Common genetic variants on chromosome 9p21 are associated with myocardial infarction and type 2 diabetes in an Italian population

<p>Abstract</p> <p>Background</p> <p>A genomic region on chromosome 9p21 has been identified as closely associated with increased susceptibility to coronary artery disease (CAD) and to type 2 diabetes (T2D) although the evidence suggests that the genetic variants within chromosome 9p21 that contribute to CAD are different from those that contribute to T2D.</p> <p>We carried out an association case-control study in an Italian population to test the association between two single nucleotide polymorphisms (SNPs) on the 9p21 locus, rs2891168 and rs10811661, previously reported by the PROCARDIS study, and respectively myocardial infarction (MI) and T2D. Our aim was to confirm the previous findings on a larger sample and to verify the independence of their susceptibility effects: rs2891168 associated with MI but not with T2D and rs10811661 associated with T2D but not with MI.</p> <p>Methods</p> <p>Genomic DNA samples of 2407 Italians with T2D (602 patients), who had had a recent MI (600), or had both diseases (600) and healthy controls (605) were genotyped for the two SNPs. The genotypes were determined by allelic discrimination using a fluorescent-based TaqMan assay.</p> <p>Results</p> <p>SNP rs2891168 was associated with MI, but not with T2D and the G-allele odds ratio (OR) was 1.20 (95% CI 1.02-1.41); SNP rs10811661 was associated with T2D, but not with MI, and the T-allele OR was 1.27 (95% CI 1.04-1.55). ORs estimates from the present study and the PROCARDIS study were pooled and confirmed the previous findings, with greater precision.</p> <p>Conclusions</p> <p>Our replication study showed that rs2891168 and rs10811661 are independently associated respectively with MI and T2D in an Italian population. Pooling our results with those reported by the PROCARDIS group, we also obtained a significant result of association with diabetes for rs10811661 in the European population.</p

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

<p>Abstract</p> <p>Background</p> <p>One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study.</p> <p>Methods/Design</p> <p>The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome.</p> <p>Discussion</p> <p>The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00395915</p

Il Futuro della Cybersecurity in Italia: Ambiti Progettuali Strategici

Il presente volume nasce come continuazione del precedente, con l’obiettivo di delineare un insieme di ambiti progettuali e di azioni che la comunità nazionale della ricerca ritiene essenziali a complemento e a supporto di quelli previsti nel DPCM Gentiloni in materia di sicurezza cibernetica, pubblicato nel febbraio del 2017. La lettura non richiede particolari conoscenze tecniche; il testo è fruibile da chiunque utilizzi strumenti informatici o navighi in rete. Nel volume vengono considerati molteplici aspetti della cybersecurity, che vanno dalla definizione di infrastrutture e centri necessari a organizzare la difesa alle azioni e alle tecnologie da sviluppare per essere protetti al meglio, dall’individuazione delle principali tecnologie da difendere alla proposta di un insieme di azioni orizzontali per la formazione, la sensibilizzazione e la gestione dei rischi. Gli ambiti progettuali e le azioni, che noi speriamo possano svilupparsi nei prossimi anni in Italia, sono poi accompagnate da una serie di raccomandazioni agli organi preposti per affrontare al meglio, e da Paese consapevole, la sfida della trasformazione digitale. Le raccomandazioni non intendono essere esaustive, ma vanno a toccare dei punti che riteniamo essenziali per una corretta implementazione di una politica di sicurezza cibernetica a livello nazionale. Politica che, per sua natura, dovrà necessariamente essere dinamica e in continua evoluzione in base ai cambiamenti tecnologici, normativi, sociali e geopolitici. All’interno del volume, sono riportati dei riquadri con sfondo violetto o grigio; i primi sono usati nel capitolo introduttivo e nelle conclusioni per mettere in evidenza alcuni concetti ritenuti importanti, i secondi sono usati negli altri capitoli per spiegare il significato di alcuni termini tecnici comunemente utilizzati dagli addetti ai lavori. In conclusione, ringraziamo tutti i colleghi che hanno contribuito a questo volume: un gruppo di oltre 120 ricercatori, provenienti da circa 40 tra Enti di Ricerca e Università, unico per numerosità ed eccellenza, che rappresenta il meglio della ricerca in Italia nel settore della cybersecurity. Un grazie speciale va a Gabriella Caramagno e ad Angela Miola che hanno contribuito a tutte le fasi di produzione del libro. Tra i ringraziamenti ci fa piacere aggiungere il supporto ottenuto dai partecipanti al progetto FILIERASICURA

Characterisation of RC-proteoliposomes at different RC/lipid ratios

Reconstitution of membrane proteins in phospholipid vesicles allows the investigation of such macromolecules in a biomimetic simplified environment. The often employed micelle-to-vesicle-transition method for proteoliposome preparation is a fast and reproducible technique. In this, communication is shown that the lipid/protein ratio influences the size of the proteoliposomes and the actual protein reconstitution. The results indicate that for photosynthetic reaction centres, the best conditions for ligand-interaction experiments are achieved with a lipid/protein value of 1000:1, while for complete protein incorporation, the 2000:1 ratio should be chosen

