Rural Statutes of the Upper Vicenza and Rural Charters of Trentino: Notes on the Legal Experience of Rural Border Communities

L’esame degli statuti di alcuni villaggi posti a cavaliere di un confine – quel-lo tra veneto e trentino – fattosi precoce frontiera costituisce l’occasione per una riflessione sull’esperienza giuridica delle comunità prealpine tra medioevo ed età moderna.Sulla base della comparazione di tali “carte”, frutto dell’elementare au-tonomia di “ville” che ad esse attribuirono una forte valenza identitaria, il contributo mira ad indagare se, l’esistenza di confini territoriali imposti (e contesi) da enti sovraordinati abbia o meno avuto incidenza sul diritto pro-prio delle comunità locali.The examination of the statutes of some villages which straddle a border – that between Veneto and Trentino – who became early frontier constitutes an opportunity for a reflection on the legal experience of the pre-Alpine communities between Middle Ages and the modern age.Based on the comparison of these “charters”, result of elementary autonomy of “villas” which at those attributed a strong identity value, the paper aims to investigate whether the existence of imposed (and disputed) territorial boundaries by central governments and institutions have or less had effect on the proper law of the local communities

Analisi spettrale in banda X della galassia di Seyfert NGC 5252

Nel presente lavoro di tesi è stata eseguita l'analisi spettrale in banda X (0.1÷70 keV) della ragione nucleare della galassia di Seyfert NGC 5252, tramite le osservazioni dei telescopi X Chandra, XMM-Newton e NuSTAR. Scopo principale è stato quello di determinare il valore intrinseco dell'indice spettrale "Γ" della legge di potenza che descrive l'emissione nucleare di NGC 5252. Studi precedenti avevano trovato uno spettro apparantemente piatto (Γ ~ 0.9), rispetto a quanto ci si aspeterebbe per un AGN (Γ ~ 1.8÷2). La conoscenza di "Γ" è fondamentale perché connessa ai processi fisici di origine non termica che avvengono nelle vicinanza del SMBH al centro dell'AGN. Grazie all'analisi simultanea dei dati dei tre telescopi, che ha permesso di estendere la banda ad energie più elevate, si è trovato un Γ ~ 1.8, consistente con quello degli AGN. Nello specifico il modello di best-fit (usando simultaneamente i dati XMM-Newton e NuSTAR) è costituito da una legge di potenza assorbita da un gas parzialmente ionizzato (Γ ~ 1.8 ed NH ~ 5.2·10^22 cm-2) e da un assorbitore a ~ 3.03 keV, una componente termica (kT ~ 0.15 keV) e la riga Kα del ferro (a ~ 6.40 keV). Infine è stata calcolata la luminisità X tra 2÷10 keV, da cui è stato possibile stimare la luminosità bolometrica di NGC 5252, la relativa luminosità di Eddington e infine l'Eddington ratio (λEdd ~ 0.002), che conferma il basso tasso di accrescimento del SMBH posto al centro della galassia. A fronte dei risultati ottenuti, grazie all'uso di più telescopi con caratteristiche complementari, si sottilinea l'importanza di estendere le osservazioni ad una banda energetica pià ampia (fino alla regione hard dello spettro tra 10÷100 keV), in particolare per studi futuri rivolti ad oggetti oscurati. Le osservazioni Chandra, con ottima risoluzione angolare, possono essere utilizzate in futuro per uno studio dettagliato delle regioni estese (e.g. coni di ionizzaione) visibili nella regione soft dello spettro (~ 0.1÷1 keV)

Histidine 21 is at the NAD+ binding site of diphtheria toxin.

