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Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: The growing amount of literature about G-quadruplex DNA clearly demonstrates that such a structure is no longer viewed as just a biophysical strangeness but it is instead being considered as an important target for the treatment of various human disorders such as cancers or venous thrombosis. In this scenario, with the aim of finding brand new molecular scaffolds able to interact with the groove of the DNA quadruplex [d(TGGGGT)]4, we recently performed a successful structure-based virtual screening (VS) campaign. As a result, six molecules were found to be somehow groove binders. Herein, we report the results of novel NMR titration experiments of these VS-derived ligands with modified quadruplexes, namely [d(TGGBrGGT)]4 and [d(TGGGGBrT)]4. The novel NMR spectroscopy experiments combined with molecular modelling studies, allow for a more detailed picture of the interaction between each binder and the quadruplex DNA. Noteworthy, isothermal titration calorimetry (ITC) measurements on the above-mentioned compounds revealed that 2, 4, and 6 besides their relatively small dimensions bind the DNA quadruplex [d(TGGGGT)]4 with higher affinity than distamycin A, to the best of our knowledge, the most potent groove binder identified thus far. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Targeting of DNA secondary structures, such as G-quadruplexes,is now considered an appealing opportunity for drug intervention inanticancer therapy. So far, efforts made in the discovery of chemotypesable to target G-quadruplexes mainly succeeded in the identificationof a number of polyaromatic compounds featuring end-stacking bindingproperties. Against this general trend, we were persuaded that theG-quadruplex grooves can recognize molecular entities with betterdrug-like and selectivity properties. From this idea, a set of smallmolecules was identified and the structural features responsible forG-quadruplex recognition were delineated. These compounds were demonstratedto have enhanced affinity and selectivity for the G-quadruplex overthe duplex structure. Their ability to induce selective DNA damageat telomeric level and to induction of apoptosis and senescence ontumor cells is herein experimentally proven. [ABSTRACT FROM AUTHOR]

Abstract: The chemical synthesis and 1H NMR analysis of a novel bicyclic uridine derivative, with a 18-crown-6 ether moiety fused at the ribose 2- and 3-positions, as first example of a hitherto unknown class of ribose-modified nucleosides, are here described. NMR-based conformational analysis studies showed for the modified nucleoside a marked preference for an N-type sugar puckering and the nucleobase in the anti conformation, with the uracil favouring the coordination of a sodium ion hosted in the crown ether. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article presents the research that evaluates the efficacy of Virtual Screening (VS) and nuclear magnetic resonance experiments in identifying molecular chemotypes to bind the grooves of DNA quadruplex structures. Researchers used the two schemes because it furnished valuable alternative series in lead optimization to identify new pharmacological tools. Moreover, these tools are also useful in clarifying mechanism and targeting and as therapeutic potential of G-quadruplexes.

Triplex als Alternative: Metadynamikrechnungen deuten darauf hin, dass das Thrombin bindende Aptamer (TBA) neben dem üblichen G ‐ Quadruplex auch eine stabile G ‐ Triplex ‐ Struktur einnehmen kann (siehe Schema; rote Kugel: K+ ‐ Ion). Ein 11 ‐ mer ‐ Oligonucleotid bildet ebenfalls einen stabilen G ‐ Triplex, dessen Struktur und thermodynamische Eigenschaften charakterisiert wurden. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]