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991.
992.
Jakob Lykke Lindhardt Per Mose Nielsen Esben Svs Szocska Hansen Haiyun Qi Rasmus Stilling Tougaard Christian
stergaard Mariager Lotte Bonde Bertelsen Won Yong Kim Christoffer Laustsen 《NMR in biomedicine》2020,33(10)
Renal ischemia‐reperfusion injury (IRI) is one of the most common types of acute kidney injury. Spironolactone has shown promising kidney protective effects in renal IRI in rats. We investigated the hemodynamic and metabolic effects of spironolactone (100 mg/kg) administered immediately after 40 min unilateral kidney ischemia in rats. Hyperpolarized MRI using co‐polarized [1‐13C]pyruvate and [13C,15N2]urea as well as 1H dynamic contrast‐enhanced (DCE) MRI was performed 24 h after induction of ischemia. We found a significant decrease in renal blood flow (RBF) in the ischemic kidney compared with the contralateral one measured using DCE and [13C,15N2]urea. The RBF measured using [1‐13C]pyruvate and [13C,15N2]urea was significantly altered by spironolactone. The RBFs in the ischemic kidney compared with the contralateral kidney were decreased similarly as measured using both [13C,15N2]urea and [1‐13C]pyruvate in the spironolactone‐treated group. Spironolactone treatment increased the perfusion‐corrected pyruvate metabolism by 54% in both the ischemic and contralateral kidney. Furthermore, we showed a correlation between vascular permeability using a histological Evans blue analysis and the ratio of the volumes of distribution (VoDs), ie VoD‐[13C,15N2]urea/VoD‐[1‐13C]pyruvate. This suggests that [13C,15N2]urea/[1‐13C]pyruvate VoD ratio may be a novel indicator of renal vascular permeability associated with renal damage in rodents. 相似文献
993.
Jack Hou Anatol Manaenko Jakob Hakon Jacob Hansen-Schwartz Jiping Tang John H Zhang 《Journal of cerebral blood flow and metabolism》2012,32(12):2201-2210
The inflammatory response plays a pivotal role in propagating injury of intracerebral hemorrhage (ICH). Glucagon-like-peptide-1 (GLP-1) is a hormone with antidiabetic effect and may also have antiinflammatory properties. Despite consensus that the glucoregulatory action is mediated by the GLP-1 receptor (GLP-1R), mechanisms in the brain remain unclear. We investigated the effect of a long-acting GLP-1 analog, liraglutide, and its truncated metabolite, GLP-1(9-36)a from dipeptidyl peptidase-4 (DPP-4) cleavage in ICH-induced brain injury. Primary outcomes were cerebral edema formation, neurobehavior, and inflammatory parameters. GLP-1(9-36)a, GLP-1R inhibitor, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation inhibitor and DPP-4 inhibitor were administered to examine the mechanisms of action. Liraglutide suppressed neuroinflammation, prevented brain edema and neurologic deficit following ICH, which were partially reversed by GLP-1R inhibitor and AMPK phosphorylation inhibitor. Liraglutide-mediated AMPK phosphorylation was unaffected by GLP-1R inhibitor, and was found to be induced by GLP-1(9-36)a. GLP-1(9-36)a showed salutary effects on primary outcomes that were reversed by AMPK phosphorylation inhibitor but not by GLP-1R inhibitor. Liraglutide and DPP-4 inhibitor co-administration reversed liraglutide-mediated AMPK phosphorylation and antiinflammatory effects. Liraglutide exerted duals actions and the antiinflammatory effects are partially mediated by its metabolite in a phosphorylated AMPK-dependent manner. Therapies that inhibit GLP-1 degradation may weaken the metabolite-mediated effects. 相似文献
994.
995.
Jakob H. Mikkelsen Zachary T. Resch Bhanu Kalra Gopal Savjani Ajay Kumar Cheryl A. Conover Claus Oxvig 《Oncotarget》2014,5(4):1014-1025
The insulin-like growth factor (IGF) signaling pathway is involved in certain human cancers, and the feasibility of directly targeting the IGF receptor has been actively investigated. However, recent evidence from clinical trials suggests that this approach can be problematic. We have developed an alternative strategy to indirectly inhibit the IGF signaling by targeting the metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). PAPP-A associated with the cell surface cleaves IGF binding protein-4 (IGFBP-4), when IGF is bound to IGFBP-4, and thereby increases IGF bioavailability for receptor activation in an autocrine/paracrine manner. We hypothesized that inhibition of PAPP-A would suppress excessive local IGF signaling in tissues where this is caused by increased PAPP-A proteolytic activity. To test this hypothesis, we developed an inhibitory monoclonal antibody, mAb 1/41, which targets a unique substrate-binding exosite of PAPP-A. This inhibitor selectively and specifically inhibits proteolytic cleavage of IGFBP-4 with an inhibitory constant (Ki) of 135 pM. In addition, it inhibited intracellular signaling of the IGF receptor (AKT phosphorylation) in monolayers of A549 cells, an IGF-responsive lung cancer-derived cell line found to express high levels of PAPP-A. We further showed that mAb 1/41 is effective towards PAPP-A bound to cell surfaces, and that it is capable of inhibiting PAPP-A activity in vivo. Using a murine xenograft model of A549 cells, we demonstrated that mAb 1/41 administered intraperitoneally significantly inhibited tumor growth. Analysis of xenograft tumor tissue recovered from treated mice showed penetration of mAb 1/41, reduced IGFBP-4 proteolysis, and reduced AKT phosphorylation. Our study provides proof of concept that IGF signaling can be selectively reduced by targeting a regulatory proteinase that functions extracellularly, upstream of the IGF receptor. PAPP-A targeting thus represents an alternative therapeutic strategy for inhibiting IGF receptor signaling. 相似文献
996.
