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121.
Recombinant human macrophage colony-stimulating factor (rhM-CSF) was given to cynomolgus monkeys by continuous intravenous infusion or subcutaneous injection, at a dose of 50 to 100 micrograms/kg/d in repetitive 14-day cycles. Starting within 24 to 48 hours of initiation of rhM-CSF, there was a progressive increase in the number of circulating monocytes, from a baseline of 811 +/- 253 cells/microL to a peak of 3,495 +/- 712 cells/microL on day 5 to 7. Many of these cells were large, granular, and extensively vacuolated. The expanded cell population expressed HLA-DR, LFA3, CD11b (904), and CD14 (MY4), and was 77% CD16 (FcRIII) positive by two-color cytofluorometry. In functional assays, fresh monocytes showed little cytotoxicity against cultured human melanoma cells (SKMel-1), with or without prior rhM-CSF treatment. However, after 3 days of in vitro culture in rhM-CSF, monocytes from treated animals mediated efficient antibody-dependent cytotoxicity (ADCC) against SKMel-1 using the murine monoclonal antibody 3F8 (IgG3, anti-ganglioside GD2). Under the same conditions, monocytes from control animals showed little ADCC (17% versus 82%, P less than .05). Antitumor cytotoxicity in the absence of antibody was less efficient and was not significantly different between the two groups. There was a mild decrease in platelet count during rhM-CSF treatment, without clinical symptoms. No abnormalities of serum biochemical parameters were seen. We conclude that parenteral rhM-CSF increases the number of circulating monocytes in nonhuman primates, and that these monocytes mediate increased antitumor ADCC after a brief period of in vitro differentiation. This study has implications for the design of possible future clinical trials combining antitumor monoclonal antibodies and rhM-CSF. 相似文献
122.
123.
A simple approach to prenatal diagnosis of beta-thalassemia in a geographic area where multiple mutations occur 总被引:5,自引:0,他引:5
We describe a simple approach for detecting beta-thalassemia mutations in geographic areas such as southern China where multiple mutations are known to occur. Segments of the beta-globin gene were amplified in vitro by using the polymerase chain reaction. Dot blot hybridization of the amplified DNA with oligonucleotide probes corresponding to the six mutations found in southern China could directly identify the mutations causing beta-thalassemia in the affected families. The increased number of target sequences after amplification allows the use of 35S-labeled probes, which are reusable for up to 3 months. The mutations can be determined in two days. 相似文献
124.
BackgroundChemokines are small molecules that act through G-protein coupled receptors to mediate primarily lymphocyte migration. CXCL16, which interacts with only one receptor (CXCR6), can mediate lymphocyte recruitment and has been implicated in various disease conditions. Steatohepatitis, caused by metabolic syndrome or alcohol misuse, is the commonest cause of liver disease in the UK. We investigated the role of CXCL16 and CXCR6 in the development of steatohepatitis.MethodsExpression of CXCL16 in whole liver and isolated cells was investigated with real-time PCR and immunohistochemistry. Serum and supernatant concentrations of soluble CXCL16 were measured with ELISA. Expression of CXCR6 on lymphocytes was investigated with flow cytometry. Lymphocyte adhesion was assessed with freshly isolated lymphocytes from liver or peripheral blood flowed over confluent layer of isolated human hepatic sinusoidal endothelium (HSEC).FindingsWhole liver expression of CXCL16 was increased relative to normal liver in fatty liver disease with increasing expression seen with increasing steatohepatitis and fibrosis. Immunohistochemistry showed CXCL16 expressed throughout regenerative nodules in both alcoholic and non-alcoholic liver disease. Isolated HSEC, biliary epithelial cells, and hepatoma cell lines increased expression of CXCL16 and released soluble CXCR6 in response to pro-inflammatory cytokines, particularly the combination of tumour necrosis factor α and interferon γ. Peripheral blood lymphocyte CXCR6 expression was confined to CD4 cells; however in the liver CD8+ cells and CD56+ cells more commonly expressed CXCR6. Inhibition of CXCR6 or CXCL16 inhibited transmigration of lymphocytes across HSEC.InterpretationCXCL16 is expressed in diseased liver where it has a role in the transmigration of lymphocytes across endothelium. This may represent a new therapeutic target in liver disease.FundingUK Medical Research Council. 相似文献
125.
Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk 总被引:21,自引:16,他引:21
Ryberg D; Skaug V; Hewer A; Phillips DH; Harries LW; Wolf CR; Ogreid D; Ulvik A; Vu P; Haugen A 《Carcinogenesis》1997,18(7):1285-1289
The A-G polymorphism at codon 104 in the glutathione S-transferase P1
(GSTP1) gene was examined in 138 male lung cancer patients and 297 healthy
controls. The patients had significantly higher frequency of the GG
genotype (15.9%) and a lower frequency of AA (38.4%) than the controls
(9.1% and 51.5%, respectively). The level of hydrophobic DNA- adducts were
determined in lung tissue from 70 current smokers. Patients with the GG
genotype had a significantly higher adduct level than patients with AA
(15.5 +/- 10.2 vs 7.9 +/- 5.1 per 10(8) nucleotides, P = 0.006). We also
analyzed the deletion polymorphism in the GSTM1 gene in 135 male patients
and 342 controls. The patients were stratified according to histology,
smoking dose, age, adduct level and mutational types found in the tumors
(Ki-ras and p53 genes). The results consistently indicated that the GSTM1
null genotype was associated with a slightly increased lung cancer risk.
