Calprotectin blockade inhibits long-term vascular pathology following peritoneal dialysis-associated bacterial infection

Bacterial infections and the concurrent inflammation have been associated with increased long-term cardiovascular (CV) risk. In patients receiving peritoneal dialysis (PD), bacterial peritonitis is a common occurrence, and each episode further increases late CV mortality risk. However, the underlying mechanism(s) remains to be elucidated before safe and efficient anti-inflammatory interventions can be developed. Damage-Associated Molecular Patterns (DAMPs) have been shown to contribute to the acute inflammatory response to infections, but a potential role for DAMPs in mediating long-term vascular inflammation and CV risk following infection resolution in PD, has not been investigated. We found that bacterial peritonitis in mice that resolved within 24h led to CV disease-promoting systemic and vascular immune-mediated inflammatory responses that were maintained up to 28 days. These included higher blood proportions of inflammatory leukocytes displaying increased adhesion molecule expression, higher plasma cytokines levels, and increased aortic inflammatory and atherosclerosis-associated gene expression. These effects were also observed in infected nephropathic mice and amplified in mice routinely exposed to PD fluids. A peritonitis episode resulted in elevated plasma levels of the DAMP Calprotectin, both in PD patients and mice, here the increase was maintained up to 28 days. In vitro, the ability of culture supernatants from infected cells to promote key inflammatory and atherosclerosis-associated cellular responses, such as monocyte chemotaxis, and foam cell formation, was Calprotectin-dependent. In vivo, Calprotectin blockade robustly inhibited the short and long-term peripheral and vascular consequences of peritonitis, thereby demonstrating that targeting of the DAMP Calprotectin is a promising therapeutic strategy to reduce the long-lasting vascular inflammatory aftermath of an infection, notably PD-associated peritonitis, ultimately lowering CV risk

Oltre il Segno/OltreMare

La realizzazione di un volume contenente le incisioni scelte all’interno della Scuola di Grafica d’Arte dell’Accademia di Belle Arti di Palermo, coordinata dai Proff. Giovanni D’Alessandro e Riccardo Mazzarino rappresenta motivo di orgoglio e di soddisfazione per la nostra Istituzione che costruisce i percorsi didattici dei propri corsi a partire dall’esperienza laboratoriale. L’incisione grafica è tra le tecniche artistiche più antiche ma nel contempo più contemporanee. La gestualità intrinseca al segno, che si manifesta nella carta, svela universi della visione inaspettati.(Mario Zito - Direttore dell’Accademia di Belle Arti di Palermo) Il segno è il risultato di un gesto a volte deciso, a volte contorto, a volte leggero, i cui risultati spesso sono inattesi e sorprendenti. Il volume contiene esemplari di incisioni fortemente caratterizzanti della scuola di Grafica d’Arte che vanta all’interno del proprio corso di studi docenti-artisti che consapevoli della ricchezza del loro bagaglio esperienziale offrono agli studenti gli strumenti necessari per far sì che l’arte del saper fare artigianale, si trasformi in mera poetica artistica

LC-MS/MS analytical procedure to detect small peptides in biological samples:evaluation of different SPE extraction sorbents and protocols

Recently a wide variety of peptide hormones were included in the World Anti-Doping Agency list of prohibited substances and methods [1]. Traditionally, the analytical procedures used to detect macromolecules in the anti-doping field were based on immunological techniques. The increasing availability of recombinant peptides and other macromolecules with minimal differences in the molecular structure with respect to those produced endogenously has imposed the development of more selective techniques, mostly based on mass spectrometry. Several analytical procedures were already published to detect antidiuretic peptides [2-3], growth hormone releasing factors [4-5], ACTH and its analogues, IGF1 and its analogues and insulin analogues [6] in biological fluids (urine and blood). Here we present an analytical method for the combined screening of different small peptides, based on LC-MS/MS with SRM as acquisition mode after solid phase extraction

Characterization of the phase I and phase II metabolic profile of tolvaptan by in vitro studies and liquid chromatography–mass spectrometry profiling: Relevance to doping control analysis

Phase I and phase II biochemical reactions involved in the biotransformation pathways of tolvaptan were characterized by LC–MS-based techniques and in vitro models to identify the most appropriate marker(s) of intake. The effects of physiological and non-physiological factors on the metabolic profile of tolvaptan were also evaluated. In vitro approaches were based on the use of pooled human liver microsomes and recombinant isoforms of cytochrome P450 and uridine diphospho glucuronosyl-transferase. Sample preparation included liquid/liquid extraction at neutral pH with tert-butyl methyl-ether. In the case of the study of phase II metabolism an additional enzymatic hydrolysis step was performed. The chromatographic separation was carried out using reversed-phase chromatography, whereas detection was performed by either triple-quadrupole or time-of-flight analyzers in positive electrospray ionization and different acquisition modes. Our data show that tolvaptan is metabolized to at least 20 phase I metabolites, the biotransformation reactions being catalyzed mainly by CYP3A4 and CYP3A5 isoforms. The phase-I reactions include hydroxylation (in different positions), carboxylation, oxidation, hydrogenation, dealkylation, isomerization and a combination of the above. Most of the phase I metabolites undergo glucuronidation, carried out mostly by UGT2B7 and UGT2B17 isoforms. Dealkylated, mono-hydroxylated and carboxylated metabolites both in the free and in the glucuronidated form appear to be the most suitable urinary diagnostic markers for the detection of tolvaptan intake in doping control. Concerning the effects of physiological and non-physiological factors on the metabolic profile of tolvaptan, our results show that (i) no significant gender differences were detected; (ii) significant differences were registered in the presence of different CYP3A5 allelic variants, and finally (iii) a marked reduction of the detected metabolites was registered in the presence of antifungals, and, to a lesser extent, of steroidal progestins

