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91.
Olivier Simard Marie‐Chantal Grégoire Mélina Arguin Marc‐André Brazeau Frédéric Leduc Isabelle Marois Martin V. Richter Guylain Boissonneault 《Human mutation》2014,35(11):1280-1284
Transient DNA breaks and evidence of DNA damage response have recently been reported during the chromatin remodeling process in haploid spermatids, creating a potential window of enhanced genetic instability. We used flow cytometry to achieve separation of differentiating spermatids into four highly purified populations using transgenic mice harboring 160 CAG repeats within exon 1 of the human Huntington disease gene (HTT). Trinucleotic repeat expansion was found to occur immediately following the chromatin remodeling steps, confirming the genetic instability of the process and pointing to the origin of paternal anticipation observed in some trinucleotidic repeats diseases. 相似文献
92.
93.
《Neurologia i neurochirurgia polska》2014,48(4):236-241
Background and purposeHuntington disease (HD) is a neurodegenerative disease leading to involuntary movements, cognitive and behavior decline. The juvenile variant of HD (JHD) manifests in people younger than 21 and is characterized by a different clinical presentation, i.e. rigidity and bradykinesia. Rapid eye movements were not extensively studied in patients with JHD. Aims of our study were to describe the saccadic eye movements in JHD patients and to find a correlation between the saccade abnormalities, severity of the disease and cognitive and behavior deterioration.Materials and methodsWe studied 10 patients with JHD and 10 healthy subjects. Reflexive and volitional saccades were assessed with the Saccadometer Advanced. The battery of cognitive and behavior tests was performed as well.ResultsWe found a prolonged latency, slowness and decreased velocity of reflexive and voluntary saccades and reduced amplitude of voluntary saccades. Moreover, patients with JHD executed a significantly lower number of volitional saccades and made more incorrect cued saccades than controls. We noted a significant correlation between prolonged latency of reflexive saccades with gap task and disease severity and significant inverse correlation between prolonged latency of reflexive saccades with overlap task, an increased number of incorrect saccades made on a cue and impairment in working memory.ConclusionAbnormalities of saccade eye movements in patients with JHD were similar to those reported in patients with HD. Our findings did not confirm abnormalities previously reported in patients with early onset HD. Abnormal saccade parameters correlated also with a disease severity and cognitive deterioration. 相似文献
94.
AT van der Goot W Zhu RP Vázquez-Manrique RI Seinstra K Dettmer H Michels F Farina J Krijnen R Melki RC Buijsman M Ruiz Silva KL Thijssen IP Kema C Neri PJ Oefner EA Nollen 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(37):14912-14917
Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer's diseases. Here, we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity in a Caenorhabditis elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that tdo-2 functions as a general regulator of protein homeostasis. Analysis of metabolite levels in C. elegans strains with mutations in enzymes that act downstream of tdo-2 indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of tdo-2 increases tryptophan levels, and feeding worms with extra l-tryptophan also suppresses toxicity, suggesting that tdo-2 regulates proteotoxicity through tryptophan. Depletion of tdo-2 extends lifespan in these worms. Together, these results implicate tdo-2 as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases. 相似文献
95.
Sonia Franciosi PhD Yaein Shim BSc Margaret Lau BCom Michael R. Hayden MB ChB PhD Blair R. Leavitt MD CM 《Movement disorders》2013,28(14):1987-1994
Treatment effect in Huntington disease (HD) clinical trials has relied on primary outcome measures such as total motor score or functional rating scales. However, these measures have limited sensitivity, particularly in pre‐ to early stages of the disease. We performed a systematic review of HD clinical studies to identify endpoints that correlate with disease severity. Using standard HD keywords and terms, we identified 749 published studies from 1993 to 2011 based on the availability of demographic, biochemical, and clinical measures. The average and variability of each measure was abstracted and stratified according to pre‐far, pre‐close, early, mild, moderate, and severe HD stages. A fixed‐effect meta‐analysis on selected variables was conducted at various disease stages. A total of 1,801 different clinical variables and treatment outcomes were identified. Unified Huntington Disease Rating Scale (UHDRS) Motor, UHDRS Independence, and Trail B showed a trend toward separation between HD stages. Other measures, such as UHDRS Apathy, Verbal Fluency, and Symbol Digit, could only distinguish between pre‐ and early stages of disease and later stages, whereas other measures showed little correlation with increasing HD stages. Using cross‐sectional data from published HD clinical trials, we have identified potential endpoints that could be used to track HD disease progression and treatment effect. Longitudinal studies, such as TRACK‐HD, are critical for assessing the value of potential markers of disease progression for use in future HD therapeutic trials. A list of variables, references used in this meta‐analysis, and database is available at http://www.cmmt.ubc.ca/research/investigators/leavitt/publications . © 2013 International Parkinson and Movement Disorder Society 相似文献
96.
