Non enzymatic upregulation of tissue factor expression by gamma-glutamyl transferase in human peripheral blood mononuclear cells

Background Besides maintaining intracellular glutathione stores, gamma-glutamyltransferase(GGT) generates reactive oxygen species and activates NFkB, a redox-sensitive transcription factor key in the induction of Tissue Factor (TF) gene expression, the principal initiator of the clotting cascade. Thus, GGT might be involved in TF-mediated coagulation processes, an assumption untested insofar. Methods Experiments were run with either equine, enzymatically active GGT or human recombinant (hr) GGT, a wheat germ-derived protein enzymatically inert because of missing post-translational glycosylation. TF Procoagulant Activity (PCA, one-stage clotting assay), TF antigen(ELISA) and TFmRNA(real-time PCR) were assessed in unpooled human peripheral blood mononuclear cell(PBMC) suspensions obtained from healthy donors through discontinuous Ficoll/Hystopaque density gradient. Results Equine GGT increased PCA, an effect insensitive to GGT inhibition by acivicin suggesting mechanisms independent of its enzymatic activity, a possibility confirmed by the maintained stimulation in response to hrGGT, an enzymatically inactive molecule. Endotoxin(LPS) contamination of GGT preparations was excluded by heat inactivation studies and direct determination(LAL method) of LPS concentrations <0.1 ng/mL practically devoid of procoagulant effect. Inhibition by anti-GGT antibodies corroborated that conclusion. Upregulation by hrGGT of TF antigen and mRNA and its downregulation by BAY-11-7082, a NFkB inhibitor, and N-acetyl-L-cysteine, an antioxidant, was consistent with a NFkB-driven, redox-sensitive transcriptional site of action. Conclusions GGT upregulates TF expression independent of its enzymatic activity, a cytokine-like behaviour mediated by NFκB activation, a mechanism contributing to promote acute thrombotic events, a possibility in need, however, of further evaluation

Una crisi internazionale. L'annessionismo valdostano tra censure, rimozioni e nuove ipotesi di ricerca

Alla fine della Seconda Guerra Mondiale la Francia di De Gaulle suscitò nelle vallate italiane ai suoi confini movimenti annessionistici allo scopo di conquistare quelle zone per via diplomatica. Tra questi, particolare vitalità e durata ebbe quello valdostano, la cui vicenda rimane ancora oggi poco nota, a causa delle reticenze e censure che hanno caratterizzato gli studi sull’argomento. Recenti acquisizioni archivistiche effettuate dalla Fondation Chanoux di Aosta permettono oggi di ampliare le conoscenze sulla vicenda e di collegarne le origini a gruppi cattolici tradizionalisti, nostalgici del Ducato di Savoia, che agivano nel solco culturale degli Hélvétistes svizzeri di inizio Novecento. At the end of World War II De Gaulle’s France stirred up pro-annexation movements in the Italian valleys along its borders in order to conquer these areas through diplomatic means. For its vitality and persistence, the most important of these movements was the one in the Aosta Valley, whose development has so far been little known, also because of the reticence and censorship that have characterized the studies on the topic. The recent acquisitions of new archival funds by the Chanoux Foundation in Aosta allow us now to widen our knowledge of those events and to trace their origins in some groups of Catholic traditionalists, nostalgic of the Duchy of Savoy, which operated in the cultural wake of early-twentieth-century Swiss Hélvétistes. 

Contraddizioni valdostane: i motivi di una fedeltà monarchica

L’articolo prende in esame i mezzi usati dai Savoia per mantenere il consenso tra la popolazione valdostana: la valorizzazione della tradizione militare locale sviluppatasi in età moderna; lo svolgimento di battute di caccia, che integravano il reddito di centinaia di valligiani, impiegati come battitori o guardiacaccia; la sistematica elargizione di sussidi a singoli e comunità; infine, la ricerca continua del favore del clero, i cui principali esponenti furono nominati cavalieri dell’Ordine dei SS. Maurizio e Lazzaro o commendatori della Corona. La fedeltà al Regno fu così legata a quella al sovrano, soluzione che separava la figura del re dalle responsabilità politiche dei governi, secondo una strategia già illustrata da Catherine Brice per l’ambito militare.L’article s’attache à examiner les moyens employés par la Maison de Savoie afin de maintenir la faveur des Valdôtains: la valorisation de la tradition militaire locale développée pendant l’âge moderne; le chasses royales, par lesquelles l’on payait plusieurs centaines de batteurs et garde-chasses; la bienfaisance envers les particuliers et les communautés et la recherche continuelle de l’appui du clergé, dont les principaux représentants furent nommés chevaliers de l’ordre des Saints Maurice et Lazare ou commandeur de la Couronne. Ainsi, la fidélité envers le nouvel Royaume fut une conséquence de la fidélité envers le roi, une solution qui separait le souverain des responsabilités politiques des gouvernements, selon une stratégie décrite par Catherine Brice dans le domaine militaire.The article describes how the Savoy monarchy maintained the support of the valdostan population. This was based on four elements: the enhancement of the local military tradition in the modern age;the hunts that implemented the income of hundreds of villagers, employed as beaters or keepers; systematic grants to individuals and communities and, ultimately, the search for the favor of the clergy, whose main representatives were appointed knights of the Order of SS. Maurice and Lazarus or commanders of the Crown. In this way, the loyalty to the Kingdom was conveyed through the loyalty to the sovereign. Through this solution the king was taken away from political responsibilities, as it was outlined by Catherine Brice for the army

