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51.
For most of the 20th century, most drugs labeled by the United States Food and Drug Administration (USFDA) have not been adequately studied in the pediatric population. This lack of data has necessitated the continued dependence of practitioners on sub-optimal prescribing data placing pediatric patients at great risk of serious therapeutic misadventures. Recently, the USFDA has enacted and begun to enforce the Final Rule of 1997 which became effective on 1 April 1999. This rule is the culmination of the persistent efforts of numerous professional organizations, clinicians, academicians, the USFDA and others, to ensure the ready availability of appropriate data for medications intended for or that will be used in children. Unlike the 1994 Rule which voluntarily required pharmaceutical manufacturers to submit pediatric data, the Final Rule mandates submission of such data and, most importantly, empowers the USFDA to afford incentives and penalties for non-compliance including possible removal of already marketed products. This overview addresses many of the important components which must be included in the performance of a comprehensive clinical pharmacologic evaluation serving as the foundation for optimal dosing across the broad age range encompassing pediatric practice. Furthermore, the possible risk and/or benefits of the study must be reasonably defined prior to undertaking the study and clearly shared with the patient's caregivers. Consent should always be obtained from the caregiver and, when appropriate, assent obtained from the underage child. To facilitate such clinical investigations and to foster collaborative efforts with innovators and clinical research programs, the National Institutes of Health through the National Institute of Child Health and Human Development of the NIH established a network of Pediatric Pharmacology Research Units. These units have worked closely together and with other pediatric research centers to facilitate USFDA labeling of a number of commonly used medications. All of these very positive efforts highlight the many challenges that remain for the pediatric investigator and practitioner while underscoring the very positive environment in support of these efforts. 相似文献
52.
Although exposure of LLC-PK1 epithelial cell sheets to phorbol esters (TPA)
causes a near immediate and total decrease of transepithelial electrical
resistance (TER), continuation of exposure for 3 to 4 days results in a
tachyphylactic response as TER begins to return to control levels. Recovery
of TER is maximal by 5 to 6 days, but reaches only 70 to 80% of control
level. A reciprocal change in the transepithelial flux of D-mannitol
indicates that the TER decrease is indicative of an increase in tight
junction permeability. Exposure of cell sheets to TPA for several days also
results in the appearance of multilayered polyp- like foci (PLFs) across
the otherwise one cell layer thick cell sheets. The pattern of penetration
of the electron dense dye, ruthenium red, from the apical surface, across
the tight junction and into the lateral intercellular space indicates that
the tight junctions of the cell sheet become uniformly leaky after acute
exposure to TPA. However, when exposure is continued for several days, only
the junctions of cells in the PLFs manifest leakiness. The decrease in TER
following acute TPA exposure correlates with the translocation of protein
kinase C-alpha (PKC alpha) into a membrane-associated compartment. With
exposure of several days, only a trace of PKC alpha is visible by Western
immunoblot, and this is in the membrane-associated compartment.
Immunofluorescent microscopy indicates that the trace of PKC alpha seen in
the Western immunoblots is ascribable distinctly to cells of the PLFs.
Monolayer areas between PLFs show no discernible immunofluorescent signal.
The data therefore indicate that tight junction barrier function may be
restored in certain areas by the down regulation of PKC alpha from the
membrane-associated compartment. Failure to down regulate may result in the
paracellular leakiness and abnormal cell architecture of the PLFs. Possible
implications of this model for in vivo epithelial tumor promotion are
discussed.
相似文献
53.
