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101.
Parisi MA Doherty D Chance PF Glass IA 《European journal of human genetics : EJHG》2007,15(5):511-521
Joubert syndrome (JS) and related disorders are characterized by the 'molar tooth sign' (cerebellar vermis hypoplasia and brainstem anomalies) on MRI, hypotonia, developmental delay, ataxia, irregular breathing pattern and abnormal eye movements. Combinations of additional features such as polydactyly, ocular coloboma, retinal dystrophy, renal disease, hepatic fibrosis, encephalocele, and other brain malformations define clinical sub-types. Recent identification of the NPHP1, AHI1, and CEP290 genes has started to reveal the molecular basis of JS, which may implicate the primary cilium in these disorders. Additional genes remain to be identified. 相似文献
102.
Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant. 总被引:2,自引:0,他引:2 下载免费PDF全文
C F Kenyon D C Knoppert S K Lee H M Vandenberghe G W Chance 《Antimicrobial agents and chemotherapy》1990,34(2):265-268
The pharmacokinetics of amikacin administered intravenously at currently recommended doses (7.5 mg/kg every 12 h for infants with less than 7 days of life; 7.5 mg/kg every 8 h for infants with greater than 7 days of life) were studied in 28 preterm infants weighing less than 2,500 g (mean +/- standard deviation, 1.38 +/- 0.47 kg; postconceptional age, 30.50 +/- 2.86 weeks). The medication was infused over 45 min. Trough and peak serum samples as well as two additional samples were taken at steady state. The results showed a statistically significant inverse relationship between half-life (8.42 +/- 2.55 h) and postconceptional age (P = 0.002) and a direct correlation between total body clearance (0.84 +/- 0.28 ml/min per kg) and postconceptional age (P = 0.02). These pharmacokinetic data were used to calculate a new dosage schedule for preterm infants. The derived intravenous dosage of amikacin for infants of less than 30 weeks of postconceptional age was 9 mg/kg every 18 h. For infants of greater than 30 weeks of postconceptional age, the dosage was 9 mg/kg every 12 h. Peak and trough levels of amikacin in serum that fell within the therapeutic range were compared by using the currently recommended dosage schedule and the dosage schedule derived from our pharmacokinetic data. There was a reduction in the number of peak and trough levels that fell outside the accepted therapeutic range which was not statistically significant. Extension of the dosing interval and a further increase in the dosage may result in further improvement. Based on these data, the current recommendations are inadequate for the preterm infant. Our derived dosage schedule improved but did not eliminate high trough and low peak levels of amikacin in all infants. The current recommendations should be adjusted for the preterm infant. Ongoing therapeutic drug monitoring is essential to tailor the amikacin dosage to the individual patient. 相似文献
103.
Sanjeev Shukla Rajnee Kanwal Eswar Shankar Manish Datt Mark R. Chance Pingfu Fu Gregory T. MacLennan Sanjay Gupta 《Oncotarget》2015,6(31):31216-31232
IKKα has been implicated as a key regulator of oncogenesis and driver of the metastatic process; therefore is regarded as a promising therapeutic target in anticancer drug development. In spite of the progress made in the development of IKK inhibitors, no potent IKKα inhibitor(s) have been identified. Our multistep approach of molecular modeling and direct binding has led to the identification of plant flavone apigenin as a specific IKKα inhibitor. Here we report apigenin, in micro molar range, inhibits IKKα kinase activity, demonstrates anti-proliferative and anti-invasive activities in functional cell based assays and exhibits anticancer efficacy in experimental tumor model. We found that apigenin directly binds with IKKα, attenuates IKKα kinase activity and suppresses NF-ĸB/p65 activation in human prostate cancer PC-3 and 22Rv1 cells much more effectively than IKK inhibitor, PS1145. We also showed that apigenin caused cell cycle arrest similar to knockdown of IKKα in prostate cancer cells. Studies in xenograft mouse model indicate that apigenin feeding suppresses tumor growth, lowers proliferation and enhances apoptosis. These effects correlated with inhibition of p-IKKα, NF-ĸB/p65, proliferating cell nuclear antigen and increase in cleaved caspase 3 expression in a dose-dependent manner. Overall, our results suggest that inhibition of cell proliferation, invasiveness and decrease in tumor growth by apigenin are mediated by its ability to suppress IKKα and downstream targets affecting NF-ĸB signaling pathways. 相似文献
104.
