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991.
John E. Campbell Kevin W. Kuntz Sarah K. Knutson Natalie M. Warholic Heike Keilhack Tim J. Wigle Alejandra Raimondi Christine R. Klaus Nathalie Rioux Akira Yokoi Satoshi Kawano Yukinori Minoshima Hyeong-Wook Choi Margaret PorterScott Nigel J. Waters Jesse J. Smith Richard Chesworth Mikel P. Moyer RobertA. Copeland 《ACS medicinal chemistry letters》2015,6(5):491-495
992.
993.
Anna E. Kornadt Isabelle Albert Martine Hoffmann Elke Murdock Josepha Nell 《European journal of ageing》2021,18(2):173
In the Covid-19 pandemic, being older means being in a special focus: Probabilities for severe infections and mortality rise with increasing age and protective measures for this population group have been increased. This was accompanied by public discourse that portrayed older adults stereotypically as vulnerable and frail but also highlighted the hardships younger people have to endure to protect them. Given the possibly detrimental effects of ageism on individuals and societies, we were interested in older adults’ perception of ageism in the Corona-crisis and its relation to their health and well-being. Furthermore, we were interested in subjective aging variables as moderators in the ageism–health relationship. In June 2020, N = 611 independently living people aged 60 + from the Grand Duchy of Luxembourg were recruited via a survey research institute and interviewed online or by phone. They reported on perceived ageism in different contexts, their life satisfaction, subjective health, subjective age and self-perceptions of aging. Depending on context, ageism was perceived by around 20% of participants, and overall negatively related to subjective health and life satisfaction after the onset of the pandemic. Moderated hierarchical regressions showed that a younger subjective age buffered the negative effect of ageism on subjective health, while perceiving aging as social loss increased its effect on life satisfaction. We discuss the importance of addressing and reducing ageism (not only) in times of crisis and the consequences for individuals and societies. 相似文献
994.
995.
996.
Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo 下载免费PDF全文
Lin B Catley L LeBlanc R Mitsiades C Burger R Tai YT Podar K Wartmann M Chauhan D Griffin JD Anderson KC 《Blood》2005,105(1):350-357
In this study, we investigated the in vitro and in vivo efficacy of patupilone (epothilone B, EPO906), a novel nontaxane microtubule stabilizing agent, in treatment of multiple myeloma (MM). Patupilone directly inhibited growth and survival of MM cells, including those resistant to conventional chemotherapies, such as the taxane paclitaxel. Patupilone induced G2M arrest of MM cells, with subsequent apoptosis. Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1), 2 known growth and survival factors for MM, did not protect MM.1S cells against patupilone-induced cell death. Proliferation of MM cells induced by adherence to bone marrow stromal cells (BMSCs) was also inhibited by patupilone and was paralleled by down-regulation of vascular endothelial growth factor (VEGF) secretion. Importantly, stimulation of cells from patients with MM, either with IL-6 or by adherence to BMSCs, enhanced the anti-proliferative and proapoptotic effects of patupilone. Moreover, patupilone was effective against MM cell lines that overexpress the MDR1/P-glycoprotein multidrug efflux pump. In addition, patupilone was effective in slowing tumor growth and prolonging median survival of mice that received orthotopical transplants with MM tumor cells. Taken together, these preclinical findings suggest that patupilone may be a safe and effective drug in the treatment of MM, providing the framework for clinical studies to improve patient outcome in MM. 相似文献
997.