Changes in morphology, cell wall composition and soluble proteome in Rhodobacter sphaeroides cells exposed to chromate

The response of the carotenoidless Rhodobacter sphaeroides mutant R26 to chromate stress under photosynthetic conditions is investigated by biochemical and spectroscopic measurements, proteomic analysis and cell imaging. Cell cultures were found able to reduce chromate within 3-4 days. Chromate induces marked changes in the cellular dimension and morphology, as revealed by atomic force microscopy, along with compositional changes in the cell wall revealed by infrared spectroscopy. These effects are accompanied by significant changes in the level of several proteins: 15 proteins were found up-regulated and 15 down-regulated. The protein content found in chromate exposed cells is in good agreement with the biochemical, spectroscopic and microscopic results. Moreover at the present stage no specific chromate-reductase could be found in the soluble proteome, indicating that detoxification of the pollutant proceeds via aspecific reductants

The binding of quinone to the photosynthetic reaction centers: kinetics and thermodynamics of reactions occurring at the Q(B)-site in zwitterionic and anionic liposomes

Liposomes represent a versatile biomimetic environment for studying the interaction between integral membrane proteins and hydrophobic ligands. In this paper, the quinone binding to the Q(B)-site of the photosynthetic reaction centers (RC) from Rhodobacter sphaeroides has been investigated in liposomes prepared with either the zwitterionic phosphatidylcholine (PC) or the negatively charged phosphatidylglycerol (PG) to highlight the role of the different phospholipid polar heads. Quinone binding (K (Q)) and interquinone electron transfer (L (AB)) equilibrium constants in the two type of liposomes were obtained by charge recombination reaction of Q(B)-depleted RC in the presence of increasing amounts of ubiquinone-10 over the temperature interval 6-35 A degrees C. The kinetic of the charge recombination reactions has been fitted by numerically solving the ordinary differential equations set associated with a detailed kinetic scheme involving electron transfer reactions coupled with quinone release and uptake. The entire set of traces at each temperature was accurately fitted using the sole quinone release constants (both in a neutral and a charge separated state) as adjustable parameters. The temperature dependence of the quinone exchange rate at the Q(B)-site was, hence, obtained. It was found that the quinone exchange regime was always fast for PC while it switched from slow to fast in PG as the temperature rose above 20 A degrees C. A new method was introduced in this paper for the evaluation of constant K (Q) using the area underneath the charge recombination traces as the indicator of the amount of quinone bound to the Q(B)-site

The binding of quinone to the photosynthetic reaction centers: kinetics and thermodynamics of reactions occurring at the QB-site in zwitterionic and anionic liposomes

Liposomes represent a versatile biomimetic environment for studying the interaction between integral membrane proteins and hydrophobic ligands. In this paper, the quinone binding to the QB-site of the photosynthetic reaction centers (RC) from Rhodobacter sphaeroides has been investigated in liposomes prepared with either the zwitterionic phosphatidylcholine (PC) or the negatively charged phosphatidylglycerol (PG) to highlight the role of the different phospholipid polar heads. Quinone binding (KQ) and interquinone electron transfer (LAB) equilibrium constants in the two type of liposomes were obtained by charge recombination reaction of QB-depleted RC in the presence of increasing amounts of ubiquinone-10 over the temperature interval 6-35 °C. The kinetic of the charge recombination reactions has been fitted by numerically solving the ordinary differential equations set associated with a detailed kinetic scheme involving electron transfer reactions coupled with quinone release and uptake. The entire set of traces at each temperature was accurately fitted using the sole quinone release constants (both in a neutral and a charge separated state) as adjustable parameters. The temperature dependence of the quinone exchange rate at the QB-site was, hence, obtained. It was found that the quinone exchange regime was always fast for PC while it switched from slow to fast in PG as the temperature rose above 20 °C. A new method was introduced in this paper for the evaluation of constant KQ using the area underneath the charge recombination traces as the indicator of the amount of quinone bound to the QB-site

Reversible Binding of Metal Ions onto Bacterial Layers Revealed by Protonation-Induced ATR-FTIR Difference Spectroscopy

The ability of microorganisms to adhere to abiotic surfaces and the potentialities of attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy have been exploited to study protonation and heavy metal binding events onto bacterial surfaces. This work represents the first attempt to apply on bacteria the recently developed method known as perfusion-induced ATR-FTIR difference spectroscopy.(1,2) Such a technique allows measurement of even slight changes in the infrared spectrum of the sample, deposited as a thin layer on an ATR crystal, while an aqueous solution is perfused over its surface. Solutions at different pH have been used for inducing protonation/deprotonation of functional groups lying on the surface of Rhodobacter sphaeroides cells, chosen as a model system. The interaction of Ni2+ with surface protonable groups of this microorganism has been investigated with a double-difference approach exploiting competition between nickel cations and protons. Protonation-induced difference spectra of simple model compounds have been acquired to guide band assignment in bacterial spectra, thus allowing identification of major components involved in proton uptake and metal binding. The data collected reveal that carboxylate moieties on the bacterial surface of R. sphaeroides play a role in extracellular biosorption of Ni2+, establishing with this ion relatively weak coordinative bonds