When the combined GST M1 and P1 genotypes were examined, patients with the
combination null and AG or GG had significantly higher adduct levels than
all other genotype combinations (P = 0.011). The distribution of combined
genotypes was also significantly different in cases and controls, mainly
due to increased frequency of the combination GSTM1 null and GSTP1 AG or GG
among patients.
相似文献
126.
The metabolic activation of tamoxifen and alpha-hydroxytamoxifen to DNA- binding species in rat hepatocytes proceeds via sulphation 总被引:1,自引:1,他引:1
The biotransformation pathway of tamoxifen and alpha-hydroxytamoxifen to
DNA-binding species was investigated in rat hepatocytes in vitro. Rat
hepatocytes were isolated by in situ collagenase perfusion and then
maintained in sulphate-free Dulbecco's modified Eagle's medium. Magnesium
sulphate was added to the medium to give concentrations of 0- 10 microM,
prior to treatment for 18 h with solvent vehicle (DMSO), tamoxifen (10
microM), alpha-hydroxytamoxifen (1 microM) or benzo[a]pyrene (BaP) (10 and
50 microM). DNA was isolated and analysed by 32P-post-labelling. For
tamoxifen and alpha-hydroxytamoxifen, the level of DNA adduct formation was
directly proportional to the concentration of sulphate in the medium.
Between 0 and 10 microM MgSO4, the DNA adduct level increased 10-fold with
both compounds. Rat hepatocytes were also maintained in normal Dulbecco's
modified Eagle's medium and pretreated with
dehydroisoandrosterone-3-sulphate (DHEAS, a sulphotransferase inhibitor) at
concentrations ranging from 0-1 mM, prior to treatment with solvent vehicle
(DMSO), tamoxifen (10 microM), alpha-hydroxytamoxifen (1 microM) or BaP (50
microM). For tamoxifen and alpha-hydroxytamoxifen the level of DNA adducts
was reduced to approximately one-fifth by the addition of DHEAS (0.1 mM).
BaP-DNA adduct formation, which proceeds by a pathway that does not require
sulphation, was not significantly affected by sulphate concentration or by
addition of DHEAS, which demonstrates that the general metabolic capacity
and viability of the hepatocytes were not compromised. It is concluded that
the activation of tamoxifen in rat liver cells to DNA binding products
proceeds predominantly through hydroxylation followed by sulphate ester
formation at the alpha-position of the ethyl side chain.
相似文献
127.
The heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ),
2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl-
6-phenylimidazo[4,5-b]pyridine (PhIP) are pyrolysis products formed when
meat is cooked and are rodent mammary carcinogens. They are thought to be
metabolically activated by N-hydroxylation, catalysed by cytochrome P450
(CYP), followed by O-acetylation catalysed by N- acetyltransferases.
Primary cultures of human mammary epithelial cells (HMECs) prepared from up
to 26 individuals for each compound, were treated with IQ, MeIQ, or PhIP
(500 microM) or with N-hydroxy-2-amino-1-
methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) or N-hydroxy-2-amino-
3-methylimidazo[4,5-f]quinoline (N-OH-IQ) (20 microM) and the levels of
adduct formation in their DNA analysed by 32P-post-labelling. In order to
investigate whether pharmacogenetic polymorphisms influence DNA adduct
formation, the NAT2 genotype of each individual was determined by a
polymerase chain reaction-restriction fragment length polymorphism
(PCR-RFLP) method that distinguishes between the wild-type and four variant
alleles. Presence of two variant alleles designates a slow NAT2 acetylator,
whereas individuals with one or two wild-type alleles are designated fast
NAT2 acetylators. Interindividual variations in total DNA adduct levels
ranged for IQ from 0.64-63.1 DNA adducts per 10(8) nucleotides (mean 7.80),
for MeIQ from 1.99-17.8 (mean 6.63), for PhIP from 0.13-4.0 (mean 0.96),
for N-OH-PhIP from 6.32-497 (mean 176) and for N-OH-IQ from 0.92-30.6 (mean
9.24). The higher adduct levels observed in cells treated with the N-OH
metabolites suggests that N- hydroxylation is the rate-limiting step in
HMECs and this may be due to low CYP levels. In contrast, the Phase II
reaction catalysed by N- acetyltransferases is probably the major step in
the metabolic activation of heterocyclic amines that occurs in the breast.
