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11.
K Suzuki T Ezoe J Tohyama J Matsuda MT Vanier K Suzuki 《Acta paediatrica (Oslo, Norway : 1992)》2003,92(S443):54-62
Spontaneously occurring genetic lysosomal storage diseases are as rare in other mammalian species as in man. However, the advent of gene targeting technology has revolutionized the state of animal models of genetic diseases. Nearly all lysosomal storage diseases known in man have been duplicated in the mouse. The technology now allows, not only complete inactivation of endogenous genes, but also the introduction of essentially any type of mutation. These animal models can overcome many of the limitations inherent in studies of human patients - rarity of the disease, extremely complex genetic background and logistical and ethical constraints in the design and execution of experiments with human subjects. For example, genetic manipulations of germ cells or cross-breeding experiments between two mutants are readily feasible with animal models. Two major areas of the utility of animal models are the clarification of the pathophysiology/pathogenetic mechanism of disease and the exploration of therapeutic approaches. Examples of experiments using animal models of lysosomal storage disease are presented, primarily from studies undertaken in our own laboratory.
Conclusion : Animal models have proved invaluable in extending our knowledge of the lysosomal storage diseases and exploring potential therapies. 相似文献
Conclusion : Animal models have proved invaluable in extending our knowledge of the lysosomal storage diseases and exploring potential therapies. 相似文献
12.
Hemoglobin and albumin adducts of benzene oxide among workers exposed to high levels of benzene 总被引:3,自引:0,他引:3
Yeowell-O'Connell K; Rothman N; Smith MT; Hayes RB; Li G; Waidyanatha S; Dosemeci M; Zhang L; Yin S; Titenko-Holland N; Rappaport SM 《Carcinogenesis》1998,19(9):1565-1571
Benzene oxide (BO) reacts with cysteinyl residues in hemoglobin (Hb) and
albumin (Alb) to form protein adducts (BO-Hb and BO-Alb), which are
presumed to be specific biomarkers of exposure to benzene. We analyzed
BO-Hb in 43 exposed workers and 42 unexposed controls, and BO-Alb in a
subsample consisting of 19 workers and 19 controls from Shanghai, China, as
part of a larger cross-sectional study of benzene biomarkers. The adducts
were analyzed by gas chromatography-mass spectrometry following reaction of
the protein with trifluoroacetic anhydride and methanesulfonic acid. When
subjects were divided into controls (n = 42) and workers exposed to < or
=31 (n = 21) and >31 p.p.m. (n = 22) benzene, median BO-Hb levels were
32.0, 46.7 and 129 pmol/g globin, respectively (correlation with exposure:
Spearman r = 0.67, P < 0.0001). To our knowledge, these results
represent the first observation in humans that BO-Hb levels are
significantly correlated with benzene exposure. Median BO-Alb levels in
these 3 groups were 103 (n = 19), 351 (n = 7) and 2010 (n = 12) pmol/g Alb,
respectively, also reflecting a significant correlation with exposure
(Spearman r = 0.90, P < 0.0001). The blood dose of BO predicted from
both Hb and Alb adducts was very similar. These results clearly affirm the
use of both Hb and Alb adducts of BO as biomarkers of exposure to high
levels of benzene. As part of our investigation of the background levels of
BO-Hb and BO-Alb found in unexposed persons, we analyzed recombinant human
Hb and Alb for BO adducts. Significant levels of both BO-Hb (19.7 pmol/g)
and BO-Alb (41.9 pmol/g) were detected, suggesting that portions of the
observed background adducts reflect an artifact of the assay, while other
portions are indicative of either unknown exposures or endogenous
production of adducts.
相似文献
13.
Increased aneusomy and long arm deletion of chromosomes 5 and 7 in the lymphocytes of Chinese workers exposed to benzene 总被引:4,自引:1,他引:4
Zhang L; Rothman N; Wang Y; Hayes RB; Li G; Dosemeci M; Yin S; Kolachana P; Titenko-Holland N; Smith MT 《Carcinogenesis》1998,19(11):1955-1961
Two of the most common cytogenetic changes in therapy- and chemical-
related leukemia are the loss and long (q) arm deletion of chromosomes 5
and 7. The detection of these aberrations in lymphocytes of individuals
exposed to potential leukemogens may serve as useful biomarkers of
increased leukemia risk. We have used a novel fluorescence in situ
hybridization (FISH) procedure to determine if specific aberrations in
chromosomes 1, 5 and 7 occur at an elevated rate in the blood cells of
workers exposed to benzene. Forty-three healthy workers exposed to a wide
range of benzene concentrations (median 31 p.p.m., 8 h time-weighted
average) and 44 unexposed controls from Shanghai were studied. Whole blood
was cultured and metaphase spreads were harvested at 72 h. Benzene exposure
was associated with increases in the rates of monosomy 5 and 7 but not
monosomy 1 (P < 0.001, P < 0.0001 and P = 0.94, respectively) and
with increases in trisomy and tetrasomy frequencies of all three
chromosomes. Long arm deletion of chromosomes 5 and 7 was increased in a
dose-dependent fashion (P = 0.014 and P < 0.0001) up to 3.5-fold in the
exposed workers. These results demonstrate that leukemia-specific changes
in chromosomes 5 and 7 can be detected by FISH in the peripheral blood of
otherwise healthy benzene-exposed workers. We suggest that aberrations in
chromosomes 5 and 7 may be useful biomarkers of early biological effect for
benzene exposure.
相似文献
14.
