Therapeutic and immunomodulatory activities of short-course treatment of murine visceral leishmaniasis with KALSOME™10, a new liposomal amphotericin B

Visceral leishmaniasis (VL), a potentially fatal disease, is most prevalent in the Indian subcontinent, East Africa and South America. Since the conventional antileishmanial drugs have many limitations we evaluated a new ergosterol rich liposomal amphotericin B formulation, KALSOME™10 for its leishmanicidal efficacy, tolerability and immunomodulatory activity. Normal healthy mice were treated with 3.5 mg/kg single and 7.5 mg/kg single and double doses ofKALSOME™10. Liver and kidney function tests were performed fourteen days after treatment. Next, normal mice were infected with Leishmania donovani amastigotes. Two months post infection they were treated with the above mentioned doses of KALSOME™10 and sacrificed one month after treatment for estimation of parasite burden in the liver and spleen by Limiting Dilution Assay. Leishmanial antigen stimulated splenocyte culture supernatants were collected for cytokine detection through ELISA. Flow cytometric studies were performed on normal animals treated with KALSOME™10, Amphotericin B (AmB) and AmBiosome to compare their immunomodulatory activities. The drug was found to induce no hepato- or nephrotoxicities at the studied doses. Moreover, at all doses, it led to significant reduction in parasite burden in two month infected BALB/c mice, with 7.5 mg/kg double dose resulting in almost complete clearance of parasites from both liver and spleen. Interestingly, the drug at 7.5 mg/kg double dose could almost completely inhibit the secretion of disease promoting cytokines, IL-10 and TGFβ, and significantly elevate the levels of IFNγ and IL-12, cytokines required for control of the disease. Mice treated with KALSOME™10 showed elevated levels of IFNγ and suppressed IL-10 secretion from both CD4+ and CD8+ subsets of T cells, as well as from culture supernatants of splenocytes, compared to that of normal, AmB and AmBisome treated animal Treatment of infected mice with 7.5 mg/kg double dose of KALSOME™10 was safe and effective in clearing the parasites from the sites of infection. The drug maintains the inherent immunomodulatory activities of AmB by effectively suppressing disease promoting cytokines IL-10 and TGFβ, thereby boosting IL-12 and IFNγ levels. This emphasizes KALSOME™10 as a promising drug alternative for lifelong protection from VL

Deregulated expression of TANK in glioblastomas triggers pro-tumorigenic ERK1/2 and AKT signaling pathways

Signal transmission by the noncanonical IkappaB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IKKɛ, requires interaction with adapter proteins such as TRAF associated NF-κB activator (TANK). Although increased expression or dysregulation of both kinases has been described for a variety of human cancers, this study shows that deregulated expression of the TANK protein is frequently occurring in glioblastomas (GBMs). The functional relevance of TANK was analyzed in a panel of GBM-derived cell lines and revealed that knockdown of TANK arrests cells in the S-phase and prohibits tumor cell migration. Deregulated TANK expression affects several signaling pathways controlling cell proliferation and the inflammatory response. Interference with stoichiometrically assembled signaling complexes by overexpression or silencing of TANK prevented constitutive interferon-regulatory factor 3 (IRF3) phosphorylation. Knockdown of TANK frequently prevents constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). TANK-mediated ERK1/2 activation is independent from the canonical MAP kinase or ERK kinase (MEK) 1/2-mediated pathway and utilizes an alternative pathway that uses a TBK1/IKKɛ/Akt signaling axis, thus identifying a novel pathway suitable to block constitutive ERK1/2 activity.Peer reviewe

Antifungal activity of amphotericin B conjugated to nanosized magnetite in the treatment of paracoccidioidomycosis

This study reports on in vitro and in vivo tests that sought to assess the antifungal activity of a newly developed magnetic carrier system comprising amphotericin B loaded onto the surface of pre-coated (with a double-layer of lauric acid) magnetite nanoparticles. The in vitro tests compared two drugs; i.e., this newly developed form and free amphotericin B. We found that this nanocomplex exhibited antifungal activity without cytotoxicity to human urinary cells and with low cytotoxicity to peritoneal macrophages. We also evaluated the efficacy of the nanocomplex in experimental paracoccidioidomycosis. BALB/c mice were intratracheally infected with Paracoccidioides brasiliensis and treated with the compound for 30 or 60 days beginning the day after infection. The newly developed amphotericin B coupled with magnetic nanoparticles was effective against experimental paracoccidioidomycosis, and it did not induce clinical, biochemical or histopathological alterations. The nanocomplex also did not induce genotoxic effects in bone marrow cells. Therefore, it is reasonable to believe that amphotericin B coupled to magnetic nanoparticles and stabilized with bilayer lauric acid is a promising nanotool for the treatment of the experimental paracoccidioidomycosis because it exhibited antifungal activity that was similar to that of free amphotericin B, did not induce adverse effects in therapeutic doses and allowed for a reduction in the number of applications

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Application of EKF to Parameters Estimation for Speed Sensorless Vector Control of Two-Phase Induction Motor

The two-phase induction machine (TPIM) is widely used in many light-duty applications were three-phase supply is not readily available also a two phases symmetrical or unsymmetrical can be shift auxiliary winding. Therefore, in the indirect field oriented control, the rotor circuit time constant is an important parameter. Incorrect estimation of the rotor time constant also leads to incorrect flux angle calculations and can cause significant performance deterioration if no means for compensation or identification is applied. The magnetic saturation, the operating temperature and difficulties in using sensors for speed measurement are one of the sources of parameters variations, caused by non-linear nature of the magnetizing curve and the variations of the rotor resistance. The classical indirect field-oriented control is highly sensitive to the inductance values decrease when increasing the saturation level

A Complete Transmitted Message in DTNs with a Stable Coalition in Dynamic Structures

In this paper, we propose a model for Delay Tolerant Networks (DTNs) based coalition and stable structure of all relay nodes to deliver a complete message from one source to one destination using the Epidemic Forwarding Policy. The message is viewed as a series of uniformly sized chunks that are produced by a fixed source. For a message to be considered successfully delivered, all of its chunks must arrive at the fixed destination within the validated time. The Age of Information (AoI) provides a deadline by which all message chunks must reach the destination to be considered timely. Mobile relays within the network will facilitate the transfer of chunks using an insensitive reward mechanism. We propose a distributed coalition algorithm that aims to establish a state of stability among all participating relays in the game. Through this algorithm, we were able to determine that the formation of stable coalitions results in higher payoffs for relay nodes compared to acting alone, as shown in our performance evaluation results

A survey of perceptual image processing methods

Perceptual approaches have been widely used in many areas of visual information processing. This paper presents an overview of perceptual based approaches for image enhancement, segmentation and coding. The paper also provides a brief review of image quality assessment (IQA) methods, which are used to evaluate the performance of visual information processing techniques. The intent of this paper is not to review all the relevant works that have appeared in the literature, but rather to focus on few topics that have been extensively researched and developed over the past few decades. The goal is to present a perspective as broad as possible on this actively evolving domain due to relevant advances in vision research and signal processing. Therefore, for each topic, we identify the main contributions of perceptual approaches and their limitations, and outline how perceptual vision has influenced current state-of-the-art techniques in image enhancement, segmentation, coding and visual information quality assessment