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61.
Acetylcholine release in the rat cortex in vivo has been shown to be modulated by alpha2-adrenoceptor ligands. We have previously reported that the systemic administration of selective alpha2-antagonists including (+)-efaroxan increase, while alpha2-adrenoceptor agonists such as UK-14304 reduce the release of acetylcholine in the medial prefrontal cortex of conscious rats as measured by microdialysis. To evaluate the extent to which noradrenergic afferent inputs are required for the expression of these different effects, the present study examined the drug-induced changes in cortical acetylcholine release in rats which had undergone prior noradrenergic deafferentation. Rats were pretreated with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (40 mg/kg, i.p.), which after three days had reduced noradrenaline levels in the medial prefrontal cortex by 84%. At that time, slices of cortex were incubated with [3H]choline, superfused and stimulated by consecutive exposures to increasing concentrations of K+. In N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated tissue, the [3H] outflows evoked by 20, 35 and 45 mM K+ were lower by 12%, 22% and 43%, respectively, in comparison to slices prepared from vehicle-pretreated control animals. For in vivo microdialysis experiments, rats were pretreated as above with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, or prepared seven to eight days in advance with bilateral 6-hydroxydopamine lesions of the locus coeruleus. Neither of these lesioning procedures significantly affected the basal outflow of endogenous acetylcholine in the cortex. In control rats, cortical acetylcholine outflow was increased by up to 300% of baseline values by (+)-efaroxan (0.63 mg/kg, i.p.), and was reduced to 21% of baseline by UK-14304 (2.5 mg/kg, i.p.), confirming our previous findings. In N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated rats, the inhibitory effect of UK-14304 on acetylcholine outflow persisted, while the ability of (+)-efaroxan to increase outflow was essentially eliminated. In locus coeruleus-lesioned rats, where cortical noradrenaline levels were reduced by 64%, (+)-efaroxan still increased acetylcholine outflow, but this effect was significantly attenuated and less sustained in comparison to sham-operated control rats. Viewed together with complimentary biochemical, electrophysiological and neuroanatomical evidence in the literature, a model is presented to account for these findings, and indicates that alpha2-adrenoceptors both on noradrenergic neurons (autoreceptors) and on non-noradrenergic cells (heteroreceptors) can participate in mediating drug-induced changes in medial prefrontal cortical acetylcholine release in vivo. The acetylcholine release-enhancing effect of (+)-efaroxan appears to be dependent on at least a partially intact cortical noradrenergic innervation. 相似文献
62.
Wurch T Boutet-Robinet EA Palmier C Colpaert FC Pauwels PJ 《The Journal of pharmacology and experimental therapeutics》2003,304(1):380-390
Neuroleptic drugs have been suggested to act as inverse agonists at the dopamine D2 receptor, but no link between therapeutic efficacy and ligand's intrinsic activity could be determined. Since the resolving capacity to monitor inverse agonism at dopamine D2 receptors is limited, we speculated that receptor constitutive activation could be enhanced by constructing chimeric D2/alpha 1B receptors. Marked inverse agonist responses with a series of dopamine antagonists were obtained by: 1) exchange of the D 2short receptor's 3ICL by that of the alpha 1B-adrenoceptor, 2) incorporation of an activating mutation (Ala 279 Glu) in the distal portion of its 3ICL, and 3) coexpression with a G alpha11 protein. This chimeric D2/alpha 1B receptor construct displayed a ligand binding profile comparable to that of the wild-type (wt) D 2short receptor and an effector activation profile close to that of the wt alpha 1B-adrenoceptor. Most of the dopamine antagonists attenuated by -54 to -59% basal inositol phosphates (IP) formation, thus clearly acting as inverse agonists. Ziprasidone behaved as a silent antagonist (+5% versus basal IP level) and antagonized both dopamine-mediated (pK B, 7.61) and tropapride-mediated (pK B, 8.52) IP responses. Clozapine, olanzapine, and raclopride displayed partial inverse agonist properties (-31, -67, and -71% versus tropapride, respectively), whereas bromerguride (+63%) and cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino tetralin) [(+)-UH 232] (+88%) demonstrated positive agonism. In conclusion, analyses with the chimeric D2/alpha 1B Ala 279 Glu 3ICL receptor construct suggest that neuroleptic drugs can be differentiated on the basis of their intrinsic activity, as they can either activate, inhibit, or be silent at this receptor construct. 相似文献
63.
