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171.
172.
CAG repeat expansion in autosomal dominant familial spastic paraparesis: novel expansion in a subset of patients 总被引:1,自引:0,他引:1
Benson KF; Horwitz M; Wolff J; Friend K; Thompson E; White S; Richards RI; Raskind WH; Bird TD 《Human molecular genetics》1998,7(11):1779-1786
Autosomal dominant familial spastic paraplegia (FSP) is a genetically
heterogeneous neurodegenerative disorder displaying anticipation for which
three loci have been mapped to the chromosomal positions 14q11.2- q24.3
(SPG3), 2p21-p24 (SPG4) and 15q11.1 (SPG6). The repeat expansion detection
(RED) method has been used to demonstrate expanded CAG repeats in some FSP
families that map to SPG4. We analyzed 20 FSP families, including four for
which there is evidence for linkage to SPG4, and found that in most cases
the repeat expansion detected by RED is due to non-pathogenic expansions of
the chromosome 18q21.1 SEF2-1 or 17q21.3 ERDA1 locus. Polymorphic
expansions at SEF2-1 and ERDA1 appear frequent and may confound RED studies
in the search for genes causing disorders demonstrating anticipation. In
six FSP families, however, CAG repeat expansion was detected in a subset of
affected and at-risk individuals that did not result from expansion of the
SEF2-1 and ERDA1 loci. Overall, 11 of 37 (30%) of the FSP patients with a
CAG/CTG repeat expansion are unaccounted for by the SEF2-1 and ERDA1 loci,
compared with two of 23 (9%) of the unaffected at-risk individuals and none
of 19 controls. In the majority of cases these novel expansions were
shorter than those previously reported.
相似文献
173.
Production of human factor IX in animals by genetically modified skin fibroblasts: potential therapy for hemophilia B 总被引:14,自引:1,他引:14
Inherited diseases might be treated by introducing normal genes into a patient's somatic tissues to correct the genetic defects. In the case of hemophilia resulting from a missing clotting factor, the required gene could be introduced into any cell as long as active factor reached the circulation. We previously showed that retroviral vectors can efficiently transfer genes into normal skin fibroblasts and that the infected cells can produce high levels of a therapeutic product in vitro. In the current study, we examined the ability of skin fibroblasts to secrete active clotting factor after infection with different retroviral vectors encoding human clotting factor IX. Normal human fibroblasts infected with one vector secreted greater than 3 micrograms factor IX/10(6) cells/24 h. Of this protein, greater than 70% was structurally and functionally indistinguishable from human factor IX derived from normal plasma. This suggests that infected autologous fibroblasts might provide therapeutic levels of factor IX if transplanted into patients suffering from hemophilia B. By transplanting normal diploid fibroblasts infected with the factor IX vectors, we showed that human factor IX can be produced and is circulated at readily detectable levels in rats and mice. 相似文献
174.
MT Sanchez-Santos A Judge M Gulati TD Spector DJ Hart JL Newton NK Arden S Kluzek 《Seminars in arthritis and rheumatism》2019,48(5):791-798
Objective
It is unclear whether the association between osteoarthritis (OA) and metabolic syndrome (MetS) varies with the site of the affected joint and the presence of pain. Our aim was to describe the association between MetS and radiographic OA (ROA) affecting the knee or the hand in the presence or absence of concurrent joint pain.Methods
Cross-sectional data of 952 women, aged 45–65years from the Chingford study, a population-based longitudinal cohort of middle-aged women initiated in 1988–1989 in London (UK), was analysed. MetS was defined using the National Cholesterol Education Program Treatment Panel III criteria. Data was collected on components of MetS: waist circumference, triglycerides, high-density lipoprotein (HDL), blood pressure and blood glucose. The outcome was four knee and hand OA groups: painful ROA, ROA only, pain only and neither ROA nor pain (reference category). Multinomial logistic regression models adjusted for age and body mass index (BMI) were used to evaluate the effect of presence of MetS and its individual components on OA subgroups for knee and hand separately.Results
952 eligible women, aged 45–65years was analysed. A significant association was observed between the presence and the number of MetS with painful knee ROA when adjusted for age; however, this association disappeared when BMI was included in the model. In contrast, the presence and the number of MetS were associated with painful interphalangeal (IPJ) OA after adjusting for both age and BMI. Four out of the five MetS components, including triglycerides, HDL-c, hypertension and glucose, were associated with painful IPJ OA.Conclusions
MetS is associated with painful IPJ OA but not with knee OA once BMI is taking into consideration. Further attention to MetS and OA at different sites is needed to understand the metabolic phenotype in OA. 相似文献175.
In Myanmar, hepatitis C virus (HCV) infection prevalence is 2%. A combination therapy of pegylated interferon alfa-2a and ribavirin (PEG-IFNa/RBV) is a standard treatment, but the effect of this antiviral therapy needs evaluation as to determine the efficacy and safety of dual PEG-IFNa/RBV therapy in treating patients infected with HCV in Myanmar.This was a retrospective analysis of data from a single clinic exclusively for gastrointestinal diseases in Yangon, Myanmar. We assessed treatment responses at the defined time points and stratified by genotypes of HCV. We also determined incidences of adverse events (AEs). We investigated independent predictors of sustained virologic response (SVR) in the participants.A total of 362 HCV-infected cases were included in this study. The majority were females (51.7%) with mean age of 47.12 years (±11.6) and noncirrhosis patients (82%). Rapid virologic response (RVR), early virologic response (EVR), end of treatment response (ETR), and SVR 24 weeks after completion of the dual treatment were 50.3% (178/362), 88% (314/357), 80.1% (286/357), and 85.6% (167/195), respectively. The most frequently reported AEs were nausea/anorexia (72.8%) and flu-like symptoms (62.4%). In multivariate analysis, 4 factors were independently associated with SVR; SVR to genotype 3 (odds ratio [OR] 2.4, 95% CI: 1.24–4.62), EVR (OR 0.54, 95% CI: 0.3–0.95), and duration of treatment (OR 1.52, 95% CI: 1.18–1.98). Study limitations were acknowledged.The efficacy and safety of the dual therapy in treating HCV-infected patient in Myanmar was acceptable. We recommend a prospective randomized control trial looking at duration of therapy and rates of achieving SVR, which could significantly impact the care of HCV-infected patients in Myanmar and perhaps other countries as well. 相似文献
176.
