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81.
Andréa G. K. Ferreira Daniela D. Lima Débora Delwing Vanize Mackedanz Bárbara Tagliari Janaína Kolling Patrícia F. Schuck Moacir Wajner Angela T. S. Wyse 《Metabolic brain disease》2010,25(2):161-168
In the present study we investigated the effect of acute hyperprolinemia on some parameters of energy metabolism, including
the activities of succinate dehydrogenase and cytocrome c oxidase and 14CO2 production from glucose and acetate in cerebral cortex of young rats. Lipid peroxidation determined by the levels of thiobarbituric
acid-reactive substances, as well as the influence of the antioxidants α-tocopherol plus ascorbic acid on the effects elicited
by Pro on enzyme activities and on the lipid peroxidation were also evaluated. Wistar rats of 12 and 29 days of life received
one subcutaneous injection of saline or proline (12.8 or 18.2 μmol/g body weight, respectively) and were sacrificed 1 h later.
In another set of experiments, 5- and 22-day-old rats were pretreated for a week with daily intraperitoneal administration
of α-tocopherol (40 mg/kg) plus ascorbic acid (100 mg/kg) or saline. Twelve hours after the last injection, rats received
one injection of proline or saline and were sacrificed 1 h later. Results showed that acute administration of proline significantly
reduced cytochrome c oxidase activity and increased succinate dehydrogenase activity and 14CO2 production in cerebral cortex, suggesting that Pro might disrupt energy metabolism in brain of young rats. In addition, proline
administration increased the thiobarbituric acid-reactive substances levels, which were prevented by antioxidants. These findings
suggest that mitochondrial dysfunction and oxidative stress may be important contributors to the neurological dysfunction
observed in some hyperprolinemic patients and that treatment with antioxidants may be beneficial in this pathology. 相似文献
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Wajner A Bürger C Dutra-Filho CS Wajner M de Souza Wyse AT Wannmacher CM 《Metabolic brain disease》2007,22(1):77-88
The objective of the present study was to investigate the in vitro effects of the branched-chain α-keto acids accumulating in maple syrup urine disease, namely L-2-ketoisocaproic acid, L-2-keto-3-methylvaleric
acid and L-2-ketoisovaleric acid on Na+, K+-ATPase activity in synaptic plasma membranes from cerebral cortex of 35-day-old rats. All keto acids significantly inhibited
Na+, K+-ATPase activity at concentrations similar (1 mM) or even lower (0.5 mM) than those found in blood and cerebrospinal fluid
of maple syrup urine disease patients. We also tested the effects of alanine on this enzyme activity. Alanine per se did not alter Na+, K+-ATPase activity, but totally prevented the branched-chain α-keto acids-induced Na+, K+-ATPase inhibition, indicating that alanine and the keto acids may possibly bind to the same site on the enzyme. We also observed
that the branched-chain amino acids leucine, isoleucine and valine also inhibited Na+ K+-ATPase activity to a similar degree as that of the branched-chain α-keto acids and that alanine was able to fully prevent
these effects. Considering that Na+, K+-ATPase is a critical enzyme for normal brain development and functioning, it is presumed that these findings may be involved
in the pathophysiology of the neurological dysfunction of maple syrup urine disease. 相似文献
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87.
C. Matté L.O. PereiraT.M. Dos Santos V. MackedanzA.A. Cunha C.A. NettoA.T.S. Wyse 《Neuroscience》2009
In the present study, we first investigated the effect of single homocysteine administration on consolidation of short- and long-term memories of inhibitory avoidance task in Wistar rats. We also measured brain-derived neurotrophic factor levels in the hippocampus and parietal cortex of rats. The influence of pretreatment with folic acid on behavioral and biochemical effects elicited by homocysteine was also studied. Wistar rats were subjected to a folic acid or saline pretreatment from their 22nd to 28th day of life; 12 h later they were submitted to a single administration of homocysteine or saline. For motor activity and memory evaluation we performed open-field and inhibitory avoidance tasks. Hippocampus and parietal cortex were obtained for brain-derived neurotrophic factor immunocontent determination. Results showed that homocysteine impaired short- and long-term memories and reduced brain-derived neurotrophic factor levels in the hippocampus. Pretreatment with folic acid prevented both the memory deficit and the reduction in the brain-derived neurotrophic factor immunocontent induced by homocysteine injection. Further studies are required to determine the entire mechanism by which folic acid acts and its potential therapeutic use for memory impairment prevention in homocystinuric patients. 相似文献
88.
