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41.
Iron-overload diseases frequently develop hepatocellular carcinoma. The
genotoxic mechanism whereby iron is involved in hepatocarcinogenesis might
involve an oxidative process via the intermediate production of reactive
oxygen species. This was presently investigated by examining kinetics of
formation and repair of DNA base lesions in primary rat hepatocyte cultures
supplemented with the iron chelate, ferric nitrilotriacetate Fe-NTA (10 and
100 microM). Seven DNA base oxidation products have been identified in DNA
extracts by gas chromatography- mass spectrometry, which showed a
predominance of oxidized-purines (8- oxo-guanine, xanthine, fapy-adenine,
2-oxo-adenine) above oxidized pyrimidines (5-OHMe-uracil, 5-OH-uracil,
5-OH-cytosine) in control cultures. All these DNA oxidation products
revealed a significant dose- dependent increase at 4 to 48 h after Fe-NTA
supplementation, among which fapy-adenine showed the highest increase and
5-OH-cytosine was the least prominent. Involvement of iron in this
oxidative process was established by a correlation between extent in DNA
oxidation and intracellular level of toxic low molecular weight iron. DNA
excision- repair activity was estimated by release of DNA oxidation
products in culture medium. All the seven DNA oxidation products were
detected in the medium of control cultures and showed basal repair
activity. This DNA repair activity was increased in a time- and
dose-dependent fashion with Fe-NTA. Oxidized-pyrimidines, among which was
5-OHMe-Uracil, were preferentially repaired, which explains the low levels
detected in oxidized DNA. Since oxidized bases substantially differed from
one another in terms of excision rates from cellular DNA, specific
excision- repair enzymes might be involved. Our findings, however,
demonstrate that even though DNA repair pathways were activated in
iron-loaded hepatocyte cultures, these processes were not stimulated enough
to prevent an accumulation of highly mutagenic DNA oxidative products in
genomic DNA. The resulting genotoxic effect of Fe-NTA might be relevant in
understanding the hepatocarcinogenic evolution of iron-overload diseases.
相似文献
42.
Shurkalin BK Kriger AG Gorskiĭ VA Chugunov AO Rzhebaev KE Cherevatenko AM Glushkov PS Shogenov AA 《Khirurgiia》2000,(2):33-37
1310 patients with various forms of peritonitis were operated during 1989-1998. The tactics of the treatment was determined depending on bacterial contamination of the abdominal cavity. In abscesses of the abdominal cavity with massive bacterial contamination (6-7 CFU/g) drainage procedure was used. Mortality rate made up 4.8%. In local extended and diffuse peritonitis with a slight bacterial contamination of the abdominal cavity (3-5 CFU/g) and in absence of fibrinous deposition fixed on peritoneum, the drainage of the abdominal cavity was not used, and laparoscopy was performed in postoperative period for the control of the course of infectious process. Mortality rate was 0.6%. In extended peritonitis with massive bacterial contamination (6-8 CFU/g) the method of repeated explorations and sanitations of the abdominal cavity was used, mortality rate being 17.8%. The overall lethality made up 7.8%. Postoperative wound infection occurred in 6.7%, intraabdominal infection as abscesses or progressing peritonitis--in 2.1% of cases. 相似文献
43.
Vitamin A and thyroid hormone status have been shown previously to alter the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. In the present study, we have examined the effects of a vitamin A-excess and a vitamin A-deficient diet on thyroid hormone levels, on selected drug-metabolizing enzymes in liver microsomes, and on their inducibility by TCDD in male Sprague-Dawley rats. Except for a slight increase in serum T3 levels, none of these end points was affected by feeding rats the vitamin A-deficient diet. In contrast, excess dietary vitamin A caused a decrease in serum thyroxine (T4) and triiodothyronine (T3) levels, although the levels of T3 remained in the euthyroid range (60-80 ng/dl). The concentration of liver microsomal cytochromes P-450 and b5 and the basal activity of benzo[a]pyrene hydroxylase and 7-ethoxyresorufin O-de-ethylase were unaffected by excess dietary vitamin A. This result is consistent with our previous observation that the basal activity of these enzymes is dependent more on T3 than on T4 levels. Vitamin A excess markedly suppressed the activity of liver microsomal UDP-glucuronosyl transferase toward 1-naphthol. However, no such enzyme suppression was observed in thyroidectomized rats. This suggests that the suppressive effect of vitamin A on UDP-glucuronosyl transferase activity may be dependent on T3. Neither vitamin A nor thyroid status had any major effect on the inducibility of UDP-glucuronosyl transferase and cytochrome P-450-dependent enzyme activities by TCDD. However, vitamin A and TCDD had a nearly additive effect on suppression of serum T4. It is concluded that liver microsomal enzyme induction is not associated with the modulatory effect of vitamin A and thyroid hormones on the toxicity of TCDD. 相似文献
44.