Treatment of fragment A chain of diphtheria toxin (DT-A) with diethylpyrocarbonate modifies His-21, the single histidine residue present in the chain, without alteration of other residues. Parallel to histidine modification, NAD+ binding and the NAD-glycohydrolase and ADP-ribosyltransferase activities of DT-A are lost. Both NAD+ and adenosine are very effective in protecting DT-A from histidine modification and in preserving its biological properties, while adenine is ineffective. Reversal of histidine modification with hydroxylamine restores both NAD+ binding and enzymatic activities of the toxin. The possible role of His-21 in the activity of diphtheria toxin is discussed in relation to the available three-dimensional structure of the related toxin produced by Pseudomonas aeruginosa

Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects

Sarcoglycanopathies are a group of autosomal recessive muscle-wasting disorders caused by genetic defects in one of four cell membrane glycoproteins, α-, β-, γ- or δ-sarcoglycan. These four sarcoglycans form a subcomplex that is closely linked to the major dystrophin-associated protein complex, which is essential for membrane integrity during muscle contraction and provides a scaffold for important signalling molecules. Proper assembly, trafficking and targeting of the sarcoglycan complex is of vital importance, and mutations that severely perturb tetramer formation and localisation result in sarcoglycanopathy. Gene defects in one sarcoglycan cause the absence or reduced concentration of the other subunits. Most genetic defects generate mutated proteins that are degraded through the cell's quality control system; however, in many cases, conformational modifications do not affect the function of the protein, yet it is recognised as misfolded and prematurely degraded. Recent evidence shows that misfolded sarcoglycans could be rescued to the cell membrane by assisting their maturation along the ER secretory pathway. This review summarises the etiopathogenesis of sarcoglycanopathies and highlights the quality control machinery as a potential pharmacological target for therapy of these genetic disorders

Who should be screened for secondary causes of hypertension?

The case of a 34-year-old patient with uncontrolled hypertension is described in this article, together with the diagnostic path followed in order to make the diagnosis, that finally reveals an arteriovenous fistula due to an old kidney biopsy. Uncontrolled or resistant hypertension may be caused by unrecognized secondary hypertension: we revise the clinical and laboratory criteria for selecting hypertensive patients in whom to look for secondary hypertension through the most appropriate diagnostic work up. A synthesis of the main causes of secondary hypertension is also provided in the discussion

Differential Analysis of Gly211Val and Gly286Val Mutations Affecting Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1) in Congenital Pseudomyotonia Romagnola Cattle.

Congenital pseudomyotonia in cattle (PMT) is a rare skeletal muscle disorder, clinically characterized by stiffness and by delayed muscle relaxation after exercise. Muscle relaxation impairment is due to defective content of the Sarco(endo)plasmic Reticulum Ca2+ ATPase isoform 1 (SERCA1) protein, caused by missense mutations in the ATP2A1 gene. PMT represents the only mammalian model of human Brody myopathy. In the Romagnola breed, two missense variants occurring in the same allele were described, leading to Gly211Val and Gly286Val (G211V/G286V) substitutions. In this study, we analyzed the consequences of G211V and G286V mutations. Results support that the reduced amount of SERCA1 is a consequence of the G211V mutation, the G286V mutation almost being benign and the ubiquitin-proteasome system (UPS) being involved. After blocking the proteasome using a proteasome inhibitor, we found that the G211V mutant accumulates in cells at levels comparable to those of WT SERCA1. Our conclusion is that G211/286V mutations presumably originate in a folding-defective SERCA1 protein, recognized and diverted to degradation by UPS, although still catalytically functional, and that the main role is played by G211V mutation. Rescue of mutated SERCA1 to the sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca2+ concentration and prevent the appearance of pathological signs, paving the way for a possible therapeutic approach against Brody disease

Histone deacetylases: molecular mechanisms and therapeutic implications for muscular dystrophies