Dumaine CS Leswick DA Fladeland DA Lim HJ Toews LJ 《Journal l'Association canadienne des radiologistes》2012,63(3):183-191
Purpose
Follow-up study to observe if provincial mean effective radiation dose for head, chest, and abdomen-pelvis (AP) computed tomographies (CTs) remained stable or changed since the initial 2006 survey.Methods
Data were collected in July 2008 from Saskatchewan's 13 diagnostic CT scanners of 3358 CT examinations. These data included the number of scan phases and projected dose length product (DLP). Technologists compared projected DLP with 2006 reference data before scanning. Projected DLP was converted to effective dose (ED) for each head, chest, and AP CT. The total dose that the patients received with scans of multiple body parts at the same visit also was determined.Results
The mean (± SD) provincial ED was 3.4 ± 1.6 mSv for 1023 head scans (2.7 ± 1.6 mSv in 2006), 9.6 ± 4.8 mSv for 588 chest scans (11.3 ± 8.9 mSv in 2006), and 16.1 ± 9.9 mSv for 983 AP scans (15.5 ± 10.0 mSv in 2006). Single-phase multidetector row CT ED decreased by 31% for chest scans (9.5 ± 3.9 mSv vs 13.7 ± 9.7 mSv in 2006) and 17% for AP scans (13.9 ± 6.0 mSv vs 16.8 ± 10.6 mSv in 2006) and increased by 19% for head scans (3.2 ± 1.2 mSv vs 2.7 ± 1.5 mSv in 2006). The total patient dose was highest (33.8 ± 10.1 mSv) for the 20 patients who received head, neck, chest, and AP scans during a single visit. Because of increased utilisation and the increased CT head dose, Saskatchewan per capital radiation dose from CT increased by 21% between 2006 and 2008 (1.14 vs 1.38 mSv/person per year).Conclusion
Significant dose and variation reduction was seen for single-phase CT chest and AP examinations between 2006 and 2008, whereas CT head dose increased over the same interval. These changes, combined with increased utilisation, resulted in per capita increase in radiation dose from CT between the 2 studies. 相似文献105.
106.
C Michael Dunham Charlene Rabel Barbara M Hileman Jason Schiraldi Elisha A Chance Mark T Shima Alddo A Molinar David A Hoffman 《Thrombosis journal》2014,12(1):1-5
Background
Thromboelastography® (TEG) utilizes kaolin, an intrinsic pathway activator, to assess clotting function. Recent published studies suggest that TEG results are commonly normal in patients receiving warfarin, despite an increased International Normalized Ratio (INR). Because RapidTEG? includes tissue factor, an extrinsic pathway activator, as well as kaolin, we hypothesized that RapidTEG would be more sensitive in detecting a warfarin-effect.Methods
Included in this prospective study were 22 consecutive patients undergoing elective cardioversion and receiving warfarin. Prior to cardioversion, blood was collected to assess INR, Prothrombin Time, TEG, and RapidTEG.Results
INR Results: 2.8?±?0.5 (1.6 to 4.2). Prothrombin Time Results: 19.1?±?2.2 (13.9. to 24.3). TEG Results (Reference Range): R-Time: 8.3?±?2.7 (2–8); K-Time: 2.1?±?1.4 (1–3); Angle: 62.5?±?10.3 (55–78); MA: 63.2?±?10.3 (51–69); G: 9.4?±?3.5 (4.6-10.9); R-Time within normal range: 10 (45.5%) with INR 2.9?±?0.3; Correlation coefficients for INR and each of the 5 TEG variables were insignificant (P?>?0.05). RapidTEG Results (Reference Range): ACT: 132?±?58 (86–118); K-Time: 1.2?±?0.5 (1–2); Angle: 75.4?±?5.2 (64–80); MA: 63.4?±?5.1 (52–71); G: 8.9?±?2.0 (5.0-11.6); ACT within normal range: 9 (40.9%) with INR 2.7?±?0.5; Correlation coefficients for INR and each of the 5 RapidTEG variables were insignificant (P?>?0.05).Conclusions
TEG, using kaolin activation, and RapidTEG, with kaolin and tissue factor activation, were normal in a substantial percent of warfarin patients, despite an increased INR. The false-negative rate for detecting warfarin coagulopathy with either test is unacceptable. The lack of correlation between INR and all TEG and RapidTEG components further indicates that these methodologies are insensitive to warfarin effects. Findings suggest that intrinsic pathway activation may mitigate detection of an extrinsic pathway coagulopathy. 相似文献107.
Molecular mechanisms underlying the long QT syndrome. 总被引:4,自引:0,他引:4
Recent studies of the molecular basis of the long QT syndrome (LQTS) have advanced our understanding of the mechanisms responsible for the abnormal prolongation of ventricular repolarization and revealed associations between LQTS and other primary electrical diseases of the heart such as Brugada syndrome. The role of DNA single nucleotide polymorphisms in acquired LQTS and differences between the Romano-Ward and Jervell-Lange-Nielsen forms of congenital LQTS are gradually coming into focus. In this brief review, our goal is to summarize the molecular mechanisms proposed to underlie the susceptibility to arrhythmias in LQTS and discuss the direction of current and future research. 相似文献
108.
