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11.
Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin 下载免费PDF全文
Ryoko Sawamura Hidetaka Sakurai Naoya Wada Yumi Nishiya Tomoyo Honda Miho Kazui Atsushi Kurihara Akira Shinagawa Takashi Izumi 《Biopharmaceutics & drug disposition》2015,36(6):352-363
Loxoprofen (LX) is a prodrug‐type non‐steroidal anti‐inflammatory drug which is used not only as an oral drug but also as a transdermal formulation. As a pharmacologically active metabolite, the trans‐alcohol form of LX (trans‐OH form) is generated after oral administration to humans. The objectives of this study were to evaluate the generation of the trans‐OH form in human in vitro skin and to identify the predominant enzyme for its generation. In the permeation and metabolism study using human in vitro skin, both the permeation of LX and the formation of the trans‐OH form increased in a time‐ and dose‐dependent manner after the application of LX gel to the skin. In addition, the characteristics of permeation and metabolism of both LX and the trans‐OH form were examined by a mathematical pharmacokinetic model. The Km value was calculated to be 10.3 mm in the human in vitro skin. The predominant enzyme which generates the trans‐OH form in human whole skin was identified to be carbonyl reductase 1 (CBR1) by immunodepletion using the anti‐human CBR1 antibody. The results of the enzyme kinetic study using the recombinant human CBR1 protein demonstrated that the Km and Vmax values were 7.30 mm and 402 nmol/min/mg protein, respectively. In addition, it was found that no unknown metabolites were generated in the human in vitro skin. This is the first report in which LX is bioactivated to the trans‐OH form in human skin by CBR1. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
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Hideaki Kanki Hideo Mitamura Seiji Takatsuki Kouichiro Sueyoshi Kaori Shinagawa Toshiaki Sato Satoshi Ogawa 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》1998,12(5):475-482
The antifibrillatory effect of pilsicainide, a sodium channel blocker with slow recovery kinetics, was investigated in a canine model of atrial fibrillation. Prolonging the atrial effective refractory period is an important mechanism for pharmacological termination of atrial fibrillation. However, the effectiveness of potassium channel blockers has been questioned because of their reverse-use–dependent property. In eight open-chest dogs, the duration of the atrial endocardial monophasic action potential and the atrial effective refractory period were determined using a Franz catheter. Conduction velocity was obtained from a 96-channel mapping electrode at multiple cycle lengths. Inducibility of sustained atrial fibrillation (>30 minutes) was confirmed by atrial burst pacing during bilateral vagal stimulation, and local fibrillation cycle lengths were measured. Five minutes after restarting fibrillation, pilsicainide (0.6 mg/kg + 0.04 mg/kg/min) was administered. After fibrillation was terminated, measurements were repeated. Pilsicainide successfully terminated atrial fibrillation in 7 of 8 dogs after the median time of 5.1 minutes. The conduction velocity decreased significantly. Although pilsicainide did not affect monophasic action potential duration, it caused use-dependent prolongation of the atrial effective refractory period (P < 0.05), creating postrepolarization refractoriness. Accordingly, pilsicainide prolonged the atrial fibrillation cycle length from 80.6 to 113.8 ms (P < 0.05) before termination of fibrillation. Sodium channel blockers with slow recovery kinetics can prolong the atrial effective refractory period without affecting monophasic action potential duration. Unlike potassium channel blockers, these sodium channel blockers maintain postrepolarization refract 相似文献
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Toshimi Koitabashi Takayuki Inomata Shinichi Niwano Mototsugu Nishii Ichiro Takeuchi Hironari Nakano Hisahito Shinagawa Hitoshi Takehana Tohru Izumi 《Circulation journal》2005,69(7):823-830
