A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease

Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophila melanogaster) deacetylates histones and other proteins including transcription factors. Genetically reducing, but not eliminating, Sir2 has been shown to suppress HD pathology in model organisms. To date, small molecule inhibitors of sirtuins have exhibited low potency and unattractive pharmacological and biopharmaceutical properties. Here, we show that highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) can suppress HD pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. We have validated Sir2 as the in vivo target of selisistat by showing that genetic elimination of Sir2 eradicates the effect of this inhibitor in Drosophila. The specificity of selisistat is shown by its effect on recombinant sirtuins in mammalian cells. Reduction of HD pathology by selisistat in Drosophila, mammalian cells and mouse models of HD suggests that this inhibitor has potential as an effective therapeutic treatment for human disease and may also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for H

A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease

Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophila melanogaster) deacetylates histones and other proteins including transcription factors. Genetically reducing, but not eliminating, Sir2 has been shown to suppress HD pathology in model organisms. To date, small molecule inhibitors of sirtuins have exhibited low potency and unattractive pharmacological and biopharmaceutical properties. Here, we show that highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) can suppress HD pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. We have validated Sir2 as the in vivo target of selisistat by showing that genetic elimination of Sir2 eradicates the effect of this inhibitor in Drosophila. The specificity of selisistat is shown by its effect on recombinant sirtuins in mammalian cells. Reduction of HD pathology by selisistat in Drosophila, mammalian cells and mouse models of HD suggests that this inhibitor has potential as an effective therapeutic treatment for human disease and may also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for HD

Early Diagnosis of Type-2 Cardio-renal Syndrome by Doppler Sonographic Evaluation of Renal Vasoconstriction

Renal failure of type-2 cardio-renal syndrome is due to renal hypoperfusion secondary to heart failure and is mediated by an imbalance between vasoconstrictors and vasodilators. The decrease in glomerular filtration rate does not correlate with left ventricular ejection fraction. Aim of this study was to evaluate, by Doppler sonography, renal hemodynamic alterations in heart failure. Thirty patients (age: 51\ub115yr) with dilated cardiomyopathy (DCM) and 20 normal subjects (C) were studied. Cardiomyopathy was essential in 36.6%, post-ischemic in 36.6%, alcoholic in 16.7%, post-myocarditis in 10% of patients. All patients were hemodynamically stable. In each patient, echocardiography and renal Doppler sonography (interlobar arterial pulsatility index, PI-K) were performed the same day, together with BUN, creatinine, NT-proBNP measurement. Patients with DCM had normal kidneys morphology and volume. LVEF was 26\ub16.8%. PI-K was increased compared to C (1.74\ub10.71 vs 0.95\ub10.19, p<0.001) and also renal function was impaired (creatinine 128.5\ub184 vs 70\ub130 umol/L, p<0.01, BUN 11.6\ub15.8 vs 7\ub11.5 mmol/L, p<0.01). Prevalence of renal failure was 36.6% (NYHA 1-2: 23%, NYHA 3-4: 52.9%) while prevalence of increased PI-K was 83.3% (NYHA 1-2: 69.2%, NYHA 3-4: 94.1%). PI-K was increased already in mild heart failure (NYHA 1-2) (PI-K: 1.37\ub10.3 p<0,01), but more so in patients with more severe heart dysfunction (NYHA 3 e 4) (PI-K: 2,1\ub10,8 p<0.01) without significant correlation with LVEF or right atrial pressure. There were no differences in creatinine or BUN among patients with different severity of heart dysfunction (creatinine 105\ub123 vs 140\ub1104 umol/L, urea 10.3\ub15.7 vs 12.3\ub16 mmol/L). NT-proBNP was increased in patients with DCM (6249.61\ub13.963 ng/L) and did not correlate with LVEF, PI-K, renal function, right atrial pressure. In conclusion, in patients with chronic heart failure renal vasoconstriction can be demonstrated by Doppler-sonography in the early stage, when renal function is still normal, and increases with the worsening of heart failure. Renal Doppler resistance indices may be used for early diagnosis of type-2 cardiorenal syndrome and for prevention of acute, diuretic-induced, renal failure. Author Disclosures: D. Sacerdoti: None. S. Gaiani: None. S. Tonello: None. E. Franceschini: None. P. Pesce: None. P. Bizzotto: None. G. Bombonato: None. C. Sarais: None. M. Bolognesi: None. Key Words: Heart failure \u2022 Renal circulation \u2022 Renal function \u2022 Doppler ultrasoun

Early Diagnosis of Type-2 Cardio-renal Syndrome by Doppler Sonographic Evaluation of Renal Vasoconstriction

