Management of Atrial Fibrillation in Patients Undergoing Percutaneous Coronary Intervention

Atrial fibrillation (AF) is the most common cardiac arrhythmia, occurring in 1-2% of overall population, involving more than 6 millions of European people. It is associated to a reduced quality of life and an increased morbidity and mortality. The Framingham study showed the link between angina and AF. The same risk factors, such as hypertension, diabetes and obesity promote both AF and coronary artery disease (CAD). About 1/4 of AF patients develop a CAD and, in this setting, about 1/5 undergoes a percutaneous coronary intervention (PCI). In patients with both AF and CAD, the optimal medical strategy is challenging and it is still debated in cardiological community, since patients treated by dual (two antiplatelets drugs ore one antiplatelets drug and an oral anticoagulant drug) or triple therapy (two antiplatelets drugs and an oral anticoagulant drug) are exposed to divergent risk of bleeding or thromboembolic and ischemic complications. Aim of this paper is to focus the attention on the different problems arising from the presence of AF in patients undergoing PCI, such as the risk of stroke, bleeding and stent thrombosis

Effects, but no interactions, of ubiquitous pesticide and parasite stressors on honey bee (Apis mellifera) lifespan and behaviour in a colony environment

Interactions between pesticides and parasites are believed to be responsible for increased mortality of honey bee (Apis mellifera) colonies in the northern hemisphere. Previous efforts have employed experimental approaches using small groups under laboratory conditions to investigate influence of these stressors on honey bee physiology and behaviour, although both the colony level and field conditions play a key role for eusocial honey bees. Here, we challenged honey bee workers under in vivo colony conditions with sublethal doses of the neonicotinoid thiacloprid, the miticide tau-fluvalinate and the endoparasite Nosema ceranae, to investigate potential effects on longevity and behaviour using observation hives. In contrast to previous laboratory studies, our results do not suggest interactions among stressors, but rather lone effects of pesticides and the parasite on mortality and behaviour, respectively. These effects appear to be weak due to different outcomes at the two study sites, thereby suggesting that the role of thiacloprid, tau-fluvalinate and N. ceranae and interactions among them may have been overemphasized. In the future, investigations into the effects of honey bee stressors should prioritize the use of colonies maintained under a variety of environmental conditions in order to obtain more biologically relevant data

Phosphorylation of SRSF1 is modulated by replicational stress

DNA ligase I-deficient 46BR.1G1 cells show a delay in the maturation of replicative intermediates resulting in the accumulation of single- and double-stranded DNA breaks. As a consequence the ataxia telangiectasia mutated protein kinase (ATM) is constitutively phosphorylated at a basal level. Here, we use 46BR.1G1 cells as a model system to study the cell response to chronic replication-dependent DNA damage. Starting from a proteomic approach, we demonstrate that the phosphorylation level of factors controlling constitutive and alternative splicing is affected by the damage elicited by DNA ligase I deficiency. In particular, we show that SRSF1 is hyperphosphorylated in 46BR.1G1 cells compared to control fibroblasts. This hyperphosphorylation can be partially prevented by inhibiting ATM activity with caffeine. Notably, hyperphosphorylation of SRSF1 affects the subnuclear distribution of the protein and the alternative splicing pattern of target genes. We also unveil a modulation of SRSF1 phosphorylation after exposure of MRC-5V1 control fibroblasts to different exogenous sources of DNA damage. Altogether, our observations indicate that a relevant aspect of the cell response to DNA damage involves the post-translational regulation of splicing factor SRSF1 which is associated with a shift in the alternative splicing program of target genes to control cell survival or cell death

Photodynamic Therapy Can Induce a Protective Innate Immune Response against Murine Bacterial Arthritis via Neutrophil Accumulation

Background: Local microbial infections induced by multiple-drug-resistant bacteria in the orthopedic field can be intractable, therefore development of new therapeutic modalities is needed. Photodynamic therapy (PDT) is a promising alternative modality to antibiotics for intractable microbial infections, and we recently reported that PDT has the potential to accumulate neutrophils into the infected site which leads to resolution of the infection. PDT for cancer has long been known to be able to stimulate the innate and adaptive arms of the immune system. Methodology/Principal Findings: In the present study, a murine methicillin-resistant Staphylococcus aureus (MRSA) arthritis model using bioluminescent MRSA and polystyrene microparticles was established, and both the therapeutic (Th-PDT) and preventive (Pre-PDT) effects of PDT using methylene blue as photosensitizer were examined. Although Th-PDT could not demonstrate direct bacterial killing, neutrophils were accumulated into the infectious joint space after PDT and MRSA arthritis was reduced. With the preconditioning Pre-PDT regimen, neutrophils were quickly accumulated into the joint immediately after bacterial inoculation and bacterial growth was suppressed and the establishment of infection was inhibited. Conclusions/Significance: This is the first demonstration of a protective innate immune response against a bacterial pathogen produced by PDT.National Institutes of Health (U.S.) (Grant number R01AI050875

