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991.
Molenaar P Savarimuthu SM Sarsero D Chen L Semmler AB Carle A Yang I Bartel S Vetter D Beyerdörfer I Krause EG Kaumann AJ 《Naunyn-Schmiedeberg's archives of pharmacology》2007,375(1):11-28
Activation of either coexisting β1- or β2-adrenoceptors with noradrenaline or adrenaline, respectively, causes maximum increases of contractility of human atrial myocardium.
Previous biochemical work with the β2-selective agonist zinterol is consistent with activation of the cascade β2-adrenoceptors→Gsα-protein→adenylyl cyclase→cAMP→protein kinase (PKA)→phosphorylation of phospholamban, troponin I, and C-protein→hastened
relaxation of human atria from nonfailing hearts. However, in feline and rodent myocardium, catecholamines and zinterol usually
do not hasten relaxation through activation of β2-adrenoceptors, presumably because of coupling of the receptors to Gi protein. It is unknown whether the endogenously occurring
β2-adrenoceptor agonist adrenaline acts through the above cascade in human atrium and whether its mode of action could be changed
in heart failure. We assessed the effects of (-)-adrenaline, mediated through β2-adrenoceptors (in the presence of CGP 20712A 300 nM to block β1-adrenoceptors), on contractility and relaxation of right atrial trabecula obtained from nonfailing and failing human hearts.
Cyclic AMP levels were measured as well as phosphorylation of phospholamban, troponin I, and protein C with Western blots
and the back-phosphorylation procedure. For comparison, β1-adrenoceptor-mediated effects of (-)-noradrenaline were investigated in the presence of ICI 118,551 (50 nM to block β2-adrenoceptors). The positive inotropic effects of both (-)-noradrenaline and (-)-adrenaline were accompanied by reductions
in time to peak force and time to reach 50% relaxation. (-)-Adrenaline caused similar positive inotropic and lusitropic effects
in atrial trabeculae from failing hearts. However, the inotropic potency, but not the lusitropic potency, of (-)-noradrenaline
was reduced fourfold in atrial trabeculae from heart failure patients. Both (-)-adrenaline and (-)-noradrenaline enhanced
cyclic AMP levels and produced phosphorylation of phospholamban, troponin I, and C-protein to a similar extent in atrial trabeculae
from nonfailing hearts. The hastening of relaxation caused by (-)-adrenaline together with the PKA-catalyzed phosphorylation
of the three proteins involved in relaxation, indicate coupling of β2-adrenoceptors to Gs protein. The phosphorylation of phospholamban at serine16 and threonine17 evoked by (-)-adrenaline through
β2-adrenoceptors and by (-)-noradrenaline through β1-adrenoceptors was not different in atria from nonfailing and failing hearts. Activation of β2-adrenoceptors caused an increase in phosphorylase a activity in atrium from failing hearts further emphasizing the presence of the β2-adrenoceptor–Gsα-protein pathway in human heart. The positive inotropic and lusitropic potencies of (-)-adrenaline were conserved
across Arg16Gly- and Gln27Glu-β2-adrenoceptor polymorphisms in the right atrium from patients undergoing coronary artery bypass surgery, chronically treated
with β1-selective blockers. The persistent relaxant and biochemical effects of (-)-adrenaline through β2-adrenoceptors and of (-)-noradrenaline through β1-adrenoceptors in heart failure are inconsistent with an important role of coupling of β2-adrenoceptors with Giα-protein in human atrial myocardium. 相似文献
992.
Glasl S Tsendayush D Batchimeg U Holec N Wurm E Kletter C Gunbilig D Daariimaa K Narantuya S Thalhammer T 《Planta medica》2007,73(1):59-66
Saussurea amara is used in traditional Mongolian medicine for the treatment of hepato-biliary disorders. To determine the plant's effect on the bile-salt independent bile flow (hydrocholeresis) as a measure of liver exocrine functions, different extracts were investigated in the isolated rat liver perfusion system. The methanolic extract (3) exerted a dose-dependent increase in bile flow (16%, 37%, 53%, 61%) in concentrations of 50 mg/L, 100 mg/L, 250 mg/L and 500 mg/L. The aqueous crude extract (1) and the ethyl acetate extract (2) also showed a dose-dependent increase, whereas at the highest concentrations (1000 mg/L and 100 mg/L, respectively) a continuous decrease in bile flow could be observed. Cynaropicrin also provoked a dose-dependent increase in bile flow, but caused liver damage at the highest dose tested (20 mg/L). Apigenin 7- O-glucoside, present in extracts 2 and 3, induced a dose-dependent increase of 20%, 30% and 40% (5 mg/L, 10 mg/L, 20 mg/L) and showed a significantly higher effect than the reference substance cynarin. The total flavonoid content was determined by spectrophotometry. To quantify the absolute amount of cynaropicrin in the crude drug and in the tested extracts, an HLPC system was established with santonin as internal standard. 相似文献
993.
