325,004 research outputs found
I Fiori della Poesia ...
No full textMarca tip en ambas portsSign.: [cruz latina]\p6\s, a-g\p8\s, h\p4\s A-X8, Y4; a-h\p8\s, i\p4\
Unusual cerebral malformations in the Apert syndrome. A report of two newborn infants [Rare malformazioni cerebrali nella sindrome di Apert. Descrizione di due casi in età neonatale]
No full textMulti-target strategy for Parkinsonian patients: the role of deep brain stimulation in the centromedian-parafascicularis complex.
No full textBrain Res Bull. 2009 Feb 16;78(2-3):113-8. doi: 10.1016/j.brainresbull.2008.08.007. Epub 2008 Sep 21.
Multi-target strategy for Parkinsonian patients: the role of deep brain stimulation in the centromedian-parafascicularis complex.
Stefani A, Peppe A, Pierantozzi M, Galati S, Moschella V, Stanzione P, Mazzone P.
SourceIRCCS Fondazione S. Lucia, Roma, Italy. [email protected]
Abstract
The intra-laminar (IL) thalamic complex, composed of centromedian (CM) and parafascicular (Pf) nucleus, is a strategic crossroad for the activity of the basal ganglia and is recently regaining its position has a putative neurosurgical target for Parkinsonian syndromes. The multi-target approach we have encouraged since the late nineties has allowed the combined implantation of a standard target (the subthalamic nucleus-STN or the internal pallidus-GPi) plus an innovative one (CM/Pf) in well-identified Parkinson's disease (PD) patients; hence, it is possible to study, in the same PD patients, the specific target-mediated effects on different clinical signs. Here, we focus on the potential usefulness of implanting the CM/Pf complex when required in the management of contra-lateral tremor (resistant to standard deep brain stimulation-DBS - in STN - , n=2) and disabling involuntary movements, partially responsive to GPi-DBS (n=6). When considering global UPDRS scores, CM/Pf-DBS ameliorate extra-pyramidal symptoms but not as strongly as STN (or GPi) does. Yet, CM/Pf acts very powerfully on tremor and contributes to the long-term management of l-Dopa-induced involuntary movements. The lack of cognitive deficits and psychic impairment associated with the improvement of their quality of life, in our small cohort of CM/Pf implanted patients, reinforces the notion of CM/Pf as a safe and attractive area for surgical treatment of advanced PD, possibly affecting not only motor but also associative functions
The autism-spectrum quotient - Italian version: A cross- cultural confirmation of the broader autism phenotype
No full textThe Autism Spectrum Quotient (AQ) has been used to define the 'broader' (BAP), 'medium' (MAP) and 'narrow' autism phenotypes (NAP). We used a new Italian version of the AQ to test if difference on AQ scores and the distribution of BAP, MAP and NAP in autism parents (n = 245) versus control parents (n = 300) were replicated in a Sicilian sample. Parents of children with autism spectrum conditions scored higher than the control parents on total AQ, social skills and communication subscales, and exhibited higher rates of BAP, MAP and NAP. We conclude that the Italian AQ is a cross-culturally reliable measure of these different phenotypes, and can be used to identify a phenotypic gradient of severity of autistic traits in families. To understand the molecular basis of these phenotypes will require its use in genetic association studies
Un giornale cattolico degli Stati Uniti durante la prima guerra mondiale: <<The Pilot>> di Boston
No full textSi ricostruisce la vicenda del giornale cattolico della Diocesi di Boston (USA) durante il primo conflitto mondiale al fine di mostrare l'atteggiamento della Chiesa cattolica americana nei confronti del conflitto
Design of histone methyltransferase and deacetylase modulators: applications in cancer and non-cancer diseases
No full textIn our two previous studies, we reported the discovery and the optimization of novel 1,4-dihydropyridine-based sirtuin ligands. Starting from SIRT1-activating 1,4-DHPs, bearing benzyl group at N1, we identified carbonyl group at N1 to be responsible for an increased SIRT3 activation (MC2791 (1a) and MC2789 (1u)). However, the moderate potencies of 1a and 1u prompted us to screen for more potent derivatives. We generated new series of compounds by varying their “top” or “bottom” with other substituents at C1 or C4 position of the DHP scaffold, respectively. Hence, we reported the discovery and characterization of potent and specific activators for Sirt3 and/or Sirt5. The 1,4-DHP-based activators bind to the sirtuin catalytic core independent of bound substrates and increase the enzyme’s turnover. The compounds are selective for Sirt3 or Sirt5 and show cellular activity. Overall, our results provided a scaffold for potent and specific sirtuins activation and an activation model for Sirt3 and Sirt5 as a basis for functional studies and further drug development. Additionally, HBV-infected cells treated with our potent and selective Sirt3 activator 1a, demonstrated that 1a regulates the antiviral activity of cccDNA in HepAD38 cells. The treatment of HBV-infected cells with 1a through SIRT3 stimulation led to histone H3 and/or H4 hypoacetylation and reduction in the transcription from a viral cccDNA template, accompanied by a reduction in HBV replication. Together these results indicate that the Sirt3 activator 1a can modulate the acetylation