Photodynamic and Antibiotic Therapy Impair the Pathogenesis of Enterococcus faecium in a Whole Animal Insect Model

Enterococcus faecium has emerged as one of the most important pathogens in healthcare-associated infections worldwide due to its intrinsic and acquired resistance to many antibiotics, including vancomycin. Antimicrobial photodynamic therapy (aPDT) is an alternative therapeutic platform that is currently under investigation for the control and treatment of infections. PDT is based on the use of photoactive dye molecules, widely known as photosensitizer (PS). PS, upon irradiation with visible light, produces reactive oxygen species that can destroy lipids and proteins causing cell death. We employed Galleria mellonella (the greater wax moth) caterpillar fatally infected with E. faecium to develop an invertebrate host model system that can be used to study the antimicrobial PDT (alone or combined with antibiotics). In the establishment of infection by E. faecium in G. mellonella, we found that the G. mellonella death rate was dependent on the number of bacterial cells injected into the insect hemocoel and all E. faecium strains tested were capable of infecting and killing G. mellonella. Antibiotic treatment with ampicillin, gentamicin or the combination of ampicillin and gentamicin prolonged caterpillar survival infected by E. faecium (P = 0.0003, P = 0.0001 and P = 0.0001, respectively). In the study of antimicrobial PDT, we verified that methylene blue (MB) injected into the insect followed by whole body illumination prolonged the caterpillar survival (P = 0.0192). Interestingly, combination therapy of larvae infected with vancomycin-resistant E. faecium, with antimicrobial PDT followed by vancomycin, significantly prolonged the survival of the caterpillars when compared to either antimicrobial PDT (P = 0.0095) or vancomycin treatment alone (P = 0.0025), suggesting that the aPDT made the vancomycin resistant E. faecium strain more susceptible to vancomycin action. In summary, G. mellonella provides an invertebrate model host to study the antimicrobial PDT and to explore combinatorial aPDT-based treatments

Effetto Leverage: correlazione tra volatilita´ e rendimenti nel mercato italiano dei futures

Sommario Negli ultimi venti anni, da parte della comunitµa scientifica in generale, e dei fisici in particolare, e´ cresciuto notevolmente l'interesse per lo studio dei mercati finanziari, tanto che oggi si indica con il termine di "econofisica" quel settore della fisica dedicato agli studi di questo settore. La notevole quantita´ di dati registrati nei database di tutte le borse internazionali ha permesso ai fisici di osservare la dinamica dei mercati e, in principio di avanzare e testare le ipotesi che fanno da fondamenta per il sistema dinamico, e successivamente di proporre modelli in grado di riprodurre i comportamenti tipici. Anche lo spirito del lavoro di questa tesi e´ stato quello di osservare una particolare dinamica, stimare le grandezze coinvolte con un metodo molto recente e testare uno dei modelli avanzati in grado di riprodurre i comportamenti osservati. La dinamica in questione e´ l'evoluzione della correlazione tra i rendimenti di un prodotto finanziario e la varianza dei prezzi del medesimo prodotto; quest'ultima viene piu´ comunemente indicata con il termine volatilita´. L'osservazione empirica di questo fenomeno era gia´ nota fin dal 1976, ma uno studio sistematico e quantitativo su questo fenomeno, chiamato Effetto Leverage, si e´ avuto solo di recente. L'effetto leverage consiste nell'anticorrelazione tra i rendimenti passati e la volatilita´ futura di un determinato prodotto finanziario, cio´ significa che una dimunuzione (aumento) del prezzo "oggi" e´ causa di un aumento (diminuzione) della fluttuazione del prezzo "domani", ma non vale il viceversa, cioe´, il fenomeno non e´ invariante sotto inversione temporale. Le nostre osservazioni, e il loro confronto con la letteratura, hanno evidenziato che l'effetto decade con un tempo caratteristico che dipende non solo dal prodotto finanziario, ma anche dallo stesso mercato e dal periodo analizzato. La funzione di correlazione tra le due grandezze e´ stata stimata con un metodo diverso da quello usato negli altri lavori sull'argomento. Si tratta di un metodo basato sull'analisi dello sviluppo in serie di Fourier, particolarmente adatto per i dati ad alta frequenza come quelli che abbiamo utilizzato. I risultati ottenuti rappresentano una conferma della validitµa del modello a volatilita´ stocastica utilizzato, anche dopo aver analizzato, seppur in maniera esplorativa, la correlazione tra i rendimenti e le variazioni di volatilita´; argomento non ancora affrontato nella letteratura

