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11.
Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens 总被引:31,自引:0,他引:31 下载免费PDF全文
Nathan C Shiloh MU 《Proceedings of the National Academy of Sciences of the United States of America》2000,97(16):8841-8848
This review summarizes recent evidence from knock-out mice on the role of reactive oxygen intermediates and reactive nitrogen intermediates (RNI) in mammalian immunity. Reflections on redundancy in immunity help explain an apparent paradox: the phagocyte oxidase and inducible nitric oxide synthase are each nonredundant, and yet also mutually redundant, in host defense. In combination, the contribution of these two enzymes appears to be greater than previously appreciated. The remainder of this review focuses on a relatively new field, the basis of microbial resistance to RNI. Experimental tuberculosis provides an important example of an extended, dynamic balance between host and pathogen in which RNI play a major role. In diseases such as tuberculosis, a molecular understanding of host-pathogen interactions requires characterization of the defenses used by microbes against RNI, analogous to our understanding of defenses against reactive oxygen intermediates. Genetic and biochemical approaches have identified candidates for RNI-resistance genes in Mycobacterium tuberculosis and other pathogens. 相似文献
12.
The human genetic disorder ataxia-telangiectasia (A-T) is due to lack of functional ATM, a protein kinase which is involved in cellular responses to DNA double strand breaks (DSBs) and possibly other oxidative stresses, as well as in regulation of several fundamental cellular functions. Studies regarding responses in A-T cells to the induction of DSBs utilize ionizing radiation or radiomimetic chemicals, such as neocarzinostatin (NCS), which induce DNA DSBs. This critical DNA lesion activates many defense systems, such as the cell cycle checkpoints. The cell cycle is also regulated through a timed and coordinated degradation of regulatory proteins via the ubiquitin pathway. Our recent studies indicate that the ubiquitin pathway is influenced by the cellular redox status and that it is the major cellular pathway for removal of oxidized proteins. Accordingly, we hypothesized that the absence of a functional ATM protein might involve perturbations to the ubiquitin pathway as well. We show here that upon treatment with NCS, there was a transient 50-70% increase in endogenous ubiquitin conjugates in A-T and wt lymphoblastoid cells. Ubiquitin conjugation capabilities per se and levels of substrates for conjugation were also similarly enhanced in wt and A-T cells upon NCS treatment. We also compared the ubiquitination response in A-T and wt cells using H(2)O(2) as the stress, in view of preexisting evidence of the effects of H(2)O(2) on ubiquitination capabilities in other types of cells. As with NCS treatment, there was an approximately 45% increase in endogenous ubiquitin conjugates by 2-4 h after exposure to H(2)O(2). Both cell types showed a rapid 50-150% increase in de novo formed 125I-ubiquitin conjugates. As compared with wt cells, unexposed A-T cells had higher endogenous levels of conjugates and enhanced conjugation capability. However, A-T cells mounted a more muted ubiquitination response to the stress. The enhanced ubiquitin conjugation in unstressed A-T cells and attenuated ability of these cells to respond to stress are consistent with the A-T cells being under oxidative stress and with their having an 'aged' phenotype. The indication that ubiquitin conjugate levels and ubiquitin conjugation capabilities are enhanced upon oxidative stress without significant changes in GSSG/GSH ratios indicates that assays of ubiquitination provide a sensitive measure of cellular stress. The data also add support to the impression that potentiated ubiquitination response to mild oxidative stress is a generalizable phenomenon. 相似文献
13.
The therapeutic approach to patients with autoimmune disorders is in the midst of a dramatic change. Monoclonal antibody technology has allowed us to dissect and now manipulate the human immune system with greater precision. It is now widely recognized that B lymphocytes play a role in the pathogenesis of many autoimmune diseases, though the extent and contribution is a matter of debate and active investigation. There is emerging data to suggest that both antibody-dependent and independent mechanisms contribute to disease pathogenesis. However, given the heterogeneous nature of autoimmune diseases, and the varied responses to B lymphocyte reduction, the role of B lymphocytes is likely disease-specific. The two clinical trials discussed in this review demonstrate remarkable consistency in the ability of B cell reduction to ameliorate the clinical manifestations of rheumatoid arthritis with minimal toxicity. B lymphocyte targeted approaches to autoimmune disease in general, and RA specifically, will not only provide an effective and potentially less toxic alternative treatment option, but also allow for a better understanding of the pathogenesis of these complex and morbid diseases. 相似文献
14.
15.
Hospitalized patients' views on in-ward psychological counseling 总被引:2,自引:0,他引:2
This qualitative study explores the feelings and beliefs of patients hospitalized in an orthopedic rehabilitation ward for receiving psychological help in that setting. Semi-structured interviews with 10 hospitalized patients were audiotaped, transcribed verbatim, and analyzed using interpretative phenomenological analysis (IPA). Themes of an approach-avoidance conflict towards receiving psychological help were identified, some of them unique to the hospital setting. Approach tendencies were associated with high psychological distress, awareness of free accessibility, and beliefs in body-mind relationship. Avoidance tendencies were associated with fears of psychotherapy, misconceptions, and perceived threats to one's independence and self-esteem. The implications of these findings for the provision of psychological counseling in hospital settings are discussed. 相似文献
16.
Shiloh R Bodinger L Katz N Sigler M Stryjer R Hermesh H Munitz H Weizman A 《Neuropsychobiology》2003,48(1):1-4
Antipsychotic drugs (APDs) can decrease core body temperature in schizophrenia patients. Core temperature may correlate with corneal temperature and thus, we hypothesized that neuroleptic-treated schizophrenia patients would display lower corneal temperature compared with drug-free patients. Corneal temperature of 12 typical APD-treated and 9 drug-free male schizophrenia patients was assessed using a FLIR thermal imaging camera. The APD-treated patients exhibited substantially and significantly lower corneal temperature compared with the drug-free patients (31.57 +/- 0.98 degrees C vs. 34.55 +/- 1.65 degrees C; p < 0.0001). Our results suggest that APDs may decrease corneal/core temperature in schizophrenia patients. The relevance of this finding to the pathophysiology of schizophrenia or to the antipsychotic effect of neuroleptics merit further investigation. 相似文献
17.
