全文获取类型
收费全文 | 121篇 |
免费 | 23篇 |
专业分类
儿科学 | 4篇 |
妇产科学 | 6篇 |
基础医学 | 27篇 |
临床医学 | 16篇 |
内科学 | 11篇 |
皮肤病学 | 1篇 |
神经病学 | 14篇 |
外科学 | 25篇 |
综合类 | 19篇 |
预防医学 | 15篇 |
药学 | 5篇 |
肿瘤学 | 1篇 |
出版年
2015年 | 2篇 |
2014年 | 2篇 |
2013年 | 3篇 |
2012年 | 4篇 |
2011年 | 3篇 |
2010年 | 3篇 |
2009年 | 5篇 |
2008年 | 4篇 |
2007年 | 8篇 |
2006年 | 4篇 |
2005年 | 4篇 |
2004年 | 2篇 |
2003年 | 3篇 |
2002年 | 1篇 |
2001年 | 2篇 |
2000年 | 4篇 |
1999年 | 4篇 |
1998年 | 2篇 |
1997年 | 3篇 |
1996年 | 2篇 |
1995年 | 2篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1991年 | 5篇 |
1990年 | 11篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1972年 | 2篇 |
1971年 | 1篇 |
1970年 | 2篇 |
1969年 | 5篇 |
1968年 | 5篇 |
1967年 | 2篇 |
1966年 | 6篇 |
1964年 | 2篇 |
1937年 | 1篇 |
1934年 | 1篇 |
1932年 | 1篇 |
1930年 | 1篇 |
1927年 | 2篇 |
排序方式: 共有144条查询结果,搜索用时 46 毫秒
61.
62.
Liposome-DNA complexes infused intravenously inhibit tumor angiogenesis and elicit antitumor activity in dogs with soft tissue sarcoma 总被引:2,自引:0,他引:2
Kamstock D Guth A Elmslie R Kurzman I Liggitt D Coro L Fairman J Dow S 《Cancer gene therapy》2006,13(3):306-317
Intravenous gene delivery using liposome-DNA complexes (LDC) has previously been shown to elicit antitumor activity, but only in rodent tumor models. Therefore, we conducted a study to determine in a large animal spontaneous tumor model whether intravenous infusions of LDC could target gene expression to cutaneous tumor tissues and whether repeated treatments had an effect on tumor growth or angiogenesis. A total of 13 dogs with cutaneous soft tissue sarcomas were enrolled in the study and were randomized to receive a series of 6 weekly infusions of LDC containing either canine endostatin DNA or DNA encoding an irrelevant gene (luciferase). Serial tumor biopsies were obtained to assess transgene expression, tumor microvessel density (MVD), and intratumoral leukocyte inflammatory responses. We found that intravenous infusion of LDC did not result in detectable gene expression in cutaneous tumor tissues. However, two of 13 treated dogs had objective tumor responses and eight dogs had stable disease during the treatment period. In addition, a significant decrease in tumor MVD was noted in six of 12 treated dogs at the completion of six treatments. These results suggest that intravenous infusions of LDC may elicit nonspecific antitumor activity and inhibit tumor angiogenesis. 相似文献
63.
Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q 总被引:5,自引:0,他引:5
Elmslie FV; Rees M; Williamson MP; Kerr M; Kjeldsen MJ; Pang KA; Sundqvist A; Friis ML; Chadwick D; Richens A; Covanis A; Santos M; Arzimanoglou A; Panayiotopoulos CP; Curtis D; Whitehouse WP; Gardiner RM 《Human molecular genetics》1997,6(8):1329-1334
The epilepsies are a group of disorders characterised by recurrent seizures
caused by episodes of abnormal neuronal hyperexcitability involving the
brain. Up to 60 million people are affected worldwide and genetic factors
may contribute to the aetiology in up to 40% of patients. The most common
human genetic epilepsies display a complex pattern of inheritance. These
are categorised as idiopathic in the absence of detectable structural or
metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive
and common variety of familial idiopathic generalised epilepsy (IGE) with a
prevalence of 0.5- 1.0 per 1000 and a ratio of sibling risk to population
prevalence (lambda(s)) of 42. The molecular genetic basis of these familial
idiopathic epilepsies is entirely unknown, but a mutation in the gene
CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine
receptor (nAChR), was recently identified in a rare Mendelian variety of
idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR
subunits were therefore tested for linkage to the JME trait in 34
pedigrees. Significant evidence for linkage with heterogeneity was found to
polymorphic loci encompassing the region in which the gene encoding the
alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at
alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to
genetic susceptibility to JME in a majority of the families studied.