Purification of human plasma fibronectin using immobilized gelatin

This protocol describes a method for purification of fibronectin (Fn) from human plasma based on a combination of gel filtration and affinity chromatography steps. Clarified plasma is first loaded onto a Sepharose CL-4B column and unbound material is sequentially purified on columns containing covalently coupled gelatin and Arg. The elution conditions are optimized to obtain a homogeneous preparation of Fn on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Although the Fn yield is expected to be lower than that obtained using other methods, affinity adsorbents based on gelatin and Arg and gentle elution steps offer advantages including a high purity of the preparation and a correctly folded protein. The preparation can be useful for interaction studies and analysis of biological and immunological activities of Fn

The A domain of fibronectin-binding protein B of Staphylococcus aureus contains a novel fibronectin binding site.

The fibronectin-binding proteins FnBPA and FnBPB are multifunctional adhesins than can also bind to fibrinogen and elastin. In this study, the N2N3 subdomains of region A of FnBPB were shown to bind fibrinogen with a similar affinity to those of FnBPA (2 μM). The binding site for FnBPB in fibrinogen was localized to the C-terminus of the γ-chain. Like clumping factor A, region A of FnBPB bound to the γ-chain of fibrinogen in a Ca(2+)-inhibitable manner. The deletion of 17 residues from the C-terminus of domain N3 and the substitution of two residues in equivalent positions for crucial residues for fibrinogen binding in clumping factor A and FnBPA eliminated fibrinogen binding by FnBPB. This indicates that FnBPB binds fibrinogen by the dock-lock-latch mechanism. In contrast, the A domain of FnBPB bound fibronectin with K(D) = 2.5 μM despite lacking any of the known fibronectin-binding tandem repeats. A truncate lacking the C-terminal 17 residues (latching peptide) bound fibronectin with the same affinity, suggesting that the FnBPB A domain binds fibronectin by a novel mechanism. The substitution of the two residues required for fibrinogen binding also resulted in a loss of fibronectin binding. This, combined with the observation that purified subdomain N3 bound fibronectin with a measurable, but reduced, K(D) of 20 μM, indicates that the type I modules of fibronectin bind to both the N2 and N3 subdomains. The fibronectin-binding ability of the FnBPB A domain was also functional when the protein was expressed on and anchored to the surface of staphylococcal cells, showing that it is not an artifact of recombinant protein expression

The effect of photodynamic treatment combined with antibiotic action or host defence mechanisms on Staphylococcus aureus biofilms.

Staphylococcus aureus is one of the most important etiological agents of infections associated with medical devices. This is in part due to the ability of the organism to form biofilm, which provides a microenvironment that protects from attack by the host's immune system and by antibiotics. In this study we examined the structure of polysaccharide intercellular adhesin (PIA)-dependent or protein-based S. aureus biofilms. We defined new strategies aimed at treatment of mature established biofilms using photodynamic treatment (PDT) combined with chemotherapy or phagocytosis. Significant inactivation of bacteria was observed when structurally distinct biofilms were exposed to the cationic porphyrin, tetra-substituted N-methyl-pyridyl-porphine (TMP), and simultaneously to visible light. Moreover, PDT-treated biofilms exposed to vancomycin or subjected to the phagocytic action of whole blood resulted in their almost complete eradication. The drastic reduction in staphylococcal survival and the disruption of biofilms were confirmed by confocal laser scanning microscopy and scanning electron microscopy. The results suggest that PDT combined with vancomycin and the host defences may be a useful approach for the inactivation of staphylococcal biofilms adhering to medical implant surfaces

Activation of human basophils by staphylococcal protein A. I. The role of cyclic AMP, arachidonic acid metabolites, microtubules and microfilaments.

Protein A from Staphylococcus aureus (Staph A) induces histamine secretion from human basophil leucocytes in the concentration range 10(-4) - 10 micrograms/ml. This reaction has great similarities to that of antigen or anti-IgE-induced release. It is characterized by a two stage reaction, requires extracellular calcium and is optimal at 37 degrees C. The rate of release is similar to that of IgE-mediated reactions. Histamine release induced by Staph A is inhibited by metabolic inhibitors, drugs which increase intracellular cyclic AMP levels, inhibitors of lipoxygenase pathways and a phospholipase A2 inhibitor. D2O and cytochalasin B which affect microtubules and microfilaments respectively, enhance histamine release induced by Staph A. These results suggest that Staph A-induced release is modulated by intracellular cyclic AMP, arachidonic acid metabolites, requires energy and is enhanced by the disruption of microfilaments and stabilization of microtubules