Galectin-9 Regulates Monosodium Urate Crystal-Induced Gouty Inflammation Through the Modulation of Treg/Th17 Ratio

Gout is caused by depositing monosodium urate (MSU) crystals within the articular area. The infiltration of neutrophils and monocytes drives the initial inflammatory response followed by lymphocytes. Interestingly, emerging evidence supports the view that in situ imbalance of T helper 17 cells (Th17)/regulatory T cells (Treg) impacts the subsequent damage to target tissues. Galectin-9 (Gal-9) is a modulator of innate and adaptive immunity with both pro- and anti-inflammatory functions, dependent upon its expression and cellular location. However, the specific cellular and molecular mechanisms by which Gal-9 modulates the inflammatory response in the onset and progression of gouty arthritis has yet to be elucidated. In this study, we sought to comprehensively characterise the functional role of exogenous Gal-9 in an in vivo model of MSU crystal-induced gouty inflammation by monitoring in situ neutrophils, monocytes and Th17/Treg recruited phenotypes and related cyto-chemokines profile. Treatment with Gal-9 revealed a dose-dependent reduction in joint inflammation scores, knee joint oedema and expression of different pro-inflammatory cyto-chemokines. Furthermore, flow cytometry analysis highlighted a significant modulation of infiltrating inflammatory monocytes (CD11b+/CD115+/LY6-Chi) and Th17 (CD4+/IL-17+)/Treg (CD4+/CD25+/FOXP-3+) cells following Gal-9 treatment. Collectively the results presented in this study indicate that the administration of Gal-9 could provide a new therapeutic strategy for preventing tissue damage in gouty arthritic inflammation and, possibly, in other inflammatory-based diseases

Intraoperative measurement of parathyroid hormone: A Copernican revolution in the surgical treatment of hyperparathyroidism

Intraoperative parathyroid hormone (PTH) monitoring in the setting of the operating room represents a valuable example of the rationale use of the laboratory diagnostic in a patient-oriented approach. Rapid intraoperative PTH (ioPTH) assay is a valid tool for an accurate evaluation of the success of parathyroid surgery. The reliability of the user-friendly portable systems as well as the collaboration between operators and surgical staff allow the one-site monitoring of the ioPTH decrements on the course of the surgical management of hyperparathyroidism.The rapid answer provided by an effective decrement of PTH during parathyroidectomy contributes dramatically to the efficacy of parathyroid surgery and the reduction of the number of re-operations. Therefore the dose of ioPTH is a valid and reliable support for the success of the intervention of parathyroidectomy at controlled costs

Antinociceptive effects of tetrazole inhibitors of endocannabinoid inactivation: Cannabinoid and non-cannabinoid receptor-mediated mechanisms

Background and purpose: Tetrazoles were recently developed as inhibitors of the cellular uptake of the endocannabinoid anandamide or of its hydrolysis by fatty acid amide hydrolase (FAAH), but were proposed to act also on non-endocannabinoid-related serine hydrolases. Experimental approach: We tested, in a model of inflammatory pain induced in mice by formalin, five chemically similar inhibitors: (i) OMDM119 and OMDM122, two potent carbamoyl tetrazole FAAH inhibitors with no effect on anandamide uptake; (ii) LY2183240, a carbamoyl tetrazole with activity as both FAAH and uptake inhibitor; (iii) OMDM132, a non-carbamoyl tetrazole with activity only as uptake inhibitor and iv) OMDM133, a non-carbamoyl tetrazole with no activity at either FAAH or uptake. Results: All compounds (2.5-10 mg kg -1, i.p.) inhibited the second phase of the nocifensive response induced by intraplantar injection of formalin. The effects of OMDM119, OMDM122 and OMDM133 were not antagonized by pretreatment with cannabinoid CB 1 receptor antagonists, such as rimonabant or AM251 (1-3 mg kg -1, i.p.). The effects of LY2183240 and OMDM132 were fully or partially antagonized by rimonabant, respectively, and the latter compound was also partly antagonized by the CB 2 receptor antagonist, AM630. Conclusions and implications: (i) non-FAAH hydrolases might be entirely responsible for the antinociceptive activity of some, but not all, tetrazole FAAH inhibitors, (ii) the presence of a carbamoylating group is neither necessary nor sufficient for such compounds to act through targets other than FAAH and (iii) inhibition of anandamide uptake is responsible for part of this antinociceptive activity, independently of effects on FAAH. © 2008 Macmillan Publishers Limited All rights reserved