Higher mean levels of heterocyclic amine-DNA adduct formation were detected
in the cells of NAT2 fast acetylators compared with slow acetylators, with
mean adduct levels per 10(8) nucleotides following IQ treatment, of 12.74
and 3.57 respectively, following PhIP treatment, of 1.20 and 0.74,
respectively, following MeIQ treatment, of 7.90 and 5.08, respectively and
following N-OH-PhIP-treatment, of 243.1 and 130.0, respectively. However,
due to the large variations in adduct levels, these differences in mean
values were not statistically significant with the limited number of
individuals studied. This appears to be the first pilot study to
demonstrate interindividual variations in the metabolic activation of
heterocyclic amines and their metabolic intermediates in primary cultures
of HMECs in vitro.
相似文献
128.
Risk factors for endometriosis in the rhesus monkey (Macaca mulatta): a case-control study 总被引:3,自引:0,他引:3
Hadfield RM; Yudkin PL; Coe CL; Schefler J; Uno H; Barlow DH; Kemnitz JW; Kennedy SH 《Human reproduction update》1997,3(2):109-115
The autopsy records between 1980 and 1995 of 399 female rhesusmonkeys (Macaca mulatta) at the Wisconsin Regional Primate ResearchCenter were examined. Spontaneous endometriosis was found in81 (20%) of the animals. The mean (±SD) ages at deathfor animals with and without endometriosis were 20.7±5.5(range 10-35) and 13.4±7.7 (range 4-37) years respectively.Many of the animals had been exposed to experimental procedures,including laparoscopies, hysterotomies and oestradiol implants,and these were examined as possible risk factors for endometriosis.Of the 81 affected animals, 62 were matched to unaffected controlsfor age at death (to within 1 year) and year of death (to within2 years) and the effect of various factors on the developmentof endometriosis was determined using conditional logistic regression.Exposure to three or more oestradiol implants or one or morehysterotomies were both significant risk factors, with estimatedrelative risks of 9.7 (95% confidence interval 2.5-37.2) and5.8 (95% confidence interval 1.6-20.2) respectively. Animalsthat had been exposed to one or more laparoscopies showed noincreased risk for developing endometriosis. These findingsprovide insight into the aetiology of the disease in women. 相似文献
129.
A new multivalent B cell activation model--anti-IgD bound to Fc gamma RI: properties and comparison with CD40L-mediated activation 总被引:1,自引:0,他引:1
CHO cells permanently transfected with mouse Fc gamma RI alpha chain were
prepared and used as a model to polyclonally activate murine B cells. The
transfected CHO cells were treated with mitomycin C and placed into culture
with varying quantities of anti-IgD. Using this model, murine splenic B
cells (from BALB/c or C57Bl/6) were activated by mouse IgG2a-anti-IgD
(10.4.22 or AF3.33) in a manner that is analogous to the activation of B
cells seen with highly polyvalent anti- IgD (H delta(a)/1) prepared by
chemical cross-linking to dextran. Efficient B cell activation was seen
with nanogram quantities of anti- IgD. In the presence of IL-4 and IL-5,
IgG1 production levels were equivalent to or better than seen when
stimulation was with H delta(a)/1-dextran; however, IgE induction was not
seen in either situation. The Ig production capacity was compared to that
seen when B cells were activated with CD40L, using either CD40L-transfected
CHO or a soluble CD40L construct. In the presence of IL-4 and IL-5, once a
critical threshold of B cells was present, IgE and to a lesser extent IgG1
production was inversely proportional to B cell number when CD40L was the
activating agent. In contrast, with Fc gamma RI-anti-IgD, IgM and IgG1
production was directly proportional to B cell number, while IgE production
was never seen. Finally, when B cells were co-activated with immobilized
anti-IgD and CD40L simultaneously, the IgE production from B cells induced
by CD40L was strongly inhibited, while IgG1 and IgM production were not
affected. Since B cell co-activation via sIg and CD40L would be a common
scenario in secondary follicles, this inhibition of IgE production may be
one of the reasons why serum IgE levels are much below IgG in normal immune
situations.
相似文献
130.
Trinucleotide expansion mutations in the cartilage oligomeric matrix protein (COMP) gene 总被引:6,自引:1,他引:5
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are
two human autosomal dominant skeletal dysplasias characterized by variable
short stature, joint laxity and early-onset degenerative joint disease.
Both disorders can result from mut-ations in the gene for cartilage
oligomeric matrix protein (COMP), an extracellular matrix glycoprotein.
About one-third of PSACH cases result from heterozygosity for deletion of
one codon within a very short triplet repeat, (GAC)5, which encodes five
consecutive aspartic acid residues within the calmodulin-like region of the
COMP protein. We have identified two expansion mut-ations in this repeat:
an MED patient carrying a (GAC)6allele and a PSACH patient carrying a
(GAC)7allele. These are among the shortest disease-causing triplet repeat
expansion mutations described thus far, and are the first identified in a
GAC repeat. A unique feature of this sequence is that expansion as well as
shortening of the repeat can cause the same disease. In cartilage, both
patients have rough endoplasmic reticulum inclusions in chondrocytes. The
inclusions are also present in tendon tissue and can be reproduced in
cultured tendon cells, suggesting that the pathophysiology of disease is
similar in both cartilage and tendon.
相似文献