Valle d\u2019Aosta militare. Esercito, cultura e societ\ue0 in una regione di frontiera 1848-1940

Dopo un\u2019introduzione dedicata alla figura del combattente valdostano nella letteratura e nel fumetto italiani, la tesi descrive, nella prima parte, le ragioni e le modalit\ue0 della presenza militare in Valle d\u2019Aosta, tra il 1848 e il 1940, e, nella seconda, le conseguenze di tale presenza sulla popolazione, a livello sociale, politico e culturale. Nelle conclusioni, si presentano le possibili spiegazioni del silenzio che ha interessato, dopo il 1945, la tradizione militare valdostan

Rifrancesizzare i Valdostani

L’articolo ripercorre le vicende politiche e legislative relative alla Scuola della Valle d’Aosta negli ultimi settant’anni. La Scuola fu scelta quale strumento per rifrancesizzare una popolazione che in seguito alle trasformazioni demografiche e alle politiche antifrancesi dello Stato liberale, prima, e del regime mussoliniano, poi, stava perdendo la tradizionale francofonia. Tale compito fu ostacolato dalle dinamiche della lotta politica locale, dalle resistenze dello Stato centrale e dalle scelte dei governi regionali. L’articolo analizza l’evoluzione delle norme che regolano l’organizzazione delle scuole della Valle d’Aosta in relazione all’evoluzione delle vicende politiche e sindacali locali e mette in particolare evidenza come le esigenze del consenso elettorale abbiano progressivamente svuotato la spinta ideale che aveva animato i dibattiti sulla Scuola tra gli anni Quaranta e Settanta.The article retraces the political and legislative events related to the school of Aosta Valley in the last seventy years. The school was chosen as a tool to make again francophone a population that was losing her traditional Francophonie, due to the demographic transformations and the antifrench policies of the liberal state, first, and the Mussolini regime, after. This task was hampered by the dynamics of local political struggle, by the resistance of the central State and by regional governments ‘ choices. The article analyses the evolution of the laws ruling the organization of the Aosta Valley schools in relation to the evolution of local political and trade union events and highlights how the needs of the electoral consensus have gradually deleted the ideal thrust that animated the debates about the school between the 1940s and 1970s

Inhalation therapy in the next decade : Determinants of adherence to treatment in asthma and COPD

Peer reviewedPublisher PD

Aliskiren, a renin inhibitor, downregulates TNF-α-induced tissue factor expression in HUVECS

Angiotensin (Ang)II, the effector arm of the locally active renin—angiotensin system (RAS), modulates Tissue Factor (TF), the principal initiator of blood coagulation and a key promoter of atherothrombotic events. Consistent with that knowledge, previous data showed inhibitory properties of angiotensin-converting enzyme inhibitor (ACEI)s and angiotensin II type-1 receptor blocker (ARB)s, but no data are available about the effect of renin inhibition. We aimed to evaluate whether aliskiren, a direct renin inhibitor (DRI), modulates TNF-α-stimulated TF expression in cultured human umbilical vein endothelial cells (HUVECs). Zofenopril, an ACEI, and olmesartan, an ARB, were the controls. HUVECs were incubated with experimental drugs (1 nM) 30 min prior to TNF-α stimulation (0.1 ng/ml × 4 h). Main evaluation variables were procoagulant activity (single-stage clotting assay), TF antigen (ELISA) and mRNA expression (real-time polymerase chain reaction) in cell lysates. TNF-α stimulated procoagulant activity and increased TF antigen and mRNA expression. Aliskiren inhibited TNF-α-mediated TF stimulation; zofenopril and olmesartan exerted a comparable effect. We conclude that aliskiren, a DRI, downregulates TNF-α-stimulated TF expression in HUVECs, possibly as a reflection of endothelial renin activation by the cytokine

Pulmonary embolism: yet another cause of hypoxaemic respiratory failure in COVID-19

Pulmonary embolism represents an overlooked cause of worsening respiratory failure in COVID-19. A regular bedside evaluation for atypical features like pleuritic chest pain or pleural effusion could help identify suspected cases for appropriate management

The effect of angiotensin receptor blockers on C-reactive protein and other circulating inflammatory indices in man

Anti-inflammatory properties may contribute to the pharmacological effects of angiotensin II receptor blockers (ARBs), a leading therapeutic class in the management of hypertension and related cardiovascular and renal diseases. That possibility, supported by consistent evidence from in-vitro and animal studies showing pro-inflammatory properties of angiotensin II, has been evaluated clinically by measuring the effect of ARBs on C-reactive protein and other circulating indices of inflammation (e-selectin, adhesion molecules, interleukin-6, tissue necrosis factor-alpha, monocyte chemoattractant protein-1) of potential clinical relevance, a body of evidence that this paper aims to review