status of cccDNA-bound H3/H4 histones, thus providing a novel therapeutic approach for the treatment of chronic HBV infection.Very recently, the trend to shift towards epi-polypharmacology drugs has been taken into account in order to acquire a superior therapeutic effect and eventually reduce drug-related doses and toxicity, as well. Based on these evidence, we design and synthesize novel dual HDAC/EZH2 inhibitors to achieve higher anticancer effect by regulating sinergically the expression of a huge number of tumor suppressor genes. For our purpose, we chose the HDAC pharmacophoric model due to its wide structural variety and feasibility to accommodate on the surface binding cap a high degree of different chemical entities. In our first investigation, we combined the well-known vorinostat HDACi moiety to the already optimised pyrazole and pyrrole EZH2i scaffolds MC3629 and MC3707, respectively. The first preliminary screening of our two hybrid compounds MC4134 and MC4128 showed that only the pyrrole derivative MC4128 was able to simultaneously inhibit EZH2 and HDAC, also exhibiting an interesting isoform selectivity for HDAC6. Prompted by these findings, we decided to develop a series of dual inhibitors of EZH2 and HDAC (8a-g and 6a-g), combining the well-known HDACi moieties to the already optimised EZH2i scaffold MC3707. Therefore, according to the HDACi pharmacophoric model, we have chosen different types of spacer: the aliphatic one (Vorinostat), the benzoic one (Entinostat) and the cinnamic one (Panobinostat and Belinostat). As zinc binding group we used, in turn, a hydroxamic acid or an ortho-amino anilide. Overall, compounds 8a-g and 6a-g have been confirmed to be dual inhibitors of EZH2 and HDACs in vitro, showing an interesting selectivity profile towards HDAC isoforms. In preliminary assays in U-937 AML cells, 8c (MC4128) decreased cell viability and induced apoptosis, with increased levels of acetyl-histone H3 and acetyl-α–tubulin. Importantly, we expect that our novel HDAC/EZH2 dual inhibitors can display a potent and synergic anti-cancer activity in vivo, thus becoming an attractive therapeutic approach to fight cancer.Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative mitochondrial disorder caused by an unstable GAA trinucleotide (TTC) repeat expansion in the first intron of the frataxin gene (FXN). In FRDA patients, the expanded GAA·TTC repeats lead to partial transcriptional silencing resulting in expression of structurally and functionally normal frataxin, but at lower levels compared to the normal. FRDA can be considered as an epigenetic disease due to the identification of several associated epigenetic marks, including 1) increased levels of methylated histones (H3K9me2, H3K9me3, H4K20me3) in regions flanking the GAA repeats, 2) increased DNA methylation at specific CpG sites upstream of the GAA repeats and, 3) reduced acetylation of several H3 and H4 lysine residues. Due to the importance of H4K20me to genomic integrity, very recently A-196 has been discovered as the first-in-class chemical probe of Suv4-20H1 and Suv4-20H2, with an IC50= 25 nM and IC50=144 nM, respectively. Despite the in vitro potency of A-196, confirmed by biochemical and cellular assays, preliminary in vitro metabolic studies in human liver microsomes (HLM) have shown some metabolic liability and potentially low solubility, with a Clint (μL/min/mg protein) =191 and a t1/2 (min)=7.28. Prompted by these findings, a lead chemical optimisation has been carried out with the aim to ameliorate chemical and physical properties of A-196. Preliminary biological results of our final compounds (1a-m and 2c) in HEK293 cell model of FRDA showed that only compound 1b (RM02) demonstrated similar effects (or slight better) than the reference compound A-196, with a luciferase fold reactivation of 1.20. The other compounds, unfortunately, showed no increase in frataxin expression beyond that one induced by the vehicle DMSO. Preliminary data for the evaluation of the cytotoxicity (adenylate kinase scores) showed that our compounds are probable non-toxic to the cells
Correction to: Outcomes on safety and efficacy of left atrial appendage occlusion in end stage renal disease patients undergoing dialysis (Journal of Nephrology, (2021), 34, 1, (63-73), 10.1007/s40620-020-00774-5)
No full textThe article Outcomes on safety and efficacy of left atrial appendage occlusion in end stage renal disease patients undergoing dialysis, written by Simonetta Genovesi, Luca Porcu, Giorgio Slaviero, Gavino Casu, Silvio Bertoli, Antonio Sagone, Monique Buskermolen, Federico Pieruzzi, Giovanni Rovaris, Alberto Montoli, Jacopo Oreglia, Emanuela Piccaluga, Giulio Molon, Mario Gaggiotti, Federica Ettori, Achille Gaspardone, Roberto Palumbo, Francesca Viazzi, Marco Breschi, Maurizio Gallieni, Gina Contaldo, Giuseppe D’Angelo, Pierluigi Merella, Fabio Galli, Paola Rebora, Mariagrazia Valsecchi, and Patrizio Mazzone, was originally published electronically on the publisher’s internet portal on 6 June 2020 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on 10 July 2020 to © The Author(s) 2020 and this article is licensed under a Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/ by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The original article has been updated
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