G-quadruplex DNA (G4-DNA) structures are four-stranded helical DNA (or RNA) structures, comprising stacks of G-tetrads, which are the outcome of planar association of four guanines in a cyclic ...Hoogsteen hydrogen-bonding arrangement. In the last decade the number of publications where CD spectroscopy has been used to study G4-DNAs, is extremely high. However, with very few exceptions, these investigations use an empirical interpretation of CD spectra. In this interpretation two basic types of CD spectra have been associated to a single specific difference in the features of the strand folding, i.e. the relative orientation of the strands, "parallel" (all strands have the same 5' to 3' orientation) or "antiparallel". Different examples taken from the literature where the empirical interpretation is not followed or is meaningless are presented and discussed. Furthermore, the case of quadruplexes formed by monomeric guanosine derivatives, where there is no strand connecting the adjacent quartets and the definition parallel/antiparallel strands cannot apply, will be discussed. The different spectral features observed for different G-quadruplexes is rationalised in terms of chromophores responsible for the electronic transitions. A simplified exciton coupling approach or more refined QM calculations allow to interpret the different CD features in terms of different stacking orientation (head-to-tail, head-to-head, tail-to-tail) between adjacent G-quartets irrespectively of the relative orientation of the stands (parallel/antiparallel).
The correct identification of the appropriateness of fluid administration is important for the treatment of critically ill patients. Static and dynamic indices used to identify fluid responsiveness ...have been developed throughout the years, nonetheless fluid responsiveness does not indicate that fluid administration is appropriate, and indexes to evaluate appropriateness of fluid administration are lacking. The aim of this study was to evaluate if central venous pressure (CVP) anddynamic indices could correctly identify fluid appropriateness for critically ill patients.
Data from 31 ICU patients, for a total of 53 observations, was included in the analysis. Patients were divided into two cohorts based on the appropriateness of fluid administration. Fluid appropriateness was defined in presence of a low cardiac index (< 2.5 l/min/m2) without any sign of fluid overload, as assessed by global end-diastolic volume index, extravascular lung water index or pulmonary artery occlusion pressure.
For 10 patients, fluid administration was deemed appropriate, while for 21 patients it was deemed inappropriate. Central venous pressure was not different between the two cohorts (mean CVP 11 (4) mmHg in the fluid inappropriate group, 12 (4) mmHg in the fluid appropriate group, p 0.58). The same is true for pulse pressure variation (median PPV 5 2, 9 % in the fluid inappropriate group, 4 3, 13 % in the fluid appropriate group, p 0.57), for inferior vena cava distensibility (mean inferior vena cava distensibility 24 (14) % in the fluid inappropriate group, 22 (16) % in the fluid appropriate group, p 0.75) and for changes in end tidal carbon dioxide during a passive leg raising test (median d.ETCO2 1.5 0.0, 2.0% in the fluid inappropriate group, 1.0 0.0, 2.0 % in the fluid appropriate group, p 0.98). There was no association between static and dynamic indices and fluid appropriateness.
Central venous pressure, pulse pressure variation, changes in end tidal carbon dioxide during a passive leg raising test, inferior vena cava distensibility were not associated with fluid appropriateness in our cohorts.
The study of DNA G-quadruplex stabilizers has enjoyed a great momentum in the late years due to their application as anticancer agents. The recognition of the grooves of these structural motifs is ...expected to result in a higher degree of selectivity over other DNA structures. Therefore, to achieve an enhanced knowledge on the structural and conformational requisites for quadruplex groove recognition, distamycin A, the only compound for which a pure groove binding has been proven, has been chemically modified. Surprisingly, structural and thermodynamic studies revealed that the absence of Coulombic interactions results in an unprecedented binding position in which both the groove and the 3′ end of the DNA are occupied. This further contribution adds another piece to the so far elusive puzzle of the recognition between ligands and DNA quadruplexes and will serve as a platform for a rational design of new groove binders.