Determination of malondialdehyde-induced DNA damage in human tissues using an immunoslot blot assay 总被引:3,自引:4,他引:3
Leuratti C; Singh R; Lagneau C; Farmer PB; Plastaras JP; Marnett LJ; Shuker DE 《Carcinogenesis》1998,19(11):1919-1924
Malondialdehyde (MDA) is a product of lipid peroxidation and prostaglandin
biosynthesis. It is mutagenic and carcinogenic and the major adduct formed
by reaction with DNA, a highly fluorescent pyrimidopurinone (M1-dG), has
been detected in healthy human liver and leukocyte DNA. Analytical methods
used so far for the detection of M1- dG have not been applied to a large
number of individuals or variety of samples. Often, only a few microg of
DNA from human tissues are available for analysis and a very sensitive
assay is needed in order to detect background levels of M1-dG in very small
amounts of DNA. In this paper, the development of an immunoslot blot (ISB)
assay for the measurement of MI-dG in 1 microg of DNA is described. The
limit of detection of the assay is 2.5 adducts per 10(8) bases. A series of
human samples were analysed and levels of 5.6-9.5 (n = 8) and 3.1-64.3 (n =
42) of M1-dG per 10(8) normal bases were detected in white blood cell and
gastric biopsy DNA, respectively. Results on four human samples were
compared with those obtained using an HPLC/32P-post- labelling (HPLC/PPL)
method previously developed and indicated a high correlation between M1-dG
levels measured by the two assays. The advantages of ISB over other assays
including HPLC/PPL, such as the possibility of analysing 1 microg
DNA/sample and the fact that it is less time-consuming and laborious, means
that it can be more easily used for routine analysis of a large number of
samples in biomonitoring studies.
相似文献
45.
肿瘤治疗存在的问题及中西医结合的研究重点 总被引:17,自引:3,他引:17
目前的肿瘤治疗主要存在以下几个问题:(1)肿瘤的过度治疗普遍存在;(2)急功近利而缺乏长远规划;(3)综合治疗缺乏合理的内涵;(4)缺少有效的个体化治疗方案;(5)对中医药的优势认识不足、发挥不够。中西医结合在肿瘤防治中大有可为,应重点围绕以下几个方面开展研究工作:(1)加强中医对恶性肿瘤基础知识的认识和研究;(2)加强中西医结合治疗肿瘤合理化、规范化方案的研究;(3)加强中西医结合治疗恶性肿瘤疗效标准的研究;(4)加强中西医结合防治肿瘤术后复发、转移的研究。 相似文献
46.
Eimear C Morrissey Sean F Dinneen Michelle Lowry Eelco JP de Koning Marleen Kunneman 《Journal of diabetes investigation.》2022,13(8):1294
Young adults living with type 1 diabetes often struggle to achieve what clinicians consider to be optimal levels of metabolic control. Despite the impact that this can have on a young person''s future risk of complications, there are relatively few studies reporting new ways of organizing or delivering care to this cohort. In this article, we explore some of the reasons why young adult diabetes care is challenging, and describe approaches to “re‐imagining” how care might be improved. The work is informed by the ‘Making Care Fit’ collaborative and by a program of research, entitled D1 Now, involving co‐design of a complex person‐centered intervention with young adults. 相似文献
47.
严重烧伤患者外周血T淋巴细胞亚群、NK细胞活性及sIL-2R水平的变化 总被引:1,自引:0,他引:1
目的观察严重烧伤患者伤后T淋巴细胞亚群、NK细胞活性和sIL2R水平的变化,探讨其免疫功能改变的可能机制。方法测定35例严重烧伤患者伤后T淋巴细胞亚群,NK细胞活性和sIL2R的水平,并与正常对照组进行比较。结果与正常对照组比较,烧伤组:CD3+、CD4+和CD4+/CD8+比值均明显下降(P均<0.01),CD8+明显升高(P<0.05),烧伤组NK细胞活性明显下降(P<0.05),sIL-2R明显升高(P<0.01)。结论严重烧伤患者T淋巴细胞亚群中细胞比例发生了明显改变,NK细胞活性降低sIL-2R水平升高,三者互相影响,共同构成烧伤患者伤后免疫功能紊乱的因素之一。 相似文献
48.
J. C. Gorski D. R. Jones M. A. Hamman S. A. Wrighton S. D. Hall 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(9):931-944
1. To aid in the prediction of drug interactions with alprazolam, the human CYP involved in the 1'- and 4-hydroxylation of alprazolam were characterized using human liver microsomes, expressed enzymes and selective chemical inhibitors. 2. The formation of 4-hydroxyalprazolam and 1-hydroxyalprazolam at an alprazolam concentration of 62.5 μM were reduced by the prototypic CYP3A inhibitor, troleandomycin (50 μM), by 97 and 99% respectively. Only microsomes from B-lymphoblastoid cells expressing CYP3A4 were capable of catalysing the 1'- and 4-hydroxylation of alprazolam. 3. The formation rates of 1'-hydroxyalprazolam and 4-hydroxyalprazolam at an alprazolam concentration of 1 mM were significantly correlated (n=19, r=0.95, p<0.01) indicating that the same enzyme(s) mediated these biotransformations. A significant (p<0.01) correlation was observed between alprazolam 4- and 1'-hydroxylase activity and CYP3A-mediated midazolam 4-hydroxylase, midazolam 1'-hydroxylase, dextromethorphan N-demethylase and erythromycin N-demethylase activities. 4. In conclusion, in adult human liver the CYP3A subfamily members are the principal enzymes involved in the 1'- and 4-hydroxylation of alprazolam. Thus, clinically significant drug-drug interactions between alprazolam and other CYP3A substrates are to be expected. 相似文献
49.
50.
A new technique is described for reversing the direction of the catheter tip during translumbar aortography, without the need for partial withdrawal of the catheter from the aortic lumen. The method ensures optimal delivery of contrast medium at the desired level, while avoiding the risk of retroperitoneal bleeding or dislodgement during catheter manipulation. 相似文献