Impact of the peptide wmr-k on dual-species biofilm candida albicans/klebsiella pneumoniae and on the untargeted metabolomic profile

In recent years, the scientific community has focused on the development of new antibiotics to address the difficulties linked to biofilm-forming microorganisms and drug-resistant infections. In this respect, synthetic antimicrobial peptides (AMPs) are particularly regarded for their therapeutic potential against a broad spectrum of pathogens. In this work, the antimicrobial and antibiofilm activities of the peptide WMR-K towards single and dual species cultures of Candida albicans and Klebsiella pneumoniae were investigated. We found minimum inhibitory concentration (MIC) values for WMR-K of 10 µM for K. pneumoniae and of 200 µM for C. albicans. Furthermore, sub-MIC concentrations of peptide showed an in vitro inhibition of biofilm formation of mono and polymicrobial systems and also a good biofilm eradication even if higher concentrations of it are needed. In order to provide additional evidence for the effect of the examined peptide, a study of changes in extracellular metabolites excreted and/or uptaken from the culture medium (metabolomic footprinting) in the poly-microbial association of C. albicans and K. pneumoniae in presence and absence of WMR-K was performed. Comparing to the untreated dual species biofilm culture, the metabolomic profile of the WMR-K treated culture appears significantly altered. The differentially expressed compounds are mainly related to the primary metabolic pathways, including amino acids, trehalose, pyruvic acid, glycerol and vitamin B6

The membranotropic peptide gh625 to combat mixed candida albicans/klebsiella pneumoniae biofilm: Correlation between in vitro anti-biofilm activity and in vivo antimicrobial protection

The antibiofilm activity of a gH625 analogue was investigated to determine the in vitro inhibition and eradication of a dual-species biofilm of Candida albicans and Klebsiella pneumoniae, two leading opportunistic pathogens responsible for several resistant infections. The possibility of effectively exploiting this peptide as an alternative anti-biofilm strategy in vivo was assessed by the investigation of its efficacy on the Galleria mellonella larvae model. Results on larvae survival demonstrate a prophylactic efficacy of the peptide towards the infection of each single microorganism but mainly towards the co-infection. The expression of biofilm-related genes in vivo showed a possible synergy in virulence when these two species co-exist in the host, which was effectively prevented by the peptide. These findings provide novel insights into the treatment of medically relevant bacterial–fungal interaction

Sisters acts: converging signaling between CaMKII and CaMKIV, two members of the same family

Calcium (Ca2+ ) is a universal second messenger that regulates a number of diverse cellular processes including cell proliferation, development, motility, secretion, learning and memory1, 2. A variety of stimuli, such as hormones, growth factors, cytokines, and neurotransmitters induce changes in the intracellular levels of Ca2+. The most ubiquitous and abundant protein that serves as a receptor to sense changes in Ca2+ concentrations is Calmodulin (CaM), thus mediating the role as second messenger of this ion. The Ca2+/CaM complex initiates a plethora of signaling cascades that culminate in alteration of cell functions. Among the many Ca2+/CaM binding proteins, the multifunctional protein kinases CaMKII and CaMKIV play pivotal roles in the cell

Renal allograft compartment syndrome: is it possible to prevent?