BACKGROUND: The prognostic significance of atrial fibrillation (AF) in chronic heart failure (CHF) remains poorly understood. METHODS AND RESULTS: Death and rehospitalizaion for CHF exacerbation for 427 consecutive patients hospitalized from 1996 to 2002 were retrospectively analyzed in relation to cardiac rhythm: sinus rhythm (SR; n=239) or AF (n=188). The AF group was classified according to an Intervention (n=57) or Non-Intervention (n=131) group for defibrillating AF. During the follow-up of 34+/-23 months, there was no significant difference of mortality or morbidity between the SR and AF groups, or between the Intervention and Non-Intervention groups, respectively. However, the Non-Intervention group consisted of 28 patients with paroxysmal AF (PAF), which spontaneously converted to SR during hospitalization, and 103 with chronic AF (CAF). The rehospitalization for CHF exacerbation was significantly higher in PAF than that in CAF and SR (p=0.00005 and 0.002, respectively). Multivariate Cox analysis demonstrated that, PAF, but not CAF, was a predictor of readmission (relative risk 2.30, p=0.004, 95% confidence interval 1.30 to 4.05). CONCLUSIONS: The present data implied that PAF coincident with cardiac decompensation could be a new predictor of prognosis for CHF. The management strategies of AF in CHF should be discussed according to the phenotype of AF. 相似文献
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T. Matsushige Y. Akiyama T. Okazaki K. Shinagawa N. Ichinose K. Awai K. Kurisu 《AJNR. American journal of neuroradiology》2015,36(8):1507
BACKGROUND AND PURPOSE:Inflammation and degeneration of the intracranial saccular aneurysm wall play a major role in aneurysm formation, development and subsequent rupture. The aim of this study was to characterize the walls of unruptured intracranial aneurysms by using a hybrid of opposite-contrast MRA at 3T.MATERIALS AND METHODS:Fourteen consecutive patients with 17 unruptured intracranial aneurysms who initially underwent clipping surgery were prospectively evaluated. All aneurysms were scanned preoperatively by using a hybrid of opposite-contrast MRA in 3T high-resolution MR imaging. We classified intraoperative findings of atherosclerotic plaques in the aneurysms into 3 grades: grade A (major plaques), grade B (minor plaques), and grade C (no plaques). The contrast ratio of the high-intensity area was also measured relative to the background low-intensity area inside the carotid artery.RESULTS:Findings from preoperative plaque imaging of the aneurysm corresponded to the intraoperative findings in 15 of 16 aneurysms (excluding 1 that was impossible to visualize in its entirety due to anatomic reasons). Overall sensitivity and specificity of the hybrid of opposite-contrast MRA were 88.9% and 100%, respectively. During the operation, 4 aneurysms were classified as grade A; 5, as grade B; and 7, as grade C. The means of the contrast ratio for grades A, B, and C were 0.72 ± 0.03, 0.34 ± 0.30, and −0.02 ± 0.09, respectively.CONCLUSIONS:The hybrid of opposite-contrast MRA can detect visible atherosclerotic plaques in the unruptured aneurysm wall, and the contrast ratio in intracranial aneurysms correlated with their presence and extent. A study including a larger series is needed to validate the diagnostic potential of this imaging technique.Intracranial aneurysms are common vascular lesions, often consisting of a saccular dilation of a cerebral artery vessel. The prevalence of intracranial aneurysms in the general population is estimated between 2.5% and 5%.1,2 Aneurysmal rupture occurs with a 1% risk per year, depending on the size, location, and morphometry of the aneurysm, and leads to subarachnoid hemorrhage with associated high morbidity and mortality rates.1,2 Intracranial aneurysms with an estimated high risk of rupture undergo management via a surgical or endovascular approach, depending on the specific risks of treatment.3,4 Therefore, it is important to accurately assess the risk of aneurysmal rupture.The pathogenesis of intracranial aneurysms and their natural history are not well-understood. Histopathologic studies have shown that the infiltration of inflammatory cells and the degeneration of the aneurysm wall with atherosclerosis correlates with the formation, development, and rupture risk of cerebral aneurysms.5–9 However, characterization of the aneurysm wall is limited by imaging data quality and the need to harvest surgical specimens.In this regard, the characteristics of high-field-strength MR imaging, which has a favorable SNR and changes in relaxation time and susceptibility, can depict the intracranial vessel walls and their pathologies, including small vessels with atherosclerosis.10,11The hybrid of opposite-contrast