Renal failure of type-2 cardio-renal syndrome is due to renal hypoperfusion secondary to heart failure and is mediated by an imbalance between vasoconstrictors and vasodilators. The decrease in glomerular filtration rate does not correlate with left ventricular ejection fraction. Aim of this study was to evaluate, by Doppler sonography, renal hemodynamic alterations in heart failure. Thirty patients (age: 51\ub115yr) with dilated cardiomyopathy (DCM) and 20 normal subjects (C) were studied. Cardiomyopathy was essential in 36.6%, post-ischemic in 36.6%, alcoholic in 16.7%, post-myocarditis in 10% of patients. All patients were hemodynamically stable. In each patient, echocardiography and renal Doppler sonography (interlobar arterial pulsatility index, PI-K) were performed the same day, together with BUN, creatinine, NT-proBNP measurement. Patients with DCM had normal kidneys morphology and volume. LVEF was 26\ub16.8%. PI-K was increased compared to C (1.74\ub10.71 vs 0.95\ub10.19, p<0.001) and also renal function was impaired (creatinine 128.5\ub184 vs 70\ub130 umol/L, p<0.01, BUN 11.6\ub15.8 vs 7\ub11.5 mmol/L, p<0.01). Prevalence of renal failure was 36.6% (NYHA 1-2: 23%, NYHA 3-4: 52.9%) while prevalence of increased PI-K was 83.3% (NYHA 1-2: 69.2%, NYHA 3-4: 94.1%). PI-K was increased already in mild heart failure (NYHA 1-2) (PI-K: 1.37\ub10.3 p<0,01), but more so in patients with more severe heart dysfunction (NYHA 3 e 4) (PI-K: 2,1\ub10,8 p<0.01) without significant correlation with LVEF or right atrial pressure. There were no differences in creatinine or BUN among patients with different severity of heart dysfunction (creatinine 105\ub123 vs 140\ub1104 umol/L, urea 10.3\ub15.7 vs 12.3\ub16 mmol/L). NT-proBNP was increased in patients with DCM (6249.61\ub13.963 ng/L) and did not correlate with LVEF, PI-K, renal function, right atrial pressure. In conclusion, in patients with chronic heart failure renal vasoconstriction can be demonstrated by Doppler-sonography in the early stage, when renal function is still normal, and increases with the worsening of heart failure. Renal Doppler resistance indices may be used for early diagnosis of type-2 cardiorenal syndrome and for prevention of acute, diuretic-induced, renal failure. Author Disclosures: D. Sacerdoti: None. S. Gaiani: None. S. Tonello: None. E. Franceschini: None. P. Pesce: None. P. Bizzotto: None. G. Bombonato: None. C. Sarais: None. M. Bolognesi: None. Key Words: Heart failure \u2022 Renal circulation \u2022 Renal function \u2022 Doppler ultrasoun

Prospective Study on Incidence, Risk Factors and Outcome of Recurrent Clostridioides difficile Infections

Background: Limited and wide-ranging data are available on the recurrent Clostridioides difficile infection (rCDI) incidence rate. Methods: We performed a cohort study with the aim to assess the incidence of and risk factors for rCDI. Adult patients with a first CDI, hospitalized in 15 Italian hospitals, were prospectively included and followed-up for 30 d after the end of antimicrobial treatment for their first CDI. A case\u2013control study was performed to identify risk factors associated with 30-day onset rCDI. Results: Three hundred nine patients with a first CDI were included in the study; 32% of the CDI episodes (99/309) were severe/complicated; complete follow-up was available for 288 patients (19 died during the first CDI episode, and 2 were lost during follow-up). At the end of the study, the crude all-cause mortality rate was 10.7% (33 deaths/309 patients). Two hundred seventy-one patients completed the follow-up; rCDI occurred in 21% of patients (56/271) with an incidence rate of 72/10,000 patient-days. Logistic regression analysis identified exposure to cephalosporin as an independent risk factor associated with rCDI (RR: 1.7; 95% CI: 1.1\u20132.7, p = 0.03). Conclusion: Our study confirms the relevance of rCDI in terms of morbidity and mortality and provides a reliable estimation of its incidence

A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease.

Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophila melanogaster) deacetylates histones and other proteins including transcription factors. Genetically reducing, but not eliminating, Sir2 has been shown to suppress HD pathology in model organisms. To date, small molecule inhibitors of sirtuins have exhibited low potency and unattractive pharmacological and biopharmaceutical properties. Here, we show that highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) can suppress HD pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. We have validated Sir2 as the in vivo target of selisistat by showing that genetic elimination of Sir2 eradicates the effect of this inhibitor in Drosophila. The specificity of selisistat is shown by its effect on recombinant sirtuins in mammalian cells. Reduction of HD pathology by selisistat in Drosophila, mammalian cells and mouse models of HD suggests that this inhibitor has potential as an effective therapeutic treatment for human disease and may also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for HD

Fused 3‑Hydroxy-3-trifluoromethylpyrazoles Inhibit Mutant Huntingtin Toxicity

Here, we describe the selection and optimization of a chemical series active in both a full-length and a fragment-based Huntington’s disease (HD) assay. Twenty-four thousand small molecules were screened in a phenotypic HD assay, identifying a series of compounds bearing a 3-hydroxy-3-trifluoromethylpyrazole moiety as able to revert the toxicity induced by full-length mutant Htt by up to 50%. A chemical exploration around the series led to the identification of compound <b>4f</b>, which demonstrated to be active in a Htt171–82Q rat primary striatal neuron assay and a PC12-Exon-1 based assay. This compound was selected for testing in R6/2 mice, in which it was well-tolerated and showed a positive effect on body weight and a positive trend in preventing ventricular volume enlargment. These studies provide strong rationale for further testing the potential benefits of 3-hydroxy-3-trifluoromethylpyrazoles in treating HD

