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101.
Genetic variation at the chromosome 9p21 risk locus promotes cardiovascular disease; however, it is unclear how or which proteins encoded at this locus contribute to disease. We have previously demonstrated that loss of one candidate gene at this locus, cyclin-dependent kinase inhibitor 2B (Cdkn2b), in mice promotes vascular SMC apoptosis and aneurysm progression. Here, we investigated the role of Cdnk2b in atherogenesis and found that in a mouse model of atherosclerosis, deletion of Cdnk2b promoted advanced development of atherosclerotic plaques composed of large necrotic cores. Furthermore, human carriers of the 9p21 risk allele had reduced expression of CDKN2B in atherosclerotic plaques, which was associated with impaired expression of calreticulin, a ligand required for activation of engulfment receptors on phagocytic cells. As a result of decreased calreticulin, CDKN2B-deficient apoptotic bodies were resistant to efferocytosis and not efficiently cleared by neighboring macrophages. These uncleared SMCs elicited a series of proatherogenic juxtacrine responses associated with increased foam cell formation and inflammatory cytokine elaboration. The addition of exogenous calreticulin reversed defects associated with loss of Cdkn2b and normalized engulfment of Cdkn2b-deficient cells. Together, these data suggest that loss of CDKN2B promotes atherosclerosis by increasing the size and complexity of the lipid-laden necrotic core through impaired efferocytosis.  相似文献   
102.
Background. It is well known that serum urea concentration is not a good predictor of mortality in hemodialysis patients. On the other hand, urea kinetic modeling has been very successfully used to measure dialysis dose by the Kt/V index, which was found to be a good predictor of mortality. Could there be a relation between urea and mortality, but in some more complex way? Methods. This is a post-hoc analysis of a single center observation study that included 242 patients and an 11-year observation period. Mortality rates between the quartiles of serum urea levels were examined by a 2 × 4 table with the χ2 test. Both univariate and multivariate survival analyses were performed with standard and segmented extended Cox regression. Results. The relation between mean urea in the baseline period and mortality showed an irregular U-shaped curve. The lowest mortality was observed in the third quartile (28 to 31 mmol/L). The relation between mean urea in the whole observation period and mortality was a J-shaped curve. The lowest mortality was in the second quartile (25–27 mmol/L). Urea was not a predictor of mortality in the whole cohort, but low-urea (binary) and high-urea (binary) were independent predictors of mortality in the corresponding models using standard or extended Cox regression. Conclusion. This study revealed a complex relationship between urea and mortality in hemodialysis patients. Patients with low or high urea levels exhibited higher mortality than those with medium levels, while both low and high levels of urea were independent predictors of all-cause mortality.  相似文献   
103.
The celiac disease is an autoimmune gastrointestinal disorder caused by gluten from wheat, rye or barley. In genetically predisposed persons, gluten induces the immune-mediated inflammation of small intestinal mucosa. Histological lesions include intraepithelial lymphocytosis, crypt hypertrophy and villous atrophy, resulting in malabsorption of micro- and macronutrients. The only treatment for celiac patients is a permanent gluten-free diet (GFD). Reactive oxygen species (ROS) and oxidative stress are strongly associated with the celiac disease. Glutathione (GSH) is a main detoxifier of endogenous and exogenous ROS in the intestine. In order to explain the role of glutathione redox cycle in celiac patients, we examined the activities of GSH-related antioxidant (AO) enzymes glutathione peroxidase (GPx) and glutathione reductase (GR), as well as the concentration of GSH in small intestinal biopsies and peripheral blood of children affected by the celiac disease. The concentration of lipid hydroperoxides (LOOH) as markers of oxidative damage was measured in the same samples. The results clearly demonstrate a significant malfunction of GSH redox cycle with a concomitant decrease in the capacity to regenerate GSH and detoxify LOOH in celiac patients, even after several years of GFD. The oral administration of GSH and a diet rich in natural antioxidants, as well as appropriate dietary supplements, could be of great benefit to the patients.  相似文献   
104.
