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61.
62.
63.
Recent Advances in Elucidating Niemann-Pick C Disease 总被引:3,自引:0,他引:3
Lysosomal sequestration of endocytosed LDL-derived cholesterol, premature and abnormal enrichment of cholesterol in trans Golgi cisternae and accompanying anomalies in intracellular sterol trafficking are the hallmark phenotypic features of the Niemann-Pick C (NPC) lesion. A variable severity of these alterations has been observed, with only partial correlation between clinical and biochemical phenotypes. NPC also affects the metabolism of sphingolipids, and other biochemical abnormalities have been reported. Occurrence of neurofibrillary tangles in the brain of patients with a slowly progressive course is a recent intriguing observation. Genetic heterogeneity was established by cell hybridization and linkage studies. The two complementation groups could not be distinguished from each other by clinical, cellular or biochemical criteria, suggesting that the two gene products may interact or function sequentially. The major (> 90% of patients) NPC1 gene was mapped to 18q11 and recently isolated by positional cloning. The cDNA sequence predicts a 1278-amino acid protein, with 13 to 16 possible transmembrane regions and a putative cholesterol-sensing domain. Two murine models of the disease involving the same gene are known. The murine cDNA and the npcnih mutation have been characterized. Described homologies of the NPC1 protein are in line with its putative involvement in cellular cholesterol traffic. 相似文献
64.
Hiroaki Nakamura Marie Yamada Makoto Fukae Hidehiro Ozawa 《Journal of bone and mineral metabolism》1997,15(4):184-192
We investigated the immunohistochemical localization of CD44, hyaluronate receptor, and moesin, of the ezrinradixin-moesin
(ERM) family, in osteoclasts after calcitonin adminstration using confocal laser scanning microscopy and transmission electron
microscopy to clarify the role of CD44 and moesin in their cytoskeletal organization and cell polarity. We also elucidated
the localization of osteopontin (OPN) to confirm its possible role in cell-matrix recognition via CD44. In untreated mice,
intense immunoreactivities for CD44 and moesin were detected on the basolateral plasma membrane of osteoclasts. Rhodamine-phalloidin
reactivity was seen in a bandlike pattern on the region of contact between osteoclasts and bone and was also detected moderately
along their basolateral plasma membrane. At 30 min after calcitonin administration, osteoclasts did not show either clear
zones or ruffled borders. The bandlike reactivity of rhodamine-phalloidin in the contact region was diminished, although labeling
was seen along osteoclasts. CD44 and moesin were colocalized along their plasma membranes, including the region facing the
bone surface. Electron microscopic observation revealed that the microvillus processes in the contacting region with bone
surface, as well as the basolateral plasma membrane, showed immunoreactivities to CD44 and moesin. At 60 min, some osteoclasts
attached to bone and showed a bandlike pattern of rhodamine-phalloidin. On the other hand, OPN was localized under CD44-positive
cytoplasmic processes and the clear zone of osteoclasts. These findings suggest that calcitonin effects on the cell polarity
of osteoclasts and the CD44-moesin-actin filament system in osteoclasts plays an imporant role in cell polarity and cell-matrix
recognition. 相似文献
65.
The AIDS epidemic has caused hysteria among the public and concern to many healthcare workers in the past 12 years. Currently, legislation exists for mandatory AIDS testing in some populations. The questions remain: Should healthcare workers be routinely tested? If so, is mandatory testing ethical? The author explores the incidence and prevalence of AIDS among healthcare workers, discusses why mandatory testing for healthcare workers is an issue, and examines the legal and ethical principles involved in mandatory testing. 相似文献
66.
67.
Marie V. St-Pierre K. Sandy Pang 《Journal of pharmacokinetics and pharmacodynamics》1995,23(3):243-266
Previous mouse liver studies with diazepam (DZ),N-desmethyldiazepam (NZ), and temazepam (TZ) confirmed that under first-order conditions, DZ formed NZ and TZ in parallel.
Oxazepam (OZ) was generatedvia NZ and not TZ despite that preformed NZ and TZ were both capable of forming OZ. In the present studies, the concentration-dependent
sequential metabolism of DZ was studied in perfused mouse livers and microsomes, with the aim of distinguishing the relative
importance of NZ and TZ as precusors of OZ. In microsomal studies, theK
ms andV
maxs, corrected for binding to microsomal proteins, were 34 μM and 3.6 nmole/min per mg and 239 μM and 18 nmole/min per mg, respectively,
forN-demthylation andC
3-hydroxylation of DZ. TheK
ms andV
maxs forN-demethylation andC
3-hydroxylation of TZ and NZ, respectively, to form OZ, were 58 μM and 2.5 nmole/min per mg and 311 μM and 2 nmole/min per
mg, respectively. The constants suggest that at low DZ concentrations, NZ formation predominates and is a major source of
OZ, whereas at higher DZ concentrations, TZ is the important source of OZ. In livers perfused with DZ at input concentrations
of 13 to 35 μM, the extraction ratio of DZ (E{DZ}) decreased from 0.83 to 0.60. NZ was the major metabolite formed although its appearance was less than proportionate
with increasing DZ input concentration. By contrast, the formation of TZ increased disporportionately with increasing DZ concentration,
whereas that for OZ decreased and paralleled the behavior of NZ. Computer simulations based on a tubular flow model and thein vitro enzymatic parameters provided a poorin vitro-organ correlation. TheE{DZ}, appearance rates of the metabolites, and the extraction ratio of formed NZ (E{NZ, DZ}) were poorly predicted; TZ was incorrectly identified as the major precursor of OZ. Simulations with optimized parameters
imporved the correlations and identified NZ as the major contributor of OZ. Saturation of DZN-demethylation at higher DZ concentrations increased the role of TZ in the formation of OZ. The poor aqueous solubility (limiting
the concentration range of substrates usedin vitro), avid tissue binding and the coupling of enzymatic reactions in liver, favoring sequential metabolism, are possible explanations
for the poorin vitro-organ correlation. This work emphasizes the complexity of the hepatic intracellular milieu for drug metabolism and the need
for additional modeling efforts to adequately describe metabolite kinetics.