Leppek R Hoos O Sattler A Kohle S Azzam S Al Haffar I Keil B Ricken P Klose KJ Alfke H 《Herz》2004,29(1):32-46
PURPOSE: This article describes the potential of dynamic contrast- enhanced magnetic resonance tomography (DCE-MRT) for the visualization and quantification of blood flow of lower leg muscles at rest and after individually adjusted muscular exercise. PATIENTS AND METHODS: Five cases were chosen to exemplify the qualitative and semi-quantitative blood flow evaluation in the lower leg muscles. The crural muscle state was determined with an isometric maximal strength measurement from a female patient with peripheral arterial occlusive disease (pAVK), a male patient with coronary heart disease (KHK) without clinical signs of a pAVK, a volunteer with sufficient physical activity in accordance with the Freiburg Questionnaire of Physical Activity and two professional athletes. After calibration of the plantarflexion ergometer MR-PEDALO (Figures 2a and 2b) for the execution of auxotonic muscle work a 1- minute alternating foot extension and flexion exercise on MRPEDALO was performed in the MR machine. Instead of the lower leg splint shown in Figures 2a and 2b the MR coil fits exactly in MR-PEDALO used for DCE-MRT. Mechanical work performed during the 1-minute exercise ranged from 52 watt seconds (Ws) to 244 Ws (0.65 W to 4.07 W), indicating similar interindividual work loads in relation to the individual maximum isometric strength. DCE-MRT was performed at rest and immediately after auxotonic exercise test (T1w 2DFLASH- GE sequence with TR/TE/alpha: 100 ms/6 ms/70 degrees; field of view: 400; matrix: 81 x 256; slice thickness: 10 mm; acquisitions: 73 at 8.3 s each; total examination time: 9.24 min; bolus application of Magnevist, Schering, 0.02 ml/kg kg, 20 ml bolus NaCl, flow 2 ml/s, 22G cannula in a cubital vein). Signal intensity (SI) curves were analyzed with DynaVision (MeVis gGmbH, Bremen, Germany). RESULTS: Measuring peripheral blood flow needs appropriate muscular stress tests. The SI-curves of the region of interest (ROI) representing the peroneus, tibialis anterior and gastrocnemius muscle run almost parallel at rest. Workloads between 52 Ws and 244 Ws (0.65 W and 4.07 W), similar in relation to the individual maximum isometric strength, induce distinctive changes of the upslope, wash-in, peak and washout of SI-curves preferably for the peroneus muscle and less predominant also for the tibialis anterior muscle and gastrocnemius muscle respectively. The first case, a 55-year-old female patient with peripheral arterial occlusive disease (pAVK) stage Fontaine IIb before (Figure 3a) and after (Figure 3b) percutaneous transluminal angioplasty (PTA) of a right femoral artery stenosis shows after interventional treatment a rapid post-exercise SI-increase in the peroneus muscle. The steeper SI-curve indicates a better contrast medium inflow due to an improved perfusion. The second case, a 65-year-old man suffering from coronary heart disease without clinical signs of pAVK (Figure 4) exercised with a workload of 92 Ws. After stress test the ROI for the peroneus muscle shows a clear intensity increase. After exercise the SI-curve for the tibialis anterior muscle shows a similar, but less predominant change while the shape of the SI-curve of the gastrocnemius muscle remains mainly identical. A 23-year-old male person with average physical activity (Figure 5) performed DCE-MRT of the left lower leg after stress test with 172 Ws demonstrating a rapid signal increase in the peroneus muscle while the synergistic tibialis anterior muscle and antagonistic gastrocnemius muscle show a comparatively slow contrast-medium wash-in. A 26-year-old male athlete (Figure 6) exercised with 196 Ws showing a rapid contrast medium inflow in the peroneus muscle and initially also in the synergistic tibialis anterior muscle. A contrast-medium wash-out appears in both muscles, while the shape of the gastrocnemius muscle SI-curve remains substantially unchanged. A 26-year-old female athlete (Figure 7) exercised with 244 Ws. Post exercise SI-curves show a distinctive and rapid increase of contrast medium wash-in with a sharp peak particularly in the peroneus muscle and similarly in the tibialis anterior and gastrocnemius muscle. After exercise all SI-curves show a wash-out phase. CONCLUSION: SI-curves show relative increase in correlation with Time-to-Peak (TTP) decrease and Mean-Intensity to Time Ratio (MITR) increase indicating blood flow reserve mobilization after exercise. Individual muscle state seems to be linked to muscle recruitment and muscle coordination reflected by post-exercise SI-curves. The gastrocnemius muscle shows comparatively low SI-curve changes after muscular load test. Further methodological standardization and optimization of the stress test is mandatory to assure intra- and interindividual comparisons. Due to direct visualization and quantitative evaluation of the peripheral microcirculation DCE-MRT has a diagnostic potential for monitoring therapeutic response in peripheral circulation disorders and sports medicine. 相似文献
998.
