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21.
Wilkie SE Newbold RJ Deery E Walker CE Stinton I Ramamurthy V Hurley JB Bhattacharya SS Warren MJ Hunt DM 《Human molecular genetics》2000,9(20):3065-3073
Three different mutations in codon 838 of GUCY2D, the gene for retinal guanylate cyclase 1, have been linked to autosomal dominant cone-rod dystrophy at the CORD6 locus. To examine the relationship between enzyme activity and disease severity, the three disease-causing substitutions (R838C, R838H and R838S) and four artificial mutations (R838A, R838E, R838L and R838K) were generated. Assay of GCAP1-stimulated cyclase activity in vitro shows that, compared with wild-type, R838E, R838L and R838K possess only low activity, whereas R838A, R838C, R838H and R838S have activity equal or superior to wild-type at low Ca(2+) concentrations. These four latter mutants showed a higher apparent affinity for GCAP1 than did wild-type. The Ca(2+) sensitivity of the GCAP1 activation was also altered with marked residual activity at high Ca(2+), the effect increasing: wild-type < R838C < R838H < R838A < R838S. Within the photoreceptor, this would result in a failure to inactivate cyclase activity at high physiological Ca(2+ )concentrations. Amongst the three disease-associated mutations, the effect correlates directly with disease severity. The wild-type and R838H mutant displayed a difference in pH sensitivity, with the mutant showing a higher specific activity with pH > 6.0. Site 838 is in the dimerization domain that forms a coiled-coil in the active protein. A computer-aided structure prediction of this region indicates that R838 in the wild-type breaks the structure at four helical turns, and there is an increasing tendency for the structure to continue for further turns in the order R838C < R838H,S,K < R838E < R838A < R838L. 相似文献
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Seven new HLA-B alleles associated with antigens in the B7 CREG 总被引:1,自引:0,他引:1
This paper describes seven novel HLA-B alleles. Five of these new alleles contain polymorphic motifs previously reported in HLA-B alleles, suggesting an origin resultant from a gene conversion mechanism. B*0723 contains a polymorphism previously unreported in class I HLA molecules. B*4105 contains a nucleotide substitution previously unreported in class I HLA molecules, which encodes a protein sequence previously reported only in HLA-C locus alleles. 相似文献
24.
Rania El Fekih James Hurley Vasisht Tadigotla Areej Alghamdi Anand Srivastava Christine Coticchia John Choi Hazim Allos Karim Yatim Juliano Alhaddad Siawosh Eskandari Philip Chu Albana B. Mihali Isadora T. Lape Mauricio P. Lima Filho Bruno T. Aoyama Anil Chandraker Kassem Safa James F. Markmann Leonardo V. Riella Richard N. Formica Johan Skog Jamil R. Azzi 《Journal of the American Society of Nephrology : JASN》2021,32(4):994
BackgroundDeveloping a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells’ proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection.MethodsUsing 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets.ResultsAn exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature’s negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell–mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature’s negative predictive value was 90.6% and its positive predictive value was 77.8%.ConclusionsOur findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making. 相似文献
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Hurley RE 《Frontiers of health services management》1993,9(4):5-35; discussion 45
Slowly mounting interest in the provider community in delivery system reform badly underestimates the extent to which major reconfiguration is already being engineered by aggressive purchasers. The once widely held view that provider-sponsored integrated firms represent the ideal health care system is being challenged by purchasers who are crafting, through short- and long-term selective contracting, provider networks that offer many of the same advantages ascribed to integrated firms. Three alternative approaches to restructuring delivery systems are examined and appraised in terms of how each may or may not be able to satisfy purchaser demands. The relentless pursuit of better cost management will have profound consequences for health care providers and their managers. Major redeployment of resources will occur as the industry converts from a hospital-centered to a continuum of care-centered management philosophy. 相似文献
27.
Terkelsen KG McCarthy RH Munich RL Hurley BE 《Journal of mental health administration》1994,21(3):298-312
When a time-limited day treatment program was reconfigured to serve individuals with long-standing psychotic disorders, the number of treatment episodes exceeding six months rose to 70%. To justify this concentration of resources, the program needed methods to identify individuals for whom sustained treatment was appropriate. This report describes development of utilization review methods adapted to publicly funded day treatment of individuals with serious mental illness and training of clinicians in new documentation skills. Data from three years of operation suggest that symptom severity is not a reliable indicator of medical necessity in day treatment. As expected with a clinically based system, a composite measure of benefit and medical necessity indicators weighted toward functioning in living, learning, working, and socializing environments predicted physician reviewer denial of continued day treatment, but length of stay did not. 相似文献
28.
Olendzki B Hurley TG Hebert JR Ellis S Merriam PA Luippold R Rider L Ockene IS 《Journal of the American Dietetic Association》1999,99(11):1433-1439
The Dietary Risk Assessment (DRA) is a brief dietary assessment tool used to identify dietary behaviors associated with cardiovascular disease. Intended for use by physicians and other nondietitians, the DRA identifies healthful and problematic dietary behaviors and alerts the physician to patients who require further nutrition counseling. To determine the relative validity of this tool, we compared it to the 7-Day Dietary Recall (an instrument developed to assess intake of dietary fat) and to the average of 7 telephone-administered 24-hour dietary recalls. Forty-two free-living subjects were recruited into the study. The 7-Day Dietary Recall and DRA were administered to each subject twice, at the beginning and the end of the study period, and the 24-hour recalls were conducted during the intervening time period. Correlation coefficients were computed to compare the food scores derived from the 3 assessment methods. Correlations between the DRA and 7-Day Dietary Recall data were moderate (r = .47, on average, for postmeasures); correlations between the DRA and 24-hour recalls were lower. The ability of the DRA to assess dietary fat consumption and ease of administration make it a clinically useful screening instrument for the physician when counseling patients about dietary fat reduction. 相似文献
29.
Screening methods for thyroid hormone disruptors 总被引:15,自引:0,他引:15
DeVito M Biegel L Brouwer A Brown S Brucker-Davis F Cheek AO Christensen R Colborn T Cooke P Crissman J Crofton K Doerge D Gray E Hauser P Hurley P Kohn M Lazar J McMaster S McClain M McConnell E Meier C Miller R Tietge J Tyl R 《Environmental health perspectives》1999,107(5):407-415
The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen. 相似文献
30.