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41.
42.
Phenobarbital and clofibrate, two non-genotoxic carcinogens, have been
investigated regarding the relationship between reactive oxygen species,
antioxidant enzyme expression and apoptosis in primary cultures of rat
hepatocytes. Low toxicity concentrations, 200 and 100 microg/ml for
phenobarbital and clofibrate respectively, were used to examine their
effect on spontaneous or transforming growth factor beta1
(TGFbeta1)-induced apoptosis and on the expression of antioxidant defence
enzymes (superoxide dismutases and catalase). The increased incidence of
apoptotic nuclei was visualized in TGFbeta1-treated cultures with the
fluorescent dye Hoechst 33258 and was quantified under all experimental
conditions by measurement of the hypodiploid peak in DNA histograms
obtained by flow cytometry. Both substances, when added separately to
hepatocyte cultures and incubated for 24 and 48 h, significantly diminished
spontaneous apoptosis and exhibited a slight suppression of
TGFbeta1-induced apoptosis. Endogenous peroxide production by hepatocytes
increased with TGFbeta1, phenobarbital or clofibrate and the increase was
greater with phenobarbital and in the presence of TGFbeta1 with both drugs.
Gene expression of catalase and Mn- and Cu,Zn superoxide dismutases (SOD)
was evaluated by northern blot analysis of hepatocytes incubated in the
presence of phenobarbital or clofibrate with or without TGFbeta1 and the
following differences were detected: phenobarbital induced a significant
decrease in both dismutases (to 56%, P < 0.05, and 55%, P < 0.05, for
Mn- and Cu,Zn-SOD respectively) and a 2-fold increase (P < 0.01) in
catalase; clofibrate induced a slight decrease in both SODs and a 4-fold
increase (P < 0.05) in catalase; TGFbeta1 significantly decreased to 37%
(P < 0.05) expression of catalase while not significantly affecting
expression of both SODs. We conclude that inhibition of spontaneous
apoptosis induced by either phenobarbital or clofibrate is accompanied by
increases in the endogenous levels of peroxides and by significant
induction of catalase gene expression. Furthermore, the lack of effect of
both compounds on TGFbeta1-induced apoptosis could be a consequence of the
inability of these two compounds to counteract the depressing effect of
TGFbeta1 on expression of catalase.
相似文献
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45.
AM Halefoglu 《Journal of Medical Imaging and Radiation Oncology》2005,49(3):242-245
A pulmonary arteriovenous fistula is an abnormal connection between pulmonary arteries and veins. Patients with Rendu–Osler–Weber syndrome may present with this vascular malformation, which is a typical finding of the disease. Approximately 5–15% of Rendu–Osler–Weber syndrome patients have pulmonary arteriovenous malformations (AVM) and there is usually a family history of AVM in these patients. The malformations are usually located in the lower lobes. In this paper, I describe a 49‐year‐old male patient with dyspnoea, cough, haemoptysis and epistaxis. Physical examination showed nasal telangiectasias, cyanosis of the lips and nails, and a systolic bruit over the left lung. Chest X‐ray revealed a 5‐cm mass in the left lower lobe and after magnetic resonance examination, together with 3‐D magnetic resonance angiography, it was demonstrated to be a pulmonary arteriovenous fistula. The history of a niece with a similiar history of suspected pulmonary arteriovenous fistula led me to consider the possibility of Rendu–Osler–Weber syndrome presenting with a pulmonary arteriovenous fistula. 相似文献
46.
Jacqueline AM Smith DL Patil OT Daniels Y-S Ding J-D Gallezot S Henry KHS Kim S Kshirsagar WJ Martin GP Obedencio E Stangeland PR Tsuruda W Williams RE Carson ST Patil 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2015,18(2)
Background:
Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.Methods:
We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.Results:
TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC50 of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [11C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [11C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.Conclusions:
These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation. 相似文献47.
48.
Monika Oláhová Tobias B Haack Charlotte L Alston Jessica AC Houghton Langping He Andrew AM Morris Garry K Brown Robert McFarland Zofia MA Chrzanowska-Lightowlers Robert N Lightowlers Holger Prokisch Robert W Taylor 《European journal of human genetics : EJHG》2015,23(7):935-939
Isolated mitochondrial complex IV (cytochrome c oxidase) deficiency is an important cause of mitochondrial disease in children and adults. It is genetically heterogeneous, given that both mtDNA-encoded and nuclear-encoded gene products contribute to structural components and assembly factors. Pathogenic variants within these proteins are associated with clinical variability ranging from isolated organ involvement to multisystem disease presentations. Defects in more than 10 complex IV assembly factors have been described including a recent Lebanese founder mutation in PET100 in patients presenting with Leigh syndrome. We report the clinical and molecular investigation of a patient with a fatal, neonatal-onset isolated complex IV deficiency associated with multiorgan involvement born to consanguineous, first-cousin British Asian parents. Exome sequencing revealed a homozygous truncating variant (c.142C>T, p.(Gln48*)) in the PET100 gene that results in a complete loss of enzyme activity and assembly of the holocomplex. Our report confirms PET100 mutation as an important cause of isolated complex IV deficiency outside of the Lebanese population, extending the phenotypic spectrum associated with abnormalities within this gene. 相似文献
49.
50.
Development of large numbers of mast cells at sites of idiopathic chronic dermatitis in genetically mast cell-deficient WBB6F1-W/Wv mice 总被引:15,自引:1,他引:15
The normal skin and other tissues of adult mast cell-deficient WBB6F1- W/Wv or WCB6F1-Sl/Sld mice contain less than 1.0% the number of mast cells present in the corresponding tissues of the congenic normal (+/+) mice. As a result, genetically mast cell-deficient WBB6F1-W/Wv or WCB6F1-Sl/Sld mice are widely used for studies of mast cell differentiation and function. We found that mast cells developed at sites of idiopathic chronic dermatitis in WBB6F1-W/Wv mice and that the number of mast cells present in the skin of WBB6F1-W/Wv mice was proportional to the severity of the dermatitis (in ear skin, there were 33 +/- 4 mast cells/mm2 of dermis at sites of severe dermatitis v 9 +/- 3 at sites of mild dermatitis, 0.8 +/- 0.3 in skin without dermatitis, and 100 +/- 7 in the normal skin of congenic WBB6F1-+/+ mice; in back skin, the corresponding values were 2.0 +/- 0.6, 1.1 +/- 0.9, 0.025 +/- 0.025, and 26.2 +/- 3.2). The development of mast cells was a local, not systemic, consequence of the dermatitis. Thus, WBB6F1-W/Wv mice with severe dermatitis lacked mast cells in skin not showing signs of dermatitis and also in the peritoneal cavity, stomach, cecum, and tongue. Idiopathic chronic dermatitis was not associated with the local development of mast cells in WCB6F1-Sl/Sld mice, a mutant whose mast cell deficiency is due to a mechanism distinct from that of WBB6F1-W/Wv mice. These findings may have implications for understanding the nature of the mast cell deficiency in WBB6F1-W/Wv and WCB6F1-Sl/Sld mice and for the use of these mutants to analyze mast cell differentiation and function. 相似文献