Self-rated evaluation of outcome of the implantation of interspinous process distraction (X-Stop) for neurogenic claudication 总被引:3,自引:0,他引:3
Paul Brussee Jakob Hauth Roland D. Donk André L. M. Verbeek Ronald H. M. A. Bartels 《European spine journal》2008,17(2):200-203
The treatment of lumbar spinal stenosis is either conservative or surgical decompression. Recently, an interspinous decompression
device (X-Stop) has been developed as an alternative. Patients treated with an X-Stop between 2003 and 2006 are subject of
this study. The SF-36 Health Survey and Zürich Questionnaires are used. The data of pre- and post-operative self-rated questionnaires
are collected and analysed by independent investigators. The data were statistically analysed. A good outcome was defined
when the mean score at the ZQ for satisfaction was at maximal 2.0, and the mean improvement of the severity score was at least
0.5, and also for vitality score. For relations between outcome and gender, smoking, BMI, orthopaedic co-morbidity, number
of implanted X-Stops were sought. The change in SF-36 scales was related to the outcome. Sixty-five patients did undergo implantation
of an X-Stop. The mean age was 64.4 ± 10.0 years (range: 37.0–85.0 years). 31.1% Of the patients had a good outcome. A good
outcome was not related to smoking, BMI, number of implanted X-Stops. However, a good outcome was related to the absence of
orthopaedic co-morbidity or male gender. Patients with a good outcome had significantly a better improvement of the scales
of the SF-36 concerning physical pain or impairment. The X-Stop does improve the clinical situation. However, a good outcome
is achieved less often than previously reported. Probable explanations are discussed. 相似文献
997.
The cardinal features of Kabuki (Niikawa-Kuroki) syndrome (KS) include characteristic facial dysmorphic features, mild to moderate mental deficiency, skeletal abnormalities, dermatoglyphic abnormalities, and postnatal growth retardation. We identified 8 patients with KS in a genetics clinic over the past 5 years. All were Caucasians, except for 2 who were of mixed Aboriginal and Caucasian descent. All had the facial gestalt, the dermatoglyphic abnormalities characteristic of the syndrome, and developmental delay. Dental abnormalities of permanent teeth were seen in all 8 cases; 6 had missing lower incisors. Five patients had uniquely abnormal upper incisor teeth shape; the upper incisors had a 'flat head' screwdriver-shaped appearance. Other dental abnormalities included missing lower lateral incisors, missing second premolars, and ectopic upper 6-year molars. We believe the presence of the unique dental findings will prove useful in the diagnostic assessment of individuals with KS. 相似文献
998.
Jakob Halborg Jan Ulrik Prause Peter Bjerre Toft Karen Skjødt Niels Rath Tommerup Ole Faurskov Nielsen Steffen Heegaard 《Acta ophthalmologica. Supplement》2009,87(6):672-675
Purpose: Stones (dacryoliths) in the lacrimal drainage system are relatively common. However, stones in the lacrimal gland itself are very rare. We present three cases of lacrimal gland stones and describe the clinical and histopathological characteristics and composition of the stones. Methods: Three patients presented with swelling in the lateral canthal region of several months’ duration. Clinical examination in each case revealed a mass adjacent to the lacrimal gland. We carried out surgical excision, histological examination and Raman spectroscopy. Results: Histopathological examination of the excised material showed an eosinophilic, amorphic material organized in lamellae and localized in a ductule. The findings were consistent with a stone in the lacrimal gland in all three cases. All stones were composed of proteins of similar types. After surgery, the three patients healed without complications. Conclusions: Lacrimal gland stones represent a very rare but relevant differential diagnosis when a patient presents with unilateral persistent conjunctivitis or with a tumour in the lateral canthus. Treatment is excision under local anaesthesia. 相似文献
999.
1000.
Paulus Schurr Edda Lentz Suzette Block Jussuf Kaifi Helge Kleinhans Guellue Cataldegirmen Asad Kutup Claus Schneider Tim Strate Emre Yekebas Jakob Izbicki 《Journal of gastrointestinal surgery》2008,12(7):1232-1238
Background To date, the survival benefit of redo surgery in locally recurrent rectal adenocarcinoma remains unclear.
Study Design In an institutional study, operations for recurrence were retrospectively analyzed. Survival was calculated using the Kaplan–Meier
plot and Cox regression analysis.
Results A total of 72 patients with local recurrence were explored or resected. In 38 patients, there was synchronous distant organ
recurrence. Forty-five of 72 were re-resected and in 37 of 45 cases, R0 situations were achieved. In 11 of 38 metastasized
patients, both local and distant organ recurrence were successfully removed. For obtaining tumor control, resections of inner
genitals, bladder, and sacral bone were necessary in 10, 4, and 11 patients, respectively. Survival was better for patients
re-resected with a median overall survival of 54.9 months, as compared with 31.1 months among non-resected patients (p = 0.0047, log-rank test). Subgroup analysis revealed that a benefit of re-resection was observed to a lesser extent in synchronous
local and in distant disease. Cox analysis showed that initial Dukes stage and complete resections of local recurrences were
independently determining prognosis (relative risk 1.762 and 0.689, p = 0.008 and p = 0.002, respectively).
Conclusions Radical surgery for local recurrence can improve survival if complete tumor clearance is achieved, and concomitant distant
tumor load should not principally preclude re-resection. 相似文献