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71.
Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases 总被引:5,自引:5,他引:5
The expansion of trinucleotide repeat sequences is associated with several
neurodegenerative diseases. The mechanism of this expansion is unknown but
may involve slipped-strand structures where adjacent rather than perfect
complementary sequences of a trinucleotide repeat become paired. Here, we
have studied the interaction of the human mismatch repair protein MSH2 with
slipped-strand structures formed from a triplet repeat sequence in order to
address the possible role of MSH2 in trinucleotide expansion. Genomic
clones of the myotonic dystrophy locus containing disease-relevant lengths
of (CTG)n x (CAG)n triplet repeats were examined. We have constructed two
types of slipped-strand structures by annealing complementary strands of
DNA containing: (i) equal numbers of trinucleotide repeats (homoduplex
slipped structures or S-DNA) or (ii) different numbers of repeats
(heteroduplex slipped intermediates or SI-DNA). SI-DNAs having an excess of
either CTG or CAG repeats were structurally distinct and could be separated
electrophoretically and studied individually. Using a band-shift assay, the
MSH2 was shown to bind to both S-DNA and SI-DNA in a structure- specific
manner. The affinity of MSH2 increased with the length of the repeat
sequence. Furthermore, MSH2 bound preferentially to looped-out CAG repeat
sequences, implicating a strand asymmetry in MSH2 recognition. Our results
are consistent with the idea that MSH2 may participate in trinucleotide
repeat expansion via its role in repair and/or recombination.
相似文献
72.
Cecily P. Vaughn Jorge Robles Jeffrey J. Swensen Christine E. Miller Elaine Lyon Rong Mao Pinar Bayrak‐Toydemir Wade S. Samowitz 《Human mutation》2010,31(5):588-593
Germline mutation detection in PMS2, one of four mismatch repair genes associated with Lynch syndrome, is greatly complicated by the presence of numerous pseudogenes. We used a modification of a long‐range PCR method to evaluate PMS2 in 145 clinical samples. This modification avoids potential interference from the pseudogene PMS2CL by utilizing a long‐range product spanning exons 11–15, with the forward primer anchored in exon 10, an exon not shared by PMS2CL. Large deletions were identified by MLPA. Pathogenic PMS2 mutations were identified in 22 of 59 patients whose tumors showed isolated loss of PMS2 by immunohistochemistry (IHC), the IHC profile most commonly associated with a germline PMS2 mutation. Three additional patients with pathogenic mutations were identified from 53 samples without IHC data. Thirty‐seven percent of the identified mutations were large deletions encompassing one or more exons. In 27 patients whose tumors showed absence of either another protein or combination of proteins, no pathogenic mutations were identified. We conclude that modified long‐range PCR can be used to preferentially amplify the PMS2 gene and avoid pseudogene interference, thus providing a clinically useful germline analysis of PMS2. Our data also support the use of IHC screening to direct germline testing of PMS2. Hum Mutat 31:588–593, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
73.
Anna L. Alimonda Julio Núñez Eduardo Núñez Oliver Husser Juan Sanchis Vicent Bodí Gema Miñana Rocio Robles Luis Mainar Pilar Merlos Helene Darmofal Ángel Llácer 《European Journal of Internal Medicine》2009,20(1):74-79
BackgroundHyperuricemia is a prevalent condition in chronic heart failure (CHF), describing increased oxidative stress and inflammation. Although there is evidence that serum uric acid (UA) predicts mortality in CHF, its role as a prognostic biomarker in acute heart failure (AHF) has not yet been well assessed. The aim of this study was to determine if UA levels predict all-cause mortality. Additionally, as a secondary endpoint we sought the clinical predictors of UA serum level in this population.MethodsWe analyzed 560 consecutive patients with AHF admitted in a single university center. UA (mg/dl) was measured during early hospitalization. Patient survival status was followed up after discharge (median follow-up: 330 days). The independent association of UA level with all-cause mortality was analyzed using Cox regression analysis.ResultsDuring follow-up 165 (29.5%) deaths were identified. Patients with UA levels above the median value (≥ 7.7 mg/dl) exhibited higher mortality rates (21.1 vs. 37.9%; p < 0.001). In multivariable analysis, after adjusting for recognized prognostic factors and potential confounders, UA ≥ 7.7 mg/dl and per change in 1 mg/dl of UA was associated with an increased risk of mortality (HR 1.45, CI 95% = 1.03–2.44; p = 0.03 and HR 1.08, CI 95% = 1.01–1.15; p = 0.03, respectively).ConclusionUA serum levels is an independent predictor of all-cause mortality in an unselected patients admitted with AHF. 相似文献
74.