Klein HH Pich S Lindert-Heimberg S Nebendahl K Sprengel U Müller HH Schaper J 《Journal of thrombosis and thrombolysis》1996,3(4):361-366
This study investigated whether reperfusion results in an increase of ultrastructurally determined myocardial injury in pig hearts. The left anterior descending coronary artery (LAD) was distally occluded in 12 pigs for 35–45 minutes and then reperfused for 3 hours. At the end of ischemia, as well as after 3 hours of reperfusion, one transmural biopsy was removed from the center of the risk region and subdivided into four specimens, representing the subendocardial (I), subendo-midmyocardial (II), subepi-midmyocardial (III), and subepicardial layers (IV). The degree of injury was assessed by electronmicroscopy and was scored as reversible (1), an almost equal mixture of reversible and irreversible (2), and totally irreversible (3) damage. In addition, infarct size was determined as the ratio of infarcted (tetrazolium stain) to ischemic (dye technique) myocardium. Infarct sizes ranged from 29.3% to 93% (mean 61.2%). The scores of injury of the four tissue layers before and after reperfusion did not differ significantly: layer I, 2.4 ± 0.8/2.3 ± 0.9; layer II, 2.2 ± 0.9/2.0 ± 0.9; layer III, 1.8 ± 0.9/2.0 ± 0.9; and layer IV, 1.6 ± 0.9/1.3 ± 0.6. The means of the four layers were almost identical at the end of ischemia (2.1 ± 0.8) and after 3 hours of reperfusion (2.0 ± 0.6). A linear regression analysis with 95% confidence limits of the score values before and after reperfusion indicated that maximally 25% of a mean final infarct size of about 50% may be due to lethal reperfusion injury. This study suggests that cell death in regional ischemia and reperfusion occurs predominantly during ischemia and not during reperfusion. 相似文献
999.
Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease 总被引:1,自引:0,他引:1
Andersen S Pedersen KM Bruun NH Laurberg P 《The Journal of clinical endocrinology and metabolism》2002,87(3):1068-1072
High individuality causes laboratory reference ranges to be insensitive to changes in test results that are significant for the individual. We undertook a longitudinal study of variation in thyroid function tests in 16 healthy men with monthly sampling for 12 months using standard procedures. We measured serum T(4), T(3), free T(4) index, and TSH. All individuals had different variations of thyroid function tests (P < 0.001 for all variables) around individual mean values (set points) (P < 0.001 for all variables). The width of the individual 95% confidence intervals were approximately half that of the group for all variables. Accordingly, the index of individuality was low: T(4) = 0.58; T(3) = 0.54; free T(4) index = 0.59; TSH = 0.49. One test result described the individual set point with a precision of +/- 25% for T(4), T(3), free T(4) index, and +/- 50% for TSH. The differences required to be 95% confident of significant changes in repeated testing were (average, range): T(4) = 28, 11-62 nmol/liter; T(3) = 0.55, 0.3--0.9 nmol/liter; free T4 index = 33, 15-61 nmol/liter; TSH = 0.75, 0.2-1.6 mU/liter. Our data indicate that each individual had a unique thyroid function. The individual reference ranges for test results were narrow, compared with group reference ranges used to develop laboratory reference ranges. Accordingly, a test result within laboratory reference limits is not necessarily normal for an individual. Because serum TSH responds with logarithmically amplified variation to minor changes in serum T(4) and T(3), abnormal serum TSH may indicate that serum T(4) and T(3) are not normal for an individual. A condition with abnormal serum TSH but with serum T(4) and T(3) within laboratory reference ranges is labeled subclinical thyroid disease. Our data indicate that the distinction between subclinical and overt thyroid disease (abnormal serum TSH and abnormal T(4) and/or T(3)) is somewhat arbitrary. For the same degree of thyroid function abnormality, the diagnosis depends to a considerable extent on the position of the patient's normal set point for T(4) and T(3) within the laboratory reference range. 相似文献
1000.