This work was supported by the Medical Research Council of Canada (MA-9104). 相似文献
68.
B. J. Young R. O’Regan F. Kinsella A. Benedict-Smith M. McDermott M. Hillery L. M. T. Collum M. Hickey-Dwyer P. Mullaney J. Blake M. Hope-Ross S. Travers D. Mooney P. S. Phelan P. E. Cleary D. F. P. Larkin D. Roden P. Eustace H. N. O’Donoghue J. D. McAdoo J. G. Madden J. P. Burke M. O’Keefe R. Bowell M. O’Sullivan P. T. McLister D. J. Wilson J. Walsh 《Irish journal of medical science》1988,157(3):91-94
69.
Erica KNEIPP Richard MURRAY Kevin WARR Cherelle FITZCLARENCE Marie WEARNE Graeme MAGUIRE 《Nephrology (Carlton, Vic.)》2004,9(S4):S121-S125
SUMMARY: The incidence of end-stage renal failure (ESRF) in the Kimberley region at the top end of Western Australia far exceeds known national rates and trend analysis demonstrates a close parallel to what is occurring in the Northern Territory. Dialysis prevalence in the Kimberley has nearly tripled in the last decade and has increased at a much faster rate than the rest of Western Australia. Almost all of these people with ESRF are Aboriginal Australians living in remote communities.
In January 2004, the Western Australia Country Health Service and Kimberley Aboriginal Medical Services' Council, under the auspices of the Kimberley Aboriginal Health Planning Forum, embarked upon a review of renal disease in the Kimberley funded by the Western Australia Department of Health. The main purpose of the review was to identify the scope of the problem and make projections upon which to base programme and service development over the next 10 years.
This paper outlines the findings of the Review of Renal Disease in the Kimberley and presents, for the first time, regional data analysis and comparisons. In addition, future projections on the impact of ESRF and recommendations for improving current service delivery are discussed. Given the challenges of remoteness and individuals' desire to return home, this review recommends development of locally-based expertise capable of providing training and support to patients and their families, reinvigoration of community-based dialysis modalities, and the initiation of planning for a second satellite service in the Kimberley. 相似文献
In January 2004, the Western Australia Country Health Service and Kimberley Aboriginal Medical Services' Council, under the auspices of the Kimberley Aboriginal Health Planning Forum, embarked upon a review of renal disease in the Kimberley funded by the Western Australia Department of Health. The main purpose of the review was to identify the scope of the problem and make projections upon which to base programme and service development over the next 10 years.
This paper outlines the findings of the Review of Renal Disease in the Kimberley and presents, for the first time, regional data analysis and comparisons. In addition, future projections on the impact of ESRF and recommendations for improving current service delivery are discussed. Given the challenges of remoteness and individuals' desire to return home, this review recommends development of locally-based expertise capable of providing training and support to patients and their families, reinvigoration of community-based dialysis modalities, and the initiation of planning for a second satellite service in the Kimberley. 相似文献
70.
Manfred Kopf Suzanne Herren Michael V. Wiles Mark B. Pepys Marie H. Kosco-Vilbois 《The Journal of experimental medicine》1998,188(10):1895-1906
Mice rendered deficient for interleukin (IL) 6 by gene targeting were evaluated for their response to T cell–dependent antigens. Antigen-specific immunoglobulin (Ig)M levels were unaffected whereas all IgG isotypes showed varying degrees of alteration. Germinal center reactions occurred but remained physically smaller in comparison to those in the wild-type mice. This concurred with the observations that molecules involved in initial signaling events leading to germinal center formation were not altered (e.g., B7.2, CD40 and tumor necrosis factor R1). T cell priming was not impaired nor was a gross imbalance of T helper cell (Th) 1 versus Th2 cytokines observed. However, B7.1 molecules, absent from wild-type counterparts, were detected on germinal center B cells isolated from the deficient mice suggesting a modification of costimulatory signaling. A second alteration involved impaired de novo synthesis of C3 both in serum and germinal center cells from IL-6–deficient mice. Indeed, C3 provided an essential stimulatory signal for wild-type germinal center cells as both monoclonal antibodies that interrupted C3-CD21 interactions and sheep anti–mouse C3 antibodies caused a significant decrease in antigen-specific antibody production. In addition, germinal center cells isolated from C3–deficient mice produced a similar defect in isotype production. Low density cells with dendritic morphology were the local source of IL-6 and not the germinal center lymphocytes. Adding IL-6 in vitro to IL-6–deficient germinal center cells stimulated cell cycle progression and increased levels of antibody production. These findings reveal that the germinal center produces and uses molecules of the innate immune system, evolutionarily pirating them in order to optimally generate high affinity antibody responses. 相似文献