Cardiac safety of second-generation H1 -antihistamines when updosed in chronic spontaneous urticaria

The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second-generation H1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA2 LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off-label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H1 antihistamines to block hERG (human Ether-a-go-go-Related Gene) voltage-gated K+ channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism

Flavonoids and ω3-polyunsaturated fatty acid supplementation in renal transplant recipients: new arguments from COVID-19

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Steatosis, steatohepatitis and cancer immunotherapy: An intricate story

Immune checkpoint inhibitors represent one of the most significant recent advances in clinical oncology, since they dramatically improved the prognosis of deadly cancers such as melanomas and lung cancer. Treatment with these drugs may be complicated by the occurrence of clinically-relevant adverse drug reactions, most of which are immune-mediated, such as pneumonitis, colitis, endocrinopathies, nephritis, Stevens Johnson syndrome and toxic epidermal necrolysis. Drug-induced steatosis and steatohepatitis are not included among the typical forms of cancer immunotherapy-induced liver toxicity, which, instead, usually occurs as a panlobular hepatitis with prominent lymphocytic infiltrates. Nonetheless, non-alcoholic fatty liver disease is a risk factor for immunotherapy-induced hepatitis, and steatosis and steatohepatitis are frequently observed in this condition. In the present review we discuss how these pathology findings could be explained in the context of current models suggesting immune-mediated pathogenesis for steatohepatitis. We also review evidence suggesting that in patients with hepatocellular carcinoma, the presence of steatosis or steatohepatitis could predict a poor therapeutic response to these agents. How these findings could fit with immune-mediated mechanisms of these liver diseases will also be discussed

Findings from studies are congruent with obesity having a viral origin, but what about obesity-related nafld?

Infection has recently started receiving greater attention as an unusual causative/inducing factor of obesity. Indeed, the biological plausibility of infectobesity includes direct roles of some viruses to reprogram host metabolism toward a more lipogenic and adipogenic status. Furthermore, the probability that humans may exchange microbiota components (virome/virobiota) points out that the altered response of IFN and other cytokines, which surfaces as a central mechanism for adipogenesis and obesity-associated immune suppression, is due to the fact that gut microbiota uphold intrinsic IFN signaling. Last but not least, the adaptation of both host immune and metabolic system under persistent viral infections play a central role in these phenomena. We hereby discuss the possible link between adenovirus and obesity-related nonalcoholic fatty liver disease (NAFLD). The mechanisms of adenovirus-36 (Ad-36) involvement in hepatic steatosis/NAFLD consist in reducing leptin gene expression and insulin sensitivity, augmenting glucose uptake, activating the lipogenic and pro-inflammatory pathways in adipose tissue, and increasing the level of macrophage chemoattractant protein-1, all of these ultimately leading to chronic inflammation and altered lipid metabolism. Moreover, by reducing leptin expression and secretion Ad-36 may have in turn an obesogenic effect through increased food intake or decreased energy expenditure via altered fat metabolism. Finally, Ad-36 is involved in upregulation of cAMP, phosphatidylinositol 3-kinase, and p38 signaling pathways, downregulation of Wnt10b expression, increased expression of CCAAT/enhancer binding protein-beta, and peroxisome proliferator-activated receptor gamma 2 with consequential lipid accumulation

Non-coding RNAs and other determinants of neuroinflammation and endothelial dysfunction: Regulation of gene expression in the acute phase of ischemic stroke and possible therapeutic applications

Ischemic stroke occurs under a variety of clinical conditions and has different pathogeneses, resulting in necrosis of brain parenchyma. Stroke pathogenesis is characterized by neuroinflammation and endothelial dysfunction. Some of the main processes triggered in the early stages of ischemic damage are the rapid activation of resident inflammatory cells (microglia, astrocytes and endothelial cells), inflammatory cytokines, and translocation of intercellular nuclear factors. Inflammation in stroke includes all the processes mentioned above, and it consists of either protective or detrimental effects concerning the 'polarization' of these processes. This polarization comes out from the interaction of all the molecular pathways that regulate genome expression: the epigenetic factors. In recent years, new regulation mechanisms have been cleared, and these include non-coding RNAs, adenosine receptors, and the activity of mesenchymal stem/stromal cells and microglia. We reviewed how long non-coding RNA and microRNA have emerged as an essential mediator of some neurological diseases. We also clarified that their roles in cerebral ischemic injury may provide novel targets for the treatment of ischemic stroke. To date, we do not have adequate tools to control pathophysiological processes associated with stroke. Our goal is to review the role of non-coding RNAs and innate immune cells (such as microglia and mesenchymal stem/stromal cells) and the possible therapeutic effects of their modulation in patients with acute ischemic stroke. A better understanding of the mechanisms that influence the 'polarization' of the inflammatory response after the acute event seems to be the way to change the natural history of the disease

The ECAPS Experiment for Solar Cell Characterization in the Stratosphere

The ECAPS project (Experimental Characterization of Advanced Photovoltaics in the Stratosphere) aims at the characterization of performance of a number of different solar cells in the stratospheric environment. ECAPS has been selected to fly as a zero-pressure balloon payload in the frame of the HEMERA H2020 project. Flight is scheduled for August 2022 from CNES’ base in Timmins, Canada. Testing solar cells in the stratosphere is of great interest for the development of High-Altitude Pseudo Satellite (HAPS) platforms, which will be equipped with high efficiency, flexible solar cells capable to operate at 20-30 km altitude for weeks or months, as well as to perform high-quality calibration of spacecraft solar cells in a near-air mass zero environment. The experiment includes a panel with up to 4 solar cells of different kinds (multi-junction GaAs, CIGS, perovskite, etc.), a dedicated I/V curve recording circuit, temperature and irradiance sensors, and an inertial measurement unit to monitor the instantaneous attitude of the gondola. During the ascent part of the flight, the I/V characteristic curves of the cells will be continuously recorded so to allow for comparison of performance of the different photovoltaic technologies in identical, real stratospheric flight conditions, as well as to detect performance changes with external temperature, irradiance and altitude. Upon recovery of the experiment, post-flight inspection will also yield useful information on the solar cell compatibility with the high altitude environment

ATLAS RPC Quality Assurance results at INFN Lecce

The main results of the quality assurance tests performed on the Resistive Plate Chamber used by the ATLAS experiment at LHC as muon trigger chambers are reported and discussed. Since July 2004, about 270 RPC units has been certified at INFN Lecce site and delivered to CERN, for being integrated in the final muon station of the ATLAS barrel region. We show the key RPC characteristics which qualify the performance of this detector technology as muon trigger chamber in the harsh LHC enviroments. These are dark current, chamber efficiency, noise rate, gas volume tomography, and gas leakage.Comment: Comments: 6 pages, 1 table, 9 figures Proceedings of XXV Physics in Collision-Prague, Czech Republic, 6-9 July 200