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91.
Gang Luo C Edwin Garner Hao Xiong Hanbo Hu Lauren E Richards Kim L R Brouwer Jingwu Duan Carl P Decicco Thomas Maduskuie Helen Shen Frank W Lee Liang-Shang Gan 《Drug metabolism and disposition》2007,35(6):835-840
DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] is a potent human tumor necrosis factor alpha-converting enzyme inhibitor with potential therapeutic implications for rheumatoid arthritis. Methotrexate (MTX), a drug for the treatment of rheumatoid arthritis, is eliminated primarily unchanged via renal and biliary excretion in humans as well as in rats and dogs. The objective of the present study was to investigate the potential effect of DPC 333 on the disposition of MTX. In dogs, DPC 333 administered orally at 1.7 mg/kg 15 min before the intravenous administration of [14C]MTX (0.5 mg/kg) did not alter the plasma concentration-time profile of MTX; however, the total amount of radioactivity excreted in urine increased from 58.7% to 92.2% of the dose, and the renal clearance increased from 1.8 ml/min/kg to 2.9 ml/min/kg, suggesting a decrease in MTX disposition via biliary excretion. The biliary excretion of MTX was investigated in isolated perfused livers prepared from wild-type and TR(-) [multidrug resistance-associated protein 2 (Mrp2)-deficient] Wistar rats in the absence and presence of DPC 333. Mrp2-mediated biliary excretion of MTX was confirmed with 95.8% and 5.1% of MTX recovered in the bile of wild-type and TR(-) Wistar rats, respectively. DPC 333 at an initial perfusate concentration of 50 microM completely blocked the biliary excretion of MTX, but not the clearance from perfusate, in both wild-type and TR(-) rats. These results suggest that the enhanced renal elimination of MTX may be due to the potent inhibition of biliary excretion and active renal reabsorption by DPC 333 and/or its metabolites. 相似文献
92.
Eye movements of subjects with visual field defects due to ocular pathology were monitored while performing a dot counting task and a visual search task. Subjects with peripheral field defects required more fixations, longer search times, made more errors, and had shorter fixation durations than control subjects. Subjects with central field defects performed less well than control subjects although no specific impairment could be pinpointed. In both groups a monotonous relationship was observed between the visual field impairment and eye movement parameters. The use of eye movement parameters to predict viewing behavior in a complex task (e.g. driving) was limited. 相似文献
93.
Brouwer KC Ndhlovu PD Wagatsuma Y Munatsi A Shiff CJ 《The American journal of tropical medicine and hygiene》2003,68(4):456-462
Disease outcome in persons infected with Schistosoma haematobium varies dramatically, ranging from mild symptoms to severe damage of the kidneys and/or bladder. We used ultrasonography to characterize the extent of urinary tract pathology of infected children in Zimbabwe, and random genetic markers to examine the relationship between genetic diversity of S. haematobium and clinical outcome. One hundred thirty-three parasite isolates from 12 students with mild lesions and 13 with severe lesions were compared. Using four randomly amplified polymorphic DNA (RAPD) markers, we scored parasite allelic frequencies at 53 loci. Although parasite heterogeneity did not differ, allelic frequencies at eight loci differed significantly between the mild and severe groups. Parasite isolates were analyzed further using a modified cluster analysis that segregated the population into 13 clusters of associated genotypes. Three clusters were significantly over-represented in children with severe lesions. Our findings, although preliminary, suggest that parasite genetic associations may be important in clinical outcome. 相似文献
94.
95.