G. Halverson BS MT E. Shanahan I. Santiago R. Mabile T. Thurrell A. M. Strupp C. F. W. Wolf P. Spruell and M. K. Moulds 《Vox sanguinis》1994,66(3):206-209
The antibodies of the Dombrock blood group system have only rarely been encountered in transfusion practice, and anti-Dob has not previously been implicated in an acute hemolytic transfusion reaction. We have encountered the first such case involving a chronically transfused black female with hemoglobin SS disease and multiple antibodies in her serum. During a previous admission for sickle cell crisis, the patient received 3 units of compatible blood with no untoward effects. Serum obtained 21 days later contained, in addition to the known antibodies, anti-S plus an unidentified antibody showing characteristics of HTLA. Blood lacking the E, K1, Fy(a), Jk(b) and S antigens was obtained, and 2 least incompatible units were transfused. While administering the second unit, the patient complained of fever and low back pain, and hemoglobinemia was detected. Anti-Dob was identified in the post-reaction samples by absorption-elution tests, and the patient was confirmed to be Do(a+b–). The first unit transfused during this hemolytic episode tested Do (b+). This case, and a similar case involving anti-Doa reported in 1986, strengthens the belief that Dombrock antibodies are clinically significant and illustrates the need for their differentiation, prior to transfusion from less clinically significant HTLA antibodies. 相似文献
15.
Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance 总被引:29,自引:0,他引:29 下载免费PDF全文
Kim JK Fillmore JJ Chen Y Yu C Moore IK Pypaert M Lutz EP Kako Y Velez-Carrasco W Goldberg IJ Breslow JL Shulman GI 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(13):7522-7527
Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which insulin resistance occurs may be related to alterations in fat metabolism. Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic-euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. Muscle-lipoprotein lipase mice had a 3-fold increase in muscle triglyceride content and were insulin resistant because of decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity. In contrast, liver-lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity. These defects in insulin action and signaling were associated with increases in intracellular fatty acid-derived metabolites (i.e., diacylglycerol, fatty acyl CoA, ceramides). Our findings suggest a direct and causative relationship between the accumulation of intracellular fatty acid-derived metabolites and insulin resistance mediated via alterations in the insulin signaling pathway, independent of circulating adipocyte-derived hormones. 相似文献
16.
Dr. Michael D. Schuffler MD Lawrence R. Kaplan MD Linda Johnson BS MT ASCP 《Digestive diseases and sciences》1978,23(9):821-828
The purpose of this investigation was to determine the frequency and severity of small intestinal mucosal damage in pseudoobstruction syndromes. One hundred eighty-nine interpretable biopsies from 12 patients were blindly reviewed by two investigatiors. The underlying disorders were scleroderma in 7 and idiopathic intestinal pseudoobstruction in 5. All 12 had small-intestinal dilatation on small-bowel series. Eight of the 12 patients had biopsies characterized by moderate, to severe mucosal damage; 3 of these had some biopsies which were flat. The damage did not correlate with: (1) types and numbers of organisms recovered from small intestinal aspirates; (2) duration of illness; (3) degree of dilatation of the proximal small bowel; (4) concentrations of deconjugated bile salts in small intestinal fluid; or (5) amount of fat absorbed in fat-balance studies. We conclude that mucosal damage is common in pseudoobstruction syndromes. The pathogenesis of the damage and its relationship to intraluminal bacteria remain undefined. 相似文献
17.
Mark T. Fillmore M. Vogel-Sprott 《Alcoholism, clinical and experimental research》1998,22(7):1476-1482
This study tested the hypothesis that the intensity of behavioral impairment under alcohol is related to social drinkers' expectancies about impairment and their rates of rise in blood alcohol concentration (BAC). After subjects ( n = 30) were trained on a psychomotor task, they rated the impairment they expected from alcohol and then performed the task under alcohol (0.56 g/kg) or a placebo. Alcohol impaired performance, compared with placebo. Drinkers' expectations about impairment and their rates of rise in BAC were independent, and each factor predicted a significant portion of the variance in alcohol impairment among drinkers. More intense impairment under alcohol was associated with expectations of greater impairment and with swifter rates of rise in BAC. BACs obtained by drinkers during task performance were not related to the intensity of impairment they displayed. The study shows that a pharmacological and nonpharmacological variable can each affect a drinker's behavioral impairment under alcohol, and this finding contributes to our understanding of conditions where BAC per se may be an unreliable indicator of impairment. 相似文献
18.
The finding of elevated intracellular levels of adenosine deaminase (ADA) in some patients with acute lymphoblastic leukemia has led to attempts to control this disease with the adenosine deaminase inhibitor 2'-deoxycoformycin (dCF). Because of clinical reports indicating its relative freedom from myelotoxicity, we have tested the effects of this drug on erythroid, granulocytic, and T-lymphocyte colony formation by normal marrow and peripheral blood cells. While clinically the drug has been found to be active at serum concentrations of approximately 10 microM, we have tested it at concentrations up to and including 1 mM. It was found that both erythroid and granulocytic colony growth was completely unaffected by 1 mM dCF, a concentration at least 2 magnitudes higher than that necessary to totally ablate intracellular ADA levels. T-lymphocyte colony growth was unaffected by 100 microM dCF, but at 1 mM some inhibition was observed. These findings therefore indicate that dCF, while able to cause leukemic cell lysis in vivo, has no inhibitory effect on the proliferative capacity of normal hematopoietic cells. 相似文献
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