75.
Antonio Galán Brotons Joaquín Borrás-Blasco J. Dolores Rosique Robles José María Vicent Verge Elvira Casterá 《Clinical & translational oncology》2008,10(12):844-846
A woman diagnosed of a renal cell carcinoma in 1989 had a metastatic kidney cancer localised in subcutaneous nodules, gut
and lung in 2007. Sorafenib treatment was initiated a 400 mg orally twice a day. The patient developed generalised erythematous
skin eruptions and two weeks later a widespread erythematous maculopapular eruption located exclusively on the legs and arms,
along with an objective response. The most likely cause of the generalised erythematous skin eruptions was considered to be
sorafenib because of the close temporal relationship between exposure to the drug and onset of symptoms. Furthermore, a relationship
between sorafenib skin toxicity and treatment efficacy was observed. This therapeutic efficacy of EGFR inhibitors and cutaneous
side effects should be better assessed in large cohorts or trials to determine whether the skin toxicity of patients can be
linked to an objective antitumour response. 相似文献
76.
Prenatal exposure to alcohol: effect on infant growth and morphologic characteristics 总被引:7,自引:0,他引:7
N L Day D Jasperse G Richardson N Robles U Sambamoorthi P Taylor M Scher D Stoffer M Cornelius 《Pediatrics》1989,84(3):536-541
In this prospective study of alcohol and other substance use during pregnancy, a cohort of 650 women was interviewed at each trimester of pregnancy. Data are presented concerning the status of 595 live singleton births. A relationship was demonstrated between prenatal maternal alcohol use and growth and morphologic abnormalities in the offspring. Low birth weight, decreased head circumference and length, and an increased rate of fetal alcohol effects were all found to be significantly correlated with exposure to alcohol during the first 2 months of the first trimester. 相似文献
77.
Robles L Rizo Curiel G Camarena García LM Cervantes Coles L Gómez Medrano Md Siordia González M 《Cadernos de saúde pública / Ministério da Saúde, Funda??o Oswaldo Cruz, Escola Nacional de Saúde Pública》2000,16(2):557-560
This paper examines social networks and social support among poor elderly ill in Guadalajara, Mexico. We interviewed 40 hospitalized elderly patients. The mean size of social networks was 7.5, basically involving women, multiple generations, and members of the extended family. Emotional support was more frequent than other types of social support. Elderly women had larger social networks and received more social support than men. Married elderly also had larger social networks and more social support than single patients. There were no differences between age and living arrangements with social networks and social support. Future studies are needed on the social and cultural environment of social support for the elderly. 相似文献
78.
Hammett TM Norton GD Mason TH Langenbahn S Mayer KH Robles RR Feudo R Seage GR 《Journal of women's health & gender-based medicine》2000,9(10):1071-1080
We wished to obtain potential users' perspectives on vaginal microbicides from a population of women at high risk for HIV. We conducted a face-to-face survey of convenience samples (total n = 743) of drug-using women and female sexual partners of male injection drug users in Bridgeport, Connecticut, Providence, Rhode Island, and San Juan, Puerto Rico. Ninety percent of respondents said that they would be very likely to use microbicides with paying partners and 78% with primary partners (p = 0.001). High hypothetical likelihood of use was expressed even after several potential product characteristics (e.g., causes minor vaginal irritation or burning) were rated as unacceptable. Latinas had significantly higher predicted likelihood of use with primary (p = 0. 001) and paying partners (p = 0.018) than blacks and whites. Eighty percent of respondents preferred products that enhance sexual pleasure by providing additional lubrication or "wetness." More than 80% of respondents said that they would want their primary partners to know of their microbicide use, and 42% (p = 0.001) said that they would want their paying partners to know. Women's concern about a paying partner's violent response to suggested use of risk reduction measures was inversely related to predicted likelihood of microbicide use (p = 0.045). Microbicides should be assessed in the context of the potential users' actual relationships and cultures. Achieving broad acceptability among drug-involved women will require a range of products. 相似文献
79.
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