Geelen A Brouwer IA Zock PL Kors JA Swenne CA Katan MB Schouten EG 《The Journal of nutrition》2002,132(10):3051-3054
(n-3) Fatty acids may reduce the risk of sudden death by preventing life-threatening cardiac arrhythmia. A standard electrocardiogram (ECG) may be used to detect clues as to the mechanism by which (n-3) fatty acids affect the electrophysiology of the heart. An earlier study showed that (n-3) fatty acids decreased the duration of the heart-rate corrected QT interval (QTc) in dogs. However, effects of (n-3) fatty acids on the standard ECG of humans have not been reported. Therefore, we investigated the effect of (n-3) fatty acids on QTc, QRS duration, apex-to-end-T duration, T-loop morphology and spatial QRS-T angle in apparently healthy men and women aged 50 to 70 y. Subjects (n = 42/group) received either capsules providing 1.5 g (n-3) fatty acids daily or placebo for 12 wk. ECG were recorded before and after intervention. None of the ECG characteristics were affected by (n-3) fatty acids. The QTc decreased by 0.8 ms or 0.2% (95% confidence interval, -6.1 to 4.4 ms) in subjects that consumed (n-3) fatty acids compared with the placebo group. These results do not support the hypothesis that (n-3) fatty acids prevent arrhythmia through electrophysiologic effects on heart cell membranes. However, an effect on the ECG in more susceptible populations can not be excluded. 相似文献
96.
A systematic consideration of the cost-effectiveness in decisions concerning the financing and implementation of healthcare technologies would contribute to the efficiency of the Dutch healthcare system. This consideration applies to the initial decision to finance a project, the periodic testing of this on the basis of practice data and the policy to promote a cost-effective approach in daily practice (via practice guidelines). Bearing in mind that the government has decided to allocate few additional resources to healthcare, it should undertake measures to ensure the systematic use of such information in these steps. The National Institute for Clinical Excellence (NICE) in the United Kingdom can serve as an example, where broadly supported guidelines are drawn up with systematic attention for the cost-effectiveness and the implications for healthcare. Within this context the question arises as to whether a Dutch variant of NICE is needed. 相似文献
97.
Residential radon seems to represent a major health hazard. The studies, which investigate the pulmonary risk of cancer caused by radon, are of different nature and their results are divergent. Thus, there persist scientific uncertainties concerning the real size of this risk. The application of the precautionary principle is based on an analysis of these uncertainties. Studies on miners, studies concerning residential radon (at individual and ecological level), as well as experimental data allow for the organisation of the uncertainty of each one of these specific approaches taking into account their proper limitations. The first risk that is linked to radon is the risk of pulmonary cancer. Miner occupational exposure studies appear compatible with the results of case-control studies concerning residential radon. However, the case-control studies, where the risk appears more present, are contradicted by ecological studies, often not very convincing about the existence of a risk. The case-control studies have an intrinsic advantage over the ecological studies because they limit the classification errors by the individualization of the relation-exposure effect. In addition, the experimental data are not in contradiction with the existence of effects for very small exposures. Consequently, the inherent scientific uncertainties of the totality of these data, can be classified and permit the application of the precautionary principle in a better proportioned way. The utilisation of the precautionary principle implies the necessity to limit, as far as possible, the exposure to residential radon. Precautionary principle is based on the debated hypothesis of no threshold linear relation between radon exposition and health consequences. This relation has been established on professional and residential exposures. The implementation of this epidemiological model shows the "residential radon" risk as the second cause of pulmonary cancer and responsible of about 10% of these specific cancers. 相似文献
98.
