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101.
Nicolotti O Giangreco I Introcaso A Leonetti F Stefanachi A Carotti A 《Expert opinion on drug discovery》2011,6(9):871-884
Introduction: Drug discovery and development is a typical multi-objective problem and its successes or failures depend on the simultaneous control of numerous, often conflicting, molecular and pharmacological properties. Multi-objective optimization strategies represent a new approach to capture the occurrence of varying optimal solutions based on trade-offs among the objectives taken into account. In view of this, multi-objective optimization aims to discover a set of satisfactory compromises that may in turn be used to find the global optimal solution by optimizing numerous dependent properties simultaneously. Areas covered: The authors review the potential of multi-objective strategies in a number of fields including: drug library design; substructure mining; the derivation of quantitative structure-activity relationship models; ranking of docking poses. The authors also discuss the potential of multi-objective strategies in controlling competing properties for absorption, distribution, metabolism and elimination/toxicity optimization. Expert opinion: It is very clear to those who work in drug discovery and development that the success of rational drug design is largely dependent on the control of a number of, often conflicting, objectives. Therefore, multi-objective optimization methods, which have recently been introduced to the field of molecular discovery, represent the ultimate frontier in chemoinformatics. The widespread use of these multi-objective techniques has provided new opportunities in medicinal chemistry as seen through its use in a number of applications for chemoinformatics both within academia and the pharmaceutical industry. 相似文献
102.
103.
Balducci C Mehdawy B Mare L Giuliani A Lorenzini L Sivilia S Giardino L Calzà L Lanzillotta A Sarnico I Pizzi M Usiello A Viscomi AR Ottonello S Villetti G Imbimbo BP Nisticò G Forloni G Nisticò R 《Journal of Alzheimer's disease : JAD》2011,24(4):799-816
Abnormal amyloid-β (Aβ) production and deposition is believed to represent one of the main causes of Alzheimer's disease (AD). γ-Secretase is the enzymatic complex responsible for Aβ generation from its precursor protein. Inhibition or modulation of γ-secretase represents an attractive therapeutic approach. CHF5074 is a new γ-secretase modulator that has been shown to inhibit brain plaque deposition and to attenuate memory deficit in adult AD transgenic mice after chronic treatment. To date, it is not known whether the positive behavioral effects of this compound also occur in young transgenic mice without plaque deposition. Here, we evaluated the effects of acute and subchronic treatment with CHF5074 on contextual and recognition memory and on hippocampal synaptic plasticity in plaque-free Tg2576 mice. We found that at 5 months of age, contextual memory impairment was significantly attenuated after acute subcutaneous administration of 30 mg/kg CHF5074. At 6 months of age, recognition memory impairment was fully reversed after a 4-week oral treatment in the diet (≈60 mg/kg/day). These cognitive effects were associated with a reversal of long-term potentiation (LTP) impairment in the hippocampus. A significant reduction in brain intraneuronal AβPP/Aβ levels and hyperphosphorylated tau, but no change in soluble or oligomeric Aβ levels was detected in Tg2576 mice showing functional recovery following CHF5074 treatment. We conclude that the beneficial effects of CHF5074 treatment in young transgenic mice occurred at a stage that precedes plaque formation and were associated with a reduction in intraneuronal AβPP/Aβ and hyperphosphorylated tau. 相似文献
104.
Introduction: In this study we tested the hypothesis that caffeine supplementation improves neuromuscular function, which has both nutritional and clinical relevance. Methods: Fourteen male subjects (mean ± SD: 23.8 ± 2.8 years) volunteered in a double‐blind, repeated‐measures study with placebo (PLA) or caffeine (CAFF) (6 mg kg?1). Maximal voluntary isometric contractions (MVCs), evoked maximal twitch, and maximal isokinetic contractions during elbow flexion were assessed. Mechanical and electromyographic (EMG) signals from the biceps brachii muscle were recorded, and muscle fiber conduction velocity (CV) was calculated to evaluate changes in the muscle force–velocity relationship and muscle fiber recruitment. Results: The torque–angular velocity curve was enhanced after CAFF supplementation. This was supported by a concomitant increase of CV values (8.7% higher in CAFF). Conclusions: Caffeine improves muscle performance during short‐duration maximal dynamic contractions. The concomitant improvement of mean fiber CV supports the hypothesis of an effect of caffeine on motor unit recruitment. Muscle Nerve, 2011. 相似文献
105.