Thedinga E Kob A Holst H Keuer A Drechsler S Niendorf R Baumann W Freund I Lehmann M Ehret R 《Toxicology and applied pharmacology》2007,220(1):33-44
To characterize modes of action of substances and their cytotoxic effects Bionas GmbH has developed a new screening system to allow the continuous recording of how an active substance can act (Bionas 2500 analyzing system). In the pharmaceutical industry it is important to acquire as much information as possible about the metabolic effects of an active substance. Most classical pre-clinical studies are very expensive and time-consuming. Often they are so-called end-point tests which require many individual tests before approximate statements can be made about how an effect takes its course. With the Bionas 2500 analyzing system metabolically relevant data including oxygen consumption, acidification rate and the adhesion (cell impedance) of cells can be measured in parallel, online and label-free. Using e.g. ion-sensitive field effect-transistors (ISFET) and electrode structures it is possible to observe metabolic parameters non-invasively and continuously over longer periods of time. The system has already been established for several cell models, cell lines as well as primary cells. It also offers the advantage that regenerative effects can be observed during the same test run. 相似文献
994.
Krause S Schlotter-Weigel B Walter MC Najmabadi H Wiendl H Müller-Höcker J Müller-Felber W Pongratz D Lochmüller H 《Neuromuscular disorders : NMD》2003,13(10):830-834
An adult-onset hereditary inclusion body myopathy with sparing of the quadriceps muscle was originally described in Iranian Jews and assigned to a locus on chromosome 9p12–p13. Recently, mutations of the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene were reported to cause hereditary inclusion body myopathy and one type of distal myopathy in a world-wide distribution. Importantly, the lack of muscle inflammation was used to distinguish hereditary inclusion body myopathy from the sporadic form of inclusion body myopathy. We report a case of a quadriceps-sparing myopathy in a non-Jewish, Iranian patient with a high degree of muscle inflammation. A novel homozygous G-to-A mutation (128933G→A) in exon 7 changing a valine to isoleucine (V367I) in the epimerase domain of the GNE gene was found. We conclude that muscle inflammation is not sufficient to exclude the diagnosis of hereditary inclusion body myopathy. 相似文献
995.
Socioeconomic status is a major determinant of coronary heart disease (CHD). Proinflammatory cytokines are implicated in the etiology of CHD, and are also sensitive to emotional stress. We hypothesised that concentration of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 receptor antagonist (IL-1Ra) would be inversely related to socioeconomic status, and that cytokine responses to stress would be associated with SES. One hundred and twenty-five middle-aged men and 105 women from the Whitehall II epidemiological cohort were tested, and socioeconomic status was indexed by grade of employment, with participants divided into high, intermediate, and low status groups. Plasma concentrations at rest of TNF-alpha, IL-1Ra, and IL-6 (women only) were associated with socioeconomic status, with lower levels in the high status group, but the effect was non-linear. There was no relationship between socioeconomic status and cytokine responses to stress, but sex differences were observed, with men showing greater TNF-alpha, and women greater IL-6 and IL-1Ra increases. The role of inflammatory cytokines in mediating psychosocial influences on CHD is discussed. 相似文献
996.
Ellen Rose Sabine Wever Detlef Zillikens Ruthild Linse Uwe‐Frithjof Haustein Eva‐Bettina Brcker 《Journal der Deutschen Dermatologischen Gesellschaft》2005,3(3):200-206
Background: Pemphigus is a potentially life‐threatening autoimmune blistering skin disease usually treated with high‐dose corticosteroids in combination with immunosuppressive drugs. In a multicenter, prospectively randomized study we compared efficacy and side effects of a dexamethasone‐cyclophosphamide (D/C) pulse therapy with a methylprednisolone‐azathioprine (M/A) therapy in 22 patients with newly diagnosed pemphigus vulgaris and pemphigus foliaceus. Patients and methods: The 11 patients of the M/A group were treated with daily doses of methylprednisolone (initially 2 mg/kg body weight) and azathioprine (2 – 2,5 mg/kg body weight) which were subsequently tapered. D/C pulse therapy in 11 patients consisted of intravenous administration of 100 mg dexamethasone/d on 3 consecutive days along with cyclophosphamide (500 mg) on day one. Pulses were initially repeated every 2 – 4 weeks and then at increasing intervals. In between the pulses, oral cyclophosphamide (50 mg) was given daily for 6 months. Results: Within 24 months after treatment initiation, 5/11 patients of the D/C group had a remission (complete remissions after discontinuation of therapy in 3 patients) and 6/11 patients had a progression. In the M/A group, there were remissions in 9/11 patients (complete remissions after discontinuation of therapy in 3 patients) and progression in 1/11 patients. There were more relapses in M/A therapy after remission than in D/C therapy. Side effects were more common in the M/A group. These differences were not significant (p > 0,05). Conclusion: Because of the high number of progressions in patients treated with D/C therapy, we can not confirm the encouraging results of earlier reports about pulse D/C therapy. Nevertheless D/C therapy seemed to be better tolerated and, in case of primary efficacy, was associated with fewer recurrences than M/A therapy. 相似文献
997.