目的:建立家猪胸腰段脊髓火器贯通伤模型和改良Allen's打击伤后全瘫模型,观察伤后促凋亡基因p53基因的早期表达。方法:实验于2005-05/08在解放军第一七五医院实验室完成。取健康雄性家猪20只,单纯随机分为3组:①火器伤组:9只,在全麻状态下制作胸腰段(L1~L2)脊髓火器伤模型,分为伤后1,3,6h3个时间处死。②打击伤组:9只,L1节段脊髓行改良Allen’s打击,致伤力为500g·cm,处死时间同前。③空白对照组:2只,只麻醉,不造模,伤后6h处死。伤后不同时间点(伤后1,3,6h)和不同节段(伤点、近伤点、中伤点及远伤点)取材,采用SP法进行P53蛋白免疫组化染色,用TJTY-300型全自动图像分析仪测量P53免疫组织化学染色阳性物质吸光度。结果:经补充后20只猪进入结果分析。①脊髓损伤后3h打击伤组伤点,火器伤组近伤段脊髓P53蛋白的表达高于空白对照组(P<0.001),随着时间推移,打击伤组和火器伤组P53蛋白的表达呈升高趋势(P<0.001),且火器伤组要高于打击伤组(P<0.0001)。②在脊髓损伤后6h,打击伤组仅在伤点和近伤段P53蛋白的表达高于空白对照组(5.57±0.82,3.21±0.43,P<0.05),而火器伤组近伤段、中伤段及远段伤均高于空白对照组(6.46±0.66,4.27±0.39,1.16±0.17,P<0.05)。结论:①细胞凋亡基因p53在脊髓损伤中的表达有一定的时空性,在脊髓损伤后3h出现P53蛋白表达量的增加。②脊髓火器伤的波及范围较打击伤更为广泛。 相似文献
64.
M J Millan F C Colpaert 《The Journal of pharmacology and experimental therapeutics》1991,256(3):993-1001
This study examined the effects of structurally diverse 5-hydroxytryptamine (HT)1A partial agonists upon opioid-induced antinociception against noxious heat and pressure stimuli in rats and mice. The pyrimidinylpiperazines, buspirone, ipsapirone and gepirone, the halogenated phenylpiperazine, LY 165, 163 [1-(2-(4-aminophenyl)ethyl-4-(3-trifluoromethylphenyl)-piperazine], the heterobicylic arylpiperazine, (+/-)-flexinoxan, and the benzodiaxane, MDL 728328-[(4-(1,4-benzodioxon-2-ylmethylamino)butyl-8-azasp iro-(4,5)-decane-7,9-dione], exerted little or no effect upon basal latencies. In both mice and rats, each dose-dependently attenuated the antinociceptive action of the mu-opioid, morphine, against heat and pressure. In their presence, the morphine dose-response curve was shifted in parallel to the right with no loss of maximal effect. In mice, Schild analysis of the action of ipsapirone and gepirone yielded slopes of close to -1. In contrast to the partial agonists, the buspirone metabolite, 1-pyrimidinylpiperazine, which lacks 5-HT1A affinity, and the putative 5-HT1A antagonists, methiothepin, spiperone, BMY 7378 [(8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol [4]-decane-7,9-dione) 2HCl] and alprenolol, did not reduce the action of morphine. In rats, the antagonistic effect of buspirone, gepirone and ipsapirone could be blocked by BMY 7378. The 5-HT1A partial agonists also antagonized the antinociception-induced by the mu-opioid, sufentanil, but were virtually inactive against the selective kappa-opioid agonists, U69,593 (5 alpha,7 alpha,8 beta-(+)-N-methyl-N-[7-(l-pyrrolidinyl)-1-oxaspirol-(4,5)-dec-8-yl ] benzene-acetamide) and U50,488H (trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzenacetamide methane sulfonate hydrate.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
65.
Colpaert F Koek W Kleven M Besnard J 《The Journal of pharmacology and experimental therapeutics》2007,322(1):288-298
In a two-lever, food-rewarded drug discrimination paradigm, behavior seems to be governed by a win-stay/lose-shift rule; rats continue to press the lever that yields food, and, when not rewarded, they shift responding to the alternative lever. Here, we report on the effects that antipsychotics and further neuropharmacological agents exert in those conditions. At higher doses, antipsychotics disrupt most or all behavioral parameters in this paradigm. However, at lower doses, rats may select the appropriate lever with normal latency and accuracy, obtain a first food pellet (i.e., "win"), and then, remarkably, shift responding to the alternative lever ("win-shift"). This suggests that antipsychotics can block the effects of reward selectively, i.e., at doses where the initial, secondarily reinforced behavior including the initiation of lever pressing, remains intact. Indeed, saline-treated rats that are given no reward (i.e., "lose") after having selected a lever, also press the alternative lever ("lose-shift"). The induction of selective win-shift is specific to antipsychotics, but it varies greatly among them. Perhaps relating to its alleged "incisive" action on delirium and hallucinations, and, surprisingly, in view of its extrapyramidal actions, acutely administered haloperidol (0.04-0.08 mg/kg) demonstrates win-shift to an exceptional extent, shared only with the newly proposed agent (3-cyclopent-1-enyl-benzyl)-[2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl]-amine fumarate (F 15063; 0.31-0.63 mg/kg); the more sedative antipsychotic chlorpromazine demonstrated little selectivity. The paradigm offers a novel tool to characterize antipsychotics with regard to presumably pathogenic motivational processes; mixed D(2)-antagonist/5-hydroxytryptamine(1A)-agonist agents such as F 15063 may conceivably share the powerful antipsychotic action of haloperidol while avoiding the sensitization that develops to extrapyramidal effects of haloperidol and consequent negative symptoms. 相似文献
66.
