全文获取类型
收费全文 | 436篇 |
免费 | 27篇 |
国内免费 | 2篇 |
专业分类
耳鼻咽喉 | 7篇 |
儿科学 | 15篇 |
妇产科学 | 39篇 |
基础医学 | 59篇 |
口腔科学 | 17篇 |
临床医学 | 33篇 |
内科学 | 53篇 |
皮肤病学 | 8篇 |
神经病学 | 56篇 |
特种医学 | 3篇 |
外科学 | 42篇 |
综合类 | 2篇 |
预防医学 | 37篇 |
药学 | 46篇 |
肿瘤学 | 48篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 20篇 |
2020年 | 13篇 |
2019年 | 18篇 |
2018年 | 16篇 |
2017年 | 13篇 |
2016年 | 12篇 |
2015年 | 14篇 |
2014年 | 13篇 |
2013年 | 14篇 |
2012年 | 23篇 |
2011年 | 23篇 |
2010年 | 15篇 |
2009年 | 8篇 |
2008年 | 19篇 |
2007年 | 16篇 |
2006年 | 17篇 |
2005年 | 14篇 |
2004年 | 20篇 |
2003年 | 12篇 |
2002年 | 24篇 |
2001年 | 13篇 |
2000年 | 15篇 |
1999年 | 15篇 |
1998年 | 8篇 |
1997年 | 6篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1990年 | 5篇 |
1989年 | 2篇 |
1988年 | 5篇 |
1987年 | 4篇 |
1986年 | 7篇 |
1985年 | 4篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1979年 | 2篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1973年 | 4篇 |
1972年 | 2篇 |
1924年 | 1篇 |
1923年 | 2篇 |
1922年 | 1篇 |
1920年 | 2篇 |
1917年 | 1篇 |
1900年 | 1篇 |
排序方式: 共有465条查询结果,搜索用时 46 毫秒
31.
32.
Bianca Dimitrov Nastassja Himmelreich Agnes L. Hipgrave Ederveen Christian Lüchtenborg Jürgen G. Okun Maximilian Breuer Anna-Marlen Hutter Matthias Carl Luca Guglielmi Andrea Hellwig Kai Christian Thiemann Markus Jost Verena Peters Christian Staufner Georg F. Hoffmann Annette Hackenberg Nagarajan Paramasivam Stefan Wiemann Christian Thiel 《Molecular genetics and metabolism》2018,123(3):364-374
Congenital disorders of glycosylation (CDG) are genetic defects in the glycoconjugate biosynthesis. > 100 types of CDG are known, most of them cause multi-organ diseases. Here we describe a boy whose leading symptoms comprise cutis laxa, pancreatic insufficiency and hepatosplenomegaly. Whole exome sequencing identified the novel hemizygous mutation c.542 T > G (p.L181R) in the X-linked ATP6AP1, an accessory protein of the mammalian vacuolar H+-ATPase, which led to a general N-glycosylation deficiency. Studies of serum N-glycans revealed reduction of complex sialylated and appearance of truncated diantennary structures. Proliferation of the patient's fibroblasts was significantly reduced and doubling time prolonged. Additionally, there were alterations in the fibroblasts' amino acid levels and the acylcarnitine composition. Especially, short-chain species were reduced, whereas several medium- to long-chain acylcarnitines (C14-OH to C18) were elevated. Investigation of the main lipid classes revealed that total cholesterol was significantly enriched in the patient's fibroblasts at the expense of phophatidylcholine and phosphatidylethanolamine. Within the minor lipid species, hexosylceramide was reduced, while its immediate precursor ceramide was increased. Since catalase activity and ACOX3 expression in peroxisomes were reduced, we assume an ATP6AP1-dependent impact on the β-oxidation of fatty acids. These results help to understand the complex clinical characteristics of this new patient. 相似文献
33.
Ankermann T Wiemann T Reisner A Orlowska-Volk M Köhler H Krause MF 《Intensive care medicine》2005,31(2):272-280
Objective Acute respiratory distress syndrome (ARDS) in young infants is linked with a pulmonary inflammatory response part of which are increased interleukin-8 (IL-8) levels and migration of polymorphonuclear leukocytes (PMNL) into lung tissue. A topical application of an antibody against IL-8 might therefore decrease PMNL migration and improve lung function.Design Randomized, controlled, prospective animal study.Setting Research laboratory of a university childrens hospital.Subjects and interventions Anesthetized, mechanically ventilated newborn piglets (n=22) underwent repeated airway lavage to remove surfactant and to induce lung inflammation. Piglets then received either surfactant alone (S, n=8), or a topical antibody against IL-8 admixed to surfactant (S+IL-8, n=8), or an air bolus injection (control, n=6).Measurements and results After 6 h of mechanical ventilation following intervention, oxygenation [S 169±51 (SD) vs S+IL-8 139±61 mmHg] and lung function (compliance: S 1.3±0.4 vs S+IL-8 0.9±0.4 ml/cmH2O/kg; extra-vascular lung-water: S 27±9 vs S+IL-8 52±28 ml/kg) were worse in the S+IL-8 group because reactive IL-8 production [S 810 (median, range 447–2323] vs S+IL-8 3485 (628–16180) pg/ml; P<0.05) with facilitated migration of PMNL into lung tissue occurred. Moreover, antibody application caused augmented chemotactic potency of IL-8 [linear regression of migrated PMNL and IL-8 levels: S r2=0.30 (P=ns) vs S+IL-8 r2=0.89 (P=0.0002)].Conclusion Topical anti-IL-8 treatment after lung injury increases IL-8 production, PMNL migration, and worsens lung function in our piglet lavage model. This effect is in contrast to current literature using pre-lung injury treatment protocols. Our data do not support anti-IL-8 treatment in young infants with ARDS.Financial support: supported by Hübner-Stiftung im Stifterverband, Essen; and Deutsche Forschungsgemeinschaft, Bonn, grant KR 1863/1-1 相似文献
34.