105.
Preliminary observations of the clinical efficacy of intravenous immunoglobulin in two patients with severe corticosteroid insensitive asthma are reported. In both patients treatment with intravenous immunoglobulin resulted in clinical improvement and enabled a significant reduction in the dose of prednisolone. In one of the patients fibreoptic bronchoscopy with endobronchial biopsies was performed and peripheral blood was analysed by flow cytometry before and after treatment. Immunohistological analysis of the biopsy samples after treatment showed a decrease in the number of all cell types, especially CD3+ T cells, CD4+ T cells, and activated CD25+ T lymphocytes, which was associated with a reduction in peripheral blood T cell activation. Intravenous immunoglobulin may be a valid option for the treatment of corticosteroid insensitive asthma. To elucidate the role and mode of action of intravenous immunoglobulin further studies in larger groups of patients are needed.


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106.
107.
In this open, prospective study we assessed the prevalence of antiplatelet resistance among patients subjected to intracoronary stent implantation. In patients treated with aspirin + thienopyridine (N = 32), platelet reactivity index (PRI) significantly decreased after 2 and 7 days of dual antiplatelet treatment in comparison with the same patients on aspirin monotherapy (P<0.001, both). After 7 days of aspirin + thienopyridine treatment, insufficient antiplatelet response was observed in 28% (9/32) of the patients. High interindividual variability in response to aspirin + thienopyridine treatment emphasizes the significance of thienopyridine resistance, while the influence of statins on such a treatment should be reassessed.  相似文献   
108.
Ornithine transcarbamylase (OTC) deficiency is an X-linked, semidominant genetic disorder and the most prevalent inherited defect of the urea cycle. Molecular genetic testing of the OTC gene is critically important for clinical diagnosis, carrier testing, and prenatal diagnosis. Private mutations are observed throughout the OTC gene with more than 340 reported disease-causing mutations. High-resolution melt profiling was adapted to perform homogeneous analysis of the 10 coding regions and their intronic flanks in a 96-well plate format. The 10 DNA fragments ranging from 146 bp to 266 bp are amplified in a PCR run. A common analysis condition simultaneously generates melting profiles from all 10 fragments. To streamline analysis, deviant profiles resulting from common polymorphic variants are triaged using redundant assessment with melt profile controls in selected whole-exon assays and a separate multiplex genotyping assay. The test is further streamlined by recovering dye-stained amplification product from the melt profiling plate to serve as DNA sequencing template. Described herein is the comprehensive analysis of the OTC gene in 23 OTC-deficient patients. This system provides a rapid means to localize sequence variants, markedly reducing the need for DNA sequencing, and is applicable to other genes and disorders.  相似文献   
109.
Because of the ability to induce cell death in certain conditions, the fullerenes (C60) are potential anticancer and toxic agents. The colloidal suspension of crystalline C60 (nano-C60, nC60) is extremely toxic, but the mechanisms of its cytotoxicity are not completely understood. By combining experimental analysis and mathematical modelling, we investigate the requirements for the reactive oxygen species (ROS)-mediated cytotoxicity of different nC60 suspensions, prepared by solvent exchange method in tetrahydrofuran (THF/nC60) and ethanol (EtOH/nC60), or by extended mixing in water (aqu/nC60). With regard to their capacity to generate ROS and cause mitochondrial depolarization followed by necrotic cell death, the nC60 suspensions are ranked in the following order: THF/nC60>EtOH/nC60>aqu/nC60. Mathematical modelling of singlet oxygen (1O2) generation indicates that the 1O2-quenching power (THF/nC60nC60nC60) of the solvent intercalated in the fullerene crystals determines their ability to produce ROS and cause cell damage. These data could have important implications for toxicology and biomedical application of colloidal fullerenes.  相似文献   
110.
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