Renal allograft compartment syndrome (RACS) is a complication characterized by increased pressure over 15 to 20 mm Hg of the iliac fossa site of transplanted kidney that can lead to a reduction of the blood supply to the graft, resulting in organ ischemia. This study aims to evaluate, through a review of the literature, the incidence, detection, treatment, and possible prevention of RACS. The incidence of this complication, which appears generally in the immediate post-transplantation period, is currently approximately 1% to 2% and is underestimated because of poor nosography for the presence of symptoms common to other post-transplantation complications. Doppler ultrasound is indispensable to evaluate the graft function in the immediate postoperative period and in the following days. The onset of RACS involves a surgical decompression of the graft and the subsequent closure of the abdominal wall with tension-free technique. Several authors agree that only the immediate surgical decompression following an early diagnosis can ensure a recovery of the graft. Early detection of the RACS is the key to preventing the loss of the graft. It is desirable to prevent this syndrome by reducing the discrepancy in weight between donor and recipient by 17%. However the shortage of organs makes such a selection not easy; therefore, in cases at risk for RACS, a close instrumental and clinical monitoring of the patient during post-transplantation recovery is recommended, so a prompt surgical decompression can be performed if RACS is suspected

A new estimation of the recent tropospheric molecular hydrogen budget using atmospheric observations and variational inversion

This paper presents an analysis of the recent tropospheric molecular hydrogen (H2) budget with a particular focus on soil uptake and European surface emissions. A variational inversion scheme is combined with observations from the RAMCES and EUROHYDROS atmospheric networks, which include continuous measurements performed between mid-2006 and mid-2009. Net H2 surface flux, then deposition velocity and surface emissions and finally, deposition velocity, biomass burning, anthropogenic and N2 fixation-related emissions were simultaneously inverted in several scenarios. These scenarios have focused on the sensibility of the soil uptake value to different spatio-temporal distributions. The range of variations of these diverse inversion sets generate an estimate of the uncertainty for each term of the H2 budget. The net H2 flux per region (High Northern Hemisphere, Tropics and High Southern Hemisphere) varies between −8 and +8 Tg yr−1. The best inversion in terms of fit to the observations combines updated prior surface emissions and a soil deposition velocity map that is based on bottom-up and top-down estimations. Our estimate of global H2 soil uptake is −59±9 Tg yr−1. Forty per cent of this uptake is located in the High Northern Hemisphere and 55% is located in the Tropics. In terms of surface emissions, seasonality is mainly driven by biomass burning emissions. The inferred European anthropogenic emissions are consistent with independent H2 emissions estimated using a H2/CO mass ratio of 0.034 and CO emissions within the range of their respective uncertainties. Additional constraints, such as isotopic measurements would be needed to infer a more robust partition of H2 sources and sinks

MIRA: a Multiphysics Approach to Designing a Fusion Power Plant

Fusion systems codes (SCs) are deployed to produce the baseline of the European fusion power reactor (DEMO) within its conceptual design. A DEMO baseline is mostly defined by a radial/vertical reactor sketch and major reactor parameters, such as fusion and net electric power, magnetic fields, and plasma burn time. A baseline shall also meet a set of prescribed reactor requirements, constraints, and architectural features. According to the conceptual design workflow implemented within the EU-DEMO programme, the output from the SC is transferred to the detailed physics and engineering design codes. Presently-available fusion SCs rely on rather basic physics and engineering models (mostly at zero or one-dimensional level). The design codes, instead, are very detailed but run on much longer computing times. To fill the gap between systems and design codes, the multi-fidelity systems/design tool modular integrated reactor analysis (MIRA)—has been recently developed. MIRA incorporates the physics and the engineering insights of the utmost domains of tokamak reactors and relies on a higher spatial resolution, spanning from 1D up to 3D modelling frames. The MIRA approach has been applied to the DEMO 2017 baseline, generated by the EU reference SC PROCESS and used as input to MIRA. In the paper, the architectural and mathematical insights of the MIRA package are described, along with an EU-DEMO 2017 baseline analysis