The use of β-blockers in patients with heart failure and comorbidities: Doubts, certainties and unsolved issues.

β-blockers represent a mainstay in the pharmacological approach to patients affected by heart failure with reduced ejection fraction (HFrEF). However, underuse of this class of drugs is still reported, especially in the presence of cardiovascular and non-cardiovascular comorbidities, even if they are not contraindications for prescription of a β-blocker. The prognostic benefit of β-blockers is relevant in the presence of comorbidities, and achievement of the maximum tolerated dose is an important goal to increase their favorable prognostic role. The aim of the present review is to analyze the available evidence on the use of β-blockers in HFrEF patients with the most common comorbidities. In particular, we will discuss the role and most appropriate beta-blocker in patients with pulmonary disease (bisoprolol, metoprolol, nebivolol), diabetes (carvedilol and nebivolol), atrial fibrillation (all indicated for rate control, with metoprolol as the first choice followed by bisoprolol, nebivolol, and carvedilol), erectile dysfunction (bisoprolol and nebivolol), peripheral arterial disease (nebivolol), and other conditions, in order to clarify the correct use of this class of drugs in the clinical practice

Changes of statistical structural fluctuations unveils an early compacted degraded stage of PNS myelin

Degradation of the myelin sheath is a common pathology underlying demyelinating neurological diseases from Multiple Sclerosis to Leukodistrophies. Although large malformations of myelin ultrastructure in the advanced stages of Wallerian degradation is known, its subtle structural variations at early stages of demyelination remains poorly characterized. This is partly due to the lack of suitable and non-invasive experimental probes possessing sufficient resolution to detect the degradation. Here we report the feasibility of the application of an innovative non-invasive local structure experimental approach for imaging the changes of statistical structural fluctuations in the first stage of myelin degeneration. Scanning micro X-ray diffraction, using advances in synchrotron x-ray beam focusing, fast data collection, paired with spatial statistical analysis, has been used to unveil temporal changes in the myelin structure of dissected nerves following extraction of the Xenopus laevis sciatic nerve. The early myelin degeneration is a specific ordered compacted phase preceding the swollen myelin phase of Wallerian degradation. Our demonstration of the feasibility of the statistical analysis of SmXRD measurements using biological tissue paves the way for further structural investigations of degradation and death of neurons and other cells and tissues in diverse pathological states where nanoscale structural changes may be uncovered.Comment: 16 pages, 6 figure

An IL-15 dependent CD8 T cell response to selected HIV epitopes is related to viral control in early-treated HIV-infected subjects.

In some early-treated HIV+ patients, Structured Treatment Interruption (STI) is associated to spontaneous control of viral rebound. Thus, in this clinical setting, we analyzed the immunological parameters associated to viral control. Two groups of early treated patients who underwent STI were retrospectively defined, according to the ability to spontaneously control HIV replication (Controller and Non-controller). Plasma cytokine levels were analyzed by multiplex analysis. CD8 T cell differentiation was determined by polychromatic flow cytometry. Antigen-specific IFN-Γ production was analyzed by ELISpot and intracellular staining after stimulation with HIV-peptides. Long-term Elispot assays were performed in the presence or absence of IL-15. Plasma IL-15 was found decreased over a period of time in Non-Controller patients, whereas a restricted response to Gag (aa.167–202 and 265–279) and Nef (aa.86–100 and 111–138) immunodominant epitopes was more frequently observed in Controller patients. Interestingly, in two Non-Controller patients the CD8-mediated T cells response to immunodominant epitopes could be restored in vitro by IL-15, suggesting a major role of cytokine homeostasis on the generation of protective immunity. In early-treated HIV+ patients undergoing STI, HIV replication control was associated to CD8 T cell maturation and sustained IL-15 levels, leading to HIV-specific CD8 T cell responses against selected Gag and Nef epitopes

Interferon-α Improves Phosphoantigen-Induced Vγ9Vδ2 T-Cells Interferon-γ Production during Chronic HCV Infection

In chronic HCV infection, treatment failure and defective host immune response highly demand improved therapy strategies. Vγ9Vδ2 T-cells may inhibit HCV replication in vitro through IFN-γ release after Phosphoantigen (PhAg) stimulation. The aim of our work was to analyze Vγ9Vδ2 T-cell functionality during chronic HCV infection, studying the role of IFN-α on their function capability. IFN-γ production by Vγ9Vδ2 T-cells was analyzed in vitro in 24 HCV-infected patients and 35 healthy donors (HD) after PhAg stimulation with or without IFN-α. The effect of in vivo PhAg/IFN-α administration on plasma IFN-γ levels was analyzed in M. fascicularis monkeys. A quantitative analysis of IFN-γ mRNA level and stability in Vγ9Vδ2 T-cells was also evaluated. During chronic HCV infection, Vγ9Vδ2 T-cells showed an effector/activated phenotype and were significantly impaired in IFN-γ production. Interestingly, IFN-α was able to improve their IFN-γ response to PhAg both in vitro in HD and HCV-infected patients, and in vivo in Macaca fascicularis primates. Finally, IFN-α increased IFN-γ-mRNA transcription and stability in PhAg-activated Vγ9Vδ2 T-cells. Altogether our results show a functional impairment of Vγ9Vδ2 T-cells during chronic HCV infection that can be partially restored by using IFN-α. A study aimed to evaluate the antiviral impact of PhAg/IFN-α combination may provide new insight in designing possible combined strategies to improve HCV infection treatment outcome

Scanning micro-x-ray diffraction unveils the distribution of oxygen chain nanoscale puddles in YBa2Cu3O6.33YBa_{2}Cu_{3}O_{6.33}

Oxygen chain fragments are known to appear at the insulator to superconductor transition (SIT) in YBa2Cu3O6+y. However the self organization and the size distribution of oxygen chain fragments is not known. Here we contribute to fill this gap, using scanning micro X ray diffraction which is a novel imaging method based on advances in focusing synchrotron radiation beam. This novel approach allows us to probe both real-space and k-space of a high-quality YBa2Cu3O6.33 single crystals with Tc=7K. We report compelling evidence for nanoscale striped puddles, with Ortho-II structure, made of chain fragments in the basal Cu(1) plane with local oxygen concentration 0.5. The size of the Ortho-II puddles spans a range between 2 and 9 nanometers. The real space imaging of Ortho-II puddles granular network shows that superconductivity, at low hole-doping regime, occurs in a network of nanoscale oxygen ordered patches, interspersed with oxygen depleted regions. The manipulation by thermal treatments of the striped Ortho II puddles has been investigated focusing on the spontaneous symmetry breaking near the order to disorder phase transition at 350 K.Comment: 6 pages, 5 Figure