In the past decade, DNA G-quadruplexes have come into the limelight thanks to their biological implications and to their potential druggability in anticancer therapy. In particular, it has been found ...that small molecules that stabilize G-quadruplex structures are effective inhibitors of telomerase which plays a critical role in tumorigenesis. So far, the quadruplex groove recognition, which is expected to give a higher degree of selectivity over the other DNA structures, has been demonstrated for very few compounds. Thus with the aim of detecting new and structurally diverse groove binders, a structure-based virtual screening campaign has been performed using the X-ray structure of the d(TGGGGT)4 quadruplex. Remarkable results were achieved, and six brand new different molecular entities have been found to interact with the groove through NMR experiments. The reported results will certainly stimulate further studies aimed at the design and optimization of new quadruplex-specific groove binders to be applied as anticancer agents and for other diseases.
Background: Elderly patients are at high risk of both ischaemic and bleeding events, and the low body weight is considered a risk factor for major bleeding in atrial fibrillation (AF) patients on ...anticoagulation therapy. The aim of our study was to compare the safety and effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) versus well-controlled vitamin-K antagonists (VKA) therapy among AF patients aged >75 years and with a body weight <60 kg in a prospective registry setting. Methods: Data for this study were sourced from the Italian cohorts of PREFER in AF and PREFER in AF PROLONGATION registries. The occurrence of a composite of stroke, transient ischemic attack and systemic embolism (thromboembolic events) was the primary effectiveness endpoint. The occurrence of major bleeding was the primary safety endpoint. All-cause hospitalizations and all-cause death were the secondary endpoints. The net clinical benefit (NCB) was calculated in order to obtain an integrated assessment of the anti-thromboembolic and pro-haemorrhagic effects of NOACs vs. VKA. Results: Overall, 522 patients were included; 225 were on treatment with NOACs and 317 patients with VKA. The NOAC group more frequently featured a higher BMI and a higher prevalence of history of stroke/TIA and insulin-requiring diabetes; conversely, heart failure and chronic liver disease were less frequent in the NAOC group. In the unmatched study population, 18 patients (3.6% in the NOAC vs. 3.2% in the VKA group, p = 0.79) experienced thromboembolic events; 19 patients (1.78% in the NOAC vs. 4.73% in the VKA group, p = 0.06) experienced major bleeding events; and 68 patients were hospitalized during the follow-up (9.3% vs. 14.8%, p = 0.06). After balancing for potential confounders by using the 1:1 propensity score matching technique, 426 patients (213 on NOAC and 213 on VKA) were selected. We found no significant differences in terms of thromboembolic events (3.76% vs. 4.69%, p = 0.63), major bleeding events (n: 1.88% vs. 4.22%, p = 0.15) and hospitalizations (9.9% vs. 16.9%, p = 0.06) between NOAC vs. VKA matched population. Based on these incidences, we found a positive net clinical benefit (+1.6) of NOACs vs. VKAs. Conclusions: These real-world data suggest the safety and effectiveness of using NOACs in elderly patients with low body weight.
The perception of odor and flavor of food is a complicated physiological and psychological process that cannot be explained by simple models. Quantitative descriptive analysis is a technique used to ...describe sensory features. Nevertheless, the availability of a number of instrumental techniques has opened up the possibility to calibrate the sensory perception. In this frame, we have tested the potentiality of nuclear magnetic resonance spectroscopy as a predictive tool to measure sensory descriptors. In particular, we have used an NMR metabolomic approach that allowed us to differentiate the analyzed samples based on their chemical composition. We were able to correlate the NMR metabolomic fingerprints recorded for canned tomato samples to the sensory descriptors bitterness, sweetness, sourness, saltiness, tomato and metal taste, redness, and density, suggesting that NMR might be a very useful tool for the characterization of sensory features of tomatoes.