Cristina Sánchez‐Castañeda Andrea Cherubini Francesca Elifani Patrice Péran Sara Orobello Giovanni Capelli Umberto Sabatini Ferdinando Squitieri 《Human brain mapping》2013,34(7):1625-1635
Neurodegeneration of the striatum in Huntington disease (HD) is characterized by loss of medium‐spiny neurons, huntingtin nuclear inclusions, reactive gliosis, and iron accumulation. Neuroimaging allows in vivo detection of the macro‐ and micro‐structural changes that occur from presymptomatic stages of the disease (preHD). The aim of our study was to evaluate the reliability of multimodal imaging as an in vivo biomarker of vulnerability and development of the disease and to characterize macro‐ and micro‐structural changes in subcortical nuclei in HD. Macrostructure (T1‐weighted images), microstructure (diffusion tensor imaging), and iron content (R relaxometry) of subcortical nuclei and medial temporal lobe structures were evaluated by a 3 T scanner in 17 preHD carriers, 12 early‐stage patients and 29 matched controls. We observed a volume reduction and microstructural changes in the basal ganglia (caudate, putamen, and globus pallidus) and iron accumulation in the globus pallidus in both preHD and symptomatic subjects; all these features were significantly more pronounced in patients, in whom degeneration extended to the other subcortical nuclei (i.e., thalamus and accumbens). Mean diffusivity (MD) was the most powerful predictor in models explaining more than 50% of the variability in HD development in the caudate, putamen, and thalamus. These findings suggest that the measurement of MD may further enhance the well‐known predictive value of striatal volume to assess disease progression as it is highly sensitive to tissue microimpairment. Multimodal imaging may detect brain changes even in preHD stages. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc. 相似文献
97.
Mary K. Dean William Amestoy Cristiane Takita Stuart E. Samuels 《Medical Dosimetry》2019,44(3):274-278
Regional nodal irradiation (RNI) is an essential part of the treatment of high risk early stage (Stage IIb) and locally advanced (Stage III) breast cancer. Acceptable radiation plans can usually be achieved using 3-dimensional conformal radiation therapy with deep-inspiration breath hold to limit dose to the heart, although in some cases intensity-modulated radiation therapy produces superior results. The goal of this study is to identify radiographic parameters that predict the need for IMRT when delivering RNI. We retrospectively examined breast cancer patients treated with comprehensive RNI including internal mammary lymph nodes, supraclavicular lymph nodes, and undissected axillary lymph nodes at our institution from January 2016 to February 2018. Radiographic parameters including lung volume, internal mammary lymph nodes depth, modified central lung distance (mCLD), tangent length, and target height were recorded. Univariate and multivariate logistic regression was performed using IMRT as a binary endpoint (yes/no). A total of 46 patients were evaluated, of which 9 (20%) required IMRT. Five of the 9 (56%) IMRT patients were postmastectomy with a tissue expander in place. There was an increased likelihood of IMRT per 0.5 cm increase in mCLD (odds ratios [OR]: 3.27; 95% confidence interval [CI]: 1.39 to 9.63; p = 0.01) and per 1 cm increase in target height (OR: 1.77; 95% CI: 1.08 to 3.40; p = 0.04). A threshold value of 3.38 cm was identified for mCLD (OR 10.3; 95% CI: 2.14 to 61.4; p value = 0.005), and 25.2 cm for target height (OR 10.9; 95% CI: 2.19 to 82.7; p value = 0.007). When delivering RNI, larger values of mCLD and target height corresponded to the use of IMRT. Further investigations are warranted to confirm these findings, which may improve the efficiency of the treatment planning process and in turn patient care. 相似文献
98.
Will Guest Diana Forbes Colin Schlosser Stephen Yip Robin Coope Jason Chew 《Journal l'Association canadienne des radiologistes》2019,70(1):74-82
Purpose3-D printing is an increasingly widespread technology that allows physical models to be constructed based on cross-sectional medical imaging data. We sought to develop a pipeline for production of 3-dimensional (3-D) models for presurgical planning and assess the value of these models for surgeons and patients.MethodsIn this institutional review board–approved, single-center case series, participating surgeons identified cases for 3-D model printing, and after obtaining patient consent, a 3-D model was produced for each of the 7 participating patients based on preoperative cross-sectional imaging. Each model was given to the surgeon to use during the surgical consent discussion and preoperative planning. Patients and surgeons completed questionnaires evaluating the quality and usefulness of the models.ResultsThe 3-D models improved surgeon confidence in their operative approach, influencing the choice of operative approach in the majority of cases. Patients and surgeons reported that the model improved patient comprehension of the surgery during the consent discussion, including risks and benefits of the surgery. Model production time was as little as 4 days, and the average per-model cost was $350.Conclusions3-D printed models are useful presurgical tools from both surgeon and patient perspectives. Development of local hospital-based 3-D printing capabilities enables model production with rapid turnaround and modest cost, representing a value-added service for radiologists to offer their surgical colleagues. 相似文献
99.
100.
Kenneth C. Hohmeier Benjamin Loomis Justin Gatwood 《Research in social & administrative pharmacy》2018,14(4):360-366