Kontermann RE Münkel S Neumeyer J Müller D Branschädel M Scheurich P Pfizenmaier K 《Journal of immunotherapy (Hagerstown, Md. : 1997)》2008,31(3):225-234
Tumor necrosis factor (TNF) is a recognized pathogenic mediator in a number of chronic and acute inflammatory diseases. Antibodies targeting TNF have significantly improved therapy of chronic inflammatory diseases, in particular rheumatoid arthritis. Despite this success, anti-TNF treatment shows clinical efficacy only in part of the patients and is often transient, necessitating the development of alternative reagents to combat TNF action. We here describe humanization and functional properties of a TNFR1-specific, monovalent antibody fragment, designated IZI-06.1, which binds to the cysteine-rich domain 1 of TNFR1 with high affinity and competes ligand binding. IZI-06.1 serves as a receptor-selective inhibitor of proapoptotic and antiapoptotic TNF actions, revealed from complete blockage of TNFR1-dependent apoptosis and interleukin-6 induction in Kym 1 and HeLa cells, respectively, whereas TNFR2-mediated signals remained intact, evident from TNF and interleukin-2-mediated costimulation of interferon-gamma production in T cells. Accordingly, IZI-06.1 is a TNFR1-selective TNF antagonist and holds great promise to be developed into a clinically applicable therapeutic. IZI-06.1 could be a useful therapeutic alternative in all diseases already known to clinically respond to anti-TNF treatment and particularly in those diseases, where anti-TNF treatment has failed because of complete blockade of TNF action. 相似文献
998.
Sabouraud S Testud F Descotes J Benevent M Soglu G 《Clinical toxicology (Philadelphia, Pa.)》2008,46(3):267-269
A 37-year-old man was admitted to hospital after complaining of abdominal pain for the past two weeks. On admission the abdominal radiograph showed multiple radio-opaque flecks dispersed throughout the gastrointestinal tract. Blood testing showed hemoglobin level 8.7 g/dL and a blood lead level of 112.4 microg/dL. The family interview revealed that the patient had pica-like behavior since childhood. He was a site foreman and had been ingesting pieces of roofing plates for a few weeks. The patient was treated with laxatives and CaNa(2)EDTA therapy was initiated. The blood lead level then dropped to 69.9 microg/dL. The patient received two subsequent courses of oral succimer and the blood lead level decreased to 59 microg/dL 21 days after the first course. The follow-up abdominal X-ray 20 days after the first examination was normal. Four months later, an outpatient follow-up visit showed a blood lead level within normal limits (14.5 microg/dL) and a psychiatric follow-up was initiated. Lead poisoning following the ingestion of lead-containing foreign bodies is particularly rare in adults, while it is sometimes observed in children. Pica behavior is a well-identified risk factor of lead intoxication in children but is quite exceptional in adults, where it is usually considered to be a psychiatric condition. Other unusual sources of lead poisoning include the ingestion of lead bullets, ceramic lead glaze or glazed earthenware, lead-contaminated candies, ethnic or herbal remedies. 相似文献
999.
Approximately 21% of children suffer from some form of physical abuse. It is hypothesized that when an individual hits a child some of that person's DNA will be deposited onto the child's skin. As yet, no one has reported a method of sampling DNA from the skin of this vulnerable group of individuals. We have sampled DNA from several facial areas of 30 children aged 5 years of age and under. The results show that it is possible to swab the faces of this age group without distressing them or contaminating the samples. Additionally the results indicate that the DNA obtained is almost entirely that of the subject, with little nondonor DNA being observed. 相似文献
1000.
Elliott Perry; Andersson Bert; Arbustini Eloisa; Bilinska Zofia; Cecchi Franco; Charron Philippe; Dubourg Olivier; Kuhl Uwe; Maisch Bernhard; McKenna William J.; Monserrat Lorenzo; Pankuweit Sabine; Rapezzi Claudio; Seferovic Petar; Tavazzi Luigi; Keren Andre 《European heart journal》2008,29(8):1074
We thank Dr Pieroni and colleagues for their response to theposition statement from the 相似文献