Clinical effects of use polymyxin B fixed on fibers in liver transplant patients with severe sepsis or septic shock

Abstract: Polymyxin B (PMX-B) is a polycationic antibiotic, known to bind the lipid A portion of endotoxin, a cell wall component exclusively found in gram-negative bacteria (GNB). An extracorporeal hemoperfusion device (TORAYMYXIN) has been developed: PMX is covalently bound to the surface of an insoluble carrier material to inactivate endotoxin in blood without exerting toxicity on the brain or the kidney. The aim of this study was to evaluate the efficacy, safety, and clinical effects of direct hemoperfusion with an immobilized polymyxin B fiber column (DHP-PMX) among liver transplant patients with severe sepsis or septic shock. Methods. From June 2004 to May 2005, 10 patients (6 men and 4 women) of overall mean age of 55 years (46-65 range) underwent orthotopic liver transplantation (OLT) and developed severe sepsis or septic shock according to The Consensus Conference of American College Physicians/Society of Critical Care Medicine (ACCP/SCCM) criteria. GNB were detected in all treated patients who received conventional antibiotic therapy, vasopressor or inotropic agents, and ventilatory support. The DHP-PMX treatment was performed three times in each patient. Hemodynamic and respiratory parameters and dosages of vasopressor or inotropic drugs were assessed at baseline and after each treatment. Results. No adverse events occurred. From baseline to the third treatment the mean arterial pressure increased from 64 +/- 5 mm Hg to 89 +/- 4 rum Hg; while the dosages of dobutamine and norepinephrine were reduced: 6.4 to 1 mcg/kg/min and 1.3 to 0.001 mcg/kg per min, respectively. The PaO2/FiO(2) ratio increased: 214 to 291 mm Fig. Conclusion. The use of DHP-PMX may be an important aid in patients with sepsis in association with conventional therapy

Prescription drugs misuse in “clubbers” and disco goers in Ibiza

Funding Information: This study was partly funded by the European Project entitled Analysis, Knowledge dissemination, Justice implementation and Special Testing of Novel Synthetic Opioids—JUST-2017-AG-DRUG. Publisher Copyright: © Copyright © 2020 di Giannantonio, Negri, Schiavone, Vannini, Pettorruso, De-Giorgio, Verrastro, Trabace, Corbo, Gottardo, Camuto, Mazzarino, Barra, De Berardis, Lopez, Del Villar, Schifano and Martinotti. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Prescription drugs misuse and its related risks are considered a worldwide public health issue. Current trends show that the extent of such phenomenon may not be limited to subjects with psychiatric disorders, as it also spreads to dance party and nightclub attendees, who often consume prescription drugs in combination with alcohol and psychoactive substances. This study aims to report the sociodemographic data and the psychiatric and clinical features of a sample of clubbers reporting prescription drugs use. Methods: Patients admitted to the psychiatry ward of the Can Misses Hospital in Ibiza were recruited for the study during a span of four consecutive years (2015-2018). The inclusion criteria were age 18-75 years old and the intake of psychoactive substances or more than five alcohol units during the previous 24 hours. Substances use habits, psychopathological features and use of unprescribed pharmaceuticals were investigated. Urine samples were collected and analysed using Gas Chromatography/Mass Spectrometry. Results: A total of 110 subjects with psychoactive substance intoxication were recruited for the study. Among these, 37 (40%) disclosed the use of prescription drugs without medical supervision. The most common compounds were benzodiazepines (66%), antiepileptic drugs (8%), antidepressants (6%), opioids (6%), antipsychotics (6%), stimulants (6%) and Non-Steroidal Anti Inflammatory Drugs (NSAIDs, 2%).Prescription drugs misuse was negatively associated with the use of psychodysleptics (Two-tailed Fisher’s exact test p=0,018, = -0,262). Conclusions: The use of prescription drugs is also common among clubbers, usually characterised by low propensity to be prescribed benzodiazepines, antipsychotics, or antidepressants. Prescription drugs may be an alternative to classic and novel psychoactive compounds or may be used to tamper and self-medicate the effects determined by the use of substances. Party goers should be adequately informed about possible risks of co-intake of psychoactive substances and prescription drugs to prevent serious medical and psychiatric consequences.Peer reviewe