Spring K Cross S Li C Watters D Ben-Senior L Waring P Ahangari F Lu SL Chen P Misko I Paterson C Kay G Smorodinsky NI Shiloh Y Lavin MF 《Cancer research》2001,61(11):4561-4568
ATM, the gene mutated in the human immunodeficiency disorder ataxia-telangiectasia (A-T), plays a central role in recognizing ionizing radiation damage in DNA and in controlling several cell cycle checkpoints. We describe here a murine model in which a nine-nucleotide in-frame deletion has been introduced into the Atm gene by homologous recombination followed by removal of the selectable marker cassette by Cre-loxP site-specific, recombination-mediated excision. This mouse, Atm-DeltaSRI, was designed as a model of one of the most common deletion mutations (7636del9) found in A-T patients. The murine Atm deletion results in the loss of three amino acid residues (SRI; 2556-2558) but produces near full-length detectable Atm protein that lacks protein kinase activity. Radiosensitivity was observed in Atm-DeltaSRI mice, whereas the immunological profile of these mice showed greater heterogeneity of T-cell subsets than observed in Atm(-/-) mice. The life span of Atm-DeltaSRI mice was significantly longer than that of Atm(-/-) mice when maintained under nonspecific pathogen-free conditions. This can be accounted for by a lower incidence of thymic lymphomas in Atm-DeltaSRI mice up to 40 weeks, after which time the animals died of other causes. The thymic lymphomas in Atm-DeltaSRI mice were characterized by extensive apoptosis, which appears to be attributable to an increased number of cells expressing Fas ligand. A variety of other tumors including B-cell lymphomas, sarcomas, and carcinomas not seen in Atm(-/-) mice were observed in older Atm-DeltaSRI animals. Thus, expression of mutant protein in Atm-DeltaSRI knock-in mice gives rise to a discernibly different phenotype to Atm(-/-) mice, which may account for the heterogeneity seen in A-T patients with different mutations. 相似文献
18.
ATM: a mediator of multiple responses to genotoxic stress 总被引:20,自引:0,他引:20
The ATM protein kinase is the product of the gene responsible for the pleiotropic recessive disorder ataxia-telangiectasia. ATM-deficient cells show enhanced sensitivity and greatly reduced responses to genotoxic agents that generate DNA double strand breaks (DSBs), such as ionizing radiation and radiomimetic chemicals, but exhibit normal responses to DNA adducts and base modifications induced by other agents. Therefore, DSBs are most likely the predominant signal for the activation of ATM-mediated pathways. Identification of the ATM gene triggered extensive research aimed at elucidating the numerous functions of its large multifaceted protein product. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in the nucleus where it plays a central role in the very early stages of damage detection and serves as a master controller of cellular responses to DSBs. By activating key regulators of multiple signal transduction pathways, ATM mediates the efficient induction of a signaling network responsible for repair of the damage, and for cellular recovery and survival. 相似文献
19.
M. Dirnfeld H. Shiloh D. Bider E. Harari M. Koifman S. Lahav-Baratz 《Gynecological endocrinology》2013,29(5):397-403
A prospective, randomized study was conducted to evaluate the thickness of zona pellucida (ZP) after brief or standard exposure of human oocytes to spermatozoa, and to determine the correlation between ZP thickness, fertilization rate and embryo quality. The mean ZP thickness 48?h after insemination was found to be significantly less in fertilized oocytes than in non-fertilized oocytes in all treated groups (13.72?±?3.0?µm and 15.08?±?2.5?µm, respectively; p?<?0.007). Zona pellucida thickness correlated positively with embryo quality. Brief exposure of gametes was found to influence ZP thickness. The ZP was significantly thinner after brief and intracytoplasmic sperm injection (ICSI) exposure of oocytes to spermatozoa than after standard in vitro fertilization (IVF). The mean ZP thickness 24 and 48?h after fertilization was significantly greater in standard IVF (16.43?±?2.8?µm and 15.22?±?2.7?µm, respectively) than in either the brief exposure or ICSI groups (12.78?±?2.4?µm and 13.01?±?3.5?µm vs. 13.46?±?2.2?µm and 13.16?±?2.4?µm; p?<?0.0001). 相似文献
20.
Children treated with large doses of corticosteroids were found to develop hepatomegaly within a few days. No relationship could be established between the condition for which steroids were given and the liver enlargement. Liver biopsy was thought to be indicated, and thus was performed in three children because of diagnostic uncertainty. The light and electron microscopic examinations revealed normal liver architecture, without edema, sinusoid engorgement, or inflammatory changes. The hepatocytes were distended by increased amounts of glycogen. In a pattern reminiscent of some glycogen storage diseases, mitochondria and other cytosol components were displaced toward the cell membrane or around the nucleus, which occasionally contained glycogen. Moderate sinusoidal compression, interhepatocytic free glycogen particles, and mild increase in lipid droplets were also found. It is concluded that the hepatomegaly noted in patients given short-term, high-dosage steroid therapy is due to excessive glycogen accumulation within parenchymal cells. This finding is in accordance with observations in animals, as well as with biochemical studies demonstrating hepatocytic glycogen deposition after steroid therapy. Being benign and reversible, early hepatomegaly following administration of high-dose corticosteroids should not influence the initial therapeutic plan required by the basic disease. 相似文献