Esperienze di valutazione e interventi di potenziamento in classe

Negli ultimi decenni l\u2019attenzione rivolta ai Disturbi Specifici dell\u2019Apprendimento (DSA) nel nostro paese \ue8 cresciuta in modo esponenziale. La centralit\ue0 di tale tematica in ambiente educativo e scolastico, cos\uec come la sua rilevanza sul piano sociale, ha spinto numerosi studiosi e professionisti del settore ad occuparsi del disturbo, ricercandone le cause e proponendo strumenti e strategie per il supporto ed il potenziamento delle abilit\ue0-apprendimento. Il crescente numero di diagnosi che si \ue8 riscontrato negli ultimi anni in Italia, ha portato alla luce una problematica rilevante e sentita, relativa alla necessit\ue0 di adeguare e ripensare la didattica tradizionale al fine di promuovere la creazione e l\u2019utilizzo di strategie compensative favorenti l\u2019apprendimento del bambino con DSA, la sua integrazione nel contesto classe ed evitare che dinamiche disfunzionali possano minare la serenit\ue0 e la crescita del bambino. Numerosi sono stati i passi avanti percorsi, negli ultimi anni, in ambiente clinico-sanitario cos\uec come in quello scolastico-educativo, anche grazie all\u2019inquadramento legislativo del disturbo ed alle successive linee guida del MIUR. Tale processo appare, tuttavia, ancora lungo e non privo di ostacoli e resistenze. A parere di chi scrive, la fatica caratterizzante questo percorso di cambiamento rispecchia le difficolt\ue0 riscontrate negli anni dagli studiosi che hanno tentato di inquadrare in modo univoco e deterministico il disturbo dell\u2019apprendimento scolastico, partendo dagli studi eziologici. Ad oggi, la comunit\ue0 scientifica del settore non ha ancora sviluppato un modello eziologico condiviso per i diversi DSA. Uno dei modelli pi\uf9 recenti ipotizza che le cause dei DSA sarebbero da ricercare in un complesso quadro di alterazioni neurobiologiche interagenti fra loro che si legano alla grande eterogeneit\ue0 delle manifestazioni fenotipiche del disturbo. L\u2019interazione fra fattori neurobiologici, ambientali ed emozionali concorre alla determinazione di profili funzionali anche molto differenti, nei quali le difficolt\ue0 relative alle abilit\ue0-specifiche (lettura, scrittura e calcolo) possono associarsi a difficolt\ue0 legate a domini cognitivi generali e trasversali (memoria, attenzione, percezione visiva). E\u2019 ormai riconosciuto che mentre le abilit\ue0 specifiche di lettura e scrittura giungono a maturazione solo al termine del secondo anno della scuola primaria (motivo per il quale \ue8 possibile fare diagnosi solo in tale periodo), la presenza di deficit relativi alle abilit\ue0 che si pensa siano associate al disturbo sono valutabili anche in un\u2019epoca precedente. Pertanto, negli ultimi decenni, stanno crescendo le ricerche che si occupano di studiare i fattori predittivi, ovvero quelle abilit\ue0 cognitive che, se deficitarie, non rappresentano di per s\ue9 la presenza di un disturbo specifico, ma aumentano significativamente la probabilit\ue0 di una manifestazione futura dello stesso. In tal senso, la Scuola ricoprirebbe un ruolo fondamentale non solo in termini di compensazione (adeguamento della didattica a fronte della diagnosi) ma anche in quelli di identificazione e di potenziamento precoce, seguendo un\u2019ottica di prevenzione primaria. Un attento e costante monitoraggio dello sviluppo delle abilit\ue0 predittive permetterebbe da un lato l\u2019identificazione di aree di fragilit\ue0, dall\u2019altro la strutturazione di azioni mirate al potenziamento ed al rinforzo di tali aree. Interventi di questo tipo consentirebbero di prevenire, o di ridurre, l\u2019impatto che tali deficienze possono avere sullo sviluppo delle competenze-apprendimento future, riducendo la severit\ue0 della manifestazione del disturbo. La centralit\ue0 del ruolo degli insegnanti viene inoltre ribadita dalla normativa in materia di DSA, alla quale sono seguiti diversi Decreti Interministeriali (Legge 170/2010 "Nuove norme in materia di disturbi specifici di apprendimento in ambito scolastico; Decreto Interministeriale MIUR-MS "Linee guida per la predisposizione dei protocolli regionali per le attivit\ue0 di individuazione precoce dei casi sospetti di DSA). Date queste considerazioni, si \ue8 ritenuto di raccogliere in questo nucleo monografico le esperienze e le riflessioni di ricercatori e professionisti che da anni si occupano di DSA, con lo scopo di offrire spunti di riflessione e nuove idee sui protocolli di identificazione precoce e sui programmi di prevenzione primaria che si possono effettuare nel contesto della classe