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Casiraghi G Rassu G Auzzas L Burreddu P Gaetani E Battistini L Zanardi F Curti C Nicastro G Belvisi L Motto I Castorina M Giannini G Pisano C 《Journal of medicinal chemistry》2005,48(24):7675-7687
Eleven gamma-aminocyclopentane carboxylic acid (Acpca) platforms, including four dihydroxy representatives (19-22), three hydroxy analogues (34-36), and four deoxy derivatives (30-33), were prepared in a chiral nonracemic format. These simple units were then grafted onto an Arg-Gly-Asp (RGD) tripeptide framework by a mixed solid phase/solution protocol delivering an ensemble of 11 macrocyclic analogues of type cyclo-[-Arg-Gly-Asp-Acpca-], 1-11. The individual compounds were evaluated for their binding affinity toward the alphaVbeta3 and alphaVbeta5 integrin receptors. The analogue 10 exhibited a very interesting activity profile (IC50/alphaVbeta3= 1.5 nM; IC50/alphaVbeta5= 0.59 nM), comparable to that of reference compounds EMD121974 and ST1646. Closely related congeners 6, 8, and 9 also proved to be excellent dual binders with activity levels in the low nanomolar range. The three-dimensional (3D) NMR solution structures were determined, and docking studies to X-ray crystal structure of the extracellular segment of integrin alphaVbeta3 in complex with the reference compound EMD121974 were performed on selected analogues to elucidate the interplay between structure and function in these systems and to evidence the subtle bases for receptorial recognition. The results prove that the principle of isosteric dipeptide replacement for peptidomimetics design and synthesis can be violated, without detriment to the development of highly effective integrin binders. 相似文献
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LN Barlow-Mosha DS Bagenda PK Mudiope MC Mubiru LM Butler MG Fowler PM Musoke 《African health sciences》2012,12(3):249-258
Background
Access to pediatric antiretroviral formulations is increasing in resource-limited countries, however adult FDCs are still commonly used by antiretroviral therapy (ART) programs.Objective
To describe long-term effectiveness of using adult FDC of d4T+3TC+NVP (Triomune) in children for HIV treatment.Methods
Clinical, immunologic, and virologic outcomes of HIV-infected ART-naïve children aged six months to 12 years, were evaluated up to 96 weeks post-ART initiation.Results
From March 2004 to June 2006, 104 children were followed with a median age of 5.4 years, median CD4 cell percent and HIV-1 RNA were 11.0% (IQR 6.7–13.9) and 348,846copies/mL (IQR 160,941–681,313) respectively at baseline. Using Kaplan-Meir estimates, 75% of children had undetectable viral loads (<400copies/mL) at 96weeks of ART. Children with a baseline CD4 cell percent >15% were 3 times more likely to achieve viral load <400copies/mL than those with baseline CD4 cell percent <5% after adjusting for baseline age {aHR = 3.03 (1.10–8.32), p=0.03}; no difference was found among those with CD4 cell percent >5–14.9% and <5%.Conclusion
Treatment with generic adult FDC for HIV-infected Ugandan children led to sustained clinical, immunologic and virologic response during 96 weeks of ART. Early initiation of ART is key to achieving virological success. 相似文献106.
Long‐term consequences of pain,anxiety and agitation for critically ill older patients after an intensive care unit stay
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107.
Bergantini L Cameli P d’Alessandro M Vagaggini C Refini RM Landi C Pieroni MG Spalletti M Sestini P Bargagli E 《Clinical and experimental medicine》2019,19(4):487-494
Clinical and Experimental Medicine - Background The pathogenetic and regulatory roles of natural killer (NK) and natural killer T-like cells in interstitial lung diseases (ILDs), fibrotic and... 相似文献
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Antonella Conte Lorenzo Rocchi Anna Latorre Daniele Belvisi John C. Rothwell Alfredo Berardelli 《Movement disorders》2019,34(11):1616-1628
The physiological landscape of dystonia has changed considerably over the past 10 years. Initial ideas that dystonic motor symptoms could be explained by a combination of loss of inhibition and increased plasticity, together with subtle deficits in sensory processing, have been questioned, whereas the possible role of the cerebellum has risen in importance. In addition, it has been recognized that symptoms affect more than just the motor and sensory systems and encompass independent cognitive and psychological changes. Finally, it has become clear that, despite similarities in symptoms, there may be pathophysiological differences between idiopathic, inherited, and acquired forms of dystonia. In other words, progress in the pathophysiology of dystonia has followed the usual pattern from an initial phase in which core deficits are readily explained by highly simplified models to a realization that within a highly interconnected network, effects are more nuanced with widespread changes that might either compensate or contribute to the clinical symptoms to different degrees in different individuals. © 2019 International Parkinson and Movement Disorder Society 相似文献
110.
Conte A Belvisi D Iezzi E Mari F Inghilleri M Berardelli A 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2008,186(3):393-399
We investigated whether human attentional processes influence the activity of intracortical inhibitory and excitatory circuits—short-interval
intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), and the intracortical facilitation (ICF)—elicited
by paired-pulse transcranial magnetic stimulation (TMS) in healthy subjects. In eight healthy subjects we tested SICI, LICI
and ICF under different attention-demanding conditions: “relaxed”, “target hand” and “non-target hand”. To compare the effects
of attentional levels on SICI, LICI and ICF with those produced on the MEPs elicited by repetitive TMS (rTMS), in the same
subjects we also delivered supra-threshold 5-Hz rTMS under the same three experimental conditions. To disclose whether attentional
processes act selectively on circuits engaged by TMS delivered at 5 Hz frequency and at an interstimulus interval (ISI) of
200 ms, we also investigated the effects of different attention levels on paired-pulse TMS delivered at the 200 ms ISI and
on the MEP size during 1-Hz rTMS. Attentional levels had no influence on SICI, ICF and LICI activated by paired-pulse TMS,
but increased the MEP facilitation elicited by 5-Hz rTMS. Varying the attention level left the findings from 1-Hz rTMS unchanged.
The finding that attention leaves the activity of intracortical inhibitory and excitatory circuits elicited by paired-pulse
TMS unchanged but influences the MEP facilitation elicited by 5-Hz rTMS suggests that attention operates only when the stimulation
entrains neural circuits made up of a large number of cortical cells with plasticity properties. 相似文献