immunodeficiency virus. 总被引:76,自引:13,他引:76 下载免费PDF全文
C A Rosen E Terwilliger A Dayton J G Sodroski W A Haseltine 《Proceedings of the National Academy of Sciences of the United States of America》1988,85(7):2071-2075
The art gene product of the human immunodeficiency virus is required for the expression of virion capsid and envelope gene proteins. The experiments presented here show that sequences located within the coding region of the envelope gene exert a negative effect on the expression of heterologous genes and that the negative effect of these sequences can be relieved by the art gene product. This region in the env gene contains negative regulatory sequences that inhibit gene expression, as well as a sequence necessary for the art gene product-dependent relief of repression. The experiments define the cis- and trans-acting components of a regulatory system that permits differential expression of human immunodeficiency virus virion structural and regulatory proteins. 相似文献
207.
208.
Merril T. Dayton Gordon L. Kauffman Jr Jerry F. Schlegel Dr. Charles F. Code Joseph H. Steinbach 《Digestive diseases and sciences》1983,28(5):449-455
Increasing quantities of HCO3 ? appeared in the stomach and in gastric pouches of conscious dogs with gastric infusion of increasing concentrations of ethanol. HCO3 ? appearance was closely correlated with gains of K+ and of glucose to the contents and with reductions in transmucosal potential differences, each of which is associated with increased mucosal permeability. We concluded that increased diffusion of HCO3 ? through a more permeable mucosa accounted for the appearance of HCO3 ? with the lower concentrations of ethanol we used (5–20%) and that bulk movement of the interstitial fluid into the contents added to HCO3 ? entry with the most damaging, desquamating, concentration (40%). With the gastric contents at 100 mM HCl, an unstirred layer of mucus gel over the mucosa would need to be of greater depth than previous estimates to produce mucosal surface neutrality at the rates of HCO3 ? appearance we observed. However, faster rates of HCO3 ? production combined with an unstirred layer could provide significant protection to the gastric mucosa. 相似文献
209.
Dr. John G. Moore MD Kenneth R. Larsen PhD Paolo Barattini MD Merril T. Dayton MD 《Digestive diseases and sciences》1994,39(8):1619-1624
A model for gastric mucosal injury is proposed in which a key pathogenetic event is the disruption in the normal relationships among several circadian rhythms of gastric function. In the rat a circadian rhythm in acid secretion was found to be out of phase with a circadian rhythm in gastric pepsin secretion, another aggressive factor, and several mucosal defensive factors (mucus and bicarbonate efflux and tissue prostacyclin content). Gastric corpus mucosal blood flow circadian patterns paralleled the rhythmicity in acid secretion and, therefore, was out of phase with the other measured mucosal defensive factors. Thus, gastric mucosal defense was maintained by different mechanisms over the 24-hr cycle. During the dark phase, when this species was active and when acid secretion was highest, enhanced damage by topical acidified aspirin was documented, despite increased mucosal blood flow. Natural asynchrony in circadian rhythms of gastric function can be protective of gastric mucosal integrity but disruption of this circadian interplay of gastric aggressive and defensive factors could theoretically lead to greater vulnerability to damage. In the human, a circadian rhythm in basal gastric acidity has been described but no information exists as to the possibility of similar rhythmic variation in other gastric factors (aggressive and defensive) and possible disruption of these rhythms in disease. 相似文献
210.
Nontuberculous mycobacterial lung disease. Substantiation of a less aggressive approach 总被引:1,自引:0,他引:1
A nonsurgical, less aggressive, less toxic chemotherapeutic protocol for the management of nontuberculous mycobacterial (NTB) pulmonary infections has been uniformly applied to patients in our institution between 1972 and 1985. Forty-three nonimmunocompromised patients with active lung disease caused by Mycobacterium avium-intracellulare (MAI) (n = 26), M kansasii (n = 16), and M xenopi (n = 1) were identified retrospectively. Eighteen MAI patients were treated with three or four antituberculosis agents resulting in sputum conversion and clinical improvement in 12 (67 percent). Additionally, 11 out of 16 (69 percent) patients completing therapy or still undergoing therapy for persistent MAI disease, achieved sputum conversion and clinical improvement after prolonged therapy (3.6 +/- 0.5 years [SEM]). When M kansasii was identified as the etiologic agent, all patients were treated with four or fewer antituberculosis agents and 14 out of 16 patients (88 percent) achieved sputum conversion and clinical improvement throughout the follow-up period. We conclude that the use of three or four chemotherapeutic agents in the treatment of NTM lung disease provides an excellent probability of successful outcome even in MAI infections. 相似文献