相似文献
64.
Mary Ann Werz Keith S. Elmslie Stephen W. Jones 《Pflügers Archiv : European journal of physiology》1993,424(5-6):538-545
We have investigated the effects of phosphatase and protein kinase inhibitors on calcium channel currents of bullfrog sympathetic neurons using the whole cell configuration of the patch clamp technique. Intracellular dialysis with the phosphatase inhibitors okadaic acid and calyculin A markedly enhanced the decline of inward current during a depolarizing voltage step. Tail current analysis demonstrated that this was genuine inactivation of calcium channel current, not activation of an outward current. The rapidly inactivating current is N-type calcium current (blocked by -conotoxin and resistant to nifedipine). Staurosporine, a nonselective protein kinase inhibitor, prevented the action of okadaic acid, suggesting that protein phosphorylation is involved. Under control conditions, the time course of inactivation could be described by the sum of two exponentials (= 150 ms and 1200 ms), plus a constant (apparently noninactivating) component, during depolarizations lasting 2 s. Okadaic acid induced a rapid inactivation process (=15 ms) that was absent or negligible under control conditions, without obvious effect on the two slower time constants. As in control cells, inactivation in okadaic-acid-treated cells was strongest near –20 mV, with less inactivation at more positive voltages. However, inactivation did not depend on calcium influx. Modulation of calcium channel activity by phosphorylation may underly the spontaneous shift between inactivating and noninactivating modes recently observed for N-type calcium channels. Differences in basal phosphorylation levels could also explain why N-type calcium channels, originally described as rapidly and completely inactivating, inactivate slowly and incompletely in many neurons. 相似文献
65.
Roscovitine, a cyclin-dependent kinase inhibitor, affects several gating mechanisms to inhibit cardiac L-type (Ca(V)1.2) calcium channels
下载免费PDF全文
![点击此处可从《British journal of pharmacology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
BACKGROUND AND PURPOSE: L-type calcium channels (Ca((V))1.2) play an important role in cardiac contraction. Roscovitine, a cyclin-dependent kinase inhibitor and promising anticancer drug, has been shown to affect Ca((V))1.2 by inhibiting current amplitude and slowing activation. This research investigates the mechanism by which roscovitine inhibits Ca((V))1.2 channels. EXPERIMENTAL APPROACH: Ca((V))1.2 channels were transfected into HEK 293 cells, using the calcium phosphate precipitation method, and currents were measured using the whole-cell patch clamp technique. KEY RESULTS: Roscovitine slows activation at all voltages, which precludes one previously proposed mechanism. In addition, roscovitine enhances voltage-dependent, but not calcium-dependent inactivation. This enhancement resulted from both an acceleration of inactivation and a slowing of the recovery from inactivation. Internally applied roscovitine failed to affect Ca((V))1.2 currents, which supports a kinase-independent mechanism and extracellular binding site. Unlike the dihydropyridines, closed state inactivation was not affected by roscovitine. Inactivation was enhanced in a dose-dependent manner with an IC(50)=29.5+/-12 microM, which is close to that for slow activation and inhibition. CONCLUSIONS AND IMPLICATIONS: We conclude that roscovitine binds to an extracellular site on Ca((V))1.2 channels to inhibit current by both slowing activation and enhancing inactivation. Purine-based drugs could become a new option for treatment of diseases that benefit from L-channel inhibition such as cardiac arrhythmias and hypertension. 相似文献
66.
Roscovitine potently inhibits cyclin-dependent kinases (CDK) and can independently slow the closing of neuronal (CaV2.2) calcium channels. We were interested if this drug could affect other ion channels similarly. Using whole cell recordings, we found that roscovitine specifically slows deactivation of all CaV2 channels (N, P/Q and R) by binding to the open state. This effect had a rapid onset and EC(50)=54, 120 and 54microM for N-, P/Q-, and R-type channels, respectively. Deactivation of other channel types was not slowed, including L-type calcium channels (CaV1.2, CaV1.3), potassium channels (native, Kv4.2, Kv2.1 and Kv1.3), and native sodium channels. However, most of the channels tested were inhibited by roscovitine. The inhibition was characterized by slow development and a lower affinity (EC(50)=100-300microM). Surprisingly, potassium channels were rapidly inhibited with an EC(50)=23microM, which is similar to the EC(50) for roscovitine block of cell division [Meijer, L., Borgne, A., Mulner, O., Chong, J., Blow, J., Inagaki, N., Inagaki, M., Delcros, J., Moulinoux, J., 1997. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 243, 527-536]. Potassium current inhibition seemed to result from open channel block. The high potency of these two rapid onset effects makes them complicating factors for ongoing clinical trials and research using roscovitine. Thus, the physiology and pharmacology of slow CaV2 deactivation and potassium channel block must be explored. 相似文献
67.