D'Argenio G Mazzone G Tuccillo C Grandone I Gravina AG Graziani G Fogliano V Romano M 《The British journal of nutrition》2008,100(6):1228-1236
Aspirin causes gastroduodenal ulcers and complications. Food bioactive compounds could exert beneficial effects in the gastrointestinal tract. We evaluated whether apple polyphenol extract (APE) reduced aspirin-induced injury to the rat gastric mucosa. Rats were treated with APE (10(-4) m catechin equivalent) before oral aspirin (200 mg/kg). Cyclo-oxygenase-2 (COX-2), transforming growth factor-alpha (TGF alpha) and heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) mRNA and protein expression were assessed by RT-PCR and Western blot analysis, respectively; malondialdehyde (MDA) was determined by HPLC; gastric secretion was evaluated in pylorus-ligated rats. APE decreased acute and chronic aspirin injury both macroscopically and microscopically (approximately 50 % decrease in lesion score; P < 0.05). Aspirin up-regulated mRNA and protein expression of COX-2 and HB-EGF, but not of TGF alpha; APE reduced aspirin-induced mRNA and protein over-expression of COX-2 and HB-EGF; aspirin significantly increased gastric MDA and this effect was counteracted by APE pre-treatment. APE did not significantly affect gastric acid secretion. In conclusion, APE reduces aspirin-induced gastric injury independently of acid inhibition. We speculate that APE might be of therapeutic use in the prophylaxis of aspirin-related gastropathy. 相似文献
106.
欧洲新生儿呼吸窘迫综合征防治共识 总被引:10,自引:0,他引:10
Sweet D Bevilacqua G Carnielli V Greisen G Plavka R Didrik SO Simeoni U Speer CP Soler A Valls I Halliday H;Working Group on Prematurity of the World Association of Perinatal Medicine European Association of Perinatal Medicine 《中华儿科杂志》2008,46(1):30-34
呼吸窘迫综合征(RDS)是由于肺表面活性物质(PS)缺乏及肺结构发育不成熟所致,多见于早产儿,自然病程为出生当时或生后很快发病,并在生后2d内进行性恶化,如不及时治疗,因进行性缺氧和呼吸衰竭而死亡。存活者出生后2—4d病情开始改善。RDS临床表现早期出现呼吸窘迫如紫绀、呻吟、吸凹和呼吸急促,然后进一步发展为呼吸衰竭,血气分析结果可提示呼吸衰竭的严重性。胸部X线典型的毛玻璃样改变和支气管充气征可以确诊。Vermont Oxford新生儿协作网对RDS的定义为: 相似文献
107.
Viehweger E Zürcher Pfund L Hélix M Rohon MA Jacquemier M Scavarda D Jouve JL Bollini G Loundou A Simeoni MC 《Annals of physical and rehabilitation medicine》2010,53(9):535-546
ObjectivesTreatment complexity of cerebral palsy (CP) patients imposes outcome evaluation studies, which may include objective technical analysis and more subjective functional evaluation. The Edinburgh Gait Score (EGS) was proposed as an additive or alternative when complex instrumented three-dimensional gait analysis is not available. Our purposes were to apply a translated EGS to standard video recordings of independent walking spastic diplegic CP patients, to evaluate its intraobserver and interobserver reliability with respect to gait analysis familiar and not familiar observers.MethodsTen standard video recordings acquired during routine clinical gait analysis were examined by eight observers gait analysis interpretation experienced or not, out of various specialities, two times with a two weeks interval. Kappa statistics and intraclass correlation coefficient were calculated.ResultsBetter reliability was observed for foot and knee scores than in proximal segments with significant differences between stance and swing phase. Significantly better results in gait analysis trained observers underlines the importance to either be used to clinical gait analysis interpretation, or to benefit of video analysis training before observational scoring.ConclusionVisual evaluation may be used for outcome studies to explore clinical changes in CP patients over time and may be associated to other validated evaluation tools. 相似文献
108.