We report a patient with a clinical and molecular diagnosis of LEOPARD syndrome (LS) associated with multiple granular cell tumors (MGCT). Bidirectional sequencing of exons 7, 12, and 13 of the PTPN11 gene revealed the T468M missense mutation in exon 12. This mutation has been previously reported in patients with LS. To our knowledge, this is the first report of MGCT associated with molecularly characterized LS and provides the first molecular evidence linking granular cell tumors (GCT) to the Ras/mitogen-activated protein (MAP) kinase pathway. We propose that MGCT can be associated with LS. Analysis of GCT from this case tested negatively for loss of heterozygosity (LOH) at the PTPN11 and NF1 loci and did not show deletions of the PTEN gene. The absence of LOH of PTPN11 supports published functional data that T468M is a dominant-negative mutation. 相似文献
89.
E Barrow L Robinson W Alduaij A Shenton T Clancy F Lalloo J Hill DG Evans 《Clinical genetics》2009,75(2):141-149
Lynch syndrome or hereditary non-polyposis colorectal cancer is caused by mutations of DNA mismatch repair (MMR) genes. The extracolonic tumour spectrum includes endometrial, ovarian, gastric, small bowel, pancreatic, hepatobiliary, brain, and urothelial neoplasms. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with a Lynch syndrome spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. Kaplan–Meier analysis of risk to 70 years was calculated. One hundred and eighty-four Lynch syndrome spectrum extracolonic cancers in 839 proven, obligate, or assumed mutation carriers were analysed. Cumulative risk for females of an extracolonic tumour is 47.4% (95% CI 43.9–50.8). The risk to males is 26.5% (95% CI 22.6–30.4). There was no reduction in gynaecological malignancies due to gynaecological screening (examination, transvaginal ultrasound scan, hysteroscopy and endometrial biopsy). Males have a higher risk of gastric cancer than females (p = 0.0003). Gastric cancer risk in those born after 1935 does not justify surveillance. These penetrance estimates have been corrected for ascertainment bias and are appropriate for those referred to a high-risk clinic. 相似文献
90.
Pratt CM Roy D Torp-Pedersen C Wyse DG Toft E Juul-Moller S Retyk E Drenning DH;Atrial Arrhythmia Conversion Trial 《The American journal of cardiology》2010,106(9):1277-1283
The objective of the present study was to assess the safety and effectiveness of vernakalant hydrochloride injection (RSD1235), a novel antiarrhythmic drug, for the conversion of atrial fibrillation (AF) or atrial flutter to sinus rhythm (SR). Patients with either AF or atrial flutter were randomized in a 1:1 ratio to receive vernakalant (n = 138) or placebo (n = 138) and were stratified by an arrhythmia duration of >3 hours to ≤7 days (short duration) and 8 to ≤45 days (long duration). The first infusion of placebo or vernakalant (3 mg/kg) was given for 10 minutes followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later if the arrhythmia had not terminated. A total of 265 patients were randomized and received treatment. The primary end point was conversion of AF to SR for ≥1 minute within 90 minutes of the start of the drug infusion in the short-duration AF group. Of the 86 patients receiving vernakalant in the short-duration AF group, 44 (51.2%) demonstrated conversion to SR compared to 3 (3.6%) of the 84 in the placebo group (p <0.0001). The median interval to conversion of short-duration AF to SR in the responders given vernakalant was 8 minutes. Of the entire AF population (short- and long-duration AF), 47 (39.8%) of the 118 vernakalant patients experienced conversion of AF to SR compared to 4 (3.3%) of the 121 placebo patients (p <0.0001). Transient dysgeusia and sneezing were the most common adverse events in the vernakalant patients. One vernakalant patient who had severe aortic stenosis experienced hypotension and ventricular fibrillation and died. In conclusion, vernakalant demonstrated a rapid and high rate of conversion for short-duration AF and was well tolerated. 相似文献