F J Cummings G W Crabtree M C Wiemann E N Spremulli R E Parks P Calabresi 《Clinical pharmacology and therapeutics》1988,44(5):501-509
Clinical, pharmacologic, and immunologic effects of 2'-deoxycoformycin (dCF) were evaluated in 15 patients with advanced malignancies. Toxicity was less severe with a low dose (4 mg/m2) of dCF, but this dose still resulted in suppression of cellular adenosine deaminase activity, skin test reactivity, and lymphocyte responses to mitogens. Improvement in cutaneous T cell lymphoma plaques was seen after dCF. Further investigations of antitumor efficacy with the use of this low dosage schedule should continue in patients with hematologic neoplasms, and additional preliminary studies of the combination of an adenosine deaminase inhibitor with an adenosine analog should also be considered. 相似文献
35.
Mechanistic relationships between polymer microstructure and drug release kinetics in bioerodible polyanhydrides. 总被引:3,自引:0,他引:3
Elizabeth Shen Matt J Kipper Brianne Dziadul Mee-Kyung Lim Balaji Narasimhan 《Journal of controlled release》2002,82(1):115-125
This work investigates the relationship between polymer microstructure and drug release kinetics in the bioerodible polyanhydride system, poly[(1,6-bis-p-carboxyphenoxy hexane)-co-(sebacic anhydride)] (CPH-SA). Model drugs, p-nitroaniline (PNA) and disperse yellow 3 (DY), were selected based on compatibility with CPH and SA, respectively. The polymer microstructure and compatibility of the drug with the constituent monomers were determined to have significant influence over the release kinetics of the drugs studied. Polymer systems with homogeneous microstructure, poly(SA) and 50:50 CPH-SA, showed simultaneous polymer degradation and drug release, although the solubility of the drug in the polymer influenced the shape of the release profiles. For the heterogeneous copolymers, 20:80 and 80:20 CPH-SA, individual monomer release kinetics demonstrated the effects of drug partitioning within a phase-separated microstructure. The PNA molecules partition preferentially into the CPH microdomains in the 20:80 CPH-SA copolymer while the DY molecules partition preferentially into the SA microdomains in the 80:20 CPH-SA copolymer. These studies suggest that the drug release mechanism is driven by polymer microstructure, compatibility of the drug with the constituent polymer phases, and solubility of the drug within the polymer. A thorough understanding of drug-polymer interactions as well as the polymer microstructure will pave the way for more accurate predictions of drug release from bioerodible polyanhydrides. 相似文献
36.
Stress exerts a profound, yet complex, influence on learning and memory and can enhance, impair or have no effect on these processes. Here, we have examined how the administration of stress at different times before learning affects long-term (24-hr) memory for neutral and emotional information. Participants submerged their dominant hand into a bath of ice cold water (Stress) or into a bath of warm water (No stress) for 3 min. Either immediately (Exp. 1) or 30 min (Exp. 2) after the water bath manipulation, participants were presented with a list of 30 words varying in emotional valence. The next day, participants' memory for the word list was assessed via free recall and recognition tests. In both experiments, stressed participants exhibited greater blood pressure, salivary cortisol levels, and subjective pain and stress ratings than non-stressed participants in response to the water bath manipulation. Stress applied immediately prior to learning (Exp. 1) enhanced the recognition of positive words, while stress applied 30 min prior to learning (Exp. 2) impaired free recall of negative words. Participants' recognition of positive words in Experiment 1 was positively associated with their heart rate responses to the water bath manipulation, while participants' free recall of negative words in Experiment 2 was negatively associated with their blood pressure and cortisol responses to the water bath manipulation. These findings indicate that the differential effects of pre-learning stress on long-term memory may depend on the temporal proximity of the stressor to the learning experience and the emotional nature of the to-be-learned information. 相似文献
37.
Retz W Rösler M Kissling C Wiemann S Hünnerkopf R Coogan A Thome J Freitag C 《Journal of neural transmission (Vienna, Austria : 1996)》2008,115(2):323-329
Summary. Attention deficit/hyperactivity disorder (ADHD) is a complex, highly heritable psychiatric condition. Neuropsychological and
pharmacological studies suggest a dysregulation of central noradrenergic neurotransmission in addition to dopaminergic and
serotonergic mechanisms. Only a few studies have focused on the association of noradrenergic susceptibility genes with ADHD.