MR angiography (HOP-MRA) used in this study is a modern technique that combines the advantages of 3D TOF MRA and flow-sensitive black-blood (FSBB) MRA.12 The clinical efficacy of this technique was established to improve the visualization of peripheral vessels.13,14 Theoretically, tissue with shorter T1 and T2* introduces high signal in FSBB of HOP-MRA, which demonstrates atherosclerotic plaques, including fat, as high-signal-intensity areas and demonstrates the blood space as low-signal-intensity areas in intracranial aneurysms.12 The strength of this technique is the dual-echo 3D gradient-echo sequence, which enables a shorter imaging time and minimization of misregistration. The present study investigated the utility of HOP-MRA at 3T for the characterization of visible atherosclerotic plaques in intracranial aneurysms by using subtraction between TOF and FSBB imaging. 相似文献
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H Okada M Takemoto Y Kawahara J Nasu R Takenaka S Kawano M Inoue K Ichimura T Tanaka K Shinagawa T Yoshino K Yamamoto 《Digestion》2012,86(3):179-186
Background/Aims: Few studies exist on the efficacy and long-term outcome of radiation therapy (RT) for gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Methods: Twenty-two patients with stage I or stage II(1) disease were prospectively evaluated, including 14 patients without Helicobacter pylori(H. pylori) infection and 8 patients with persistent lymphoma after H. pylori eradication. RT dose was 30 Gy in daily fractions of 1.5 Gy. All patients underwent endoscopic and histological follow-up regularly. Results: The study included 22 patients with a mean age of 63 years. The t(11;18)(q21;q21) translocation occurred in 8 of the 22 cases. All patients showed complete remission without any serious toxicity. At a median follow-up evaluation 74 months (range 27-159) after completion of RT, the overall and relapse-free survival rates after 5 years were 91 and 84%, respectively. Although no patient showed local recurrence of lymphoma, distant recurrence was detected in 3 patients, all of whom were H. pylori negative; MALT lymphoma relapsed in two patients with the t(11;18)(q21;q21) translocation, and diffuse large-cell lymphoma developed in one patient without the translocation. Conclusion: RT provides excellent local control of the gastric MALT lymphoma. However, continuous follow-up is mandatory as relapse may occur in other sites. 相似文献
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Hiroyoshi Adachi MD PhD Shunichiro Shinagawa MD PhD Kenjiro Komori MA Yasutaka Toyota MD PhD Takaaki Mori MD PhD Teruhisa Matsumoto MD PhD Naomi Sonobe MD PhD Tetsuo Kashibayashi MD PhD Tomohisa Ishikawa MD PhD Ryuji Fukuhara MD PhD Manabu Ikeda MD PhD 《Psychiatry and clinical neurosciences》2013,67(3):148-153
19.
Ritsuko Fujimitsu Mikiko Shimakura Hiroshi Urakawa Ayako Morita Yoshinobu Shinagawa Keiko Sakamoto Kengo Yoshimitsu 《Japanese journal of radiology》2016,34(7):508-514
Objective
To clarify the details of homogeneously enhancing lesions on contrast-enhanced ultrasonography (CEUS) and also to elucidate whether their differential diagnosis is possible.Methods
Seventy-three homogeneously enhancing lesions on CEUS were retrospectively selected. Two radiologists first assessed conventional US findings alone in consensus to differentiate malignant vs. benign lesions. Then, qualitative and quantitative CEUS findings were analyzed to determine the useful findings for the differential diagnosis. Determined CEUS findings were applied to the indeterminate lesions based on conventional US findings to see whether CEUS can improve the diagnostic performance.Results
There were 42 cancers (58 %) out of 73. Sensitivity and specificity using conventional US findings alone were 91 and 55 %, respectively. Among the CEUS findings tested, multivariate analysis revealed only the type 3 enhancement pattern, which indicates a larger enhancing area than the precontrast hypoechoic lesion, was related to malignancy (p < 0.05). By adding this information, however, no improvement was achieved in the diagnostic performance as determined by conventional US findings.Conclusions
Approximately half of the homogeneously enhancing lesions on CEUS are malignant, and differentiation of malignant from benign lesions may be possible, at least to some extent, by meticulous assessment of the conventional US rather than CEUS findings.20.