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We describe a new family with cathecholaminergic polymorphic ventricular tachycardia (CPVT) linked to the Triadin gene. This is the second report of such a CPVT of autosomal recessive inheritance. Using an NGS panel including 42 genes involved in cardiac sudden death, 2 heterozygous pathogenic mutations (c.613C> T/p.Gln205* and c.22 + 29 A>G) were identified in the Triadin gene in 2 sibs who experienced early severe arrhythmias without evidence of CPVT diagnosis at first cardiac evaluation. However, significant arrhythmias occurred after catecholaminergic stimulation. Each of the TRDN mutations was inherited from a healthy parent. In this family, genetic studies permit confirmation of the CPVT diagnosis in the 2 affected sibs and permit the early diagnosis of the third asymptomatic child. It also helped guide the therapeutic strategy in this family.  相似文献   
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The retro-inversion of the amide bond in kelatorphan and analogs, the first series of complete inhibitors of enkephalin metabolism, led to compounds highly efficient only against the neutral endopeptidase 24-11 (NEP). In order to increase the recognition of the aminopeptidase N (APN) and dipeptidylaminopeptidase (DAP), without loss of affinity for NEP, the malonyl group of these retro-inhibitors was replaced by diversely substituted succinyl moieties. All the molecules synthesized are highly efficient NEP inhibitors with Ki's in the 0.2–1 nM range, indicating that NEP possesses a relatively large and not very selective S2’subsite. In contrast, inhibition of DAP activity is crucially dependent on the size and the position of the substituent in the succinyl moiety. Inhibitory potencies in the nanomolar range are obtained with compounds containing a benzyl group in the α-position related to thc rctro amide bond. Finally, a relatively modest inhibition of APN was observed with Ki's in the 0.5-1 μM range for compounds with benzyl or cyclohexyl group in P2'position. However, these data demonstrate that efficient and complete inhibition of enkephalin degradation can be obtained with hydroxamate dipeptides containing a retro amide bond. The analgesic potency of the most active inhibitors was measured using the hot plate test in mice. Significant antinociceptive responses were obtained but these effects were rather weaker than those expected from the in vitro inhibitory potencies of these compounds on the three enkephalin-degrading enzymes.  相似文献   
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Several phosphoserine, phosphothreonine and phosphotyrosine synthons suitable for the stepwise synthesis of phosphopeptides were prepared. Treatment of methylthiomethyl (MTM) esters of either Z-, Boc-, Alloc-serine and threonine with phosphochloridate in pyridine followed by MgBr2 cleavage of MTM in diethyl ether afforded the title compounds in good yield. Thiophosphoserine and phosphotyrosine synthons were also obtained by the phosphoramidite method using di-(2,2,2-trichloroethyl) -N.N-diisopropylphosphoramidite and MCPBA as oxidizing reagent. Trichloroethyl proved valuable as phosphate protecting group especially in phosphotyrosine derivatives owing to its stability in acidic conditions. These synthons were involved in the liquid-phase synthesis of several phospho and/or thiophosphopeptides related to either src-protein kinase or rat liver pyruvate kinase.  相似文献   
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Modern computer power allows development of models of the heart that may be helpful for the understanding of arrhythmia mechanisms if, based on realistic physiological parameters, such models can display phenomena difficult to study in nature. Therefore, a two-dimensional model of the cardiac tissue has been implemented, where the modeling of each cell is based on membrane ionic channels (Beeler-Reuter and Luo-Rudy models). In addition, an ECG was computed based on the ionic currents simulated. This model allows us to observe the propagation of the action potentials Vm across the cardiac tissue, the evolution of Vm for any of the cardiac cells, and the underlying ionic currents. The computation of the ECG makes it possible to relate this information with an often-used diagnostic tool. Simulations of normal and pathological phenomena such as functional and anatomic reentry have been performed. Our simulation results show that the applied computer model based on ionic currents seems accurate and realistic when compared with biological models and offers a new approach to study the origin, prevention, and termination of arrhythmias.  相似文献   
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Policy Points

  • More rigorous methodologies and systematic approaches should be encouraged in the science of scaling. This will help researchers better determine the effectiveness of scaling, guide stakeholders in the scaling process, and ultimately increase the impacts of health innovations.
  • The practice and the science of scaling need to expand worldwide to address complex health conditions such as noncommunicable and chronic diseases.
  • Although most of the scaling experiences described in the literature are occurring in the Global South, most of the authors publishing on it are based in the Global North. As the science of scaling spreads across the world with the aim of reducing health inequities, it is also essential to address the power imbalance in how we do scaling research globally.
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