目的:探讨颈椎椎后肌肉组织Na -K -ATP酶活性变化与颈椎病的关系。资料来源:应用计算机检索PubMed1988-01/2004-12相关骨骼肌损伤与肌组织Na -K -ATP酶关系的文献,检索词“Na -K pump,Na -K -ATPase,muscle”,限定文献语言种类为English。同时计算机检索CNKI1990-01/2005-12相关Na -K -ATP酶与骨骼肌损伤的关系及颈椎病发病病因的文献,检索词“Na -K -ATP酶,骨骼肌,颈椎病病因”,限定文献语言种类为中文。资料选择:对资料进行初审,选取包括Na -K -ATP酶与肌组织损伤关系的文献,开始查找全文。纳入标准:Na -K -ATP酶活性变化与骨骼肌损伤密切相关的文献研究。排除标准:重复研究,Meta分析类文章。资料提炼:共检索到939篇关于Na -K -ATP酶与骨骼肌损伤相关方面的文献,最终纳入20篇符合标准的文献。资料综合:众多研究表明,Na 、K 与骨骼肌的兴奋、收缩、疲劳有密切关系,而Na -K -ATP酶又是调节细胞内外Na 、K 浓度必不可少的高分子蛋白,也就是说,骨骼肌一系列活动均离不开Na -K -ATP酶,Na -K -ATP酶活性变化与骨骼肌损伤是相互影响的。而强迫屈颈体位作为颈椎病发病的危险因素之一,可使颈椎椎后肌肉Na -K -ATP酶活性降低,酶活性降低致使肌细胞损伤,并最终导致骨骼肌损伤而发病。结论:以颈椎椎后肌肉酶活性的变化来阐释中医药对颈椎病确切疗效的相关研究未见,这有待于进一步研究,以充分展示中医药在颈椎病等相关疾病中的治疗优势。 相似文献
67.
Matthew Bower Tiffany Metzger Ken Robbins Dana Tomalty Vlatimil Válek Jean Boudny Tomas Andrasina Cliff Tatum Robert CG Martin 《HPB : the official journal of the International Hepato Pancreato Biliary Association》2010,12(1):31-36
Background:
Neoadjuvant chemotherapy for potentially resectable metastatic colorectal cancer (MCC) is becoming a more common treatment algorithm. The aim of the present study was to evaluate the efficacy of precision hepatic arterial Irinotecan therapy in unresectable MCC.Methods:
An open-label, multi-centre, multi-national single arm study of MCC patients, who received hepatic arterial irinotecan. Primary endpoints were safety, tolerance and metastatic tumour resection.Results:
Fifty-five patients with metastatic colorectal to the liver underwent a total of 90 hepatic arterial irinotecan treatments. The extent of liver involvement was <25% in 75% of the patients (n= 41), between 26 and 50% in 15% of the patients (n= 11) and >50% in 10% of the patients (n= 24). The median number of hepatic lesions was four (range 1–20), with a median total size of all target lesions of 9 cm (range 5.5–28 cm) with 50% of patients having bilobar tumour distribution. The median number of irinotecan treatments was two (range 1–5). The median treatment dose was 100 mg (range 100–200) with a median total hepatic treatment of 200 mg (range 200–650). The majority of treatments (86%) were performed as lobar infusion treatments, and 30% of patients were treated with concurrent simultaneous chemotherapy. Eleven (20%) patients demonstrated significant response and downstage of their disease or demonstrated stable disease without extra-hepatic disease progression allowing resection, ablation or resection and ablation. There were no post-operative deaths. Post-operative complications morbidity occurred in 18% of patients, with none of them hepatic related. Non-tumorous liver resected demonstrated no evidence of steatohepatitis from the irinotecan arterial infusion.Conclusions:
Hepatic arterial infusion irinotecan drug-eluting beads is safe and effective in pre-surgical therapy and helpful in evaluating the biology of metastatic colorectal cancer to the liver prior to planned hepatic resection. 相似文献68.
69.
WY Khoder AJ Becker B Schlenker S Tritschler PJ Bastian CG Stief 《European journal of medical research》2009,14(7):320-322
Introduction
Rectal polypectomy causes thinning (or even perforation) of the rectal wall in addition to thermic injury at the polypectomy site.Case report
We present a rare case of spontaneous rectal perforation after uncomplicated nerve sparing endoscopic extraperitoneal radical prostatectomy in a patient with a previous history of rectal polypectomy at the perforation site. The patient could be treated conservatively. There was complete healing of the fistula without any effect on functional results. This Conservative therapy for such rectal perforations is indicated if the patient''s general condition remains stable without any signs of infection.Conclusions
Polypectomy is an important risk factor for rectal perforation during nsEERPE. Adequate time interval should be given to allow healing and avoid adding further thermal wall damage which may obscure healing leading to complications like fistula. Conservative therapy for small missed rectal perforations constitutes an attractive, feasible and non invasive treatment entity. Following this principle we have not faced this complication in following similar cases. 相似文献70.
Silvio ST Tafuri Domenico DM Martinelli Giovanni GC Caputi Annamaria AA Arbore Cinzia CG Germinario Rosa RP Prato 《BMC health services research》2009,9(1):100-5