In this study, we investigated the association of several ADHD symptom scores (German short form of the Wender Utah Rating
Scale, WURS-k; ADHD self report, ADHD-SB, and the German validated version of the WRAADDS, WRI) with haplotypes of the catechol-O-methyltransferase
(COMT) and the norepinephrine transporter (SLC6A2) genes. Subjects were genotyped for three SLC6A2 (rs5569, rs998424, rs2242447) and two COMT single nucleotide polymorphisms (rs4680, rs4818). In addition, psychosocial adversity in childhood was assessed in order
to evaluate putative gene-environment interactions.
We did not find main effects of the COMT and SLC6A2 NET1 gene haplotypes on any ADHD symptom severity score. Childhood psychosocial adversity was strongly associated with number
of ADHD symptoms. No gene-environment interaction was found. A specific combination of two COMT and SLC6A2 gene haplotypes, containing the low functioning COMT variant was nominally associated with low ADHD scores in all scales.
Results do not support the hypothesis that common variants in the SLC6A2 and COMT genes in particular are associated with ADHD, but might give some evidence for interactive effects between these gene variants
on ADHD severity.
Correspondence: Wolfgang Retz, Institute for Forensic Psychology and Psychiatry, Saarland University Hospital, 66421 Homburg/Saar,
Germany 相似文献
38.
Zonisamide (ZNS) is an anticonvulsant drug known to affect various neuronal channels and transmitter systems. ZNS has also been reported to inhibit carbonic anhydrase activity and may thus influence neuronal activity via changes of pH. Therefore, we analyzed effects of ZNS in vitro using epileptic model systems which are sensitive to carbonic anhydrase inhibition and pH changes. Intracellular recordings from CA3 neurons (hippocampal slice, adult guinea pigs) were carried out under bicarbonate-buffered conditions. Epileptiform activity was induced by either 4-aminopyridine or theophylline. In parallel experiments, intracellular pH (pHi) was determined in the CA1 and CA3 subfields of 2′,7-bis(2-carboxyethyl)-5(6)-carboxyfluorescin-acetoxymethyl ether (BCECF-AM) loaded slices. The ammonium prepulse method was used to test for effects of ZNS on pHi regulation. ZNS (50 μM) reversibly reduced the frequency of 4-AP induced epileptiform bursting and the number of action potentials per bursts but had no effect on input resistance and membrane potential. Theophylline-induced epileptiform bursting, although sensitive to hypercapnic acidosis, was not affected by ZNS. There was also no effect on steady-state pHi and pHi regulation of BCECF-AM loaded hippocampal tissue. Clinically relevant concentrations of ZNS strongly inhibit 4-AP induced epileptiform activity of hippocampal CA3 neurons in vitro, but this effect was unlikely based on carbonic anhydrase inhibition or changes of neuronal pHi. 相似文献
39.
Wang Z McPherson PA Raccor BS Balachandran R Zhu G Day BW Vogt A Wipf P 《Chemical biology & drug design》2007,70(2):75-86
The synthesis and biological evaluation of three tubulysin analogs provides the first structure-activity relationship in this family of potent cytotoxic myxobacteria metabolites. Most importantly, the labile N,O-acetal at N(14) is not essential for biological activity. Further, structural simplifications are possible without abolishing biological activities. The N-terminal amino acid can be replaced with N-methylsarcosine, and the configuration at the acetoxy-bearing stereocenter at C(11) is important but not critical for almost all aspects of the biological profile. Our data encourage further development of these compounds as potential therapeutic agents in cancer treatment. 相似文献
40.
Jung WH Harrison C Shin Y Fournier JH Balachandran R Raccor BS Sikorski RP Vogt A Curran DP Day BW 《Journal of medicinal chemistry》2007,50(13):2951-2966
The structure-activity relationship of the crucial C16 region of (-)-dictyostatin was established through total synthesis of analogs followed by detailed biological characterization. A versatile synthetic strategy was used to prepare milligram quantities of 16-normethyldictyostatin, 16-epi-dictyostatin, and the C16-normethyl-C15Z isomer. Along the way, a number of other E/Z isomers and epimers were prepared, and a novel lactone ring contraction to make iso-dictyostatins with 20-membered macrolactones (instead of 22-membered macrolactones) was discovered. The synthesis of 16-normethyl-15,16-dehydrodictyostatin is the first of any dictyostatin by a maximally convergent route in which three main fragments are assembled, coupled in back-to-back steps, and then processed through refunctionalization and macrolactonization. Cell-based and biochemical evaluations showed 16-normethyl-15,16-dehydrodictyostatin and 16-normethyldictyostatin to be the most potent of the new agents, only 2- and 5-fold less active than (-)-dictyostatin itself. This data and that from previously generated dictyostatin analogs are combined to produce a picture of the structure-activity relationships in this series of anticancer agents. 相似文献