Berbis J Einaudi MA Simeoni MC Brévaut-Malaty V Auquier P d'Ercole C Gire C 《European journal of obstetrics, gynecology, and reproductive biology》2012,162(1):38-44
Objectives
To describe the health-related quality of life (HRQL) of a cohort of children aged 6–10 years who were born preterm; and to determine whether sociodemographic factors, neonatal features and neurocognitive status were affecting their HRQL.Study design
All singleton infants born between 24 and 32 weeks of gestation between January 1997 and December 2001 at the study hospital, who were still alive in 2007 (age 6–10 years), and who had undergone complete clinical paediatric follow-up were included in the study. Maternal and perinatal data were obtained by chart review and regular clinical examination. The ‘Battery for Rapid Evaluation of Cognitive Functions’ (BREV) was used for cognitive evaluation when children were aged 4–8 years. HRQL data were collected in 2007 using the ‘Vécu et Santé Perçue de l’Adolescent et de l’Enfant’ (VSP-A) questionnaire (parent version). The HRQL of the preterm children was compared with that of a French reference population.Results
Of 202 children who fulfilled the inclusion criteria, 82 children participated in the study. Their mean age was 7.9 years [standard deviation (SD) 1.4], mean birth weight was 1130.0 g (SD 361.4), 23 children were born before 28 weeks of gestation, 46 were female and 11 had major neurocognitive disorders. These data were not significantly different for the non-respondents (n = 120). Parents of preterm children reported a significantly lower perception of HRQL of their child compared with parents of children in the reference population, as reflected by VSP-A global index scores and scores for the ‘body image’, ‘vitality’, ‘psychological well-being’ and ‘school performance’ dimensions. In multivariate analyses, three factors were found to be significantly associated with at least one dimension in the VSP-A scale in the preterm children: presence of major neurocognitive disorders, negatively correlated with ‘vitality’, ‘relationships with friends’, ‘physical well-being’ and ‘school performance’ dimensions; maternal parity, positively correlated with the ‘psychological well-being’ dimension; and socio-economic status of family, positively correlated with the ‘relationships with friends’ dimension. The maximum R2 was 15%.Conclusion
In addition to neurocognitive disorders, other variables such as socio-economic status of the family have a significant impact on the HRQL of preterm children at 6–10 years of age. Given the low proportion of variability in HRQL explained by the models, there is a need to explore other factors (e.g. environmental). 相似文献109.
von Wurmb-Schwark N Mályusz V Fremdt H Koch C Simeoni E Schwark T 《Legal medicine (Tokyo, Japan)》2006,8(3):177-181
The forensic scientist often has to cope with problematic samples from the crime scene due to their minute size and thus the low amount of extractable DNA. The retrieval of DNA from swabs taken from the surface of the skin, for example, in cases of strangulation, can be especially difficult. We systematically investigated swabs taken from the skin (to obtain a genetic profile from the victim and also from a possible offender) and from sperm cell containing swabs using two extraction kits: the Invisorb forensic and the Invisorb spin swab kit (both Invitek, Germany). DNA quality and quantity were tested on ethidium bromide containing agarose gels and in a highly sensitive duplex-PCR, which amplifies fragments specific for mitochondrial and nuclear DNA. Absolute quantification was done using real time PCR. Samples, which were positive in the duplex-PCR, were also employed to genetic fingerprinting using the Powerplex ES and the AmpFlSTRIdentifiler(TM) kits. Our study shows that the easy-to-use Invisorb spin swab kit is very suitable for DNA isolation from swabs taken from the skin and also from sperm cells. Retrieval of cells from the skin with swabs moistened in extraction buffer, not in distilled water, led to a significant higher DNA yield. 相似文献
110.