Nowadays, the molecular basis of interaction between low molecular weight compounds and biological macromolecules is the subject of numerous investigations aimed at the rational design of molecules ...with specific therapeutic applications. In the last decades, it has been demonstrated that DNA quadruplexes play a critical role in several biological processes both at telomeric and gene promoting levels thus providing a great stride in the discovery of ligands able to interact with such a biologically relevant DNA conformation. So far, a number of experimental and computational approaches have been successfully employed in order to identify new ligands and to characterize their binding to the DNA. The main focus of this review is the description of these methodologies, placing a particular emphasis on computational methods, isothermal titration calorimetry (ITC), mass spectrometry (MS), nuclear magnetic resonance (NMR), circular dichroism (CD) and fluorescence spectroscopies.
We report the case of a man affected by polymicrobial endocarditis developed on a St. Jude Medical Riata lead with a malfunction because of the outsourcing of conductors. The patient was treated with ...antibiotic targeted therapy and showed different bacteria at the blood cultures and then underwent transvenous leads extraction. Vegetations were highlighted on the caval, atrial, and ventricular tracts of the Riata lead, but the cultures were all negative. The externalization of Riata lead may cause the malfunction but it could also promote bacterial colonies and vegetations. In conclusion, looking for early signs of infection is mandatory during Riata leads follow-up checks.
The G-Triplex DNA Limongelli, Vittorio; De Tito, Stefano; Cerofolini, Linda ...
Angewandte Chemie (International ed.),
February 18, 2013, Letnik:
52, Številka:
8
Journal Article
Recenzirano
Triplex with a twist: Through metadynamics calculations, the thrombin binding aptamer (TBA) has been shown to adopt a stable G‐triplex structural motif, in addition to the usual G‐quadruplex (see ...scheme). An 11‐mer oligonucleotide was also shown to form a stable G‐triplex, whose structural and thermodynamic properties have been characterized.
The Coronavirus disease 2019 (COVID-19) outbreak is a whole Earth health emergency related to a highly pathogenic human coronavirus responsible for severe acute respiratory syndrome (SARS-CoV-2). ...Despite the fact that the majority of infected patients were managed in outpatient settings, little is known about the clinical characteristics of COVID-19 patients not requiring hospitalization. The aim of our study was to describe the clinical comorbidity and the pharmacological therapies of COVID-19 patients managed in outpatient settings.
We performed an observational, retrospective analysis of laboratory-confirmed COVID-19 patients managed in outpatient settings in Naples, Italy between 9 March and 1 May 2020. Data were sourced from the prospectively maintained Health Search (HS)/Thales database, shared by 128 primary care physicians (PCPs) in Naples, Italy. The clinical features and pharmacological therapies of COVID-19 patients not requiring hospitalization and managed in outpatient settings have been described.
A total of 351 laboratory-confirmed COVID-19 patients (mean age 54 ± 17 years; 193 males) with outpatient management were evaluated. Hypertension was the most prevalent comorbidity (35%). The distribution of cardiovascular comorbidities showed no gender-related differences. A total of 201 patients (57.3%) were treated with at least one experimental drug for COVID-19. Azithromycin, alone (42.78%) or in combination (27.44%), was the most widely used experimental anti-COVID drug in outpatient settings. Low Molecular Weight Heparin and Cortisone were prescribed in 24.87% and 19.4% of the study population, respectively. At multivariate regression model, diabetes (risk ratio (RR): 3.74; 95% CI 1.05 to 13.34;
= 0.04) and hypertension (RR: 1.69; 95% CI 1.05 to 2.7;
= 0.03) were significantly associated with the experimental anti-COVID drug administration. Moreover, only diabetes (RR: 2.43; 95% CI 1.01 to 5.8;
= 0.03) was significantly associated with heparin administration.
Our data show a high prevalence of hypertension, more likely treated with renin-angiotensin-aldosterone system (RASS) inhibitors, among COVID-19 patients not requiring hospitalization. Experimental COVID-19 therapies have been prescribed to COVID-19 patients considered at risk for increased venous thromboembolism based on concomitant comorbidities, in particular diabetes and hypertension.
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