Cell-biologic and functional analyses of five new Aquaporin-2 missense mutations that cause recessive nephrogenic diabetes insipidus 总被引:3,自引:0,他引:3
Marr N Bichet DG Hoefs S Savelkoul PJ Konings IB De Mattia F Graat MP Arthus MF Lonergan M Fujiwara TM Knoers NV Landau D Balfe WJ Oksche A Rosenthal W Müller D Van Os CH Deen PM 《Journal of the American Society of Nephrology : JASN》2002,13(9):2267-2277
Mutations in the Aquaporin-2 gene, which encodes a renal water channel, have been shown to cause autosomal nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. Most AQP2 missense mutants in recessive NDI are retained in the endoplasmic reticulum (ER), but AQP2-T125M and AQP2-G175R were reported to be nonfunctional channels unimpaired in their routing to the plasma membrane. In five families, seven novel AQP2 gene mutations were identified and their cell-biologic basis for causing recessive NDI was analyzed. The patients in four families were homozygous for mutations, encoding AQP2-L28P, AQP2-A47V, AQP2-V71M, or AQP2-P185A. Expression in oocytes revealed that all these mutants, and also AQP2-T125M and AQP2-G175R, conferred a reduced water permeability compared with wt-AQP2, which was due to ER retardation. The patient in the fifth family had a G>A nucleotide substitution in the splice donor site of one allele that results in an out-of-frame protein. The other allele has a nucleotide deletion (c652delC) and a missense mutation (V194I). The routing and function of AQP2-V194I in oocytes was not different from wt-AQP2; it was therefore concluded that c652delC, which leads to an out-of-frame protein, is the NDI-causing mutation of the second allele. This study indicates that misfolding and ER retention is the main, and possibly only, cell-biologic basis for recessive NDI caused by missense AQP2 proteins. In addition, the reduced single channel water permeability of AQP2-A47V (40%) and AQP2-T125M (25%) might become of therapeutic value when chemical chaperones can be found that restore their routing to the plasma membrane. 相似文献
99.
W. B. F. Brouwer N. J. A. van Exel B. van Gorp W. K. Redekop 《Quality of life research》2006,15(6):1005-1021
The societal perspective in economic evaluations dictates that costs and effects of informal care are included in the analyses.
However, this incorporation depends on practically applicable, reliable and valid methods to register the impact of informal
care. This paper presents the conceptualisation and a first test of the CarerQol instrument, aimed at measuring care-related
quality of life in informal caregivers. The instrument combines the information density of a burden instrument (encompassing
seven important burden dimensions) with a valuation component (a VAS scale for happiness). The instrument was tested in a
Dutch sample of heterogeneous caregivers (n = 175) approached through regional caregiver support centres. This first test describes the feasibility as well as convergent
and clinical validity of the CarerQol instrument. The seven burden dimensions related well with differences in VAS scores.
In all instances, the average CarerQol-VAS scores decreased as the severity of problems increased. Multivariate analyses showed
that the seven burden dimensions explained 37–43% of the variation in CarerQol-VAS scores, depending on the model used. The
CarerQol seems a promising new instrument to register the impact of informal caregivers in economic evaluations. 相似文献
100.
Maciej J. Zamek-Gliszczynski Keith A. Hoffmaster Ken-ichi Nezasa Melanie N. Tallman Kim L.R. Brouwer 《European journal of pharmaceutical sciences》2006,27(5):447-486
The liver is the primary site of drug metabolism in the body. Typically, metabolic conversion of a drug results in inactivation, detoxification, and enhanced likelihood for excretion in urine or feces. Sulfation, glucuronidation, and glutathione conjugation represent the three most prevalent classes of phase II metabolism, which may occur directly on the parent compounds that contain appropriate structural motifs, or, as is usually the case, on functional groups added or exposed by phase I oxidation. These three conjugation reactions increase the molecular weight and water solubility of the compound, in addition to adding a negative charge to the molecule. As a result of these changes in the physicochemical properties, phase II conjugates tend to have very poor membrane permeability, and necessitate carrier-mediated transport for biliary or hepatic basolateral excretion into sinusoidal blood for eventual excretion into urine. This review summarizes sulfation, glucuronidation, and glutathione conjugation reactions, as well as recent progress in elucidating the hepatic transport mechanisms responsible for the excretion of these conjugates from the liver. The discussion focuses on alterations of metabolism and transport by chemical modulators, and disease states, as well as pharmacodynamic and toxicological implications of hepatic metabolism and/or transport modulation for certain active phase II conjugates. A brief discussion of issues that must be considered in the design and interpretation of phase II metabolite transport studies follows. 相似文献