Jane C. M. Bremner 《Cancer metastasis reviews》1993,12(2):177-193
Summary The nitroimidazole, RSU1069, has been shown to have a very high differential toxicity towards hypoxic cells compared to oxic cells both inin vitro andin vivo experimental conditions. However, in the clinic it was found to cause severe emesis and had to be withdrawn. After an extensive drug development programme an analogue of RSU1069, RB6145, which acts as a pro-drug for RSU1069, was found to be the most suitable candidate for further investigation. Inin vivo studies with murine tumour models, when RB6145 was used in combination with X-rays it was shown to produce a similar level of toxicity towards hypoxic cells as that observed for RSU1069. Its activity was the same whether it was administered interperitoneally or orally and the same level of anti-tumour effect was observed if the drug was given before or after X-rays. RB6145 is better tolerated systemically in mice than RSU1069 and canine studies have shown that it is less emetic than the parent drug.Bioreductive drugs can also be used in combination with treatments that preferentially increase tumour hypoxia. Photodynamic therapy (PDT) causes extensive vascular damage in tumours. If either RSU1069 or RB6145 are administered during PDT, very large increases in the growth delay induced by PDT alone are seen for the RIF-1 murine tumour.RB6145 has been accepted for clinical toxicity trials with the prospect of using it in combination with X-rays. In the future it may also be of clinical use with treatments such as PDT. 相似文献
54.
The mouse Ha-ras gene has previously been mapped to the central region of chromosome 7, 31 cM from the centromere, using an interspecific Mus musculus/Mus spretus backcross (Saunders AM, Seldin MF, Genomics 8:525–535, 1990). However, analysis of mitotic recombinations in mouse skin tumors from intraspecific F1 hybrid mice suggested a more distal location for the Ha-ras gene on chromosome 7 (Bremner R, Balmain A, Cell 61:407–417, 1990). In the study reported here, we demonstrated, by analysis of Ha-ras gene mutations in skin tumors from interspecific M. spretus/M. musculus F1 hybrids, the existence only in M. spretus of a pseudogene or other Ha-ras—related sequence that is probably the sequence originally mapped by Saunders and Seldin. The functional Ha-ras gene maps to the distal region of chromosome 7, and it is this sequence that acquires mutations in chemically induced tumors. 相似文献
55.
P Greally MJ Hussein AJ Cook AP Sampson PJ Piper JF Price 《Archives of disease in childhood》1993,68(3):389-392
It is postulated that a vigorous host inflammatory response in the cystic fibrosis lung contributes to lung injury. Tumour necrosis factor-alpha (TNF-alpha) may play a part in that process and in the generation of leukotrienes. Therefore, the relationships between sputum TNF-alpha, leukotriene concentration, and lung function abnormalities in 16 children with cystic fibrosis were investigated. Each subject provided sputum samples and performed spirometry. TNF-alpha was measured by enzyme linked immunosorbent assay; individual leukotrienes were separated using high performance liquid chromatography and quantified by radioimmunoassay. The geometric mean concentration of TNF-alpha was 129.7 pg/ml and 95% confidence interval 48.2 to 348.3. Mean (SEM) leukotriene B4 (LTB4) was 97.8 (22.9) pmol/g and total cysteinyl leukotrienes were 60.9 (14.8) pmol/g. Mean (SD) forced expiratory volume in one second (FEV1) of the group was 53 (15)% of predicted and forced vital capacity (FVC) was 65 (14)% of predicted. There was a significant positive correlation between TNF-alpha and both LTB4 and the total cysteinyl leukotriene sputum content. An inverse relationship existed between TNF-alpha and FEV1 and FVC. Moreover, a negative correlation was observed between sputum LTB4 and FEV1 and FVC. These results suggest that TNF-alpha and the leukotrienes may participate in the airways inflammation and airflow obstruction observed in cystic fibrosis subjects and support the hypothesis that TNF-alpha upregulates the 5-lipoxygenase pathway in vivo. 相似文献
56.
NRM Buist AP Prince KL Huntington JM Tuerck DD Waggoner 《Acta paediatrica (Oslo, Norway : 1992)》1994,83(S407):75-77
A new amino acid mixture for incorporation into medical foods for the treatment of hyperphenylalaninemia has been tested in a regular clinic. The mix is designed to be as unobtrusive as possible, consistent with good nutrition. After more than 1 year of trial as a beverage, we have shown that it is safe and well tolerated but that plasma phenylalanine is no better controlled than with some other products. The mix can be incorporated into a large number of different foods without affecting the taste. Occult monitoring of the quantity of medical foods purchased compared with the amounts reported to be consumed in diet histories provides an excellent way to monitor dietary compliance. 相似文献
57.
58.
59.
Myospherulosis: a previously unreported disease? 总被引:4,自引:0,他引:4
60.