Hintergrund: Die antiadrenerge Therapie mit Betablockern bei der chronischen Herzinsuffizienz hat sich nach 25 Jahren von einer Kontraindikation zu einer etablierten Behandlungsform additiv zu einer konventionellen Basistherapie mit Diuretikum, einem ACE-Hemmer (alternativ AT1-Antagonist) und optional Digitalis entwickelt. Pathophysiologie: Eine kompensatorische Überaktivierung des sympathischen Nervensystems bei chronischer Herzinsuffizienz resultiert in der Induktion verschiedener, für die Herzmuskelzelle letztlich deletärer biologischer Signale. Die Tatsache, dass diese Signale über adrenerge Rezeptoren vermittelt werden, stellt die pathophysiologische Grundlage für den Einsatz einer Betablockade bei Herzinsuffizienz dar. Therapeutische Empfehlungen nach Studienlage Die drei größten Betablockerinterventionsstudien (CIBIS II, MERIT-HF, COPERNIKUS) zeigten unter additiver Gabe von Bisoprolol, Metoprolol bzw. Carvedilol einen eindeutigen Überlebensvorteil für die mit diesen Betablockern behandelten Patienten. Nach heutiger Datenlage sollten alle Patienten mit stabiler chronischer Herzinsuffizienz (NYHA II-IV) und nachgewiesener linksventrikulärer Funktionsstörung (LVEF < 45%) einen der drei genannten Betablocker erhalten. Eine Betablockertherapie sollte grundsätzlich nur bei stabilen Patienten additiv zu einem ACE-Hemmer und einem Diuretikum mit einer sehr niedrigen Dosis begonnen und langsam über mehrere Wochen bis zur maximal vom Patienten tolerierten Dosis auftitriert werden ("start low, go slow but high"). Der Erfolg der "paradoxen Intervention" stellt sich erst nach etwa 2-3 Monaten ein. Background: Once contraindicated, beta-blockers have become an established, evidence-based, recommended treatment concept in chronic heart failure during the last years. Pathophysiology: The increased activation of the adrenergic system in heart failure syndrome, which leads to transmission of several adverse biological signals to myocytes through adrenergic receptors, provides the rationale for the use of beta-blockers in patients with chronic heart failure. Long-term treatment with different types of beta-blockers additive to an ACE-inhibitor and diuretics results in normalization of left ventricular shape, an improvement of left ventricular function, and a reduction of hospitalization rate for heart failure. Hemodynamic and clinical improvement is independent of etiology and severity of left ventricular dysfunction. Therapeutical Recommendations Accordings to Studies: Adequately powered clinical trials (CIBIS II, MERIT-HF, COPERNIcUS) testing different types of beta-blockers (bisoprolol, metoprolol, carvedilol) clearly demonstrated that total mortality and the incidence of sudden cardiac death were significantly reduced in heart failure patients by each of these agents. On the basis of all available evidence, all patients with chronic, stable heart failure (NYHA class II-IV) and with impaired left ventricular function (LVEF < 45%) should receive one of the three above mentioned beta-blockers. Protective effects of beta-blockers in heart failure comprise decrease in heart rate, a decrease of energy consumption, antifibrillatory effects, protection against adrenergic overactivation, and hence, inhibition of myocardial cell necrosis. Moreover, several beta-blockers induce an up-regulation of beta-receptors leading to an improvement of contractility during long-term treatment. It should be mentioned that even a low dosage of beta-blockers exert negative inotropic effects and may lead to a deterioration of hemodynamics and heart failure symptoms in patients with heart failure. The patients treated should be informed that the success of the "paradoxical intervention" will be obvious until 2-3 months after initiation of additional beta-blocker therapy. Beta-blocker treatment for heart failure should be started in stable patients with a very low initial dosage and then up-titrated to the maximal tolerated dosage and should be continued indefinitely. Mortality reduction by beta-blockade in heart failure is no class effect. So far, beneficial effects could only be demonstrated for lipophilic agents. Whether the non-selective beta-blocker carvedilol with additional properties has advantages over the beta-1-selective metoprolol is currently investigated in the COMET (Carvedilol or Metoprolol European Trial) study. Despite the impressive effects in terms of morbidity and mortality reduction, the transfer of these benefits to the clinical practice setting is difficult, with international data showing only 10% of patients with heart failure being treated. 相似文献