177.
Expression of murine CD38 defines a population of long-term reconstituting hematopoietic stem cells 总被引:5,自引:6,他引:5
Using a monoclonal antibody to murine CD38, we showed that a population of adult bone marrow cells that expressed the markers Sca-1 and c-kit but lacked the lineage markers Mac-1, GR-1, B220, IgM, CD3, CD4, CD8 and CD5 could be subdivided by the expression of CD38. We showed that CD38high c-kit+ Sca-1+, linlow/-cells sorted from adult bone marrow cultured with interleukin-3 (IL-3), IL-6, and kit-L produced much larger colonies in liquid culture at a greater frequency than their CD38low/- counterparts. In addition, we found that CD36low/ - cells contained most of the day-12 colony-forming units-spleen (CFU-S) but were not long-term reconstituting cells, whereas the population that expressed higher levels of CD38 contained few, but significant, day-12 CFU-S and virtually all the long-term reconstituting stem cells. Interestingly, the CD38high Sca-1+ c-kit+ linlow/- cells isolated from day-E14.5 fetal liver were also found to be long-term reconstituting stem cells. This is in striking contrast to human hematopoietic progenitors in which the most primitive hematopoietic cells from fetal tissues lack the expression of CD38. Furthermore, because antibodies to CD38 could functionally replace antibodies to Thy-1.1 in a stem cell purification procedure, the use of anti-CD38 may be more generally applicable to the purification of hematopoietic stem cells from mouse strains that do not express the Thy-1.1 allele. 相似文献
178.
The mechanism of action of the antiinflammatory agents dexamethasone and Auranofin in human polymorphonuclear leukocytes 总被引:2,自引:0,他引:2
Human polymorphonuclear neutrophils (PMN) were treated with the antiinflammatory agents dexamethasone or Auranofin. PMN treated with dexamethasone in a dose range of 0.25-1 microM or Auranofin, 5-15 mM, were stimulated with 10(-7)M N-formyl-methionyl-leucyl-phenylalanine (FMLP). These agents were shown to inhibit the functional responses of degranulation and superoxide production in a dose-dependent manner. Similarly, the change in electrophoretic mobility, reflecting cell surface charge, was blocked. While both agents inhibited change in the fluorescence of the calcium chelate probe chlorotetracycline (CTC), the pattern of inhibition was significantly different. Dexamethasone appeared to inhibit the CTC response during its latter phases, while Auranofin inhibited all aspects of the CTC response. Auranofin was additionally shown to significantly decrease specific binding of FMLP, as well as the number of FMLP receptors. The two agents thus appear to act by different mechanisms. Dexamethasone is shown to have an effect on membrane-bound calcium release as measured by CTC, while Auranofin interferes with receptor binding. 相似文献
179.
Chen GQ; Zhu J; Shi XG; Ni JH; Zhong HJ; Si GY; Jin XL; Tang W; Li XS; Xong SM; Shen ZX; Sun GL; Ma J; Zhang P; Zhang TD; Gazin C; Naoe T; Chen SJ; Wang ZY; Chen Z 《Blood》1996,88(3):1052-1061
It has been shown recently in China that arsenic trioxide (As2O3) is a very effective treatment for acute promyelocytic leukemia (APL). APL patients resistant to all-trans retinoic acid (ATRA) and conventional chemotherapy can still respond to AS2O3. In this study, we addressed the possible cellular and molecular mechanisms of this treatment by using NB4 cells as a model. The results show that: (1) As2O3 triggers relatively specific NB4 cell apoptosis at micromolar concentration, as proved by morphology, histogramic related nuclear DNA contents, and DNA gel eletrophoresis. (2) As2O3 does not influence bax, bcl-x, c-myc, and p53 gene expression, but downregulates bcl-2 gene expression at both mRNA and protein levels. (3) As2O3 induces a significant modulation of the PML staining pattern in NB4 cells and HL-60 cells. The micropunctates characteristic of PML-RAR alpha in NB4 cells dissappear after treatment with As2O3, whereas a diffuse PML staining occurs in the perinuclear cytoplasmic region. In addition, a low percentage of untreated NB4 cells exhibits an accumulation of PML positive particles in a compartment of cytoplasm. The percentage of these cells can be significantly increased after As2O3 treatment. A similar PML staining pattern is observed in apoptotic cells. (4) ATRA pretreatment does not influence As2O3-induced apoptosis. These results suggest that induction of cell apoptosis can be one of the mechanisms of the therapeutic effect of As2O3. Moreover, this apoptosis induction occurs independently of the retinoid pathway and may be mediated, at least partly, through the modulation of bcl-2, as well as PML-RAR alpha and/ or PML proteins. 相似文献
180.
SUMMARY While playing a game of cricket, a 42-year-old man was struck on the chest by the ball. The blunt trauma precipitated a myocardial infarct in the absence of other risk factors or evidence of pre-existing coronary artery disease. Probable pathophysiological mechanisms and potential problems of immediate treatment are discussed. 相似文献