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991.
Goddard-Borger ED Tropak MB Yonekawa S Tysoe C Mahuran DJ Withers SG 《Journal of medicinal chemistry》2012,55(6):2737-2745
A highly divergent route to lipophilic iminosugars that utilizes the thiol-ene reaction was developed to enable the rapid synthesis of a collection of 16 dideoxyiminoxylitols bearing various different lipophilic substituents. Enzyme kinetic analyses revealed that a number of these products are potent, low-nanomolar inhibitors of human glucocerebrosidase that stabilize the enzyme to thermal denaturation by up to 20 K. Cell based assays conducted on Gaucher disease patient derived fibroblasts demonstrated that administration of the compounds can increase lysosomal glucocerebrosidase activity levels by therapeutically relevant amounts, as much as 3.2-fold in cells homozygous for the p.N370S mutation and 1.4-fold in cells homozygous for the p.L444P mutation. Several compounds elicited this increase in enzyme activity over a relatively wide dosage range. The data assembled here illustrate how the lipophilic moiety common to many glucocerebrosidase inhibitors might be used to optimize a lead compound's ability to chaperone the protein in cellulo. The flexibility of this synthetic strategy makes it an attractive approach to the rapid optimization of glycosidase inhibitor potency and pharmacokinetic behavior. 相似文献
992.
993.
Abdel Aziz A. Jaffan Ethan A. Prince Christopher O. Hampson Timothy P. Murphy 《Cardiovascular and interventional radiology》2013,36(3):567-577
Purpose
To establish the efficacy and safety of the preclose technique in total percutaneous endovascular aortic repair (PEVAR).Methods
A systematic literature search of Medline database was conducted for series on PEVAR published between January 1999 and January 2012.Results
Thirty-six articles comprising 2,257 patients and 3,606 arterial accesses were included. Anatomical criteria used to exclude patients from undergoing PEVAR were not uniform across all series. The technical success rate was 94 % per arterial access. Failure was unilateral in the majority (93 %) of the 133 failed PEVAR cases. The groin complication rate in PEVAR was 3.6 %; a minority (1.6 %) of these groin complications required open surgery. The groin complication rate in failed PEVAR cases converted to groin cutdown was 6.1 %. A significantly higher technical success rate was achieved when arterial access was performed via ultrasound guidance. Technical failure rate was significantly higher with larger sheath size (≥20F).Conclusion
The preclose technique in PEVAR has a high technical success rate and a low groin complication rate. Technical success tends to increase with ultrasound-guided arterial access and decrease with larger access. When failure occurs, it is unilateral in the majority of cases, and conversion to surgical cutdown does not appear to increase the operative risk. 相似文献994.
995.
996.
Maturation of human central auditory system activity: evidence from multi-channel evoked potentials. 总被引:4,自引:0,他引:4
OBJECTIVE: The purpose of this study was to evaluate central auditory system maturation based on detailed data from multi-electrode recordings of long-latency auditory evoked potentials (AEPs). METHODS: AEPs were measured at 30 scalp-electrode locations from 118 subjects between 5 and 20 years of age. Analyses focused on age-related latency and amplitude changes in the P1, N1b, P2, and N2 peaks of the AEPs generated by a brief train of clicks presented to the left ear. RESULTS: Substantial and unexpected changes that extend well into adolescence were found for both the amplitude and latency of the AEP components. While the maturational changes in latency followed a pattern of gradual change, amplitude changes tended to be more abrupt and step-like. Age-related latency decreases were largest for the P1 and N1b peaks. In contrast, P2 latency did not change significantly and the N2 peak increased in latency as a function of age. Abrupt changes in P1, P1-N1b, and N2 peak amplitude (also RMS amplitude) were observed around age 10 at the lateral electrode locations C3 and C4, but not at the midline electrodes Cz and Fz. These changes in amplitude coincided with a sharp increase and plateau in AEP peak and RMS amplitude variability from 9 to 11 years of age. CONCLUSIONS: These analyses demonstrated that the observed pattern of AEP maturation depends on the scalp location at which the responses are recorded. The distinct maturational time courses observed for individual AEP peaks support a model of AEP generation in which activity originates from two or more at least partly independent central nervous system pathways. A striking parallel was observed between previously reported maturational changes in auditory cortex synaptic density and, in particular, the age-related changes in P1 amplitude. The results indicate that some areas of the brain activated by sound stimulation have a maturational time course that extends into adolescence. Maturation of certain auditory processing skills such as speech recognition in noise also has a prolonged time course. This raises the possibility that the emergence of adult-like auditory processing skills may be governed by the same maturing neural processes that affect AEP latency and amplitude. 相似文献
997.
Walter Mischel Ozlem Ayduk Marc G. Berman B. J. Casey Ian H. Gotlib John Jonides Ethan Kross Theresa Teslovich Nicole L. Wilson Vivian Zayas Yuichi Shoda 《Social cognitive and affective neuroscience》2011,6(2):252-256
In the 1960s, Mischel and colleagues developed a simple ‘marshmallow test’ to measure preschoolers’ ability to delay gratification. In numerous follow-up studies over 40 years, this ‘test’ proved to have surprisingly significant predictive validity for consequential social, cognitive and mental health outcomes over the life course. In this article, we review key findings from the longitudinal work and from earlier delay-of-gratification experiments examining the cognitive appraisal and attention control strategies that underlie this ability. Further, we outline a set of hypotheses that emerge from the intersection of these findings with research on ‘cognitive control’ mechanisms and their neural bases. We discuss implications of these hypotheses for decomposing the phenomena of ‘willpower’ and the lifelong individual differences in self-regulatory ability that were identified in the earlier research and that are currently being pursued. 相似文献
998.
Drescher C Foscue EP Kuhn CM Schramm-Sapyta NL 《Developmental cognitive neuroscience》2011,1(4):600-605
Drugs of abuse induce complex motivational states in their users which have been shown to vary developmentally. In addition to developmental variation, interindividual variation in the rewarding and aversive effects of drugs of abuse is an important consideration. A rat model was used to assess whether the conditioned rewarding/aversive effects of cocaine were maintained as individuals matured from adolescence into adulthood. We tested rats in the cocaine conditioned taste aversion task as adolescents and again in adulthood. We observed a wide range of approach/avoidance behaviors in this task, and also observed that the relative interindividual differences in approach/avoidance are remarkably stable across the two developmental stages. Furthermore, we observed that these interindividual differences are not attributable to individual differences in cocaine-induced locomotor effects or individual differences in blood or brain cocaine levels. Taken together, these findings indicate that sensitivity to cocaine's motivational effects is stable across development and part of a unique neurological process. 相似文献
999.
Adult-onset muscular dystrophy is an inherited myopathy characterized by a variable degree of progressive muscle weakness and degeneration. Although not usually fatal, significant muscle weakness results in an up-regulation of acetylcholine receptors on the less responsive postjunctional muscles. The resulting profound potassium release when these receptors are stimulated by the depolarizing muscle relaxant succinylcholine can result in potentially fatal cardiac arrhythmias. We report a case of electroconvulsive therapy safely administered in a 61-year-old man with adult-onset muscular dystrophy requiring muscle relaxation with rocuronium. 相似文献
1000.