68.
Jane L Elmslie Richard J Porter Peter R Joyce Penelope J Hunt Jim I Mann 《Bipolar disorders》2006,8(5P1):503-507
Objectives: Carnitine deficiency impairs fatty acid β -oxidation and may partly explain weight gain in valproate-treated patients. The aim of this study was to determine whether l -carnitine supplementation improves weight loss outcomes in bipolar patients taking sodium valproate.
Methods: Sixty bipolar patients with clinically significant weight gain thought to be related to sodium valproate, who had been taking sodium valproate for ≥6 months, were randomized to l -carnitine (15 mg/kg/day) or placebo for 26 weeks, in conjunction with a moderately energy-restricted, low-fat diet. The primary outcome measure was weight change.
Results: l -carnitine had no effect on mean weight loss compared with placebo (−1.9 kg versus − 0.9 kg) ( F = 0.778, df = 1,58, p = 0.381). The number of people in each group able to lose any weight was identical ( = 0, p = 1.0); more patients in the carnitine group (nine versus five) achieved a clinically significant weight loss (≥5%) but this was not statistically significant (p = 1.0, Fisher's exact test).
Conclusions: At the dose prescribed in this study carnitine supplementation did not improve weight loss outcomes in valproate-treated bipolar patients consuming an energy-restricted, low-fat diet. 相似文献
Methods: Sixty bipolar patients with clinically significant weight gain thought to be related to sodium valproate, who had been taking sodium valproate for ≥6 months, were randomized to l -carnitine (15 mg/kg/day) or placebo for 26 weeks, in conjunction with a moderately energy-restricted, low-fat diet. The primary outcome measure was weight change.
Results: l -carnitine had no effect on mean weight loss compared with placebo (−1.9 kg versus − 0.9 kg) ( F = 0.778, df = 1,58, p = 0.381). The number of people in each group able to lose any weight was identical ( = 0, p = 1.0); more patients in the carnitine group (nine versus five) achieved a clinically significant weight loss (≥5%) but this was not statistically significant (p = 1.0, Fisher's exact test).
Conclusions: At the dose prescribed in this study carnitine supplementation did not improve weight loss outcomes in valproate-treated bipolar patients consuming an energy-restricted, low-fat diet. 相似文献
69.
Michael Lever Christopher J. McEntyre Peter M. George Sandy Slow Jane L. Elmslie Helen Lunt Stephen T. Chambers Amber Parry-Strong Jeremy D. Krebs 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2014,28(5):459-468
Purpose
Betaine deficiency is a probable cardiovascular risk factor and a cause of elevated homocysteine. Urinary betaine excretion is increased by fibrate treatment, and is also often elevated in diabetes. Does fibrate further increase betaine excretion in diabetes, and does it affect the plasma concentrations and excretions of related metabolites and of other osmolytes?Methods
Samples from a previous study of type 2 diabetes were selected if participants were taking bezafibrate (n?=?32). These samples were compared with participants matched for age and gender and not on a fibrate (comparator group, n?=?64). Betaine, related metabolites, and osmolytes were measured in plasma and urine samples from these 96 participants.Results
Median urinary betaine excretion in those on bezafibrate was 5-fold higher than in the comparator group (p?0.001), itself 3.5-fold higher than the median reported for healthy populations. In the bezafibrate group, median dimethylglycine excretion was higher (9-fold, p?0.001). Excretions of choline, and of the osmolytes myo-inositol, taurine and glycerophosphorylcholine, were not significantly different between groups. Some participants excreted more betaine than usual dietary intakes. Several betaine fractional clearances were >100 %. Betaine excretion correlated with excretions of the osmolytes myo-inositol and glycerophosphorylcholine, and also with the excretion of choline and N,N-dimethylglycine, but it was inconclusive whether these relationships were affected by bezafibrate therapy.Conclusions
Increased urinary betaine excretions in type 2 diabetes are further increased by fibrate treatment, sometimes to more than their dietary intake. Concurrent betaine supplementation may be beneficial. 相似文献70.
Sulan Luo Dongting Zhangsun Peta J. Harvey Quentin Kaas Yong Wu Xiaopeng Zhu Yuanyan Hu Xiaodan Li Victor I. Tsetlin Sean Christensen Haylie K. Romero Melissa McIntyre Cheryl Dowell James C. Baxter Keith S. Elmslie David J. Craik J. Michael McIntosh 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(30):E4026-E4035