Modulation of I(Kr) inactivation by mutation N588K in KCNH2: a link to arrhythmogenesis in short QT syndrome 总被引:8,自引:0,他引:8
OBJECTIVE: Short QT syndrome (SQTS) is characterized by ventricular arrhythmias and sudden death. One form of SQTS is caused by mutation N588K in human ether-a-go-go-related gene (HERG). In this study we sought to determine the potential role of N588K in arrhythmias. METHODS: We measured the characteristics of HERG current generated by wild-type (WT) KCNH2 and the N588K mutant channel expressed in mammalian TSA201 cells. RESULTS: Whole-cell patch-clamp recordings of WT HERG currents showed the usual rapid onset of inactivation (rectification) at potentials more positive than +10 mV. In contrast, N588K currents rectified at potentials over +80 mV. Over the physiological range of potentials, N588K currents do not inactivate. During an action potential clamp, WT currents displayed a "hump" like waveform with slow activation kinetics and a rapid increase during phase 3 repolarization. In contrast, N588K currents were proportional to the amplitude of the action potential and displayed a dome-like configuration and a much larger current during the initial phases in the ventricle. Purkinje cell action potentials display a more negative phase 2 repolarization than the ventricle and elicited much smaller WT and N588K currents of similar amplitudes. CONCLUSIONS: Physiologically the N588K mutation abolishes rectification of HERG currents and specifically increases I(Kr) in the ventricle with minimal effects on the Purkinje fiber action potential duration. Such preferential prolongation may explain the separation of the T and U waves observed in the ECG of SQTS patients and lead to re-excitation of the ventricle endocardium. 相似文献
109.
C Michael Gibson Raphaelle L Dumaine Eli V Gelfand Sabina A Murphy David A Morrow Stephen D Wiviott Robert P Giugliano Christopher P Cannon Elliott M Antman Eugene Braunwald 《European heart journal》2004,25(22):1998-2005
AIMS: To determine the association of glomerular filtration rate (GFR) with clinical outcomes in the setting of non-ST-segment elevation acute coronary syndromes (NSTE-ACS). METHODS AND RESULTS: Data were pooled from five NSTE-ACS TIMI trials (TIMI 11A and B, TIMI 12, OPUS-TIMI 16 and TACTICS-TIMI 18) and were available in 13 307 patients. GFR was assessed as a continuous and a categorical variable (normal: > or = 90 mL/min/1.73 m2, n=4952; mildly decreased: 60-89 mL/min/1.73 m2, n=6262; and moderately to severely decreased GFR: <60 mL/min/1.73 m2, n=2093). There was an independent association between decreasing GFR and mortality at 30 days (OR 1.19, 95% CI 1.12-1.27, p<0.001) and at 6 months (OR 1.16, 95% CI 1.11-1.22, p<0.001). The combination of TIMI risk score (TRS) and decreasing GFR provided further mortality risk stratification with highest 30-day and 6-month mortality rates among patients with the lowest GFR who also had a TRS > or = 5 (9.1% and 15.4%, respectively). Decreasing GFR was also independently associated with stroke and recurrent ischaemia at 30-days as well as with major bleeding (p<0.001). CONCLUSION: In the setting of NSTE-ACS, impaired GFR is associated with higher mortality as well as higher rates of thrombotic and major bleeding events, independent of TRS. 相似文献
110.
Effect of dobutamine on skeletal muscle metabolism in patients with congestive heart failure 总被引:1,自引:0,他引:1
D M Mancini M Schwartz N Ferraro R Seestedt B Chance J R Wilson 《The American journal of cardiology》1990,65(16):1121-1126
Dobutamine is known to increase leg blood flow during exercise in patients with heart failure. However, it is uncertain whether the increased flow is delivered to working skeletal muscle. In 7 patients with heart failure, the effects of dobutamine were examined on calf phosphorus-31 magnetic resonance spectroscopy (MRS) spectra and femoral vein blood flow during rest and upright plantar flexion. During upright plantar flexion every 3 seconds, dobutamine increased femoral venous blood flow (control 1.7 +/- 0.1; dobutamine 2.1 +/- 1.0 liters/min; p less than 0.05) and increased femoral venous O2 saturation (control 24 +/- 5%; dobutamine 31 +/- 2%; p less than 0.05), indicating improved total leg blood flow. However, dobutamine did not change the slope of the relation between systemic VO2 and the calf inorganic phosphate to phosphocreatine relation (control 0.0054 +/- 0.0039; dobutamine 0.0056 +/- 0.0032; difference not significant) and did not change muscle pH, suggesting no improvement in blood flow to active skeletal muscle. These findings suggest that dobutamine does not improve oxygen delivery to working skeletal muscle in patients with heart failure, despite its ability to increase cardiac output and limb blood flow. 相似文献