Histone deacetylases (HDACs) are enzymes that regulate the deacetylation of numerous histone and non-histone proteins, thereby affecting a wide range of cellular processes. Deregulation of HDAC expression or activity is often associated with several pathologies, suggesting potential for targeting these enzymes for therapeutic purposes. For example, HDAC expression and activity are higher in dystrophic skeletal muscles. General pharmacological blockade of HDACs, by means of pan-HDAC inhibitors (HDACi), ameliorates both muscle histological abnormalities and function in preclinical studies. A phase II clinical trial of the pan-HDACi givinostat revealed partial histological improvement and functional recovery of Duchenne Muscular Dystrophy (DMD) muscles; results of an ongoing phase III clinical trial that is assessing the long-term safety and efficacy of givinostat in DMD patients are pending. Here we review the current knowledge about the HDAC functions in distinct cell types in skeletal muscle, identified by genetic and -omic approaches. We describe the signaling events that are affected by HDACs and contribute to muscular dystrophy pathogenesis by altering muscle regeneration and/or repair processes. Reviewing recent insights into HDAC cellular functions in dystrophic muscles provides new perspectives for the development of more effective therapeutic approaches based on drugs that target these critical enzymes

Clinicians' adherence versus non adherence to practice guidelines in the management of patients with sarcoma: a cost-effectiveness assessment in two European regions

International audienceABSTRACT: BACKGROUND: Although the management of sarcoma is improving, non adherence to clinical practice guidelines (CPGs) remains high, mainly because of the low incidence of the disease and the variety of histological subtypes. Since little is known about the health economics of sarcoma, we undertook a cost-effectiveness analysis (within the CONnective TIssue CAncer NETwork, CONTICANET) comparing costs and outcomes when clinicians adhered to CPGs and when they did not. METHODS: Patients studied had a histological diagnosis of sarcoma, were older than 15 years, and had been treated in the Rhone-Alpes region of France (in 2005/2006) or in the Veneto region of Italy (in 2007). Data collected retrospectively for the three years after diagnosis were used to determine relapse free survival and health costs (adopting the hospital's perspective and a microcosting approach). All costs were expressed in euros at their 2009 value. A 4% annual discount rate was applied to both costs and effects. The incremental cost-effectiveness ratio (ICER) was expressed as cost per relapse-free year gained when management was compliant with CPGs compared with when it was not. To capture uncertainty surrounding ICER, a probabilistic sensitivity analysis was performed based on a non-parametric bootstrap method. RESULTS: A total of 219 patients were included in the study. Compliance with CPGs was observed for 118 patients (54%). Average total costs reached 23,571 euros when treatment was in accordance with CPGs and 27,313 euros when it was not. In relation to relapse-free survival, compliance with CPGs strictly dominates non compliance, i.e. it is both less costly and more effective. Taking uncertainty into account, the probability that compliance with CPGs still strictly dominates was 75%. CONCLUSIONS: Our findings should encourage physicians to increase their compliance with CPGs and healthcare administrators to invest in the implementation of CPGs in the management of sarcoma

β1-Syntrophin Modulation by miR-222 in mdx Mice

Background: In mdx mice, the absence of dystrophin leads to the deficiency of other components of the dystrophin-glycoprotein complex (DAPC), making skeletal muscle fibers more susceptible to necrosis. The mechanisms involved in the disappearance of the DAPC are not completely understood. The muscles of mdx mice express normal amounts of mRNA for the DAPC components, thus suggesting post-transcriptional regulation. Methodology/Principal Findings: We investigated the hypothesis that DAPC reduction could be associated with the microRNA system. Among the possible microRNAs (miRs) found to be upregulated in the skeletal muscle tissue of mdx compared to wt mice, we demonstrated that miR-222 specifically binds to the 3′-UTR of β1-syntrophin and participates in the downregulation of β1-syntrophin. In addition, we documented an altered regulation of the 3′-UTR of β1-syntrophin in muscle tissue from dystrophic mice. Conclusion/Significance: These results show the importance of the microRNA system in the regulation of DAPC components in dystrophic muscle, and suggest a potential role of miRs in the pathophysiology of dystrophy. © 2010 De Arcangelis et al